Protara Therapeutics Inc Stock

Good afternoon, everyone. My name is Jim, and I will be your conference operator today. At this time, I would like to welcome everyone to the Protara Therapeutics Lymphatic Malformations KOL Webinar. [Operator Instructions]

And now for opening remarks and introductions, I am pleased to turn the floor to our host, Senior Vice President of Investor Relations, Justine O'Malley. Welcome.

Thank you, Jim. Good afternoon. Thank you all for joining us today for a review of Protara's Lymphatic Malformations program.

Before we begin, I would like to remind you that during today's call, we will be making certain forward-looking statements. These statements represent our views as of today only and should not be relied upon as representing our views as of any subsequent date. Actual results may differ from our forward-looking statements due to various factors including those described in the Risk Factors section of our most recent annual report and subsequently filed quarterly reports that are on file with the SEC. Except as required by law, we disclaim any obligation to update these statements even if our views change.

I will now turn the call over to Jesse Shefferman, Co-Founder, Director and Chief Executive Officer.

Thank you, Justine, and thank you all for joining us this afternoon. Good afternoon from the World Congress of the International Society for the Study of Vascular Anomalies or ISSVA. We are excited to provide an overview of our lymphatic malformation patients program today, including a recap of our recent FDA engagements and our plans to submit a BLA in the second half of 2027 for TARA-002 in lymphatic malformations. There is a significant unmet need in this rare disease, and we believe that TARA-002 has the potential to be the first approved therapy for patients with macrocystic and macrodominant mixed lymphatic malformations. I'm joined today by Dr. Jackie Zummo, Co-Founder and Chief R&D Officer at Protara, who will walk us through an overview of TARA-002 as a potential treatment for LMs.

We're also privileged to have STARBORN-1 investigators, Dr. Naiem Nassiri and Jesse Jones here to provide their perspective on the disease and how TARA-002 may fit into the treatment armamentarium. Dr. Nassiri is a Board-certified vascular and endovascular surgeon leading the Vascular Care Group in Stamford, Connecticut and is also an adjunct faculty member of the Yale School of Medicine and Yale New Haven Hospital.

Dr. Jones is a Board-certified interventional radiologist and an associate professor of Medicine in the Department of Neurosurgery and Radiology at the University of Alabama. We're also joined by our Chief Commercial Officer, Bill Conkling, who will provide an overview of the LMs market and our views on commercialization.

Finally, our CFO, Pat Fabbio, will join us for the Q&A. At the end of the call, we will answer questions submitted via the chat box on the lower left-hand corner of the screen. For those of you who are new to Protara, we are a clinical-stage biotechnology company developing transformative therapies for the treatment of cancer and rare diseases. Our lead asset is TARA-002, a genetically distinct strain of Streptococcus pyogenes that drives an immunologic identification and attack of cells that carry mutational burden. We are studying 002 in non-muscle invasive bladder cancer, or NMIBC, where we recently announced positive data at the American Urological Association Conference last week. Today, however, we will focus on TARA-002 in LM. In addition, we have a program in patients dependent on parenteral support, where we are studying IV Choline Chloride, an investigational phospholipid substrate replacement therapy in an ongoing registrational Phase III trial. While the focus of today's call will be exclusively on LM, we remain excited about all 3 of our pivotal programs and look forward to sharing additional milestones across the portfolio throughout the next 12 months.

Now I'd like to talk about TARA-002, our investigational genetically distinct strain of Streptococcus pyogenes that is fully inactivated while retaining into immune-stimulating properties. 002 is supported by an enormous amount of clinical data from its predecessor compound OK-432, which is approved and marketed under the brand name Picibanil in Japan by Chugai Pharmaceuticals, where it has been the standard of care in lymphatic malformations for 30 years. TARA-002 builds on the efficacy and safety demonstrated by OK-432 in LMs over the years, and is now in development by Protara using modern manufacturing techniques, which have led to potential improvements in the product profile. The clear unmet need and the potential for 002 as a treatment option in LMs is reflected in the multiple regulatory designation granted by the FDA, including rare pediatric disease designation, orphan drug designation, Breakthrough Therapy and Fast Track designations and 002 is eligible for a priority review voucher or PRV upon approval. We expect to complete enrollment of our pivotal STARBORN-1 trial in LMs in the second half of this year and intend to submit a BLA based on these data in the second half of 2027. Looking ahead, 002 has potential use beyond LMs. There is extensive historical literature on the use of OK-432 in patients with multiple other maxillofacial cyst types. And indeed, there is direct patient experience with TARA-002 and STARBORN-1 and 2 ranula patients, suggesting that this investigational therapeutic can treat other cyst types, providing strong supportive evidence for expanding the opportunity for 002.

As we announced last week, we've had productive ongoing dialogue with the FDA on our LMs program. We received confirmation that the review of 002 and LMs has been moved from the Office of Vaccines Research and Review to the Office of Therapeutic Products, or OTP. OTP is a division that has significant experience in pediatric rare disease. It is also the review division for 002 in NMIBC. The FDA has stated that they will evaluate the risk-benefit profile of 002 and LMs based on the results of STARBORN-1. They have not requested any changes to the sample size or the endpoints of the trial. They have not requested an additional pivotal study and have confirmed that our nonclinical package is complete and that no additional reactogenicity or immunogenicity studies are required. We are pleased to have actionable feedback from the FDA on the path to registration for 002 and LMs and look forward to submitting a BLA in the second half of 2027.

I will now turn the call over to Dr. Nassiri, to talk about lymphatic malformations and the unmet need in this patient population.

Good afternoon, everybody. It's a pleasure to be here. I'm Naiem Nassiri, I'm a board-certified vascular and endovascular surgeon. I think it's important to understand my background. I'm a surgeon, but I also do all my own sort of interventional radiology or endovascular therapy when it comes to vascular malformations. So that should provide a lot of good perspective regarding some of the recommendations that I will be making. I have been treating vascular malformations for nearly 20 years. I am a founder or the Founding Director of a world renowned, internationally renowned destination center for treatment of vascular malformations, and that's TVCG CARES, which stands for the Center for Anomalies and Rare Entities International, and I maintain very close academic ties with the Yale University, where I was faculty for 7 years. I treat over 400 cases of vascular malformations annually. And have been doing so for the last 15 years or so.

So vascular malformations, in general are essentially errors in the development of blood vessels, and it's a process that happens in [indiscernible], depending on what sort of subtype of blood vessel, whether it's a vein or artery or combination thereof or lymphatic channels, those configurations can manifest themselves in various forms. When we're talking about lymphatic malformations, these are channels inside our body that helps carry fluid outside veins and arteries, simply stated. And when you have these rare disorders, they can wind up with these sort of abnormal clumps of lymphatic channels that can lead to stagnation of flow of these fluids and that can cause growth irritation and a variety of different symptomatologies, some of which can be life and limb-threatening, and some of which can be relatively less impactful. Once diagnosed treatment is almost always indicated, regardless of the extent of symptomatology that you may have. So while a symptom may be asymptomatic seemingly, treatment is always indicated because of the potential complications that can ensue as a result of the lymphatic malformation being left untreated. Broadly speaking, there are three broad subtypes. The vast majority of what we're talking about here today are macrocystic lymphatic malformations. The analogy I like to use is that these are large balloon -- water balloons, right, and they can grow. And there's constant accumulation of fluid or water within this water balloon. So this water balloon is constantly growing, and they can chew through and erode into adjacent organs. The other subtype is microcystical lymphatic malformation. The analogy I like to use for that. We can think of them as these tiny little honeycomb, so they have this thick, viscous, difficult to drain fluid inside of them. And in the middle, in terms of prevalence, you have a combination thereof, and these are called mixed lymphatic malformations. We talked about current treatment paradigm, but I think it's very important for this audience to understand that there is no FDA approved or agreed upon treatment algorithm or subtype of medication that's used for treatment. Everything that we're going to talk about have sort of grandfathered its way into the treatment algorithm. And there is a desperate need for -- from treatment algorithm approaches to come up with something on label that actually targets the very molecular pathway that causes these malformations in the first place. And we'll talk more about these treatment options down the line.

I won't go into too much detail about this, but suffice it to say that the mutations that cause these channels to become abnormal reside within what are called epithelial cells that align these channels. And these are cells that we would call endothelial cells. If we were to talk about blood vessels or such as veins and arteries, but within the lymphatic channels, these are termed epithelial cells. And suffice is to say that when you have mutations inside these epithelial cells, and those mutations involve the classic PIK3CA/AKT1/mTOR pathway. Because of that abnormality, you can either regulate in a normal way or you can have it the abnormal, which is what happens when there's mutations and you wind up with a lymphatic malformation. And these happened very early on during the process of embryogenesis. So these mutations are happening before the patient is born. Whether or not you see the lesion immediately at birth, that is irrelevant. So the gross visibility of it has nothing to do whether or not that mutation actually exists. The natural history of lymphatic malformations, as I said, the vast majority of these lesions are within the head and neck, but they can be anywhere in the body, visible and nonvisible. Sometimes what you may see may only be the tip of the iceberg and deeper inside is a much bigger and much more dangerous and much more problematic problem. So these are not just cosmetically disfiguring lesions or a bubble in somebody's neck that one needs to worry about. Growth happens proportionally with the patient. There are two major environmental triggers for growth of vascular malformations in general. One is fluctuations in the hormonal milieu, which typically happens classically speaking, during puberty and the second one is during pregnancy for women. And the other is trauma and that trauma folks includes surgical intervention. So what is deemed the medical intervention can actually be an exacerbating factor. And the person telling you this is a surgeon, okay? So that's a very important nonbiased and highly accurate statement, clinically speaking. The age of diagnosis is less relevant. But because the vast majority of these tend to happen fairly early on and become grossly manifest clinically, you tend to detect them fairly early on during childhood. So by 2 years of age, the vast majority have sort of declare themselves depending on where the lesion is. You may have mixed components or [indiscernible] but you can have it within the peritoneal cavity. You can have it within musculoskeletal structures. You can have them within airway processes or adjacent to nerves. So the location of where it is has a huge clinical impact on how you go about treating it and what the risks of that treatment are going to be.

Next slide. We talked a little bit about disease burden already in the pediatric patients, but let's just not forget that this is not just the pediatric entity, it can happen in adults as well. Obviously, these are adults who never had treatment when they were younger, which is a catastrophic process, but unfortunately happens quite often. Physical symptoms and complications, we talked about that water balloon analogy. Imagine that water balloon continuing to grow and then chewing through adjacent nerves, adjacent blood vessels, arteries, veins, you can now have what we call fluid-fluid levels, which we can detect. Sometimes you have a lymphatic malformation that's of a certain size, let's say, the size of a tangerine, and all of a sudden, it abruptly goes to the size [ of a grape for ] a small water melon. Why is that happening? That's because there's abrupt bleeding into the structure, okay? And so you can now literally chew through any organ that's adjacent to this particular entity and can have potential catastrophic events. If that is within the airway, you not have airway compromise, the risk for sudden cardiac arrest, ventilatory compromise, difficulty swallowing or eating, it can compromise flow patterns to adjacent gastrointestinal structures and the list goes on and on. So it is very important that once these lesions are detected, regardless of whether or not there is imminent threat or imminent symptoms that won't be very proactive in terms of treatment, especially the macrocystic subtypes. We talked about the functional impairment. We talked about the psychological and social quality of life, especially with macrocystic lymphatic malformations and in particular, because of that water filled balloon analogy I talked about the cosmetic disfigurement of this for children who are going to be of child -- or in school age, that is absolutely impactful and can be catastrophic for the psychological development of that child and their family, right? The family is affected as well. These are chronic in nature and progression. These continue to grow. This never stops. It's not like you're going to end 17, 18 years of age and all of a sudden, your lymphatic malformations is going to stop growing. Obviously, that does not happen. And let's not forget about the immense amount of impact on the health care, especially since currently everything is being done in a hospital setting with extreme utility of cost of resources, ICU stays and all kinds of health care burden that's happening because we don't have a minimal invasive molecularly-directed compound as of yet, not until just now.

Next slide, please. Again, I'm going to emphasize that there is no FDA approval, regardless of what's said, everything that's sort of considered standard of care has sort of grandfathered its way into the treatment algorithm because we haven't had anything better to date. And because of the fact that there are -- these lesions affect all parts of the body, we have a vast array of specialists, both surgical, both interventional and non-interventional who are treating these patients. And it's great to have a multi-disciplinary approach. But what winds up happening is when you're a hammer, everything is a nail. If you're a surgeon, then you're going to want to go and resect everything. Guess what? surgery is not the right answer for all these lesions. If you're a dermatologist, you're going to want to think about some laser photocoagulation. If you're an interventional radiologist, you're going to think about embolization or sclerotherapy. But none of these things is really the way to go. And if you are going to embolize, what compound are you going to use? Are you going to use an irritant of sub sort to merely irritate the lesion? Or you're going to use a highly toxic compound that is going to burn everything along the way. These are all considerations that have to be made that make it extremely impactful in terms of what are we using, how are we approaching and what sort of compound we're using to do away with this lesion, not necessarily to cure, but to eliminate it from becoming a nuisance or a life-threatening complication so that these patients can have a normal quality duration of life and the ability to be able to go about and do what they need to do.

In terms of the embolization and the endovascular interventional treatment of these lesions, I think it's very imperative to understand that these are two broad categories that we're using. Either we're using -- and everything that I'm going to talk about, these are merely irritants. These are meant to literally just irritate the lesion, some more, some less. Ethanol, folks may have heard about ethanol as being perhaps the most effective compound that we have today. I use this analogy, I have termites in my house. I want to get rid of these termites. I'm going to get a blowtorch and I'm going to burn the entire termite colony. But guess what? Along with the termites that I've destroyed, I have now destroyed my home. My home is now burned down to the ground. And the dogma of risk versus benefit ratio, which every astute surgeon, medical doctor needs to be mindful of, to me, that risk-benefit ratio doesn't quite tilt in the favor of using something like ethanol. So I actually have never used ethanol in my practice, and I stay away from it because, in my opinion, the risks are just not justifiable. Other compounds such as bleomycin, this is a chemotherapeutic drug that we're using because of its side effects, and we're hoping that 50% to 60% efficacy will somehow be a durable approach. But let's not forget about the cumulative risk of pulmonary fibrosis and potential lethal complications that can happen with bleomycin as well. Doxycycline is perhaps the compound that's been used most commonly. Folks, this is an antibiotic. What it happens to have as a byproduct or a side effect of its antibiosis, it has antivascular endothelial growth factor to some extent, and it has some anti-matrix metalloproteinase. And we're hoping that somehow the side effect profile of this antibiotic will have a durable impact directly on the disease that we're targeting. That's just not good enough. And -- but this has been what we've been doing for decades. So obviously, there are efficacy limitations. There are risks and side effects, potentially lethal limitations, and there are anesthesia limitations. If you're using ethanol, you have to use general anesthesia because there's a huge risk of central cardiopulmonary toxicity, sudden cardiac arrest and death. You have to use what's called the Swan-Ganz catheter to measure pulmonary artery wedge pressures. Imagine the cost and that the detrimental and potential complication associated with these invasive measures for treatment of something that can be an ambulatory treatment 5, 6, 7, 8 minute procedure. So to me, again, the sheer risk of the -- what we are considering the standard of care right now does not tilt in favor of treatment.

Surgical approaches. This is a surgeon speaking, and I want to emphasize this, I told you a little bit earlier before, two things that vascular malformations love in terms of growth. I call them fertilizer for them. One is hormonal fluctuations, which happens during puberty, preadolescent and pregnancy, and the other is trauma, whether that's wear and tear against the joint space or if it's a surgical blade. A surgical blade is fertilizer for malformations. Not only that, when you're talking about surgically removing a water-filled balloon, inevitably, there will be violations of the thin mutated abnormal epithelial lining of this water balloon. Guess what? If there is a spillage, which inevitably in the vast majority of surgical cases there is, now you have a huge risk, greater than 50% risk of recurrence. And now you have to go back in, in a surgically scarred surgical field and try to reset and cause nerve damage and other adjacent organ damage to try to re-resect an area that should not have been treated by surgery in the first place. So here I am, as a vascular surgeon telling you that surgery should not and is not an appropriate first-line treatment for macrocystic lymphatic malformations and for any vascular malformations to that effect. There is a huge increased risk of mortality and potential surgical complications by virtue of uncontrolled bleeding and by virtue of who is doing these operations.

Next slide. So to summarize and sort of the -- end all be all the points that I tried to make is that there is an absolutely significant, I would go as far as saying desperate need for a more targeted minimally invasive approach to treating lymphatic malformations, particularly the macrocystic subtype. We need an FDA-approved therapy that is on label that provides a minimally invasive direct targeted mechanism that undoes the very molecular pathway that led to the formation or the pathophysiology that led to the formation of that particular lesion. This needs to be targeted therapy, as I mentioned. And we're trying to be much more sophisticated than what we have been thus more for decades. We're not trying to merely irritate the lesion folks by introducing some sort of detergents or some irritant compounds, hoping that it will be irritated enough, so I think it goes away for an extended period. We're trying to undo this molecular mutation pathway. It has to be minimally invasive and well tolerated, not requiring expensive amount of resources in general anesthesia. It has to be repeated in an easily implementable manner and require minimal sedation, and it has to be resource efficient, not only in terms of the compounds that are used, but in terms of the site of service.

And with that, I'll turn that over to the next speaker.

Thank you, Dr. Nassiri. We agree with you that an immune activating targeted therapy like TARA-002 that drives immunologic attack of cells with mutational burden has the potential to shift the treatment paradigm in LM.

Now moving on to the mechanism of action of 002 in lymphatic malformations. Following aspiration of fluid from the lymphatic cyst, TARA-002 is administered directly into the cyst via injection to activate an immune response. TARA-002 activates TLR2 and NOD2 pattern recognition pathway. The innate and adaptive immune cells within assist are activated and produce a targeted immune cascade that eliminates the mutated cells in the epithelial lining of the cyst while sparing healthy tissue. Cytokines and chemokines, such as TNF-alpha, interferon-gamma, IL-6, IL-10 and IL-12 are released. Neutrophils and macrophages are activated, and NK cells and T lymphocytes are rapidly recruited, which attack and destroy the mutated cells. This increases epithelial permeability, which allows remodeling of vessels to support normal drainage, leading to the eventual deflation and structural collapse of the cyst. Pro-fibrotic cytokines promote this tissue remodeling and the formation of mature tissue to prevent recurrence. And as observed in Japan, the Iowa data and now our data, it promotes long-term resolution of the cyst.

TARA-002 is a targeted approach that attack mutated cells using the body's own immune system and promotes tissue remodeling to prevent recurrence. It has a strong safety and tolerability profile with minimal pain and discomfort with pediatric patients. We believe this immune-mediated MOA conveys advantages to treating LMs with TARA-002, especially compared to off-label intracystic ablative agents. We aligned with the FDA on our clinical program, including the design of STARBORN-1 trial, which is a pivotal Phase II prospective baseline controlled single-arm clinical trial which is evaluating the safety and efficacy of TARA-002 for the treatment of macrocystic and mixed cystic LMs in 29 participants aged 6 months to less than 18 years. The trial has two stages. The first is an age de-escalation safety lead-in with 3 cohorts. The first cohort included children 6 to less than 18 years. The second included children, 2 years to less than 6 years. And the final, which we are actively enrolling, includes the youngest cohort of 6 months to less than 2 years. The second stage of the study includes the expansion cohort of patients across these ages. We are actively enrolling patients in the expansion cohort as well.

In the trial, patients received up to 4 injections of TARA-002 spaced approximately 6 weeks apart. The primary endpoint of the trial is the proportion of participants with macrocystic and mixed cystic LMs who demonstrate clinical success, which is defined as having either a complete response, 90% to 100% reduction from baseline in total LM volume, or a substantial response, 60% to less than 90% reduction in total LM volumes.

Now I'd like to walk you through the interim results from STARBORN-1 that we are presenting at the ISSVA World Conference. The analysis includes 16 patients as of the April 10, 2026, data cutoff. 83% of participants that completed treatment achieved clinical success. Of the participants who are assessed at the 8-week posttreatment time point, 100% of the evaluable participate achieved clinical success. In 80% of these patients, clinical success was achieved with 1 or 2 doses of TARA-002.

Looking at evaluable patients, it is clear that TARA-002 demonstrates a clinically meaningful response in macro dominant disease. As is often the case in rare disease, differential diagnosis was made in 2 evaluable patients in the trial. These patients were initially diagnosed with macrocystic disease which subsequently confirmed to be ranula. Consistent with previous understanding of the MOA of TARA-002, 1 participant achieved a complete response and 1 participant achieved a substantial response. This speaks to the potential of 002 as a possible option for other types of maxillofacial cyst.

Moving on to durability, the of TARA-002. Of the 7 participants who have reached the 32-week post-treatment assessment, all patients remain disease-free. The durable effect seen in these patients speaks to the robust effect of TARA-002. This is medical photography from 3 patients treated with TARA-002. All of these patients achieved a complete response. As you can see from the photo, 002's effect is prominent across varying sizes of macro dominant cyst. Patient on the left had a 1.7 liter cyst at baseline. The patient on the right had a 28 ml at baseline. As you can see in both patients, the resolution of the cyst is dramatic and the skin remains healthy.

Moving on to safety. The majority of adverse events were mild to moderate with no serious adverse events reported. The majority of AEs were grade 1 or 2 and the most common were swelling and fatigue and most were transient and resolved within a few days.

I'll now turn it over to Dr. Jones to give a summary of his experience as an investigator in the trial.

Thank you. I'm an interventional radiologist and Associate Professor at the University of Alabama at Birmingham. I trained at UCLA in Los Angeles, where I learned to manage complex vascular anomalies in a multidisciplinary setting.

I see about 50 vascular anomaly patients annually in my practice at Children's of Alabama, a large vascular anomalies clinic. The majority of these patients harbor macro or mixed cystic lymphatic malformation.

Here is a summary of our results so far in STARBORN-1. As you can see, we've had a remarkable safety and efficacy over the course of the trial thus far. When patients come to see me in the vascular anomalies clinic, which is a tertiary referral center, they're looking for an effective treatment. Lymphatic malformations, we can't always offer that. This represents a major unmet need. When Protara came to us with the clinical trial, we were enthused. TARA-002 is a compound built upon a strong track record of OK-432 and has a vast experience in Asia, including Japan and Korea. It has been unavailable in the U.S. for decades. I'm excited about the prospect of bringing this key treatment back into our armamentarium.

The STARBORN-1 trial offers a unique opportunity to rigorously study sclerotherapy in a disease that has previously been steeped in anecdotes and case reports. The data will enable physicians like me to treat LMs with confidence, incorporating the principles of evidence-based medicine.

I can share with you a couple of my patients I'sm especially proud of. The first is a 3-year-old boy with cystic lymphatic malformation of the peritracheal region in the neck as evidenced by the arrow here. He also was affected by cystic fibrosis, which is a genetic condition affecting primarily the lung, resulting in frequent upper respiratory tract infections, which exacerbated the lymphatic malformation, leading to multiple episodes of respiratory distress, including intubation. I and my partners treated this patient multiple times, as you can see here, with a large variety of existing sclerotherapy options. These include medications such as doxycycline, sotradecol and eventually ethanol. As you've heard earlier, when physicians reach for ethanol, you know they've reached the end of the road in terms of sclerosing agents. And unfortunately, none of these agents proved successful and the lymphatic malformation recurred yet again. Luckily for this patient, Protara was able to engage in expanded access use of TARA-002 in this young boy. With the help of their administrative staff and our IRB, we were able to secure this drug and treat this patient outside the confines of the STARBORN-1 trial. He underwent one session of sclerotherapy with TARA-002, 4 ml of fluid were aspirated and 4 ml of the treatment agent were injected per STARBORN-1 protocol. Following just one treatment, he had a remarkable response. At follow-up 2 months later, there was no visible evidence of residual malformation. We performed an ultrasound in the clinic setting. While there are no other residual lesion was seen, the boy was squirming about a bit as most kids do. Regardless, his result was so powerful, there was no need for any additional treatment. He suffered no adverse events and has been discharged from our care.

The second case I'd like to share with you is a girl, a 7-year-old female with a large cystic malformation about her chin. She also was treated multiple times with the presumed diagnosis of lymphatic malformation. Over the course of her treatment, which included fluid analysis in the laboratory setting, her diagnosis changed, as described previously, from lymphatic malformation to ranula, which is the growth of the submandibular gland that secretes a viscous fluid. She, like the other boy, underwent multiple treatments of the usual agents that we have available to us, doxycycline, sotradecol, ethanol. All of these were ineffective. The lymphatic malformation recurred. At this point, she was fortunate enough to be in the window of the STARBORN-1 trial and was enrolled. Over the course of 4 treatments of TARA-002, her malformation decreased, as you can see here in the table. At the end of the fourth treatment, she underwent an MRI, which we will show here. As you can see, her malformation has drastically reduced in size to the point where it is barely palpable and not visible on external examination. The patient and her family were quite pleased with this result. And at this point, we stopped further treatment.

This ranula, I think, shows how not just lymphatic malformations, but other cystic head and neck lesions, in this case, ranula, may be amenable to TARA-002. I look forward to continuing to enroll patients in STARBORN-1, but also exploring the expanded use of TARA-002 for other indications in the future.

I'll be happy to take questions at the end of this presentation.

Thank you.

Thank you, Dr. Jones, for sharing your perspective and experience treating patients with TARA-002. We share your excitement. The pictures you shared are clinical evidence of TARA-002's effectiveness, but they also make us think about how patients and caregivers must feel as they deal with the challenges of living with or caring for a child knowing that there are no FDA-approved treatments for macrocystic lymphatic malformations.

TARA-002 has the potential to become the first and only FDA-approved treatment for patients with macrocystic lymphatic malformations, which makes this an exciting time for us at Protara.

Our target indication for TARA-002 is macrocystic and mixed cystic lymphatic malformations. Based upon our market research, public research completed by other industry players and published literature on lymphatic malformations, approximately 1,500 patients are diagnosed with lymphatic malformations each year, and there are up to 80,000 patients currently living with lymphatic malformations. We believe that 25,000 of those patients have macrocystic or mixed cystic disease and are seeking treatment. This makes it an attractive total addressable market opportunity and which we believe is greater than $1 billion. 90% of patients with LMs are diagnosed in the community at birth or at an early age. Macrocystic lymphatic malformations by definition are larger cysts and as a result, are more often referred to a tertiary center, typically an academic medical center with a children's hospital or vascular anomaly center. Two primary treatment options for patients with a macrocystic component to their LM are surgery and sclerotherapy. These centers often utilize a multidisciplinary team to evaluate and treat patients. Our research suggests that multidisciplinary teams at vascular anomaly centers are increasingly preferring sclerotherapy over surgery and other treatment options. We believe that this trend will continue.

As Dr. Nassiri pointed out and our market research confirms, patients face a significant burden in managing their lymphatic malformations. Macrocystic LMs and their treatments can cause pain, fatigue, anxiety, sleeplessness and social isolation, while repeated interventions can cause emotional and financial distress. Today's treatment paradigm for lymphatic malformations has its challenges. There are no -- currently no FDA-approved therapies for macrocystic lymphatic malformations. The patient burden and high recurrence rates associated with surgery are well documented. The reported safety and efficacy of currently utilized sclerosants varies widely because of a lack of consensus dosing and administration guidelines and a lack of well-controlled studies. This typically results in significant variance in patient outcomes and risks based upon provider preference and experience. There is a significant opportunity to improve upon patient outcomes and patient treatment experience when compared to other options by using TARA-002 because it is a targeted therapy that leverages a patient's immune system to eliminate the cyst and restore normal tissue function. The data presented to date on TARA-002 compares favorably to currently available treatment options. TARA-002 demonstrated 100% clinical success in evaluable patients to date and no patient experienced recurrence at 32 weeks. We believe that the current TARA-002 clinical profile to date will enable it to garner orphan drug pricing. The most important reasons to note for this are the disease incidence, the product's high clinical success rate, the durability of response observed with limited numbers of doses and TARA-002 treatment being administered in the ambulatory setting. To date, the majority of patients treated with TARA-002 experienced clinical success with 1 or 2 doses. As the potential first approved treatment for macrocystic lymphatic malformations, we are excited to bring a new treatment option that can help standardize the way in which macrocystic lymphatic malformation patients are treated.

As we prepare for a potential launch of TARA-002, we anticipate a focused commercial launch that targets its efforts on vascular anomaly centers, their referral networks and key patient support networks. We see that up to 80% of lymphatic malformation sclerotherapy claims come from a limited number of centers. We are confident that we can achieve commercial success with a relatively modest-sized commercial organization, and we are excited to begin the commercial infrastructure build as we eye a BLA filing in 2H 2027.

Now I would like to turn the call back over to our CEO, Jesse Shefferman.

Thank you, Bill. The progress and strategy described today represents an important evolution of our LM program toward registration and ultimately meeting a significant unmet medical need. As we look beyond our pivotal study in LMs, we are excited to potentially expand TARA-002's reach to additional congenital and acquired cystic masses where OK-432 has demonstrated efficacy. There is substantial literature describing the effectiveness and safety of OK-432 in multiple additional types of maxillofacial cysts. The success we observed in the ranula patients who achieved clinical success with 1 or 2 doses hints at further opportunities to expand 002's reach.

In addition to ranula, the most cited non-LM cyst treated with OK-432, we've been looking at thyroglossal duct cysts as a further potential area to explore the use of 002. This is based on on OK432's historical utilization and efficacy profile in these maxillofacial cyst types. Taken together, the raw epidemiology of ranula and thyroglossal duct cysts represents a significant market expansion opportunity, and we look forward to sharing more about this as we solidify the opportunity in LM and move closer to filing.

So to summarize, we are very pleased with these initial data and 002's potential to address a significant unmet need in macro and mixed cystic patients. With no FDA-approved therapies, existing off-label treatments presenting unfavorable side effects and surgery oftentimes leading to recurrence, there is a significant therapeutic white space in LM.

We believe that TARA-002 has the potential to fill this gap as a de-risked, safe and efficacious treatment with its data to date, reflecting and potentially improving on the safety and efficacy profile of OK-432 in Japan and in multiple investigator-led studies around the world over the last 30 years.

Looking ahead, we anticipate STARBORN-1 to be fully enrolled by the end of 2026. We intend to submit a BLA to the FDA based on the results of STARBORN-1 in the second half of 2027.

I would like to thank all of the patients, families, investigators, advocates and Protara employees who have helped move this important trial forward. And Justine will now take Q&A from the chat box. Justine?

Thanks, Jesse. First question we have is, can you provide some additional context on TARA-002's durability seen in the data that you presented today?

Yes, Jacqueline will take that one.

So from a durability perspective, what we've seen is that all patients who have reached that time point have maintained their durability. And it's consistent with what we know from OK-432 in terms of duration. And we even know from OK-432 that the duration is even longer. In those studies, we had followed out to 9 years with durable responses.

This question is for Dr. Jones. Given the data that you have seen from TARA-002, if it were to be approved, what percentage of your patients would you use TARA-002 in? And would you use it ahead of some of the existing therapies that are used off label today?

When I first started enrolling in STARBORN-1, I was a little concerned because some of the patients who were coming to me had failed multiple treatments previously, and I didn't want to enroll a patient and have them fail and make the trial look bad. To my surprise, the drug has been very effective even in patients who had failed other therapies. So for that reason, it's actually become my go-to treatment. I would enroll everyone that I could in it.

What improvements have you made to the manufacturing of TARA-002 compared to OK-432?

So we have made modern manufacturing improvements. When the drug was approved in Japan several decades ago, the way that these drugs were controlled and released and just how they were actually formulated was very different than the way that we do it today. So we modernized it in a way that gave us much more control, which then allows us to have a much more predictable safety and efficacy profile.

As we think about potential positioning for TARA-002 versus sclerotherapy and surgery, is there anything else you think physicians treating LM would want to see in order to replace sclero?

I'll actually ask Dr. Jones and Dr. Nassiri to answer that question.

I think by virtue of the current MOA, I do not see a barrier to this compound becoming the go-to therapeutic mechanism. But Not only mechanism of action is directly targeted at the disease process, and we're not just relying on it's side effect profile to have some sort of cross-my-fingers effect to an unpredictable extent. And the side effect profile is nowhere near what it is that we're using. I mean if you think about it, if you're using an irritant, that irritant is going to not only irritate the lesion, but irritate everything else along with it. You use STS, you're going to have hemoglobinuria. You have this high risk for nontarget embolization. You have a risk of potentially putting the eye out of the operator. You have tons of potential issues, ulcerations, et cetera. So by virtue of a very favorable side effect profile with a nontoxic medication that is meant to put into place, an autogenous, body-mediated immunogenic response that undoes the formation of the malformation, as Dr. Jones mentioned earlier and as would be the case for me as well, this would be the go-to mechanism for treatment of malformations. And I don't think anybody would look into any other more dangerous, less efficacious compound.

One follow-up question. What is the relative size of an LM versus other cystic [ inflammation ]?

It can be quite a range. As you saw from some of the clinical photography, there was one lesion over a liter and others measured in milliliters. So it's quite a range. Regardless, they can all be treated, as you saw. And so I think that the size of the lesion is not really, at least for this agent. Other agents such as ethanol, there's a toxicity, and the same with bleomycin. We have not encountered that with TARA-002.

If you think about maybe some of these other [indiscernible], thyroglossal duct cysts, ranula, do they tend to be more homogeneous in size? I think that was the other piece of the question.

They tend to be more unilocular. You don't get a mixed microcystic ranula, for instance.

Can you talk about the practical implications of the move of TARA-002 from the vaccine division to OTP and what the impact of that could be?

Well, look, I think they are mostly speculative at this point, right? What I can sort of share is our lived experience. So I think the first is just the nature of OTP. OTP is where CAR-Ts and gene therapies and sort of viral vector treatment, that's where all these sort of drugs go within the FDA. And so again, this is speculation, but it would seem as though that is a review division, a, that is facile with small data sets that are pediatric in nature, that are employing targeted therapies where there's sort of a known mechanistic addressing of usually a genetically mediated disease or cancer. So there's just that piece, right? And again, it's just our speculation. I'm sure there are stories of drugs that have gone to OTP and failed as many as there are that have gone and won. So I think you've got to take that with a grain of salt. But what I can tell you anecdotally is that since we have been in that division, and that sort of coincided with our being awarded breakthrough therapy designation, the dialogue is active, and it is less sort of adherent to strict Type B, Type C meetings with briefing package, formal meeting over an hour and then you get the meeting minutes back. It's much more of a give and take and a back and forth with the review team. And then I would say, obviously, there is a practicality to the fact that both of our programs are now kind of being reviewed under the same roof. We know that when OTP would give us feedback, let's say, on ClinPharm or on CMC, the vaccines division had to be formally updated by the OTP division and vice versa. And so I think those are, again, just our perspective. It's a better move. But look, I mean, it's not all -- there is some getting up to speed that OTP has to do. And I think that you have to ask yourself, does that sort of insert sort of a -- kind of a learning curve and an upward slope as the OTP reviewers take on this program? Yes, I think you would be -- it would be disingenuous to say that there wasn't some type of learning curve. But what I can tell you is we get our minutes back really quickly. We get responses back well within sort of the allotted time frame under breakthrough. If you send an e-mail to the PM, they're obligated to respond within 20 days. They have never taken 20 days to get back to us. So I think there is a -- that's sort of the totality. On the whole, it has to be a positive. There is a learning curve piece. We haven't seen that drive significant delay, but it's there.

This morning, we saw Relay Therapeutics data announced. Can you tell us if you see that as a competitive threat? We know that there were some LM patients treated in this data set. What is your view on their data?

Well, I think what I'd like to do is I'd like to just state that the systemic and topical approach is utilizing agents that are active along the AKT/PI3K/mTOR pathway, this is not new. We've seen the utilization of rapamycin and the like in this setting, and looking at our 2 physicians here, that's not a new approach. What we know is that those tend to not be effective in macrocystic disease. What we do understand, and this is increasingly being borne out by data, is that they are somewhat effective, given the sort of the investigator-rated assessment of response, in microcystic disease. And so, listen, any development that helps kids that suffer from this disease, whether it's micro or macro, we're [indiscernible] champion that. But we don't see what Relay is doing or what Palvella is doing as competitive to where we are. That's really a microcystic story, and we're really the only ones out there right now in the macrocystic space. And again, you can look at the literature to see that topicals don't necessarily work with these architectures and systemics don't seem to address them in the way that 002 does, which is, as you've heard today, offering sort of functional cures for patients. So again, great for the field, but not a concern.

What are some of the learnings from the Japan experience in LMs with OK-432? How different is the market and the potential receptivity compared to the U.S.?

So what I can tell you about the Japanese experience is that it's obviously more longitudinal than what we've put together in STARBORN-1, but it generally, I think, is directionally the same. We are reconciling the fact that as our data set grows and the number of cases requiring 2 or fewer doses is seemingly more of the norm than less, whereas our understanding of the experience in Japan with OK-432 is that generally about half of those patients require kind of 2 to 3 doses when the majority require all 4. So I would say that, that's sort of just observational at the moment and that is leading us to ask ourselves -- and the other piece I would say is you've got this really substantial safety database that continues to exist in the Japanese approval dossier and the side effect profile that exists for OK-432 seems to be slightly more intense than what we've observed with 002. I think the numbers are still small, but we've seen enough now to kind of ask ourselves, is there something about 002? Is there something about the modernization of our manufacturing process that is conveying potentially enhanced safety and efficacy? I think it's a question and not one that we'll plan to flag on at the moment. But as the data set evolves, we'll continue to watch that.

Related to enrollment of the STARBORN-1 trial, can you give an update on how enrollment is going? We know that in the earlier stages of the trial, enrollment went slowly due to the design of the trial. Can you elaborate on how things are going now?

Sure. So I'll start by saying there's a lot of enthusiasm across our sites, and we are bringing on new sites just based on interest in the trial. The pediatric, vulnerable population, it's always slow and steady in the beginning. As you generate data, it gives more confidence to investigators. As Dr. Jones said, he was a little skeptical about putting patients in. As you generate data and you show a safety and efficacy profile like this, I think that both investigators in the room will agree that now it's easier to say, okay, yes, I want to put a patient into the trial. Our age de-escalation cohorts were definitely challenging. We started with a population that was 6 to 17 years old. That's a difficult set of patients to bring into a trial. If you're 16 years old, you've been living with it, your urgency to treatment is low. It took us a while to get through that. But now that we're through it, I think our sweet spot is definitely in the 2- to 10-year-old range. That's where we're seeing the majority of patients coming in. But I think we're on track to enroll the study by the end of the year.

I think also, just to jump in, I'm going to ask Dr. Jones to kind of weigh in on this. Our imaging modality that the FDA required of us is MRI. And whether it's a 6-month old or a 3-year old, I think anyone with kids probably would agree, I mean, I have kids. They're certainly not that age anymore. But MRI is not an insignificant thing. And I found it interesting in Dr. Jones' case study that for the child with the cystic fibrosis co-diagnosis, this -- the ultrasonography was utilized. And I'm imagining that in a real-world application, it's probably ultrasound that is driving a lot of this, right? And so the MRI piece just introduces, I think, a scientific experiment-based variable that in the real world, I don't think is really the way imaging is utilized.

We're doing a clinical trial here, and I'm not rushing. The company may be more impressed than the investigators. I really am excited to see high-quality data come out because that's what's been lacking for 40 years. And they are requiring a lot. The FDA is requiring a lot, and MRI is part of that. The upside is I think it's going to show without a doubt that this is a very effective and safe treatment. As the trial has gone on, some physicians have come up to me almost with a FOMO, like they want to get involved. One physician at Mount Sinai asked for a referral to see if she can get in the trial. And I think it's kind of picking up steam in the sense that the news is out there now that this trial is going on and the results are good. And I think if anything, it's just going to continue to enroll faster.

Another question for Dr. Jones. Why do you think the patients that you treated responded to 002 when they failed so many other therapies?

As talked about previously from the previous presentation with my colleague, the other therapies are all similar in the sense that they try to irritate or destroy the lesion through a mechanism of either desiccation, like dehydrating it, or denaturing it. TARA-002 works differently. It incites a targeted inflammatory response. So I really think the mechanism of action being unique is what differentiated the treatment response.

Do you have any comment on that?

I agree. I think, like I said, everything we're using thus far has, as I said before, has grandfathered its way into the treatment algorithm. And we are relying on side effects of the medication, which has not been rigorously studied, and the dosage and the efficacy thereof has not been regularly repeated. We're just hoping that it irritates it enough to an extent that is adequate and not risky enough, which, as we've seen, is not often the case at all.

With the accelerated approval pathway and submission under breakthrough designation, what do you expect could be the range of ages where TARA-002 could be approved?

Look I -- yes. We're pretty confident that it will be the whole range of ages that we've enrolled in the study. I think, again, given the breakthrough therapy designation and population, but leaning into the experience that OTP has with vulnerable patient populations with genetic diseases, I think if you're demonstrating homogeneous efficacy and you're demonstrating homogeneous safety, then the sort of range of ages is, in our experience, probably less relevant. So I don't see an approval in a certain age category followed by sort of expansion of the label to a younger age category. We're fairly confident that when it comes down to it, the label will reflect the ages that were interrogated in the study.

Two questions on mixed LM. One is, based on your FDA interactions, how do you expect that to be handled in your label?

And another question is, are there opportunities for combination therapy when you think about treating mixed LM?

So again, I think this is where we may have the -- so look, I think we will continue to enroll macrocystic-dominant mixed patients. There, I think it's our obligation to sort of articulate how a macrocystic-dominant mixed lesion is, sort of, in some respects and looking at our 2 physicians here, sort of the macro element of that mixed lesion is sort of "your index lesion", right? It's what you will treat first in that mixed environment. And so again, if you look at the data that we're generating in the STARBORN-1 study in mixed patients, and to the extent that we are able to refer back in a general way to the experience of OK-432, that gives us some opportunity to -- if, for instance, the majority of the patients we treat are going to wind up being just macrocystic patients only. I think there would be enough education of the review team to understand that, that mixed lesion is really sort of an index lesion of a macrocystic lesion, but I will refer that to you guys.

I think it's critical to understand the response rate to the macrocystic because let's not forget that we're not talking about a different genetic mutation now. It just so happens that the end product of that mutation happens to be in a microcystic environment versus a macrocystic. And what happens with the macrocystic, by definition of the channel that's formed, is it winds up accumulating more fluid. But the genetic basis and the molecular basis and the mutation is essentially the same. So I could see a scenario where, as the experience with the macrocystics and the mixed lesions grows, we could pivot into the microcystic environment and understand the inflammatory and the immune-mediated response that is generated in the macro and the mixed and apply that down the line to the microcystic lymphatic malformations as well. And as I said before, again, this is not a bash on surgery. It's just that combination therapy still will have a role. And it's just that maybe the solution is for surgery to only be present after you have adequately caused that inflammatory reaction and replaced the mutated lesion with now a fibrotic residue. Then that fibrotic residue is appropriately surgically resected.

And I think if the question inferred sort of combinatorial approaches of 002 with either topical agents in that mTOR pathway or systemic, it's not in our current strategy given the effect size that we have seen in the macrocystic setting and the macrodominant mixed setting. But look, I think as we have often said in our NMIBC program, until you are achieving 100% response of all active disease in the patients that we're lucky enough to treat, then the world will evolve. And if combo emerges as sort of a viable and economic means of addressing the mixed cystic lesions, then our objective is to treat patients that need the therapies that we hope to provide.

What proportion of prevalent patients over the course of their lifetime might be eligible for or see [indiscernible].

As Dr. Nassiri said earlier, these are macrocystic lesions. They are in need of treatment. So we believe that the incident population is actively treated. The prevalent population, as Dr. Nassiri said also, there's events that spike the need for treatment, whether it's puberty, pregnancy. Those pop up. So I would say that each of them, we believe that if we look in a time frame of 5 years, they're active in treatment. It's just whether sclerotherapy or surgery would be in that. They're seeing physicians. So they're choosing to stay active in the pool. And that's how we measure it. We measure it off of claims. So they're actively seeing physicians. We would anticipate that they would, if they're actively having their pain, they're suffering symptoms as they're coming back to physicians, that if treatment isn't immediate, it will be within a year or 2.

Yes. I think just to reiterate, these are not data that -- the prevalence estimate that we put up today of about 20,000 patients from, broadly speaking, 80,000 that have sought treatment, those are claims-based, meaning those patients are actively seeing a physician and -- under a diagnostic code of lymphatic malformation. Whether they're seeking intervention, there may be a lot of reasons. Either there's treatment fatigue or maybe they went through that ethanol phase and they're sort of at the moment with nothing quite available for them. But that is different than a patient that has sort of gone back into their community and is no longer actively seeking treatment based on the fact that, that data comes from claims. A patient is seeing a physician and under a claim for lymphatic malformation. Again, I think it's -- many of them, they are prevalent because they're not seeking intervention.

Okay. For macrocystic and mixed cystic LM, what degree of volume reduction usually translates to symptom improvement, and how does this relate to the definition of the STARBORN-1 trial, complete response of 90% to 100% reduction or substantial response?

Yes. Dr. Jones here. So just kind of looking back at some images I showed in my presentation with that ranula patient, I would say at about 60% to 70% volume reduction, you're seeing significant clinical improvement to the point where many patients may find that adequate and not desire further treatment. It is just not a cancer. We're not aiming for a complete radiographic response. The radiographic response, as Jesse mentioned earlier, is a little skewed because we're in a trial. Typically, I'll do a sclerotherapy, the patients come back and see me in 4 to 6 weeks. I'll look at them. I'll examine them. I'll ask them, how do you feel? If they feel like they're adequately treated and on examination there's minimal palpable residual, or I'll do an ultrasound in the clinic and there's minimal fluid there, we're done.

Those are all the questions well take.

Again, we want to thank everybody for joining us this afternoon. A huge thank you to Dr. Nassiri and Dr. Jones. And again, thank you to the families, the patients, the providers that have contributed to the STARBORN-1 study and especially to the Protara employees that have been working tirelessly to keep the study going and off the ground.

And with that, we'll say good evening, and thank you again for your attention today.

Ladies and gentlemen, this does conclude today's session, and we thank you all for your participation. You may now disconnect your lines, and have a good day.

Hello, and welcome to the Protara Therapeutics ASCO GU Update Call. [Operator Instructions] As a reminder, this conference call is being recorded. If you have any objections, please disconnect at this time.

With that, I would now like to turn the call over to Justine O'Malley, Senior Vice President, Investor Relations and Corporate Affairs.

Thank you, operator. Good morning. Thank you all for joining us today for a review of the updated interim analysis from our ongoing Phase II open-label ADVANCED-2 trial of TARA-002 in patients with non-muscle invasive bladder cancer. Before we begin, I would like to remind you that during today's call, we will be making certain forward-looking statements. These statements represent our views as of today only and should not be relied upon as representing our views as of any subsequent date. Actual results may differ from our forward-looking statements due to various factors, including those described in the Risk Factors section of our most recent annual report and subsequently filed quarterly reports that are on file with the SEC. Except as required by law, we disclaim any obligation to update these statements even if our views change.

Joining us on today's call are Jesse Shefferman, Co-Founder, Director and Chief Executive Officer of Protara; and Dr. Carla Beckham, who is a Board-certified urologist and the Lead Medical Director and Head of Clinical Development for the TARA-002 NMIBC program. Additionally, we are privileged to be joined by Dr. Neal Shore, Medical Director of START Carolinas/Carolina Urologic Research Center.

At the conclusion of our prepared remarks, we will open the call for Q&A and are joined by our Chief R&D Officer and Co-Founder, Dr. Jacqueline Zummo; Chief Financial Officer, Pat Fabbio; Chief Medical Officer, Dr. Leonardo Nicacio; and our Chief Commercial Officer, Bill Conkling.

I will now turn the call over to Jesse.

Thank you, Justine, and thank you all for joining us this morning. We are pleased to share positive interim results from our ongoing Phase II ADVANCED-2 trial of TARA-002 in patients with NMIBC. These data will be presented during a poster session at GU ASCO later this week. Today, we will share interim efficacy and safety data from both ADVANCED-2 trial cohorts, the BCG-unresponsive and the BCG-naive cohorts. Note that the data included in the press release we issued yesterday and the conference posters have a data cutoff of January 2026, and the abstracts that posted yesterday have an earlier data cutoff of October 2025. In both cohorts, TARA-002 continues to demonstrate compelling response rates and excellent safety and tolerability. We believe the interim results in the BCG-unresponsive cohort are exciting with top of the competitive range 6-month response rates and accumulating 12-month data with a median follow-up of 5.6 months in evaluable participants.

We are confident given the response dynamics that we've observed in both BCG-naive and BCG-unresponsive patients that 12-month response rates will be a strength for 002 as current 6- and 9-month CRs mature. These positive interim data give us confidence that TARA-002 has the potential to be an important mainstay in the NMIBC treatment paradigm. 002 has a potential best-in-class product profile with compelling response rates, encouraging durability and a favorable safety and tolerability profile. These, combined with its off-the-shelf availability and fast, simple administration, position 002 to easily address the factors that are priorities for NMIBC patients and urologists and provide key competitive advantages within the evolving NMIBC landscape. For those of you who may be new to the Protara story, we are a clinical-stage company developing transformative therapies for the treatment of cancer and rare diseases.

Our lead asset is TARA-002, which we are assessing in NMIBC as well as in lymphatic malformations, which are rare congenital malformations of lymphatic vessels typically diagnosed in childhood. And finally, our pipeline also includes IV Choline Chloride, an investigational phospholipid substrate replacement for patients dependent on parenteral support. We're excited about the potential for all of our programs to make a meaningful difference in the lives of patients. Today's focus though will be on the updated interim analysis from our ADVANCED-2 trial in NMIBC. TARA-002 has a unique profile in the NMIBC treatment landscape. It sits at the intersection of what both patients and urologists prioritize, safety, efficacy and simplicity. 002 delivers robust single-agent activity with competitive complete response rates and encouraging durability.

It does so with a clean safety profile, mostly mild, self-limited local reactions with no related serious adverse events or treatment-related discontinuations. Additionally, it is administered through a simple office-based intravesical instillation with no viral handling, no special preparation and no burdensome post-administration protocols for patients, making it easy to integrate in existing practice workflows. We believe these product attributes position 002 as a best-in-class next-generation investigational therapy with the potential to meaningfully impact care in NMIBC.

I would now like to turn the call over to Carla to walk us through the interim analyses.

Thanks, Jesse. By now you're all familiar with 002's unique mechanism of action. TARA-002 is a genetically distinct [ 2 ] strain of strep pyogenes that drives an antitumor Th1 immunological response. TARA-002 is manufactured from the same master cell bank as the originator therapy, OK-432, which was developed by Chugai Pharmaceuticals and is approved for a number of oncology indications in Japan with an over 65,000 patient safety database collected from clinical trials and commercial use. It is a pleasure to review this exciting data with you. As a reminder, the ongoing Phase II open-label ADVANCED-2 clinical trial is assessing intravesical TARA-002 in NMIBC patients with carcinoma in situ with or without papillary disease who are either BCG-unresponsive or BCG-naive. The BCG-unresponsive cohort is designed with the registrational alignment with the FDA's updated 2024 BCG-unresponsive NMIBC guidance.

Participants in the trial received 6 weekly intravesical instillations of TARA-002, followed by a maintenance course of 3 weekly instillations every 3 months. Participants are eligible for reinduction if they have residual CIS and/or recurrence of high-grade Ta at 12 weeks. They are not eligible for reinduction if they experience disease progression or treatment failure, defined as progression or recurrent T1 disease. At the request of the FDA, there was a mandatory biopsy at month 3 in our registrational BCG-unresponsive cohort. Turning to the BCG-unresponsive data. At the time of data cutoff, the complete response rate at any time was 66%, 68% at 6 months and 33% at 12 months. This initial durability is encouraging, especially in light of the small sample size and the inherent challenge intrinsic to landmark analysis with short follow-up.

In addition, responders are making their CRs -- maintaining their CRs, demonstrating good potential for a continued durable response. The Kaplan-Meier estimate probability of maintaining a CR for 6 months is 71%. And we see that 100% of evaluable responders maintain their CRs from month 9 to 12. Another exciting data point is the 62% of the participants who converted from non-CR to a CR at 6 months with reinduction. In summary, we are enthusiastic about these initial results. We have seen a steady increase in enrollment in the BCG-unresponsive cohort as we have executed our global expansion and expect to complete enrollment in this registrational study in the second half of 2026. Now for a brief update on the BCG-naive cohort, which is fully enrolled. At the point of data cutoff, the complete response rate at any time was 72%, 67% at 6 months and 58% at 12 months. This 12-month response rate marks a significant improvement from the observed at previous data cutoffs.

We are pleased to see the 12-month CR continue to increase as longer follow-ups occur. In addition, TARA-002 shows good signs of durability in BCG-naive patients. The Kaplan-Meier estimated probability of maintaining a CR for 6 months was 73%. In addition, 100% evaluable responders maintained their CRs from month 9 to 12. Importantly, 67% of reinduced patients converted to complete response at month 6. We are pleased with the strong results in BCG-naive participants. As urologists, I'd like to think about how these data inform our understanding of what we can expect from TARA-002 in the BCG-unresponsive cohort as it matures. The 3 pillars of the clinical profile are efficacy, safety and tolerability.

TARA-002 is well tolerated in this older population with significant medical comorbidities. Furthermore, we think that the clinical profile, coupled with the ease of use and low burden on the patient, physician and staff will lead to a preference for TARA-002 in the real-world setting. 002 continued to show that the majority of treatment-related adverse events, which included dysuria, bladder spasm, fatigue and urgency were Grade 1 and transient and none were grade 3 or greater. In addition, no participants discontinued treatment due to related AEs. Overall, the efficacy and safety of TARA-002 observed in both the BCG-unresponsive and naive populations are promising. And we look forward to completing enrollment in the BCG-unresponsive cohort and starting the ADVANCED-3 registrational trial in BCG-naive patients later this year.

[Operator Instructions] We'll take the first question from Stacy Ku with TD Cowen.

Congratulations on the impressive 6-month efficacy. Of course, now that we have the 6-month results, our attention does turn to the 12 months durability data. So just given your comments on 002 historically and the expected performance in BCG naive and BCG-unresponsive NMIBC patients as we look to the summer plot and as the 12-month data matures, first question is, would you expect the CR rate to improve?

And then as a follow-up, maybe elaborate on your observations regarding some of these early responders, patients that are achieving CR at maybe the 3-month time point and your views on durability. So that's the kind of first 2-part question. The next question is more on timing, if you're all willing to give us some type of guidance as to when we could get the next data update for ADVANCED-2. And I can wait for Dr. Shore to connect for my last question.

Okay. Well, thank you to everybody for bearing with this technical glitch, never a dull moment. So I'll take -- so first, Stacy, thank you for acknowledging that the 6-month number here is -- it's something that we're very proud of. Our view is that we've got just about the best landmark CR rate that has been published to date amongst our peers at that time point. I think what matters is -- and again, drawing everybody back to a common refrain from Protara, which is that as the data sets mature in both cohorts A and Cohort B of the ADVANCED-2 study, we expect that the data will converge. And really, our underlying view is that prior BCG exposure is not as important as, frankly, degree of pretreatment of patients in the unresponsive setting, the number of pretreatments. And so again, as you -- I think this data, as you look at the 6 months either CR at any time or landmark CR across the 2 cohorts, you've seen that, that has happened that those numbers have converged.

Look, I think the number at 12 months is a function of a small sample size, which I think by now, everybody on this line that's been looking at the oncology space for some time knows that landmark with low N is typically unfairly biased by early nonresponders, which every study has and not sort of benefiting from the green dots that you see here that have not made it yet to that 12-month evaluation time point. I guess as -- just keeping this swimmer's plot slide up, Stacy, as you start from the top, every green dot at the 3-month time point tends to be a green dot at 6 months and again, still at 9, there are a few that aren't. But then once these patients get to that 9-month time point, they have a 100% probability at this point of maintaining that CR. So then as you go down the swimmers plot, you see that there is a bolus of green dots at the 3-month time point, which if that dynamic maintains, they have a fairly high probability of becoming 12-month CRs.

But look, you don't even have to go to those 3-month CRs. Just look at the next three 9-month patients that are just there towards the top. Right now, we would anticipate that at least a significant percentage of those patients, if not 100% based on our previous experience, would convert to CR. So look, that's a lot of sort of pick [indiscernible] to try and get at. We are very confident that the number that you see today of our month 12 CR rate will be in the 40s by the time this data set is full, right? I think making a call on durability on the first 15 patients of a 100-patient study is not something that guides our decision-making, and we would posit that it probably shouldn't guide others' decision-making as well.

Remind me your second question, Stacy?

Timing for the next data update for ADVANCED-2.

Look, I think as it relates to our next update, if you take a look back over the past 3 years, we've been on a pretty steady cadence of trying to provide something for investors at major urologic conferences. I think to us, those conferences are GU ASCO, AUA, increasingly ESMO and the SUO conference towards the end of the year. So we're not prepared yet to guide on when the next time we would release data would be. But obviously, these -- the naive patients in Cohort A are going to continue to mature and will continue to provide, I think, a breadcrumb trail for what to expect as the unresponsive arm matures.

And obviously, we are maintaining our guidance that we'll be fully enrolled in the unresponsive arm by the end of the year. And I can say that, I think, with a measure of comfort. And so as a result, I think you can just sort of look to the medical conferences as where we have historically provided data. And our objective will be to provide answers as they are available and interpretable on that 12-month durability number.

Okay. Understood. And I don't know if Dr. Shore is back and connected. I do have a question for him, but if not, I can wait and hop back into the end of the queue.

Well, he says he's trying. We're going to keep going, Stacy. If you want, you can pop back in after we get Dr. Shore back on. Thank you, though.

Our next question comes from Leland Gershell with Oppenheimer.

Congrats on this update. My questions would await Dr. Shore's rejoining. So I will defer until he's back on.

Our next question comes from Kelsey Goodwin with Piper Sandler.

Congrats on the data. I'm going to ask my non-Dr. Shore questions and maybe can hop back in the queue with the rest of the analysts as well. But maybe just remind us, for this unresponsive cohort, were the patients allowed to see experimental agents prior to joining the study? And how does that compare to competitor data sets and kind of shape what we're looking at today? And then a second question, maybe just for the benefit of us all hearing it, a question I get asked very frequently is how your definition of high-grade CR compares to the use of just more broadly CR that the competitors use in the high-risk space. So maybe you could just clarify that for us as well.

So the question that I heard is degree of sort of other investigational treatments that we've observed and then how we're defining CR, Kelsey. So I guess I'll take the first one. Look, I think given where we are sort of in the -- sort of the time horizon of investigational agents that have sort of emerged in the last several years, you've got a number of marketed products and that are on the market, and you've got a number of other sort of investigational agents. I'll give you the numerical answer. But what I'd like to sort of highlight is at this particular moment, as you are enrolling CIS patients, the probability goes up that the patients that you have enrolled are recurring from not only BCG -- prior BCG treatment, but a number of others as well. So about 35%, Kelsey, of the patients in this data set were treated with other either investigational or approved products.

So every -- I won't sort of name names, but these patients have seen everything from Gem/Doce. They've seen checkpoint inhibitors. A number of them have seen both kind of targeted immunotherapies that are either approved or about to be approved ostensibly, and they've also seen sort of enhanced chemotherapeutic agents. We've sort of seen the gamut there. So -- and I think that, that speaks to the quality of these responses is that, that's a pretty high number of kind of previously treated patients. And look, I don't have and I don't think anybody on the line from our team has at their fingertips sort of an array of level of pretreatment from some of the competitive products that are out there. But I think you should sort of as a rule of thumb, kind of think that as folks like Protara and others who are still kind of wrapping up their pre-registrational studies, that those agents will have seen some measure or some number of prior treatments with kind of what we would consider to be competitive branded products.

And so then as it relates to kind of the definition of CR, again, what I would say is we, as a rule, really try to hew as closely as possible to FDA guidance wherever they make it available. And so we just simply use high-grade CR as it's defined by the FDA, which means any high-grade recurrence. So high-grade disease is either CIS, it's TA, it's T1 or it's CIS plus TA or T1. That is a high-grade recurrence. What is not a high-grade CR is any low-grade recurrence. It's our understanding that if everybody is hewing to FDA guidance, all of the protocols for kind of investigational or recently approved products allow for resection of low-grade disease, and that would not be a cause, for instance, at the 3-month time point for reinduction. So that is not considered a high-grade recurrence. Again, our understanding is that that's what -- that's how everybody kind of defines CR. And again, it's how the FDA wants to see it. So that's how we're going for it.

Do we have Dr. Shore back on the line?

Yes. Jesse, can you hear me?

I can.

Well, Neal, I think we can sort of move from your prepared remarks unless you have a couple of things that you'd like to say about your experience with 002 because you got a lot of questions from our listeners.

Yes, sure. Thanks, Jesse. Apologies to everybody. I think the bomb cyclone of the winter storm, it's over my house. The good news is that I have had -- I really -- I've had the privilege as a GU oncology researcher and not just in prostate, but in bladder in the last 8 years for both NMIBC naive, unresponsive and [ MIBC ] to be privileged to be part of most of the trials that I'm sure you're all familiar with. And it's been a great privilege because we've made such great advances. I will just kind of -- that's my background, and I'm the Director of START Carolinas.

I head GU Oncology for START Cancer Research. And I was one of the original founders of the bladder cancer think tank and was on the Board of BCAN for over 10 years. I'm excited to go out to ASCO GU. I'm happy to be the senior author on 2 of the posters that are getting presented that was really the crux of the call today. They're really great swimmers plots as you've seen. So I'm happy to answer any questions from the folks listening in, and I apologize for the technical mishap.

Great. So operator, if we could reopen the queue. I think there are a number of folks on the line that have questions for Dr. Shore.

We'll take the first question again from Stacy Ku.

Hopefully, you guys can hear me okay. Dr. Shore, so I was curious what your view is on the salvage rate for TARA-002. So just help us understand how important that data point is and taking the totality of the results as urologists consider the different treatment options. So just a question on salvage rate and how competitive it is.

Yes. No, I think it's a great question. And of course, we oftentimes see salvage in some therapies, not in all therapies, it varies per protocol design, but the salvage rates that we see here are remarkably impressive. I think, as was alluded to earlier, the simplicity of the delivery, which cannot be overemphasized given the challenges we have, not just in academic, but in community centers, reinduction will be highly appealing to patients and physicians and the team because of the really -- I don't -- it's always a challenge to say best-in-class, but certainly arguable that their safety profile and the extensiveness of the database going back to OK-432 and now with 002 is so well tolerated.

So if somebody needs a reinduction, I don't think there's going to be much pushback compared to what we've seen with some other therapy. So the high reinduction success baked into your question, I think it makes it remarkably compelling.

Our next question comes from Leland Gershell with Oppenheimer.

Great. Dr. Shore. So I just wanted to ask, as we step back and we look at the interim efficacy data here and then efficacy data we've seen from other agents. I mean in the medical oncology setting, where there may be less differences amongst agents in terms of their other factors like tolerability and so forth, folks are keen to kind of put a high sort of focused on even slight differences in efficacy rates. Here, we have efficacy rates that are all kind of generally comparable, but there are advantages seemingly to TARA-002 versus some other therapy.

So I wanted to ask how are you going to think as a urologist [ as well as an ] oncologist about treating patients with 002 presuming it gets approved versus other agents, either in kind of a sequence format or in a stage of disease format. And also want to ask with respect to sort of the view that there are agents that may be available and some are already available in the market that may have kind of a first-mover advantage, let's call it, to Protara. How much does that matter as Protara comes to the market?

I appreciate the question. One of the slides I thought that Jesse presented early on, I think it was in sixth slide, I sort of love that Venn diagram where you saw 2 in the center of safety, efficacy and simplicity. There's no doubt. And within your question, I really liked it because look, 95% of patients don't want to go on to become -- well, 100% don't want to become unresponsive. And then those who are unresponsive who are looking for their first line of treatment, they 95% don't want their bladders removed. So within the construct of your question is -- and in the U.S., we have this proverbial embarrassment of riches unlike anywhere else in the world in the unresponsive state.

You have multiple different options, whereas outside of the U.S., it's basically a single agent chemotherapeutic and/or bladder removal. So I think the sequencing or what some have called the stacking of therapies is really ubiquitously practiced within community and even arguably in academic centers. Of course, more sophisticated uro-oncology centers such as mine and others, we may be more likely to go for some therapies that have higher AE profiles. But I think that given that we know that 80%, 85% of cancer care NMIBC, naive or unresponsive is happening in the community where safety, possibly simplicity, with comparable efficacy is going to really win. Now you're right. I mean, there is always the possibility of first-mover advantage, but I frankly have not seen that being as durable as you would expect given the really frothy burgeoning nature of NMIBC.

We'll take our next question from Kelsey Goodwin with Piper Sandler.

My questions for Dr. Shore have been asked.

We'll take our next question from Li Watsek with Cantor.

I want to add my congrats on the impressive 6-month CR rate as well. My first question is on the trial itself. I wonder if you can share a little bit about maybe the patient baseline characteristics, particularly in a proportion of patients with papillary disease.

Li. Yes, we in the appendix of the slides that we posted, you could see that we had a high percentage of CIS-only patients. That is not by design. It's sort of how the patients have enrolled. I think as we continue to go towards full enrollment, we know that we've got to keep kind of about 20% of the study comprised of concomitant papillary patients. I think to kind of be in the same ballpark as what we've seen others present as a registrational data set. So what I can say, though, is this is our observation as we have now dosed kind of 90-plus patients with this agent is that concomitant papillary tends to -- or versus CIS only tends to be more impactful on early response.

As we have looked at -- obviously, look, I mean, we acknowledge that durability at this point remains the only outstanding question on 002 because we've certainly answered kind of the 6-month number, which is what everybody else has made hay with. I think now that we've proven that point, we're looking at durability. And what we know and what we've observed is that concomitant papillary status doesn't really convey an interpretable through line to that answer of what is the durability. It's far more important for your 3-month and 6-month response, very much not as important, again, across 90-plus patients for that durability. I think you got to have 20% concomitant papillary in your data set to have a label that says CIS plus/minus Ta/T1. I'm confident that we'll get there just knowing kind of what comprises some of our earlier not yet 3-month evaluable patients.

Look, I think we have not managed our CIS versus CIS concomitant status to date. But as we get closer to full enrollment into the second half of the year, if we have to, then we'll go back to our sites and sort of kind of like, I guess, reaffirm the fact that we need to see them enrolling a relevant number of concomitant papillary patients.

Great. My second question is for Dr. Shore about adoption. Obviously, you talked a lot about the importance of safety, ease of administration, especially in the community setting. So I just wonder if you can just give us your view in terms of 002's degree of differentiation on these aspects relative to the other options? And how would you rank these factors in terms of driving adoption? Obviously, for a lot of investors, they tend to focus more on the efficacy side as a primary sort of factor, but it seems like in this setting, maybe safety and administration could be equally dominant driving forces.

Sure. Yes. Thanks. Appreciate the question. And you're right. I mean, sometimes it seems that our focus is just trying to look at hazard ratios on efficacy with small data set. But what I really like about what the folks at Protara are doing is they recognize the importance of expansion of their data set and durability, which I think is looking very promisingly. When you think about the crux of your question, this is never going to be a supply chain issue as you see with BCG. And there are some other very important aspects to the competitive environment. There are certain types of safety equipment ranging from hoods and genetic and viral protective safety measures that have to be invoked for some of the therapies that are out there and not all sites, frankly, are up to the task for that. So that's super important.

And then even some things as simple as do you have freezer capability, do you own the equipment, do you have the storage for it? That's not an issue for 002. These are really important operational challenges and safety requirements. Additionally, as was stated, and it shouldn't go without attention from a strategic marketing standpoint is the just in time -- there's no just-in-time delivery. This is truly off the shelf product, which, in addition to the comments on safety and patient tolerability. As everybody on this call knows, and it's not unique to NMIBC or MIBC or prostate or bladder or kidney cancer, which is what I deal with, but there are person power shortages and there are supply chain issues that are really burdening the health care system.

So I think 002 fits in really well with that regarding the landscape. And then the other thing that the efficacy data is very compelling, as you've already seen, that's why it's exciting to see these 2 posters coming forward. But also, it does have a unique MOA. So it's really very consistent, but a little bit simpler in terms of being an immunopotentiator as is BCG, which goes into the historical understanding for urologists, general urologists as well as for uro-oncologists.

We'll take our next question from Andres Maldonado from H.C. Wainwright.

Congrats on the data again. I guess one for Dr. Shore. You touched upon that there are some more advanced therapies that are ahead of Protara. So in that light, so say, one proportion of those patients get a viral or non-gene therapy, the other proportion may get an intravesical chemo device. How does the algorithm change of treatment between the 2 cohorts of BCG-unresponsive and BCG-naive? And then I guess, more importantly, for those subsets, how close are we to painting a picture of patient characteristics such as cyst burden or prior BCG failure or time since last BCG to really get some traction on an algorithm that really affects these patients most effectively?

Yes. No, thanks. Appreciate the question. The -- let me take -- sort of a bunch to unpack there. But the last part of your question was addressing this BCG exposed population, which is a remarkably large population and it basically creates a sort of certain conundrums as we try to enroll patients in those who had less than an adequate induction or 5 plus 2 per FDA working group and/or they had BCG way north of 12 months prior to their recurrences. So that's a big population. And I think ultimately, where there are shortages of BCG, which is a sort of a metastable issue in the United States, who knows how that's going to play out once the new Merck plant comes online. No one can ever be completely certain of that.

Again, it doesn't appear that there should be ever an 002 shortage. The other thing that comes into play, and it's certainly not my expertise, but understanding the cost of goods being particularly low, when therapies come out and in our ever-changing health care reimbursement schedule, practices, particularly the nonphysician leadership will look at the outlier of purchase and the reimbursement based upon where we are, whether it continues to be under a Part B structure and typically looking at your ASP 6% or 4.4%. So that's basically a little bit of a long-winded way of saying the practices, and I'm seeing this more and more in academic centers, there is push towards understanding what the urology clinic practice will have to put forward in terms of purchase and what they can expect in terms of their reimbursement.

So I think that the structuring or the sequencing or the stacking is going to most likely be the sort of wanted concept of shared decision-making, which we all talk about. I'm a big proponent of it. And when you have multiple things to choose from, what will the percentage of Grade 3, 4 adverse events be of one versus another, the time to come into the clinic to receive therapy and the schedule of events and whether or not it's a monotherapy versus a combinatorial therapy and then all the other safety and equipment issues. So I think that, that is going to have an enormous impact on the BCG naive. Once you get to unresponsive and then you're sort of -- the clock is ticking faster and you're more concerned about having your bladder removed, I think then patients and caregivers and health care providers will have a more full throated discussion about efficacy versus safety tolerability.

And maybe just one quick follow-up. I guess, for Dr. Shore. Through the lens of immunological exhaustion. Do any of these therapies particularly stand out to you where 002 might be able to reengage the immune system? Is immune exhaustion something that's on your mind as you're looking at all these next-generation therapies and how to sequence them?

It does. And look, immuno-oncologic understanding whether it's the innate and adaptive pathway, which you saw in that study schema, 002 does impact both innate and adaptive pathways. So for those of us who really love the wonky nature of your question, which I do love it, and it's great, probably less impactful within the community. But I do think about the unique MOA for 002 and even potentially how it could be used in combinatorial strategies with other therapies.

Our next question comes from Charles Zhu with LifeSci Capital.

Congratulations on the data. I've got a couple of quick questions for you. First one, I think you had mentioned that about 35% of your BCG-unresponsive patients in -- unresponsive patients in the data set were treated with other investigational or approved products. Any color around potential differential CR rates for TARA-002 between patients that have versus have not seen some of these other investigational approved products? That's number one. And number two, just visually looking at your swim lanes, big swim lanes by the way. But I'm kind of wondering, it seems that for whatever reason, your BCG-naive patients, there seem to be a lower proportion of 3-month non-CR patients that are being reinduced. Any color as to why that might be the case?

Yes. So I think on the first point, as I said, on the unresponses, you're looking at 43 swim lanes here, of which, let's say, about 35 have sort of been -- have achieved a time point at which we can evaluate them. So look, I mean, 35% of 35%, you're talking about fewer than 9 patients, Charles, that have seen kind of -- I'm sorry, around 9 that have seen kind of -- if my math is correct, so early for me to be doing mental math. Whatever the number is, it's -- there are too many sort of -- I guess, too many versions of that in these swim lanes to sort of start to draw conclusions. It's a handful that have seen Gem/Doce. It's a handful that have seen investigational products that are kind of not yet approved. I can say that it doesn't -- this does not include a prior [ Inlexzo ] failure, but it does include other investigational agents. It does include PD-1 failures.

And there are a handful -- I'm just -- we follow each of these patients pretty closely and still it's a small enough and it's getting to be a point where it's not the case, but the end is still small enough where you kind of -- each patient's narrative kind of stands out. And there is a patient in here that I won't identify which one, but that patient failed BCG, of course, then Gem/Doce, then Keytruda, then another agent that we -- is still in the clinic. And that patient achieved at least a 6-month response. So too soon to sort of draw conclusions. But I think that's, again, as Dr. Shore kind of noted, and I don't know that we spend enough time talking about this, ours is the -- 002 is the only broad-spectrum immunopotentiator being interrogated in any form of bladder cancer beside BCG, right? It stands alone in its unique mechanism.

And that broad spectrum, right, that sort of multiple lines of attack that is -- and response that's sort of well conserved between the species of strep pyogenes and Homo sapiens, right, like that really super well-conserved immune point counterpoint is encouraging because it's sort of -- what we've observed is so far, again, too soon to tell, but it kind of doesn't matter what the previous thing is that these patients have failed. They all kind of tend to -- the response dynamics tend to be the same.

I think as the data set gets closer to 100 and we've got kind of good follow-up, we'll start to be able to talk about, is there a -- if there's a there that helps the world kind of -- or supports where 002 sits, obviously, we're looking at the frontline setting with the Cohort A and ADVANCED-3, that's where we kind of want to be for patients and for providers. But we'd like to be able to, in the future, talk about how 002 is likely to respond following specific prior treatments. And that was so long-winded, Charles. I forgot your second question. Can you hear me with that again?

Sure. Of course. The second question is visually looking at your swim lanes across the BCG-unresponsive and naive. So if you look at the 3-month non-CR patients, it seems that a greater proportion in the BCG naive cohort -- or I should say, a greater proportion of the BCG-unresponsive cohort were able to be reinduced. And can you just help us understand why those proportions seem to be different, the number were actually going through or the proportion going through reinduction?

Yes. It's a function of the mandatory biopsy at 3 months, Charles. So just so that the listeners are aware, we're the only sponsor out there with a mandatory 3-month biopsy. And I think that, that directly correlates to the number of patients that are reinduced. The reason is, in our conversations with FDA about that 3-month biopsy, they asked us to do what's called bladder mapping, which is -- and Dr. Shore speak to this, you take samples of tissue from all over the bladder, not just where the index lesion or the site of lesion that you are there to treat exists. And remember, this is a super recurrent disease of the urothelium of the bladder. And so if you are taking microscopic samples from all over the bladder, you're going to find microscopic disease. And this is where I really want to highlight the difference between the naive and the unresponsive.

We do not have a mandatory biopsy in the naive. We do in the unresponsive. And we are capturing disease in those biopsies that is likely months, if not years away from becoming active disease. And so as a result, you're seeing more patients requiring reinduction. What we know from our physicians and perhaps Dr. Shore can speak to this, is it's very rare that a 002 patient is just a null responder. What we observed for these patients at the 3-month time point that aren't quite all the way to disease-free status, you've seen significant tumor regression in all of these patients and sort of the way that some of our investigators characterize it is they needed like a little boost just to get over the hump. And some of those patients, if you look at our naive cohort, and again, if you're willing to come along with us that these 2 cohorts, the dynamics of response are fairly similar, if that disease that we're capturing was near term likely to be active, then you would see a lot of 6-month failures in the naive, but you don't.

The greens tend to stay green. And if you come back to the unresponsive swim lanes, we get what is your degree of confidence that, that number right now as the end goes up, will potentially get into the 40s. And from my perspective, as I look at these, our prior patients treated, 85% of a green dot at 3 months is a green dot at some further out time point. We have one 9-month failure amongst the sort of 3-month responders at the top of the swim lanes. So that's a lot of chew on. I'll leave it there.

Our next question comes from Soumit Roy with JonesTrading.

Congratulations on the data again. A quick one on the screen failure rate. If you can provide us any color on the BCG-unresponsive and the BCG-naive cohort, what percentage is for advanced papillary or any other BCG exposure or any other parameters?

Yes. Soumit, at this point, we're not disclosing kind of screen failure details. What I can tell you is that we are not spending a huge amount of time kind of looking at different patient phenotypes. The sites at this point, we've got enough sites up that they are facile in sort of identifying patients that are appropriate for the study. But what I can tell you is we are the only sponsor out there that requires central confirmation of active disease at baseline. That's a big deal. And I would argue that, that probably contributes to a screen fail rate for 002 that is higher than our peers because, again, that extra step of confirming active disease by central reader, that adds a layer of complexity to the screening process.

Got it. And the second one is as we are -- everybody trying to figure out the durability at 12 months, there are like patients at 6 months is -- I'm looking at the unresponsive in swimmers lane, but there are like 5 of them discontinuing. Anything specific for these discontinuing patients, whether BCG-unresponsive cohort or naive-cohort that stands out leading to this discontinuation?

Not really. I mean we don't see any specific disease characteristics or any relation to BCG status as it relates to whether or not a patient responds. We've conducted pretty extensive responder analyses at this point to try to look to see whether durability is predicted by any specific clinical characteristic or baseline characteristics, and we see that there's nothing that really predicts that.

Got it. And last one is if there is any evidence that as you're looking at the data that may suggest underlying mechanism of resistance to BCG that could affect TARA-002's efficacy?

No. I mean we've got patients that have been heavily pretreated, have failed multiple rounds of BCG. And in fact, most of the patients in this population in the unresponsive setting have received more than 12 doses and have had more than one sort of course of BCG that's adequate. So I don't think there's anything that we see in patients that have had less than that, that changes the response dynamic.

In fact, I think, as Jesse mentioned earlier, irrespective of whether or not they are receiving multiple lines of prior treatment, obviously, that's after they're considered to be BCG-unresponsive, we're still seeing response rates. So I think it's really -- it's agnostic to any specific mechanistic reason for BCG failure.

This concludes the Q&A session of the call. I would now like to hand back over to management for closing remarks.

Thank you, operator. And a special thanks to Dr. Shore for his time and all your comments. To conclude, listen, in our view, the value proposition for 002 in NMIBC is pretty clear at this point. It demonstrates competitive safety and efficacy data. There's an ease of administration advantage that's obvious, and we know will resonate in community practices like Dr. Shore's. Reminder, approximately 80% of NMIBC patients are treated in the community. And so that is where we're really focusing our efforts in terms of preparing the market for Protara's eventual hopeful approval and launch. There's a significant unmet need for new treatment options in the unresponsive and the naive settings. You've heard that today. And obviously, today's data bolsters our confidence that 002 represents a meaningful new treatment option for these patients.

We remain laser-focused on execution here at Protara. The goal is to benefit patients. And so while today's update represents another exciting development for our company, most importantly, it represents a potentially groundbreaking development for many patients and caregivers hoping for new treatment options in high-risk NMIBC. So thank you all for joining today's call, especially to our investigators and the patients that are in the study and that have been treated with 002. We appreciate their contribution. We appreciate their families, and we appreciate our investors for supporting us and coming along on the journey with us for 002.

And with that, we will close today's call and wish you all a comfortable day of shoveling out from the snow.

Thank you for joining. You may now disconnect.

Welcome, everyone. My name is [ Tai Pavumi ], and I'm welcoming you to the 44th JPMorgan Healthcare Conference. Our next presenting company is Protara Therapeutics. Protara is a clinical stage biotechnology company that's developing transformative therapies for people with rare cancer diseases. And presenting today is CEO, Jesse Shefferman. Please help me welcoming to the stage.

Thank you. Thanks, [ Tai ]. Thank you to the JPMorgan team for having us. I'm looking forward to talking through the Protara story. Quick forward-looking statements. So as [ Tai ] 1said, Protara is a clinical stage company focused on oncology and in rare disease. In oncology, our primary focus is in non-muscle invasive bladder cancer, where we have 2 programs in late-stage development, 2 registrational studies in BCG-Unresponsive patients and in BCG-Naïve patients.

On the rare disease side, we have 2 products in clinical development. IV Choline Chloride is a phospholipid substrate replacement therapy for patients that are on parenteral support. That program is in Phase III with a PK-based endpoint. And we also have our lymphatic malformations program, TARA-002 for macrocystic and macrocystic-dominant mixed cystic lesions.

Just gives a sense of our portfolio. For a company of our size, we have a lot of ambition, and this is represented by the various programs that we have in late-stage development. In non-muscle invasive bladder cancer, our ADVANCED-2 study is a single-arm open-label study looking at BCG-Unresponsive patients with carcinoma in situ. There, we are significantly well enrolled in a registrational study that we anticipate will complete enrollment before the end of 2026.

We also recently announced an interesting level of agreement with FDA on a BCG-Naïve study where we will be running the first ever RCT as an independent sponsor in the NMIBC setting, looking at patients who can't get, don't tolerate or refuse BCG. And we'll spend a little bit more time talking about that, which is an interesting opportunity for Protara to carve out some white space in the NMIBC setting. I talked about our choline program as well as our lymphatic malformations program, where we're looking at 002 in children with macrocystic lymphatic malformations.

So we benefit from, over the years, becoming more familiar to the investing community, and we often get questions about the complexity of our portfolio. We're an ambitious team, and so we've assembled a number of opportunities that introduces a level of complexity. And what I'd like to do today is provide some clarity that might help narrow some of the complexity that you might find in a portfolio as broad as ours. There's a lot of diversification, a lot of opportunity, but there are a number of stories embedded in this portfolio.

We get 4 questions from investors pretty regularly. Two of those questions focus on our NMIBC program and 2 of those questions focus on our LMs program. And they're as follows: In our NMIBC BCG-Unresponsive ADVANCED-2 program, we have a pretty important data release coming up in February. And the questions that we get from investors there are what can we expect? And I'm hopefully going to be able to provide some clarity on that in a couple of minutes.

In our BCG-Naïve study, we get the question, why bother? Why not do a proof-of-concept study and just use that as an opportunity to demonstrate data in a novel patient category in the NMIBC setting? We actually think that there's benefits from both a clinical perspective, from a market perspective, a market size perspective and a reimbursement perspective. And we'll come back to that in a bit.

Finally, lymphatic malformations. We've had a lot of enthusiasm as we've put out data in the past few months that is pretty compelling. We've generated response rates or clinical success rates of 100% in the patients that were evaluable at the 8-week time point. And obviously, the question there is, okay, what is the path to registration? We'll be able to talk about that in a moment. And then finally, what is the market opportunity?

In our patients that we released data in November for lymphatic malformations, 80% of those patients achieved clinical success with 2 doses or fewer. That's effectively a functional cure. So what is your market opportunity when you are effectively curing patients that suffer from the disease that you treat.

Let's take them in order. For our BCG-Unresponsive ADVANCED-2 study, we will be putting out data in February in 25 6-month evaluable patients. And the question that we get is, what can we expect?

At this point, we've treated 90 NMIBC patients with 002 across all conceivable BCG exposures. And what we've learned is that BCG -- prior BCG exposure in the setting of TARA-002 does not matter. What matters is how heavily pretreated patients are. But biologically, we've learned that a BCG experienced patient is no different than a BCG refractory patient in the setting of 002. Matters for BCG, not for 002. So what can you expect?

In December, we published data on 31 BCG-Naïve patients with follow-up for many of them up to 12 months. In that data set, we put up a 72.4% CR at any time at the 6-month time point and 50% CR at 12 months.

So what does that mean for our BCG-Unresponsive patients? As I said, we do not believe that a BCG-Unresponsive patient is biologically different from a naïve patient in the context of 002. And so if in February, we have a 72% complete response rate at 6 months and a 50% complete response rate at 12 months in our unresponsive patients, we would, a, be unsurprised; and b, be very happy with that because those numbers in the unresponsive setting are clearly through a threshold of relevance from an efficacy perspective, and that allows us to then talk about 002 in the context of what it means as a product. And that's where I think 002 shines in the NMIBC setting.

At the end of the day, 80% of patients with NMIBC are treated in the community by doctors who have necessarily made the choice that they're leaving academia to go practice in the community and make a living off of procedures in the urologic setting. And so what matters to those docs, and this is probably pretty well reversed because there are other folks in the NMIBC setting who believe the same, safety and tolerability are of primary importance. 002 has the best-in-class safety and tolerability of any of the novel therapeutics or recently approved therapeutics in the NMIBC setting.

On top of that, as I said, we anticipate that we'll be through a threshold of relevance from an efficacy perspective that will allow us to lean into a discussion about what we represent as an adoptable product in the community.

And finally, ease of use. 002 has no special handling requirements. It is administrable by catheter. The doctor doesn't have to be in the room. There's no thaw time. It's 3 years stable at 2 to 8 degrees. That's normal refrigeration. Doctors doesn't even have to be in the room. It's a 15-minute procedure. And even better, there's no post-procedure protocol, no urine bleaching, no special bathroom procedures. These patients can get off the table and go home and not worry about their post-administration protocol. When I look at that, that puts 002 at the center of what matters to physicians that are treating patients with NMIBC in the United States and abroad.

And as the narrative in NMIBC moves, which it will, moves away from heterogeneous single-arm open-label studies conducted across multiple different patient types by multiple different sponsors, we will eventually move away from that narrative to what are these products in the urology setting. And within that context, we believe 002 will be the therapy to beat in NMIBC.

So while I'm here, I've talked about our likely first to approval program, the ADVANCED-2 program in BCG-Unresponsive patients. I'll answer now the question, why go after the naïve setting. So to give -- as a reminder, we recently received feedback from the FDA that we could run a randomized controlled study of 002 against investigators' choice of gemcitabine monotherapy or mitomycin monotherapy in an RCT with a primary endpoint of 6-month landmark response and a key secondary of 12-month response rate. So no RFS, no BCG comparator, no Gem/Doce comparator, right? So we're powering against a chemotherapeutic agent that has roughly a 40% complete response rate at 6 months and a 15% complete response rate at 12 months. I just showed you 72 and 50 for 002.

So why run that study? Well, of course, the naïve setting, the frontline setting, patients that are BCG eligible that can't get BCG, that's 5x the size of BCG-Unresponsive carcinoma in situ, the single-arm open-label studies that we've all become increasingly very well familiar with. This is 5x the patient population and no one else is running that study. It's Protara and Protara alone.

Down the line, as I said, the narrative for NMIBC is going to move from clinical studies to marketed products. INLEXZO is launching. CG is around the corner. You've got ADSTILADRIN. You've got ANKTIVA. Eventually, there'll be no more clinical studies to cross compare to. And what are these products doing to drive adoption in the urology setting that is, again, 80% comprised of the community.

With this RCT, and again, in a patient phenotype that is biologically similar regardless of BCG exposure, we'll be generating the first Level 1 evidence RCT of all the independent sponsors bringing monotherapies into the NMIBC setting.

When we start talking about payers and when we start talking about sequencing and guidelines for what gets sequenced, what and when, 002 will have Level 1 evidence in the earliest setting besides some of the checkpoints plus BCG. We'll have preferential treatment and guidelines because of that, and we'll have preferential treatment from payers who will be instituting step edits into this setting, they're already doing.

So we want to skate to where the puck is going to be. I hate that analogy, but yet I've used it. Payers are going to be deciding who gets used when and in what sequence, and we want to be the first choice for payers and for physicians that are treating patients with NMIBC, irrespective of patient phenotype.

So let's move on to lymphatic malformations. For those of you that just need a quick primer, we treat macrocystic lymphatic malformations. These are large voluminous lesions that are filled with lymphatic fluid. They're driven by somatic mutations in the Akt/PI3K/mTOR pathway. But as opposed to the microcystic setting, which you may be familiar with another sponsor that's doing great work out there in lymphatic malformations in a different phenotype, we treat the ones that are balloon-like and large. Let me show you what that looks like.

On the left is a child -- these are both children and 2 kids that we've treated in our STARBORN-1 study, which is currently enrolling patients right now and where we've treated last time again, we put data out was in November, about 10 patients, 80% complete response rate across all patients -- I'm sorry, 80% clinical success across all patients, 100% clinical success in patients that were evaluable at the first time point for evaluation, which is at the 8-week time point.

Young man on the left has a 1.7 liter cyst, right? That's like a big giant coke bottle. He's 8 years old and has lived with that lesion for his entire life. Never went to school, never enrolled in school, has been home schooled, and his life was dominated by that lesion on his neck. He received 4 doses of 002. It's the most number -- it's the highest number of doses we've given any of the patients or had to give any of the patients that we treated.

And on the right, you can see that, that patient has experienced a complete response, a complete resolution of that lesion and that kids life has changed. And that's why we do what we do at this company. It's great to treat oncology. It's an important and big setting. But when you're changing lives like this, it's a real reason to get up out of bed every morning. And again, the child on the right, that's another macrocystic patient that has had, as you can see, visibly a complete resolution of that lesion.

So the question that we get, as I remind you is, what is the regulatory path from here? About 10 days ago, we received Breakthrough Therapy designation, Fast Track designation and invitation into CDRP accelerated review of CMC program that the FDA has recently initiated.

And in that correspondence with FDA, the FDA asked us to conduct a multidisciplinary meeting to sort of present the program in its totality. To us, that feels that the FDA recognizes that there's a significant unmet need here, that the effect size is unmistakable and that this is a program by definition of the designations that deserves an expedited review.

So my partner in the business, Jackie Zummo, is putting together a briefing package for a meeting with the FDA to tackle the multidisciplinary topics. But primary among that will be what do we need to do with this study to get to registration. We believe that we'll have that clarity sometime in -- towards the end of the second quarter of 2026 because if the FDA is saying, talk to us about the totality of your program, we want to talk about the totality of our program. And we want to present as though we are ready for filing.

No promises. No idea what they're going to respond to. But if you've got a setting where in 80% of the patients, you're producing a cure like these or a functional cure like these, with 2 doses supported by decades of experience of this exact same compound standard of care for this disease state in Japan, I think you got a pretty good shot when the FDA is saying, "Hey, talk to us under the auspice of Breakthrough Therapy designation," we got a pretty good shot of having a constructive conversation. So we'll be able to provide that clarity that I think the world needs to see in the second quarter of 2026.

Finally, the question that we get on LMs, how big is this market opportunity? Because effectively, it's a functional care model. So let's talk about what we see as the market opportunity. And I am greatly -- I am very grateful that our Chief Commercial Officer, Bill Conkling, has helped us sort of talk through what this looks like.

So in the United States, there are about 1,400 to 1,800 live births per year. When you're dealing with a functional cure, you're living in an incident model for the most part. So if there's about 1,400 to 1,800 live births with the diagnosis of lymphatic malformations every year, approximately 2/3 to 70% of that are going to be macrocystic or macrocystic dominant mix. That's -- again, that's the phenotype that we treat.

Our view is that, that incident model becomes the start of the discussion in the number of patients that you treat. However, there is a prevalence model. And I will tell you that, that's a really tough number to nail down. These are patients that effectively have come in to the seeking treatment pool, not gotten an effective treatment and then moved out of the seeking treatment pool. So how do you encourage them to come back with a targeted immunotherapy that's going to provide a different option for them than surgery or start a therapy.

That's the work of our patient advocacy group to remind these patients to find them where they are in their communities and say, "Hey, by the way, don't give up. There's a new therapy on the market that is producing significant effect size that might be appropriate for you."

So from our perspective, you can sort of get a significant chunk of that incident market because you're the only approved product in macrocystic disease and start to chip away at that prevalence population, you're talking about 1,000 patients, maybe more per year, right? That's a pretty good rare disease annual patient treatment number.

Obviously, very early to talk about price. But I will say this, there's a competitor out there -- not a competitor. There is another sponsor out there in the lymphatic malformation setting that treats microcystic disease. We do not treat micro, we treat macro. But that other company has presented a range of analogs for where they might come in on pricing.

And my guidance to the folks out there that are wondering what does this market look like for Protara, the very, very top end of the range of where they're talking about pricing would be the very, very bottom end of the range about where we're thinking pricing for something that offers this level of clinical benefit, this level of long-term benefit to patients who otherwise would undergo pretty significantly impeded quality of life. We think starting the conversation at that top end of that range, pretty standard rare disease pricing. That's where we want to wind up.

So we don't have time to talk about our third program, which is actually in Phase III, our IV Choline Chloride program, where we've got a phospholipid substrate replacement therapy that can treat a patient population that numbers about 40,000 patients in the United States.

So as you think about Protara from the perspective of an investor, as you look across this, albeit robust portfolio, perhaps it's a little bit less complex today. There are multiple ways to win. Every single one of our programs is in late-stage development, and we believe that we'll start to be getting drug -- I'm sorry, getting FDA approvals for our programs beginning in '27, likely another in '28, likely another in '29 and likely another in 2030.

So thank you for your time, and I'll open it up to Q&A.

Thank you very much, Jesse. We'll start with taking questions from the audience, if anyone has a question.

Could you comment what's the CR rate for BCG? And what would it take for you guys to potentially replace it in the high-risk patients? And would you have to run like a head-to-head trial?

Yes. So it's a great question. The BCG label has a 6-month response rate of about 50% and a 12-month response rate of about 45%. Now There have been studies conducted in the contemporary setting where BCG was used as a comparator against BCG plus checkpoint in the frontline setting. And there, those numbers are pretty good, right? So I think about the Pfizer CREST study where the BCG comparator arm had about an 83% complete response rate at 12 months. We're not going to beat that. We're going to be close. We're not going to beat that. And that was really the fundamental argument that we made with FDA.

When we went to the FDA, we said, "look, we've -- we're looking and we're presenting 7 years of claims data from Optum. And in that data set, approximately 35% of BCG eligible, so non-refractory, the diagnostic code for a nonrefractory patient seeking treatment. It's about between 10,000 and 12,000 patients as many as 15,000, just to give you a number. Patients per year fit this category of BCG eligible for whatever reason, doesn't get BCG.

And so by showing the FDA that these patients exist and showing that what they get instead, about 50% of that 35 get gemcitabine monotherapy, about 30% get mitomycin monotherapy and about 10% get Gem/Doce. We said, "look, that's the comparator that we want to be because I don't know that I need to replace BCG. It's effective. It's well -- generally well tolerated, but there is this other slice of the population that doesn't get it. So we'll compare to gem, we'll compare to mito, and we don't want to be a BCG replacement. We want a BCG alternative for when BCG is not appropriate. And the FDA signed up for that.

I think over time, we're going to have to demonstrate that there is a use case there. But so far, what I can tell you is that in that naïve data set that I showed that we published in December, it's about -- there is about 31 patients. About 85% to 90% of those patients came from sites that had BCG, which is small end, you're not going to hang a hat on that. But it shows that in the real world, our own lived experience is that patients who ostensibly could get BCG for some reason, don't, and there's a choice to be made.

And so that, I think, is kind of where we see ourselves slotting in. And again, that alone, the BCG eligible doesn't get BCG is at a minimum about 10,000 patients. So we don't have to run the head-to-head for FDA approval here. But I think over time, someone is probably going to run an IIT. And again, I think if you can't get it, here's a really good immunotherapeutic option. Does that help?

All right. Jesse, there's a question I have for you. So for your upcoming data readout in BCG-Unresponsive NMIBC patients this quarter, how are you setting expectations for that?

Yes. The expectation is we would not be surprised if those responses were in the same ballpark as what we demonstrated back in December with our naïve population, which, again, CR at any time is 72%, CR at 12 months of 50%.

That's compelling data right there. And so how quickly do you think like you'll be able to enroll the ADVANCED-2 trial in BCG-Naïve patients?

Yes. So interestingly, look, there are 2 wholesale bacteria used therapeutically under FDA approval in the United States. Actually, ours is not yet FDA approved. So I'm going to be very sorry. There's BCG and there's 002. There's the only 2 bacteria therapeutics. And so there's a lot of rhyming with BCG.

Now we activate pretty significantly different pattern recognition pathways. BCG is a TLR4 activator. We're a NOD2 TLR2 activator, different milieu of cytokine up regulation. But it looks, feels, kind of sounds like BCG. And so our experience is that we enroll 5 naïve patients in the U.S. for every 1 unresponsive patient that we enroll.

The end that we agreed to with the FDA for ADVANCED-3, we haven't gotten specific. We'll say publicly that it's fewer than 500, comfortably fewer than 500. And so that, in our mind, if we can replicate the enrollment rate that we experienced in that naïve data set, again, 5 naïves for every 1 unresponsive. Our expectation is that we can enroll that study fairly quickly. And that it would be a fast follower to the ADVANCED-2 study, which, again, that's going to be -- enrollment there is going to be complete in the second half of this year.

Now I want to pivot to IV Choline. I know you didn't say much about that. Now that you've initiated your registrational trial in IV Choline, what can we expect from the interim data update expected in the second half of this year?

Yes. Thanks for giving choline shout-out there. So the choline pivotal study is a seamless Phase IIb/III design where we'll start with a dose confirmation lead-in of 24 patients, 8 patients each at 3 different doses. That dose confirmation lead-in of 24 patients, we'll be measuring all the same endpoints, both primary and secondary, as we will in the Phase III seamless expansion with about another 105 patients.

The primary endpoint, just -- it's a unique one, but it was actually the FDA suggestion. Primary endpoint is demonstration of elevations without a numerical value assign of choline in serum after administering choline intravenously. So typically, when you administer something intravenously and then you measure that thing, you're likely to see an increase. And so we'll be able to talk about the primary endpoint in the first 24 patients in the middle of 2026.

And then because the secondary endpoints, which are a host of different clinical endpoints relative to liver function, relative to muscle function, bone wasting, muscle wasting, a number of sort of clinical endpoints, those are 24-month endpoints. And so you would be able to talk about those secondary clinical endpoints towards the end of 2026, necessarily if you're talking about the primary endpoint in the middle of the year.

Great. Any questions from the audience?

We can wrap it up early, guys. It's Wednesday of JPMorgan. Cocktails, all that sort of stuff. There's no other questions.

All right. I have one last question for you then. So what are you most excited for in 2026?

I am most excited -- I think kind of zooming out, Protara went public in 2020. And they always say, this is my first company as a founder. My co-founder, Jackie, it's her first sort of co-founding company. Everybody always says it's going to take 3x as long as you think it's going to take. And of course, being the type of people that we are, we're like, "well, that's b*******." Well, no, it's true. It does take 3x as long as you think it's going to take. And as I look at sort of this portfolio slide, every single one of these programs is sort of flipping the card. It's not just do you have an idea. It's your idea seems to be working. And now to what degree is that working. We're going to have that sort of understanding across the entire portfolio.

So I know you want me to say which one of my programs are I most excited for, but I'm excited that all of them are nearing the end of the journey in terms of what are they? Do the idea work? Does this crazy thing that we started on a whiteboard and a WeWork, does it work? And it kind of feels like it is. And that's what has me most excited.

All right. I'm excited to. All right. Thank you, everyone. This is the end of the presentation and buh-bye.

Go get them.

Hello, and welcome to the Protara Therapeutics SUO Update Call. [Operator Instructions] Also, as a reminder, this conference is being recorded. If you have any objections, please disconnect at this time.

With that, I would now like to turn the call over to Justine O’'Malley, Senior Vice President, Investor Relations and Corporate Affairs.

Thank you, operator. Good morning. Thank you all for joining us today for a review of the updated interim results from our ongoing Phase II open-label ADVANCED-2 trial of TARA-002 in patients with non-muscle invasive bladder cancer.

Before we begin, I would like to remind you that during today's call, we will be making certain forward-looking statements. These statements represent our views as of today only and should not be relied upon as representing our views as of any subsequent date.

Actual results may differ from our forward-looking statements due to various factors, including those described in the Risk Factors section of our most recent annual report and subsequently filed quarterly reports that are on file with the SEC. Except as required by law, we disclaim any obligation to update these statements, even if our views change.

I will now turn the call over to Jesse Shefferman, Co-Founder, Director and Chief Executive Officer.

Thank you, Justine, and thank you all for joining us this morning. Following last week's exciting release of data in our lymphatic malformations program, we are equally excited today to present another positive data readout for TARA-002.

002 has a potential best-in-class product profile in NMIBC with compelling response rates, encouraging durability and adoption-driving safety and tolerability profile. These, along with its off-the-shelf availability and simple administration, position TARA002 at the intersection of factors that are priorities for NMIBC patients and urologists.

Today, we will be presenting updated positive results from the BCG-Naive patients in our ADVANCED-2 trial. The 50% complete response rate at 12 months underscores the strength and durability of the response driven by 002, which we believe has strong potential in the BCG-Naive patient population.

In addition, we continue to enroll BCG-Unresponsive patients in the registrational cohort of ADVANCED-2 and anticipate full enrollment of this cohort in the second half of 2026. Further, we remain on track to report interim results in the first quarter of 2026 from at least 25 patients, who are at a minimum 6 months evaluable in the BCG-Unresponsive cohort.

Today, I'm joined by Dr. Leo Nicacio, our Chief Medical Officer, who will walk us through the updated data momentarily; as well as Dr. Jackie Zummo, Co-Founder and Chief Scientific Officer of Protara, who will provide an overview of next steps for the program, including recent FDA feedback on the BCG-Naive path.

Finally, we are privileged to be joined by Dr. Neal Shore, Medical Director at the Carolina Urologic Research Center. Dr. Shore will walk you through the current NMIBC treatment landscape, including key areas of unmet need and offering his thoughts on where 002 may fit in.

At the conclusion of our prepared comments, we will open the call for Q&A and are joined for that by our Chief Financial Officer, Pat Fabbio; and our Chief Commercial Officer, Bill Conkling.

For those of you who may be new to the Protara story, we are a clinical-stage company developing transformative therapies grounded in strong biologic rationale for the treatment of cancer and rare diseases. Our lead asset is TARA-002, a genetically distinct strain of strep pyogenes that drives an immunologic attack of mutated cells.

In addition to assessing 002 in NMIBC, as I said earlier, we are also interrogating 002 in lymphatic malformations, which are rare congenital malformations of lymphatic vessels, typically diagnosed in childhood. And finally, our pipeline includes IV choline chloride, an investigational phospholipid substrate replacement for patients dependent on parenteral support, for which we expect to commence a registrational study by year-end.

We are excited for the potential that all of our programs hold to make a meaningful difference in the lives of patients. Today's focus will be on the BTG-Naive cohort of patients in our ADVANCED-2 trial.

Before I turn the call over to Leo, I would like to take a moment to talk about 002's mechanism of action. TARA-002 is a unique TLR2/NOD2 agonist and an immunopotentiator that engages both the innate and adaptive immune pathways within the bladder wall to drive M1 macrophage polarization, cytokine release and recruitment of NK and cytotoxic T cells. The result is a potent localized antitumor immune cascade that directly targets abnormal urothelial and cystic cells.

In essence, 002 puts the immune system in targeted attack mode, creating a focused local response without excessive inflammation. 002 is fully inactivated, bringing a new and differentiated immunologic mechanism to NMIBC beyond BCG and other targeted approved and investigational treatment options.

002 was developed from the same master cell bank as OK-432, a broad immunopotentiator marketed as [ disecibinal ] in Japan by Chugai Pharmaceuticals, where it is approved in several oncologic indications as well as LMs and benefits from a 65,000 patient safety database. Protara has successfully shown managed manufacturing comparability between 002 and OK-432.

And as many of you are aware, across the various mechanisms and modalities employed to treat NMIBC, 002 is most similar to BCG, which is the standard of care for NMIBC. Both are bacterial immune potentiators that drive a Th1 pro-inflammatory response. Like BCG, 002 triggers an immune cascade but with a distinct cytokine signature. Compared to BCG, 002 has higher upregulation of key pro-inflammatory cytokines and chemokines, including TNF alpha and interferon gamma.

Notably, 002 downregulates IL-8. This is important because IL-8 is known to be associated with tumor recurrence in NMIBC. And of course, recurrence is the primary focus of therapeutic intervention in NMIBC.

As I mentioned, 002 is completely inactivated while BCG is attenuated. This means 002 has a more favorable safety profile compared to BCG and it is easier to administer as there are no extra precautions to manage a live bacteria, no need for post-administration burden on the patients, such as needing to use a separate bathroom or perform urine bleaching to not spread infection at home.

These important attributes position 002 to be a potentially meaningful alternative treatment option to BCG in the frontline setting.

With that, I would like to turn the call over to Leo to walk us through the data.

Thank you, Jesse. It's a pleasure to have the opportunity to review this exciting update. As a reminder, ADVANCED-2 is an ongoing Phase II open-label clinical trial assessing Intravesical TARA-002 in NMIBC patients with carcinoma [ in cyto ] with or without papillary disease, who are either BCG-Unresponsive or BCG-Naive.

The BCG-Unresponsive cohort has been designed to be registrational, in alignment with the FDA's updated 2024 BCG-Unresponsive NMIBC guidance. And the BCG-Naive cohort, which we'll be discussing today, is a proof-of-concept study.

Patients in the trial received an induction course with or without reinduction course of 6 weekly intravesical installations of TARA-002, followed by a maintenance course of 3 weekly installations every 3 months.

Patients are eligible for reinduction if they have residual CIS and/or recurrence of high-grade Ta at 12 weeks. They are not eligible for reinduction if they experience disease progression or treatment failure. The primary endpoint of this trial is CR at any time, with durability of response as a key secondary endpoint.

The data set being presented at SCU meeting includes 31 BCG-Naive patients, who received at least 1 dose of TARA-002. Of these patients, 29 completed at least 1 response assessment and were assessed for CR at any time. 26 were evaluable for efficacy at 6 months, and 14 were evaluable at 12 months. Two patients discontinued the study prior to reaching the 3-month evaluation time point as of the November 7, 2025 data cutoff.

The complete response rate at any time was 72% with a 6-month CR rate of 69% and a 12-month CR rate of 50%. Reinduction therapy successfully converted most initial nonresponders to responders at 6 months, resulting in a high conversion rate and durable responses. 80% of the reinduced patients converted to CR at 6 months, and 100% of those responders maintained the CR at 12 months.

We are pleased with the efficacy results demonstrated by TARA-002 and are highly encouraged by the strong durability at 12 months.

Moving on to safety, TARA-002 continues to demonstrate a favorable safety and tolerability profile in BCG-Naive patients. Consistent with previously reported results, the majority of the treatment-related adverse events were grade 1 and transient, with no grade 3 or higher treatment-related adverse events, as assessed by the study investigators. And no patients discontinued therapy due to treatment-related AEs.

The most commonly occurring treatment-related AEs in this cohort were [ diarrhea ], fatigue and hematuria; consistent with what we would expect for a bacterial immune potentiator. Importantly, there were no treatment-related serious adverse events and the overall profile supports continued development in both frontline and previously treated populations.

When we put all the pieces together, TARA-002 profile sits at the intersection of what both patients and urologists prioritize, safety, efficacy and simplicity. 002 delivers robust single-agent activity with competitive complete response rates and encouraging durability.

It does so with a clean safety profile, no related serious events, no discontinuations and only mild self-limited local reactions. And it is administered through a simple office-based intravesical installation, no viral handling, no special preparation, making it easy to integrate into existing workflows.

A compelling efficacy and tolerability profile, combined with practical delivery positions TARA-002 as a best-in-class next-generation investigational intravesical therapy with the potential to meaningfully advance care in NMIBC.

With that, I will now turn the call over to Dr. Shore.

Well, thanks very much, Leo, and a pleasure to be here today with everybody, and great data that's being presented at SUO.

Just really briefly, as Jesse mentioned at the beginning, I'm the Medical Director for START Cancer Research, Carolina Urologic Research Center, and I head up the GU oncology consortium for START cancer. I've had the privilege of being involved in bladder cancer research, NMIBC, MIBC, metastatic; for much of my career, was a founding member of the bladder cancer think tank and 10-year Board member of [ Beacon ] and also started the bladder cancer organ site for the SUO clinical trials consortium.

I think, I guess to just keep it to NMIBC today for the purposes of our content, we always are looking at this BCG-Unresponsive as a predicate for thinking about potentially even the BCG-Naive population. The unresponsive space, as many of you know now who are looking at it, is a quite complicated space and there are more and more folks are looking at the naive.

I actually think Slide 13, which Leo just presented that Venn diagram, beautifully positions TARA-002 for incredible success. And the proof of concept and the naive is rather impressive, given the data that's getting presented from ADVANCED-2 today and going forward.

At the end of the day, there has to be efficacy, it has to be reasonable, there has to be the other important considerations, not only the safety and tolerability for the patients, which it's impressive, the thousands and thousands of patients who've been exposed to 002 in the U.S. and primarily in Japan, but I think more importantly, at least from my perspective, is we see this plethora of alternative therapies now entering into the unresponsive, but in the BCG-Naive where there's clearly challenges in production of BCG, which everyone should be familiar with, particularly in the U.S., inconsistencies of the strain.

Alternatives such as 002 are particularly compelling to me, this is really -- this is highly non-incremental. This, to me, would be an enormous improvement for community-based, especially where challenges exist with implementation of some of the more complicated therapies. Not at my sight, I'm kind of a research wonk, I like all that. We have facility, but that's just not the case in the vast majority of community centers, frankly, not only in the U.S. but outside the U.S.

So I've had an incredibly positive experience with 002, both in the BCG-Unresponsive and now in the Naive. I'm really excited for ongoing trials to further explore that. I think it's a particularly fascinating area within the the naive because that's a huge unmet potential, given the BCG shortages, given the intolerability for some patients with BCG, given the manufacturing issues.

So I'm very enthusiastic for it. It's a crowded busy space, but I think that the 002 really kind of sets itself apart with a really robust safety profile, a simplicity. And simplicity is not to denigrate that, but it is very important in terms of throughput in practice. There is a well-recognized person power shortage of clinicians, of the team of medical assistance and nurses and LPNs.

And having, to me, something that doesn't require so much of the complexity and the biohazard concerns that were already articulated, really kind of potentially sets 002 quite apart from the field.

So let me stop with that for purposes of time, and thank you for allowing me to address you.

Thank you, Dr. Shore. Although BCG is effective when it's available and administered as intended, we know that up to 40% of frontline high-risk NMIBC patients do not receive it. The FDA recognizes there is limited approved treatment options for these patients. In addition, surveys have demonstrated that urologists consider development of non-BCG-based alternative therapies as a high priority for BCG-Naive higher patients.

With TARA-002s compelling results, we've worked with the FDA on an agreed-upon registrational path forward for TARA-002 in the BCG-Naive NMIBC patient population. The FDA has provided written feedback aligning on a registrational trial for a controlled trial in BCG-Naive patients.

Based on TARA-002 mechanism of action and existing data to date, the agency has agreed that BCG is not required for the comparator and that intravesical chemotherapy is an acceptable comparator in our BCG-Naive population. The agreed-upon trial endpoints include primary endpoint of landmark CRE at 6 months and a key secondary of duration of response. Given that BCG is not required in the study comparator, our trial will be fewer than 500 patients.

With this feedback, we are able to move forward with this registrational study in BCG-Naive patients. We have engaged the FDA on how best to study 002's efficacy and safety in the BCG-exposed patient population.

There remains a significant unmet need in the BCG-exposed population, for which no FDA-approved treatments are available and who have limited options to access the investigational treatment through our clinical trials. We look forward to providing additional information on the study population based on our interactions with the FDA.

With that, I'll now turn the call back over to Jesse.

Thank you, Jackie. We are very excited by these positive data. They further build upon 002's potential as a meaningful treatment option for high-grade NMIBC. We believe there is significant need for new treatment options in the BCG-Naive setting and we are encouraged by the consistent and durable CR rates demonstrated by 002 in this patient population.

We're enthusiastic about the potential for a randomized controlled trial to provide a level of evidence and differentiation that we believe will drive earlier-line use of 002 in high-grade, high-risk NMIBC.

At Protara, we are truly focused on the patients we hope to serve. So while today's update represents another exciting development for our company, more importantly, it represents a potentially groundbreaking development for the many patients and physicians, who require an alternative to BTG.

002's target product profile fits at the intersection that NMIBC patients and their providers prioritize. With its demonstrated efficacy and safety profile, it's observed durability and tolerability, it's ease of use as well; we believe 002 has the potential to be the seed treatment of choice among urologists treating NMIBC.

I would now like to open the call up for Q&A. And out of respect for Dr. Shore's time, we ask that you focus your questions on the NMIBC program at Protara. Operator?

[Operator Instructions] Your first question will come from Stacy Ku with TD Cowen.

Congratulations on the really competitive results in the bio-naive patient population and the really encouraging FDA feedback. I know the team has worked on this for a really long time. So just a wonderful update.

So we have a couple of questions for Dr. Shore first. So you alluded to some of the BCG shortage, and [ Merck ] is hopefully going to address some of this. But just help us understand, if there is unlimited supply as we think about induction and maintenance, how much more BCG would you have wanted to use? And of course, if TARA-002 was approved in first line, how would you differentiate 002 in BCG? So that's the first question.

And then the second question is in the real world, maybe talk about the efficacy of BCG that you're seeing. And maybe help us understand when it comes to the CIS population and the papillary patients, how do we make -- what do you make of BCG performance and how do we compare that to the efficacy we see for TARA-002? So kind of the real-world BCG versus what we're seeing today, maybe talk in a little bit more detail than what you said in the prepared remarks.

And then last, maybe help us understand the level of, I would say, SUO, the level of, I would say, community feedback or KOL feedback in terms of urologists and their level of enthusiasm for having other options in the first-line setting. And I have some follow-ups for the company.

Sure. Happy to, Stacy. Thanks. So yes, my remarks were spontaneous, but I will tell you that, yes, a lot to unpack in your question. Let me try to hope hit all your questions.

So we used to have 2 -- Sanofi dropped out, they closed down their plant. There's only one plant in the United States, the Merck plant, and it's being redesigned and hopefully will come online and be more efficient.

The BCG shortage in the [indiscernible] strain in the U.S. has been -- it comes in cycles. As you're probably aware, it's unpredictable, it's variable. I, for a long time at my site, we didn't have an issue. Currently, we're having an enormous issue. About 50 patients right now are waiting, can't get product.

And that's kind of the experience that I've seen from colleagues all over the United States. It's somewhat unpredictable, based upon historic ordering patterns. So we'll have to wait and see regarding that.

In terms of -- it is the gold standard, right? We use that word for lack of something better to look at. There are some studies that are looking to maybe replace that, the upcoming BRIDGE trial with combination chemotherapy.

The problem I see with that Gem/Doce, although it can be effective, is it's arduous to administer, it's time consuming, the economic modeling for it is poor based upon U.S. health care economic dynamics. That said, it has a sort of significant appeal within academic centers, I understand that. But honestly, I don't see it with rapid adoption in the community. We give it, but I don't really see that from a long-term practical aspect.

If 002 were to successfully complete this trial that Jesse very clearly articulated, not only in the naive, but also in the exposed; that is an enormous population. BCG, albeit an excellent product, an immunopotentiator, attenuated as opposed to completely inactivated, which is another theoretical advantage to the 002; nonetheless, has intolerability issues and the arcane nomenclature that we're moving away from.

Intolerable. We don't tend to use that, but there was a reason why that was part of the verbiage. We just don't see that in 002. So in terms of community urology, in terms of patient user friendliness, I think it's -- it can't be underestimated how important that is. So -- but yes, when given correctly in trial, BCG can be remarkably effective.

Now maybe just transition a minute to the exposed population. That is an enormous population of patients who had less than adequate 6 plus 6 or 5 plus 2 and maintenance therapies. And that's a really incredibly interesting population that frankly, Protara and other companies are looking at. And I think it's really smart of Protara to look at that in addition to the purely BCG-Naive population.

Okay. So would you characterize then, I guess, the limitation of BCG as 1x, 2x, 3x, 4x, how many times, I would say, is -- obviously, you're saying in cycles. But when it's taking the totality of the cycles, what -- how much more BCG would you have wanted to use if you had unlimited supply, to ask it differently?

I guess maybe to ask -- to answer it a little differently, if 002 were approved and I had unlimited BCG and it was not superior but just noninferior, so equivalent, given the safety profile, given the biohazard concerns we have with BCG, the bleaching, not just at home for the patients, but if they have incontinence and episodes; you have to shut down facility. You don't have that issue with 002.

So I would say, to answer that if with noninferiority, I wouldn't see a reason to use BCG.

I see. Wow, that's very helpful. Okay. And then maybe to the company, as it relates to the type of trial design that you would need versus chemotherapy, are you able -- very early as I understand, are you able to talk about maybe some of the potential powering assumptions? How -- given your experience with this study over enrollment, how quickly could you get to a potential study initiation and timing for results? I know very early days, but kind of curious if you guys could elaborate.

Yes. Thanks, Stacy. Great to hear from you. You raised a good point, it is early days. We have a first mover advantage here, given this -- where we are with the FDA. We're ready to go, is what I would say. We have answers to a lot of the questions that you raised. I think we tried to address them as directly as we can while still kind of taking into account the benefit of Protara being in a position in NMIBC with a first-mover advantage.

So what I can say is we believe that the numbers that we talked about, a number of fewer than 500 patients, is pretty set in stone for the BCG-Naive patients, who would qualify for this study. We are still in active dialogue with FDA, as Dr. Shore noted, about the very large exposed population and whether that becomes a part of this study or its own study, and that will depend on the degree to which we need to be looking at subgroup analyses.

But the opportunity presented in just the BCG-Naive, not including exposed, is quite large, it's well powered at fewer than 500 patients. And to give a sense, we have been actively enrolling our unresponsive study and are really happy with where we are on that front. But nevertheless, we know from our own experience that we enroll about 5 naive patients for every 1 unresponsive patient in the 2 cohorts of ADVANCED-2.

Another interesting point to raise, maybe germane to your conversation with Dr. Shore, is of the 31 patients that we dosed in Cohort A of ADVANCED-2, so BCG-Naive patients; approximately 90% of those patients were dosed at sites that had BCG. So a, we think that speaks to the value of 002 sort of in a BCG agnostic environment. And it also speaks, I think, to the pace at which we believe we could enroll a study with the broad parameters that I've just sort of described for you.

Our next question will come from Li Wang Watsek with Cantor.

Congrats on the data. I guess, first for Dr. Shore, just following up on your comments earlier about Gem/Doce, just curious if you can maybe elaborate a little bit more on 002's profile so far versus some of the options that are currently you're using for BCG-Naive patients, but for various reasons, they can't get access to BCG or don't want to. That's number one.

And number two is, can you just talk a little bit about what proportion of patients in your practice that will be eligible for 002? And just given the profile you've seen so far, how can this be potentially adopted in the context of not just chemotherapy, but the other competitors in the space?

Yes. Thank you. So when we have a BCG shortage, we've not had success in split vial dosing. There's a lot of complexity to that from using appropriate [ J ] coding, getting patients in, splitting vials, reimbursement concerns about not doing it appropriately. I think some sites have, but it's a bit messy to try and figure that out just from scheduling and proper coding.

When we have a BCG shortage, which is pretty well described in virtually every center in the United States now, academic and community; you run -- you have the technically non-approved but utilized intravesical chemotherapies. At least in the U.S., we have gemcitabine, docetaxel in combination with gemcitabine, almost never given by itself and then mitomycin. Mitomycin utilization, I think, has decreased significantly.

We have all three of those, largely due to its complication concerns. And so we've done some market analysis on this. And the most commonly used treatment outside of BCG in the naive is just gemcitabine. Gem/Doce, much more attractive and utilized in academic centers, markedly less so in community because of the reasons I talked about earlier, the throughput, the reimbursement methodology and some of the safety concerns.

So I do think that a product such as 002, I thought it was compelling what Jesse just said that he's absolutely right. in the BCG-Naive, these trials enroll very quickly. And one can see that in other products that have been out there, much, much faster than in the Unresponsive because of the requirement for the workshop, which I was happy to be part of with FDA, the 5 plus 2 or the 6 plus 6 or reduction.

So it's much more challenging in addition to the time typically having had the treatment, the BCG use within a 12-month period. So that exposed population is enormous, and the BCG-Naive to enroll this particular trial would go very, very quickly.

Again, because of the safety profile of 002, which I think is rather robust and very clear, the chemokine cytokine profile does lend itself to a very understandable mechanism of action that I think all uro-oncologists would recognize, both from a lot of really good preclinical work that the company has done.

So Yes, we have access to all of the intravesical chemo. Different states -- different parts of the country have nursing issues regarding the use of hoods and biohazard limitations. None of that is applicable to the use of 002.

Okay. Great. Another question on -- yes, sorry. Yes. So I have another follow-up on the BCG-Naive trial design. I wonder if you guys can confirm what the chemotherapy as a control arm would be? Is that going to be [indiscernible]? Or is it going to be physician's choice?

And in terms of the gating step for the trial, it sounds like you guys are still figuring out what patient population might be, is that sort of the main piece that you need to align with FDA? Or are there other variables that you need to get clarity on?

Thanks, Li. I'm going to ask Leo to handle the first part of your question, which is what are we thinking about? What have we discussed with FDA on comparator? And then I'll talk more broadly about where we sit in terms of our ability to stand up the study.

Leo Nicacio. So our intention is to have a very pragmatic trial. For the control arm, our intent is to use intravesical chemotherapy for physician's choice, limited to the most commonly used regimen in this setting. The intent is to reflect the real-world practice, and we are still finalizing the specifics with investigators and regulators.

I think it's safely to basically piggyback off of Neal's comments, the way that he described the utilization of Gem, Gem plus Doce, docetaxel mono and mitomycin, with the vast majority of those being Gem; that's how you probably ought to think about a comparator here.

In terms of standing up the study, what I can tell you is that we have already quietly been in touch with all of our current sites, multiple potential sites. They are aware that this is a study that we are strongly considering moving forward with. We are good to go, is what I would say. And following this call, you would expect that we would be moving quickly to kind of formalize what we would call ADVANCED-3 as a study going forward.

Our next question will come from Rohan Mathur with Oppenheimer.

This is Rohan on for [ Le Gershell ]. Congrats on the update. I just wanted to ask on the BCG-Naive setting. Given 002 similarity to BCG from an administration perspective, how are you thinking about its positioning next to BCG in the eyes of urologists as a potentially first-line choice?

Yes. Thanks, Rohan. Look, I'll take this and if Neal has any sort of real-world thoughts. But I think the reality is that the similarity in administration is, in our view, a real plus as we think about this product profile that we've described as sort of the perfect balance of the elements that physicians treating urologists and patients want to see in an NMIBC product, right?

And so of the three different domains, efficacy, I think we're showing that, that's a real strength for us. Safety, absolutely, we believe we've got best-in-class safety. But the ease of use and tolerability, right, I think you probably could tease out from Neal's comments, these urologic practices are busy. They have a lot of patient throughput coming through, always facing staffing shortages. And so anything that you can do to sort of minimize the sort of pause of a day's cases is beneficial.

And so given that this really looks like the Lamm protocol that is the protocol that defines the usage of BCG, that is another point of favorability for us. You don't have to really retrain an entire staff, who have to take time out of their day to learn how do you administer this new thing? And how many steps are there? Oh, it's just a simple reconstitution and saline, fully catheter, 15 minutes and the patients back home with their family.

So to us, it's just one piece of a mosaic of factors that we're now demonstrating with 002 that makes us feel like we've got a potential best-in-class product profile.

Got it. And if I could just ask a follow-up on the efficacy. As you interpret the efficacy in these patients who haven't really seen any immune priming from BCG, are you viewing those responses as more meaningful? And do you think that prior immunologic activation could actually make naive tumors more responsive to an immune stimulant like 002?

Yes. So we -- there's a lot that we could dive into with that question, but let me just sort of tackle, I think the most important piece, which is first, the inclusion criteria for BCG-Naive patients in this ADVANCED-2 Cohort A did not say the patient could have required 0 prior BCG exposure. I'll ask Jackie to comment on this. We saw multiple patients that fit our inclusion criteria here who had previous BCG, but outside of a window that sort of would make them characterize as BCG experience.

Do you want to expound on that?

Sure. So in our early conversations with the FDA around the design of this trial and the population that we could include in ADVANCED-2 cohort A, we did align with them on having patients that were exposed to BCG and within 24 -- more than 24 months since enrollment into the trial.

So we have a subset of patients within this data set that we're reporting where they were, in fact, exposed to BCG. And some of them had full course maintenance, some were induction only, but the reality was is that this is not a purely just naive patient population. So there is some prior exposure.

And I think that's how you should think about the patient population that we would enroll in the RCT that we've been discussing with FDA and that, again, we would nascently be calling ADVANCED- 3.

There, really, what we're looking at is any patient who would otherwise qualify for BCG, but for whatever reason, doesn't get it, refuses, that's an important piece of the population, intolerant to, that's a patient that, by definition, would have already been exposed to BCG or a pure naive patient.

I think as you start to think about what that comprises, and remember, in our comments, we said about 40% of all otherwise BCG-ligible patients in the United States do not get BCG. And there's a whole host of reasons why that would be the case.

And so when you think about what is the eventual market opportunity, when you are looking at such a wide range of sort of baseline characteristics, that should speak to you of an addressable patient population that, for sure, is larger than BCG unresponsive CIS.

Our next question will come from Andres Maldonado with H.C. Wainwright.

Congrats on the data. Two for me. Maybe one, let's start with Dr. Shore. You mentioned the BRIDGE study, which essentially was, at one point, started to really answer the question, does Gem/Doce work? How has that signal kind of evolved amongst your colleagues? Obviously, we've heard two camps of people that believe in it and others that don't. So removing all the cumbersome administrational hurdles, where do you fall in that camp?

And then maybe one for management. Looking at the data set, given the genetic heterogeneity of cyst, what proportion of the data set that you presented today may be consisted of lower-risk cysts, so smaller lesions or focal cysts? And how should we be thinking about that potentially enriching or not enriching the CR percentage compared to what we will see in the real world?

Neal, do you want to take that first question on Gem/Doce, just sort of your sense of how community broadly is thinking about it?

Yes. Yes. So look, I appreciate the question, and I appreciate as many options as possible for our patients, right? And so if you have an efficacious therapy that can be tolerated, that can be administered, that is not economically punitive; and some would argue, quite frankly, that Gem/Doce is in terms of the economic modeling of the practice, many will argue that cost of goods there is really low. That's a completely separate issue regarding the competitive landscape and a separate issue that folks from Protara could certainly weigh in on that I'm not prepared to.

So do I use Gem/Doce? Yes, I do. Is it convenient and well accepted by my administrators? No, it's not. Will I offer it to the right patient? Yes, I will. And will -- academic centers where they're set up to have the administration and the biohazard concerns, many community practices, they just ship them off there. That's what they'll tell you when they do it. I mean I'm just being candid about it.

There are some exception sites such as mine that will administer it. And I think even my colleagues in AMCs, they understand that, the issues regarding the person power challenges, not just physician, but LPNs, medical assistants, et cetera, and tying up rooms for throughput purposes makes the Gem/Doce argument for wide adoption a challenge.

And then to answer your question, Andres, sort of on baseline characteristic phenotypes, et cetera, look, I think every immune-activating agent that has either been approved or interrogated in the NMIBC setting, we absolutely recognize and have seen across the board that CIS on its own, highly immunoresponsive, considered a high-risk version of the disease and responsive to immune therapies. CIS with concomitant papillary is a different animal altogether.

And no matter whose data set, if it's us or one of the other sponsors in this setting, if you're employing an immune approach to that concomitant papillary patient, that is a tougher-to-treat patient population. And you would expect to see lower overall response rates in patients of that phenotype.

In this data set, if you look back to what we reported in April at AUA, these exact same patients, the breakout for us of CIS versus CIS with concomitant papillaries was 58%, 42%, respectively. We have not enrolled any additional patients. So you would -- by the transitive properties of numbers, you would then extrapolate that at the exact same mix of CIS versus CIS plus papillary in this data set.

Now as you look -- and I know that there are folks that are probably trying to extrapolate from this BCG-Naive data set that we're talking about today, there are some folks that may be trying to extrapolate from this to our BCG-Unresponsive registrational study, where we are anticipating a data release there in the next couple of months.

What we have been saying, and you're probably sticking hearing it by now, Andres, we've been saying for some time is that based on driver mutational burden of a BCG-Naive patient and a BCG-Unresponsive patient, we believe that those patients are far more biologically similar than they are different.

And our expectation, and we have been very vocal on this, is that over time, you should expect to see response rates in Naive and response rates in Unresponsive that are on 002 to converge. And we do not feel like we have to make any statements or modifiers to that basic core assumption.

So when you take that into account, when you take into account that eventually, we anticipate that these patient populations when being administered 002, they would converge over time. And note that as you look at registrational studies conducted by other sponsors in the unresponsive setting, generally, you see somewhere between 70% to 80% enrollment of CIS only.

So again, the way that I think about it is at 58% CIS only, this is a study that I would characterize as under enriched in CIS-only patients, given what we see in other studies and how -- where the enrollment is for those patients. And that over time, while we're looking to just have any study we conduct in NMIBC reflect the real-world population, we've now got a sample size of at least 4 other registrationally designed studies in the unresponsive setting where 70% or higher of those patients were of a CIS-only phenotype.

Does that help?

Very much. And maybe if I may, one quick last question. Maybe regarding the control arm of the study, just out of curiosity, either for Dr. Shore or the management team here, real-world data, has there been any kind of tangential kind of evidence that patients that may have been exposed to maybe gemcitabine alone, whether it be through intravesical device or other method, can be resensitized with Gem/Doce?

Any high-level thoughts there? Just trying to figure out the dynamics here of patients that are -- if one can resensitize the other and how that shifts kind of the market dynamics here.

I'm going to have to defer to Dr. Shore. We -- on the management side, are not aware of that level of dynamic. Sort of if you've had Gem before, if you've had Gem/Doce before, does that change or is that predictive of a differential response in a subsequent treatment? I don't know, Neal, is that something that you've seen?

That's an interesting question. Typically, there are some individual-site data sets. A good friend, Mike O'Donnell at University of Iowa, probably has maybe some of the largest of folks who've come in from -- who've just had Gem or maybe had mitomycin and then went on to Gem/Doce. But I'm not aware of any sort of preclinical work that would demonstrate either increased sensitivity response versus any ongoing resistance on a preclinical side.

And then even on the clinical side, I don't know of any large multicenter data sets to look at that. It's an interesting question. But yes, that's about as far as I would take that.

Our next question will come from Charles Zhu with LifeSci Capital.

Congratulations on the updates, particularly on the regulatory clarity. First one from me. Is there an opportunity to expand the TARA-002 market opportunity solely on the basis of patient refusal for those who are eligible and have access to BCG, right? Because that's one of the inclusion criteria for your registrational study.

I'm just kind of wondering if one day -- if and when one day you get approved in the setting, if patients just flood up, say, you know what, you have BCG, I can use it, but I don't want to use it for whatever reason. Is there an opportunity really to expand that pie there?

And maybe question but from the other side, as you have numerous other developmental therapies emerge in combination with BCG in the naive setting, can you also talk about the pushes and pulls here? On one hand, you got the great safety, the efficacy and the convenience of TARA-002. But maybe on the other hand, you have, let's call it, these combination therapies that will presumably have much better than BCG efficacy. Can you talk about some of the pushes and pulls there?

Sure. So let me take your first one, refusal. And maybe what I'll do is I'll just take a quick moment to sort of lay out almost sort of like storytell a little bit of where we see or what could a story look like in terms of the use case for 002, right? Because I think the question is where does 002 fit irrespective of BCG supply.

And so look, the first is a practice like Dr. Shore right now that is experiencing a shortage. You've got 50 patients that qualify for BCG use and may or may not have it. That's an obvious one.

I think to your other question, a scenario that we've heard from physicians is they'll have a conversation with their patient and say, "Look, you got a diagnosis of," let's call it, "CIS plus TA, and we want to put you on BCG. I'll put the order in for BCG. And at this stage, what I've been getting is sort of enough to put you on induction, but this is a 2-year course. And I'm not sure that I will be able to get the remaining sort of, let's call it, 18 vials to complete your maintenance course. I can induce you, but I just can't promise based on our flows." And if BCG failed a batch even with ostensibly increased capacity, that means that we're back into a shortage situation.

Let's not forget that even when Sanofi and TCE were both in the market kind of around 2017 and before, there were still periods of shortage where both manufacturers could not supply the market.

So coming back, the first and most obvious here, as we think about what the addressable population, is BCG is not around and you got 50 patients, just like Dr. Shore talked about. And that will still continue for years to come, even if Merck is able to come online with new capacity.

Then there is this other thing where you've got a whole generation of urologists that trained and did their residency and came into the urology specialty knowing and living with BCG shortage. So this idea of I can't predict that I'll be able to get you all of the BCG that you need for the optimal response, I can give you the induction course of BCG.

We also have 002, which we have thousands of vials of it in our refrigerator right now. There's an opportunity where the patient and the physician together would say, "Well, I just want to take the uncertainty off the table, let's go with 002."

And then to your other question, there are patients who have had BCG before, responded to BCG. 2 years later since their last dose of BCG, there's a recurrence. And if that patient is aware that there is an alternative with pretty similar efficacy, that patient might say, "Great, I know I qualify for BCG, and I'm sure you got a bunch of it, but I don't want to go through that again." So that's another sort of case that literally is a real-world story that we've heard.

And then the last that I'd say is a patient on the younger side, who comes in for their first diagnosis and is adamant that they don't want a cystectomy. So now that urologist has got -- let's say, it's a 45- or 50-year-old patient. That urologist is likely thinking, "I got to keep this bladder intact for the next 20 to 30 years."

I know that BCG is super -- it's a great drug when it's administered effectively. So let's start them on something else and preserve BCG for a downstream anticipated recurrence because what we know is that if you give these patients a lot of BCG over multiple recurrences, they develop an unresponsiveness or they develop tolerance or refractory.

So those are four different sort of scenarios that are among many different scenarios. And ultimately, look, patients that are informed and physicians that are informed make choices based on multiple factors. And I'm sure Dr. Shore can back us up, we would anticipate that at this stage, with what we're showing today, we are through a threshold of relevance from an efficacy perspective, kind of irrespective of the combo studies that we've seen out there in the front line.

So at the risk of now talking too long about this, patients will vote based on tolerability, based on reliability. And that's what I believe we offer patients in this sort of BCG eligible unable to get BCG or refuse.

You weren't anticipating that, yes, silence. Charles, what else do you have?

Yes. Maybe just one other very quick question here. I may have missed this earlier, but your 69% CR rate at 6 months, could you just very quickly remind us of the 6-month CR rate benchmarks that you'd expect to see from your control arm chemotherapies?

Yes. So look, there's not a lot of great work out there in the literature on [ GE or MYO ]. I think physicians like Dr. Shore that have seen a lot, have utilized these agents a fair amount; would have a view. We are basing our powering on basically claims data that we -- that covers about 7 years of utilization of some of these chemotherapeutic agents.

And what I can tell you is, and this is what we've sort of said to folks as we've been teeing up the market for this potential data release, is in general, Gem, you should consider Gem to be somewhere around 40% at 6 months and 15% at 12; [ MITO ], probably somewhere around 35% at 6 and not typically durable to 12.

And for the small number of patients that are Gem/Doce patients that may make their way into the study in the control arm, I think the BRIDGE study and some of the work that Mike O'Donnell has done shows kind of what you can expect there.

But just a reminder, the large majority of our active sites are our community sites like Dr. Shore's. And I think he's done a pretty good job of laying out how much gem dosing we're likely to encounter as we sort of get this study up and running and enrolled.

Got it. Really appreciate your very thoughtful and comprehensive answers to our questions, and congrats again on this update.

That concludes the Q&A session and the call. Thank you for joining. You may now disconnect.

Hello, and welcome to the Protara Update Call. We ask that you please hold all questions until the completion of the formal remarks at which time you will be given instructions for the question-and-answer session. Also, as a reminder, this conference is being recorded. If you have any objections, please disconnect at this time.

With that, I would now like to turn the call over to Justine O'Malley, Senior Vice President, Investor Relations and Corporate Affairs.

Thank you very much. Good morning. Thank you all for joining us today for a review of the interim results of our ongoing Phase II open-label STARBORN-1 trial of TARA-002 in pediatric patients with macrocystic and mixed cystic lymphatic malformations or LMs.

Before we begin, I would like to remind you that during today's call, we will be making certain forward-looking statements. These statements represent our views as of today only and should not be relied upon as representing our views as of any subsequent date. Actual results may differ from our forward-looking statements due to various factors, including those described in the Risk Factors section of our most recent annual report and subsequently filed quarterly reports that are on file with the SEC. Except as required by law, we disclaim any obligation to update these statements even if our views change.

I will now turn the call over to Jesse Shefferman, Co-Founder, Director and Chief Executive Officer.

Thank you, Justine, and thank you all for joining us this morning. We're excited to share positive interim results from our ongoing Phase II open-label STARBORN-1 trial, assessing TARA-002 in pediatric patients with macrocystic and mixed cystic lymphatic malformations or LMs.

I am joined today by Dr. Jacqueline Zummo, Co-Founder and Chief Scientific Operations Officer at Protara. Additionally, we are joined by Pat Fabbio, Chief Financial Officer; and Bill Conkling, Chief Commercial Officer, who will join us for Q&A at the end of the call.

Finally, we are privileged to have Dr. Jesse Jones here with us today. Dr. Jones, a STARBORN-1 investigator himself works in the Department of Neurosurgery and Radiology at the University of Alabama. He has treated many patients with various vascular anomalies, including LMs throughout the course of his career.

For those of you who are new to Protara, we are a clinical stage company developing transformative therapies for the treatment of cancer and rare diseases. Our lead asset is TARA-002, a genetically distinct strain of strep pyogenes that drives an immunologic attack of mutated cells. Our lead clinical program for TARA-002 is a non-muscle invasive bladder cancer or NMIBC. And we are pleased to be sharing positive safety and efficacy data for the treatment of LMs, one of several potential indications for 002 today.

Our pipeline also includes IV Choline Chloride, an investigational phospholipid substrate replacement for patients dependent on parenteral support, for which we expect to commence a registrational study by year-end.

While the focus of today's call will be our LMs program, we continue to be excited about our opportunity in NMIBC and look forward to presenting results from Cohort A of the ADVANCE-2 trial in BCG Naive NMIBC patients at the SUO conference in early December.

Before I turn the call over to Jackie, I would like to provide a brief overview of our LMs program. LMs are rare congenital malformations of lymphatic vessels driven by somatic genetic mutations resulting in the failure of these structures to connect or drain into the venous system. There are three subtypes of LMs: Macrocystic LMs, which are large balloon-like cysts with well-defined fluid-filled spaces; Microcystic LMs, which are small, infiltrative lesions with tiny cystic spaces; and Mixed Cystic LMs, which are a combination of both macro and micro cystic components.

Protara is focused on TARA-002 for the treatment of macro and mixed cystic LMs. Most of these cases are diagnosed in early childhood during the period of active lymphatic growth, with more than 50% of cases detected at birth and 90% of cases detected before the age of 3 years old. Most LMs are located in the head and neck region and can cause significant morbidity affecting breathing, swallowing, feeding, speaking and of course, the emotional impact of living with a visible anomaly.

On the next slide, there are approximately 1,400 to 1,800 new lymphatic malformation cases diagnosed each year. When we take a closer look at the composition of these diagnoses, we see that patients with macro and mixed cystic lesions, the populations we are pursuing account for approximately 80% of diagnoses with the remaining 20% of patients presenting with microcystic-only lesions.

And from a prevalence perspective, literature suggests approximately 20,000 patients are living with macro and mixed cystic LMs in the U.S., though we doubt, there are other contemporary estimates that have been produced recently that range much higher.

Despite the gravity of this condition, no FDA-approved therapies exist for patients with LMs. Current treatment options include surgical intervention and off-label sclerosing agents, which carry significant rates of complications and recurrence. The literature suggests that 40% to 70% of LMs interventions are unsuccessful in preventing recurrence. We often see patients having to repeat treatment cycles leading to more exposure to potential complications and a potential lasting psychosocial impact especially in pediatric patients.

When looking at the unmet need in LMs, we have confidence in the potential for 002 to serve as a meaningful treatment option for these patients. 002 is supported by an enormous amount of clinical data from its predecessor compound OK-432, which is approved and marketed under the branded name Picibanil, in Japan by Chugai Pharmaceutical, where it has been the standard of care for LMs patients for 30 years.

In a previously completed University of Iowa led compassionate use program that included a randomized Phase II clinical study. OK-432 demonstrated safety and efficacy in over 500 LMs patients. This is the largest study ever completed in this patient population and Protara has rights to that data set.

The compelling results from the University of Iowa study serve as a clinical template and impetus for our agreement with Chugai, the goal of which is to seek approval for TARA-002 in the U.S. for LMs, NMIBC and other potential indications.

Our first step was to develop GMP manufacturing for 002 as we modernize the manufacturing process to comply with U.S. and Japanese standards. Our facility is an FDA-registered biologics facility that has been inspected for GMP quality. We worked with FDA to successfully establish manufacturing comparability of OK-432 to TARA-002, which would form the basis of an eventual supply agreement with Chugai to produce commercial product for the Japanese market on Chugai's behalf.

And so today, we are excited to share that the interim data from the STARBORN-1 trial are consistent with historical results seen both in the University of Iowa study and the Japanese approval. Given these results, we feel confident that TARA-002 can represent an important much-needed option for this underserved patient population in the U.S. With these data now in hand, we plan to work with the FDA to determine a path to approval.

I will now turn the call over to Jackie to walk through TARA-002's mechanism of action in LMs as well as an overview of the data we reported today.

Thank you, Jesse. I'll start by reviewing TARA-002's mechanism of action. TARA-002 is a genetically distinct strain of strep pyogenes that is fully inactivated while retaining its immune potentiating properties. In LMs, following aspiration of fluid from the lymphatic cyst, TARA-002 is administered directly into the cyst via injection to activate an immune response.

TARA-002 activates TLR2 and NOD2 pattern recognition pathways. The innate and adaptive immune cells within a cyst are activated and produce a targeted immune cascade that eliminates the mutated cells in the epithelial lining of the cyst while sparing healthy tissue.

Cytokines and chemokines, such as tumor necrosis factor alpha, interferon gamma, IL-6, IL-10 and IL-12 are released. Neutrophils and macrophages are activated. And NK cells and T-lymphocytes are rapidly recruited which attack and destroy the mutated cells. This increases epithelial permeability, which allows remodeling of the vessels to support normal drainage leading to the eventual deflation and structural collapse of the cyst. Pro-fibrotic cytokines promote this tissue remodeling and the formation of mature tissue to prevent recurrence. And as observed in Japan, the Iowa data and now our data, it promotes long-term resolution of the cyst.

Moving on to the STARBORN-1 results. I will first briefly walk through the design of the trial. STARBORN-1 is a Phase II single-arm open-label prospective clinical trial evaluating safety and efficacy of TARA-002 for the treatment of macrocystic and mixed cystic LMs in 29 participants aged 6 months to less than 18 years. The trial has enrolled 12 patients, including age de-escalation safety leading cohorts of children ages 6 years to less than 18 years and 2 years to less than 6 years. And we are now actively enrolling the youngest cohort of 6 months to less than 2 years.

After a minimum of three patients in each of these cohorts are treated, there is an independent data monitoring committee that reviews the data and subsequently, submission of those minutes are sent to the FDA before the next safety cohort can begin. We have now begun enrolling into the patients into the expansion cohorts.

In the trial, patient receives up to four injections of TARA-002 spaced approximately 6 weeks apart. The primary endpoint of the trial is the proportion of patients with macrocystic and mixed cystic LMs who demonstrate clinical success. This is defined as having either a complete response of 90% to 100% reduction from baseline in total LM volume or a substantial response, which is 60% to less than 90% reduction in total LM volume.

The interim analysis includes a total of 12 patients. As of the November 12, 2025 data cutoff, eight patients were evaluable for an 8-week post-treatment assessment, two patients have withdrawn from the study and two remain in dosing. 80% of enrolled patients that completed dosing achieved a clinical success. 100% of patients that completed the 8-week response assessment achieved clinical success. Of the two patients who withdrew from the study, one was misdiagnosed and had a rare form of cancer and did not respond to the treatment.

The other was a 15-year-old who experienced a significant reduction in their macro cystic LM. Following two doses, the patient experienced significant lesion shrinkage from 160 ml aspirated at the time of the first dose to 10 ml aspirated at the second dose. It was indicated that missing school and general fatigue were experienced and the patient did not want to participate in the study any longer. However, we may be able to infer that from the reduction in lesion volume that this patient also had a complete resolution of their LM.

Looking at the treatment evaluable population. 83% of macrocystic patients or five out of six achieved a complete response with the remaining macrocystic patient achieving a substantial response. There was one mixed cystic patient who achieved complete response. One patient was assessed to be a ranula patient, which is a different type of cyst following treatment, and this patient achieved a complete response. A durable response was observed in the two patients who reached their 32-week post-treatment assessment by the time of the data cutoff.

Looking more closely at the patient details, we see that the ages of the patients ranged from age 2 to age 15. As I mentioned, we're now enrolling the cohort of youngest patients from ages 6 months to 2 years. When we look at dosing, we see that of the eight patients who are evaluable, seven of eight achieved clinical success with one or two doses and only one patient who presented with a 1.7 liter macro cyst required all four doses. We will show a medical photography of this patient shortly.

Moving on to safety. The majority of adverse events were mild to moderate with no severe adverse events reported. The majority of AEs were Grade 1 or Grade 2. The most common were swelling and fatigue, and they were transient and resolved within a few days.

The safety profile observed with 002 to date is consistent with the results seen with OK-432, both from the Iowa study as well as the experience in Japan.

This is medical photography from two patients treated with TARA-002 in the STARBORN-1 study who achieved a complete response. The patient on the left is the patient who started with a 1.7 liter macro cyst. As you can see, the resolution of the cyst is dramatic and the skin remains healthy. We are very pleased with the outcomes that have been demonstrated as they mirror what we would expect for this therapy based on the historical efficacy of OK-432, which I will take you through briefly.

But I want to spend a minute just to focus on this trial. This is an 8-year-old child that went through school and all the social interactions with the cyst. And after four doses of 002, the cyst was completely resolved.

TARA-002 in developed from the same master cell bank as OK-432 and as previously mentioned was deemed to be convearable by the FDA. As Jesse stated OK-432 was studied in one of the largest trials ever conducted in LMs, in which OK-432 was administered to over 500 patients in the U.S. Our goal with the STARBORN-1 trial is to establish that TARA-002 produces the same safety and efficacy profile consistent with OK-432.

Within the expanded access study led by the University of Iowa, there was a randomized clinical study that was conducted at 27 centers across the U.S. Patients were randomized to either treatment with OK-432 or observation, confirmatory imaging was utilized at baseline and at end of treatment.

The results of the clinical trial were positive, with a vast majority of patients responding well to treatment with OK-432. As you can see on the left side, 69% of patients who received treatment demonstrated a complete or substantial response. This compares with the 7.5% of patients who had spontaneous resolution in the observation group. This response rate was more profound in patients with macrocystic LMs.

On the right side, we see that 84% of patients achieved clinical success with the majority of those patients demonstrating a complete response. 60% of patients with mixed cystic LMs also achieved clinical success.

For safety, the most common reactions were limited to local site reactions, fever, fatigue and other flu-like symptoms. This is consistent with the 30-year history in Japan and is also what we have observed with TARA-002 in the STARBORN-1 study to date.

These are images of four children treated through the University of Iowa Expanded Access Program. We feel confident that based on the results that we have shown today, TARA-002 is producing consistent responses with those observed with OK-432 since its approval.

I will now turn it over to Dr. Jones to talk us through his experience treating LM patients.

Thank you, Jackie. I'm an interventional neuroradiologist at the University of Alabama Vascular Anomaly Center, who specializes in head and neck lymphatic malformations. I trained at UCLA in Los Angeles, which conducts a busy VAC. I see about 50 vascular anomaly patients annually in my practice, and the majority of those are macro and mixed LM patients. Almost all my patients are infants or children, and many have had previous treatments for LMs that were unsuccessful or recurred, leading to their referral to a vascular anomaly center, like my own.

The adverse mental and physical impact of LMs on patients is significant. Most LMs are located in the head and neck and may result in airway obstruction, difficulties with feeding and speech, chronic pain and disfigurement. In this age group, verbal abuse from peers can be devastating.

My role is to reduce the LM as much as possible in order to minimize its impact, while at the same time preserving surrounding tissues. There is a need for an FDA-approved therapy for LMs.

In the community setting, we see many patients being treated with surgery, which has high complication and recurrence rates. Sclerotherapy today relies on the use of off-label therapies, which can be toxic, especially for pediatric patients. I think TARA-002 is a promising option for patients, because it has a differentiated mechanism of action. As an immune potentiator, TARA-002 activates the body's own immune system to eliminate cyst without scarring or tissue destruction. There is a significant amount of clinical experience in LMs in a large safety database with OK-432, where efficacy and safety have been demonstrated previously.

In my own experience, TARA-002 works effectively with minimal side effects in pediatric patients. As an investigator in the STARBORN-1 trial, assessing TARA-002 in LMs, I'm pleased with the results I've achieved in my own study patients. I've treated four patients in the study successfully. And there are a couple I'd like to talk about specifically.

The first is a 4-year-old girl with a large macrocystic LM, spinning the lower neck and mediastinum, which is part of the chest cavity. She underwent several prior sclerotherapies, all of which led to recurrence. However, following a single dose of TARA-002, she experienced a complete clinical response and has remained asymptomatic. Physicians need treatment alternatives for LMs and TARA-002 is a potentially favorable option. Thus far, it has demonstrated a high clinical success rate and excellent safety profile.

We also know that TARA-002 has the potential to be effective in treating other types of maxillofacial cyst beyond LMs. Their supporting literature from OK-432 in the past as well as TARA-002 trial patient of my own. This child had undergone both sclerotherapy and surgery for a salivary duct cyst known as a ranula. Unfortunately, surgery left her with an unsightly scar from exuberant fibrosis known as keloid formation. This cyst recurred again after sclerotherapy, and so I enrolled her in STARBORN-1. She too was effectively treated with a single dose of TARA-002. I'm excited for this that they continue and look forward to enrolling more patients.

Thank you, Dr. Jones. Today's data mark a meaningful step forward in the evolution of TARA-002. We are now addressing both NMIBC and LMs, two important therapeutic areas with this promising therapy. The success we observed in the ranula patient treated in the study, hence set further opportunities to expand.

For now though, we are very pleased with these initial data in LMs and the significant unmet need in macro and mixed cystic patients. With these positive data now in hand, we plan to engage the FDA to determine the path forward to registration for 002 and LMs.

I would now like to open up the call for Q&A. As a reminder, out of respect for Dr. Jones' time, we ask that you focus your questions on the LMs program. Operator?

[Operator Instructions] Our first question comes from Li Watsek from Cantor Fitzgerald.

Congrats on the data. I guess some questions for Dr. Jones. Just can you compare and contrast TARA-002's data today versus the surgical options that you talked about on the call, especially around response rate recurrence and complications that you alluded to. And how are you thinking about using TARA-002 in your LM patients given their different subtypes here?

Yes, Dr. Jones, go ahead.

So, the question relates to how this drug may play a role vis-a-vis surgery. So, I'm seeing surgery mainly on the community kind of side of the practice where people will go and see a doctor somewhere near where they live. That may not be a vascular anomaly center, like you had found at a university setting. And they may see an ear, nose and throat surgeon who doesn't have a lot of other options for the cyst or may not treat a lot of these types of cyst because they're rare, and they will embark on a procedure to try to extirpate the cyst through a surgical incision. That's usually not effective, because if any cyst is left residually there in that tissue, it will lead to a recurrence of the cyst.

And so typically, we'll see these people after they've tried and failed the surgery and the family has been frustrated and come to see center like our own, University of Alabama or UCLA, where I trained. We do have surgeons, but they're deferring to sclerotherapy as the treatment of choice and only operating and in failures of sclerotherapy. So I think as an FDA-approved therapy becomes available, and that information is disseminated throughout not just universities, but the community, we ought to be seeing less surgery first and more sclerotherapy first.

And then, Dr. Jones, how TARA-002 may fit into your practice, I think, was the follow-up question.

Yes. So currently, sclerotherapy agents we're using now are things that we've used historically, but they don't have a lot of data behind them. Particularly, there's no clinical trial data behind them. They are things that maybe people have tried to found to work and written maybe a case report on a couple of patients. And they work by a different mechanism. I mean, they're meant to really destroy the tissue within the cyst, it's almost like a chemical warfare where you're trying to denude that tissue layer. And so these things are quite toxic.

There may be desiccants like pure alcohol. There may be detergents like a sotradecol or even some chemotherapies are being used. There's nothing really that has an immune potentiator mechanism. So based on that, I would feel much more comfortable using something like Protara than one of these other agents.

Okay. Li any follow-up?

And then, in terms of maybe next steps, what is the timeline to finish expansion portion? And Jesse, you talked about perhaps go to the FDA for a discussion around accelerated approval path. Can you maybe just give a little color around that?

Yes, I'll ask Jackie to handle this one.

Yes. So, in terms of the study, we expect to have it complete by next year. And in terms of what we plan to do with the agency, we had a good interaction with them. We're in the Vaccines division right after COVID, and we establish comparability with them. And now it's really up to us to demonstrate to the agency that TARA-002 is producing the same clinical benefits as OK-432 from an efficacy and safety perspective.

So what we plan to do is to go back to them and now with data in hand, have a conversation around what we have seen in the STARBORN-1 trial, how that can fit into registration and then also how we may be able to rely on the OK-432 data as supportive.

So Li, you should expect to hear kind of -- it's very difficult to predict FDA timelines, but we believe that we'll have certainty around the regulatory path to approval in the first half of next year. And the efforts to engage FDA on that are already underway.

Our next question comes from Soumit Roy from JonesTrading.

Congratulations on the data. If you could define a bit the clinical success, is it greater than 60% reduction in the lesion size? And maybe for Dr. Jones, how do you see the benefit is 60% or greater is applicable to these patients because there is no other options or you would really like these to go all the way down to 100%? Will multiple doses get to a curative level? Would love to get your thoughts.

So, I'll ask Jackie to give the sort of FDA definition. This is -- the clinical success is the definition of the primary endpoint that we've agreed to with FDA. So maybe, Jackie, you can define that and then Dr. Jones answer the question given that clinical success is defined as 60% to 100% reduction in the lesion by imaging. Is there an unmet need that's met by that?

So, yes. In terms of clinical success, it's complete response, which is 90% to 100% reduction from baseline in total volume or substantial response, 60% to less than 90% in total LM volume. And it is based on imaging.

The other thing that we do look at in terms of end points is also investigator assessment. So that's the FDA agreed to approach to how we define clinical success. This is the same clinical success definitions that were utilized in the University of Iowa study. So, just leveraging historical involvement with the FDA in that study and then bringing that forward for consistency, that is how we come to where we are today from a primary endpoint perspective.

And then Dr. Jones, 60% to 100% reduction in lesion, what does that mean for you in terms of your assessment of impact to patients?

Yes. I think it's a bit of an artifact of what the FDA requires for these clinical trials. Lymphatic malformations and all vascular anomalies are not like in the sense like a cancer where you need to get a complete resolution or extirpation of the lesion. These don't pose that kind of harm. Many of the patients are coming to us primarily because of -- for the disfigurement concern, the size of the lesion, they're getting made fun of at school or it's causing some pain when it flares up and enlarges, say they get like a URI, like a cold or flu and the LM will enlarge and cause some local pain.

And so for these people, really, a satisfactory response is getting the lesion to shrink to a size where it's either not noticeable even though there's still be some traces present under the skin, but if it's not obviously, noticeable, traditionally, that's been successful. And if a patient came to me after a treatment with sclerotherapy, and you couldn't see anything on exam, but if you didn't say an ultrasound and you saw a small fluid collection there, I would not treat because this is a patient who is satisfied with their response.

So I think 60%, 90%, that's kind of hard to know. We typically don't get imaging of these patients after treatment. It's only because of this trial that we're doing these MRIs and CTs after therapy. But I think the most important thing is in the patient's mind, are they happy with their response.

Got it. That's really helpful. Jacqueline, maybe since you have a lot of data from the usage in Japan. If you could give us some sense of idea how many -- how often these patients get treated? Do they get resolution happens and then they come back again after a few years, durability of response? And my last question is, since LM is genetically defined, how do you see 002 outcompete targeted small molecule therapies against PI3K alpha types in the market and in the clinic?

Yes. So Jackie will answer that first question because there's a significant history in Japan and Iowa.

So, in terms of recurrence, what we know about OK-432 is that, it's a really low rate of recurrence. In the Iowa study, patients were followed for as much as 9 years, and we have access to those data, and it was submitted to the IND, to the FDA. So, we know that it's a very low rate, less than 3% in terms of patients who recurred in that study, and it's a large trial number -- a large number of patients in that trial. So very low recurrence rates.

When we look at Chugai's data as well, it's the same thing, very low rates of recurrence. And as far as number of injections or number of required doses to shrink lesions, what we haven't been able to find is a sort of parallelism to a large lesion requires for. We have some in the Iowa data set and even in the data set from Japan, where very large lesions were shrunk with a single dose. And then you see in our study, you have a child who had a 1.7 liter ML that required four doses. We haven't been able to really get to a point where we can say that lesion size dictates required number of doses. It's really about the immune system of the child.

And then, remind me the second question, please?

I was mostly wondering since this LM is a genetically defined mutation type, how do you see clinically and in the market 002 which is really relying on the immune system of the patients out completes the targeted therapy against PI3K alpha inhibitors?

Yes. So, I think there's a couple of answers to that question. The first is just sort of basic efficacy and mechanistic activity. And the second is sort of the profile of safety of 002 relative to the targeted PI3K inhibitors. So, as it relates to the efficacy, what we know is that there needs to be complete exposure of all mutated cells in the epithelial lining of these cysts in order to drive resolution, right? I mean -- and so, what we know is that LMs can be -- the driver mutation there can be anywhere in that AKT/PI3K/mTOR pathway. And we sort of take a page out of our book from NMIBC to interpolate how 002 is working in the LM setting.

There are about 50 known driver mutations in NMIBC. And we see that 002 because it is impacting and activating so many components of the innate and the adaptive immune system, it has the opportunity to drive a response there irrespective of the driver mutation. Really, what's happening is CD8+, T cells and NK cells are looking at mutated cells and going after them. And so, as it relates to a macrocystic or a mixed macro dominant cyst, the success is a function of our ability to expose all of the epithelial cells in the lumen of cyst to the activity of 002 if you will.

As it relates to the historical application of kind of PI3K inhibitors or either topically or systemically, our understanding is that, that systemic or topical administration isn't quite as successful in macrocystic settings at addressing all of the mutated cells in the epithelial lining. And so again, what we're seeing is PI3K inhibitors utilize for microcystic lymphatic malformations, where sort of the burden of exposure to that epithelial lining in that kind of honeycomb like luminal setting of the microcyst, it tends to penetrate that epithelial setting better.

So look, I don't view the PI3K inhibitors or the novel mTORs as competitive to what we're doing. I see it as synergistic to what we're doing and more to come on that. And so obviously, as we think about the very large number of maxillofacial cysts that are not driven by mutations in that pathway, we saw it with the ranula patient, that's not PI3K associated, but we had a complete resolution with one dose. So from our perspective, I guess the answer is our mechanism covers all your bases, and doesn't necessarily kind of need to compete with something that's more targeted.

Our next question comes from Vishwesh Shah from TD Cowen.

This is Vish on for Stacy. And congrats on the data that is further confirmatory of 002's profile. So we have first one for Dr. Jones. Based on the data that we've seen so far and your experience treating LM patients, what percentage of your patients do you think you would try this -- try TARA-002 on? And we see from the data that there is a low number of mixed cystic LM patients. I think there was just one that we've seen data from so far. So -- but would you -- given your experience with the patient population and TARA-002, would you be comfortable trying it in your mix cystic patient population? And then we have a follow-up for the team.

Go ahead, Dr. Jones.

Yes. So the mixed cystic, that's again a bit of an artifact of how the FDA trial was designed in terms of what percentage has to be macro versus micro and that's just not -- I mean, that's as common in the population as pure cystic or pure like microcystic. And so, I think in general, not just me, but other investigators are not seeing as many of those kinds of patients because less of them exist.

Based on the prior efficacy of this drug, which has been around for quite a long time, the reason I got involved with this trial is because historically, among physicians, it's been known as being very effective, and we were a bit upset that it was off the market and people like in Japan and Korea had access, but we didn't. And so, I was excited to see a company picking it up and running with it because historically, it's been very desirable for us to use it. And that's kind of been borne out in these early results from the interim analysis.

So, if I were to come across the patient with the macro cystic LM, this would be my first choice of treatment just based on the profile mechanism of action. And the safety profile. With the microcystic, it's a little harder. I think we touched on this with the last question. These are really not treatable without a large enough cyst to get a needle and to inject some kind of sclerosants. And if they're purely microcytic they're going to probably go for a biopsy to see if they've got any kind of mutation where they could potentially get a different biologic.

Those agents, sometimes are effective if there's not a whole lot of activity, meaning like cell division, they tend to be less effective. They're more effective in growing lesions. And the patients would need to be on them like continuously. It's not like you get a treatment and you stop as you have to be on it. So that depends on whether insurance will cover it. And if they get side effects like oral cyst or whatnot, which can be a common side effect of those inhibitors. So if there's any cyst, I could get a needle into and treat with sclerotherapy, then I would, and that's the preference, I think, for most practitioners.

So as a follow-up, Dr. Jones, do you see any potential utilization in any type of cystic malformation where you can kind of effectively get a needle in?

Yes. And there are several of these, branchial cleft cysts, ranulas, post-operative seromas, abscess cavities. I mean, these are all basically malfunctioning epithelium that's over secreting various bodily fluids like lymphatic tissue -- like lymphatic fluid or other cysts. And so what we've seen from the ranula treatments, which traditionally are very hard to treat, because that fluid -- because it's a salivary-based fluid, it tends to be very viscous. And most of the sclerosants, which acts by a mechanism where they really need to contact the epithelium in order to dilute or destroy it. That's been quite difficult because the mucus layer serves to kind of protect the ranula lining.

Whereas what we've seen from TARA-002 with this unique machine of action, it's been more effective in those kinds of cyst. So, I would expect more of the same with these other lesions like I mentioned before, and I think that's an exciting thing to look at next.

Vish, you had a follow-up?

Got it. Yes, yes. So for the team, can you just help us sort of characterize how the enrollment is progressing in both the last safety cohort and the expansion cohorts. And can you -- we really appreciate the incidence and the prevalence of the epidemiology that you put out to. Can you help us triangulate around a potential target patient population? Because you also said that maybe 90% of these patients are treated or diagnosed before they reach 3 years old. So, can you just help us triangulate an exact sort of patient population as well? And the first question was on the enrollment, if you can characterize that.

Sure. Jackie, you'll take the enrollment question and we'll ask Bill Conkling, our Chief Commercial Officer, to tackle that second question, Vish.

So, the first thing I want to say about enrollment is that our investigators are extremely excited about the study. That's the first thing, and that's always very helpful when you're trying to enroll a trial.

The second thing I will say is that as we move into the lower age group, that will be -- there's a need within that patient population. But there's also, I think, a little hesitance from parents as it relates to having multiple imaging conducted on, say, a 6-month old.

What I will say is that, we have patients that are in screening that have been identified. We had patients that were on the wait list. And really now, at this point, it's just for us to be able to get them through the screening procedures and enrolled into the trial.

As it relates to the expansion cohorts, we have opened up those expansion cohorts and some of the patients that you see that we are presenting on here are part of the expansion from the older age group, and we -- now since we cleared the second safety sentinel, we're able to enroll patients into that 2- to 6-year-old group. And there are patients that are actively enrolled in that right now and then other patients that are in screening about to begin dosing.

So, we are seeing a lot of excitement. I think these data, we just had an investigator meeting where we shared data. I think everybody now has seen the effect of the drug and the safety profile. And so, I think that will help us to round out our enrollment through 2026.

And then, Bill, you want to?

Sure. So based on the literature, I think we're all pretty well accept the incidence numbers that we see in the marketplace for LMs. I think the bigger question is with regard to the prevalent population. And we've done research as it relates to this population. You've probably seen research from others as well, that suggests the population might be even larger. However, we believe that if you look at those that are seeking active treatment, because just getting one claim for LMs doesn't necessarily mean a year that you are actively seeking treatment, you may be coming in for a visit just to get an ultrasound to see what it looks like, as Dr. Jones had mentioned. And when it starts acting up, you're going to actually seek that treatment.

So, we've estimated about 20,000 are actively seeking treatment, because they're diagnosed early and whether they're treated early or they have watch and wait, they're still in that prevalent population and eventually may come back for treatment. And we believe that it is a quite sizable population that will have TARA-002 as an option upon FDA approval.

Our next question comes from Charles Zhu from LifeSci Capital.

Great. Congratulations on the strong and compelling data. Regarding that regulatory feedback that it sounds like you're going to get in the first half of next year, could you help us understand, what population -- what commercial opportunity does that derisk from a regulatory perspective? Because it sounds like pediatric LMs, macrocystic, mixed, pretty clear, but especially to the earlier point about thinking about the more prevalent population. Are there more patients out there? Are there any patients in that prevalent population that may not be within that initial batch of regulatory clarity?

And similarly, as a follow-up to that, how are you thinking about potential paths to either regulatory approval or some sort of reimbursement support for facial cysts that are beyond the lymphatic malformations. Given that you have the ranula patient, given that we know that OK-432 works at various different types of cysts. And really, as we all know, what this gets at is one of the top 2, 3 questions that the investment community always has is, what is the true market potential for this? And is this a rare pediatric -- or is this something much bigger?

Thanks, Charles. Great question as ever. Let me -- there's a lot in there, and let me maybe just provide you a 30,000-foot view on how we're viewing sort of the longitudinal path of 002, LMs and potentially beyond.

What I want to say first is, we are, as a company, essentially in late to -- mid- to late stage development on three different discrete programs. And we're -- we've got a lot going on, and I think that the investment opportunity in Protara requires the investing community to get fairly facile in three different therapeutic areas. And that you and your colleagues on the sell side do a great job, but it does -- the story requires a broad range of understanding of the investment community. And I think they're coming around.

So, what we want to make sure we're doing as we think about the opportunity in LMs is not overcomplicating the story further. So look, when we go to the FDA -- let me tell you what the FDA is aware of already, right? The FDA has been following the OK-432 or followed the OK-432 compassionate use program that was led by the University of Iowa. So that was a 27 center study that spanned almost 15 years before it eventually wound down. And FDA was aware of that and monitor those patients, those 500 patients that were treated.

And so, the FDA has also been made aware of the evidence of efficacy of OK-432/002 in the literature and in the Japanese experience. So, when we show them these 12 patients, there won't be kind of a cold start for them. They are also aware that there has been pretty well demonstrated efficacy in a number of other maxillofacial cysts. And that's something that they, again, are aware of.

So, I think in the operative kind of, form of, do no harm, what we have is a really robust set of data in macro and micro cystic LMs. We have already been designated a rare pediatric disease. We've got rare disease designation, which upon obviously, approval that normally would result in a PRV. I think that's going to be the case moving forward. And so, we really just want to keep that story tight and make it as easy as possible on the FDA to approve this. Because as you heard from Dr. Jones, there's a very obvious place for this in the LM population, sort of, off the bat.

I think as we think about expanding into other opportunities, I mean, you're right, the literature is pretty full of successful utilization of OK-432 and, let's say, thyroglossal duct cysts, right? There's the U.S. prevalence of 23 million patients with thyroglossal duct cysts.

Salivary mucocele, right? There's a lot of literature on OK-432 being as efficacious in that setting as it is in LM. That's a U.S. prevalence of 800,000 patients. Ranula itself is 66,000 patients in the United States. So yes, I mean, there are big populations where there's a breadcrumb trail to the utilization case of OK-432/002. But let's get this thing approved and into the hands of docs so they can help these kids and take it from there is sort of how we're thinking about it.

So that was an incredibly long answer to a short question, Charles, which, as you know, is my bailiwick.

Our next question comes from Leland Gershell from Oppenheimer.

Just a couple. First for Dr. Jones, just wondering, obviously, you're involved in development here. So you're very much up to speed on this candidate. I want to ask with respect to other positions out there who may be familiar with the data from over the years from the OK-432 but not as familiar, maybe directly with Protara's version. Do you think that the published data from University of Iowa and kind of just the general awareness of this approach, plus the data that we're seeing here in STARBORN-1 will be sufficient to provide comfort for use?

I guess a question related to that would be, for Jesse, how does the company plan to ensure that potential users have that comfort? And then I have a follow-up.

Yes, go ahead. Dr. Jones, do you want to answer that question?

Yes. So you're asking, is the data from OK-432 applicable in physicians' minds to TARA-002? Is that?

Yes. So in other words, this is a small study by itself. But of course, we have the predecessor or the analog from Asia that has much more behind it. So I'm just wondering if in the general, to find in the mid of the physician, if you think there is -- what the level of comfort from a safety as well as efficacy perspective, you think physicians will have there? And then, I wanted to ask the company if you're able to kind of -- how you can make -- how you can provide awareness to those physicians out there beyond what may be in the label in terms of just the relatively small number of patients who've been studied in STARBORN-1?

Yes. I'll admit, I thought it was like exactly the same thing. I didn't realize that the GMP was the main holdup with the FDA. So, I first heard about the study, I thought it was like OK-432. And so, that's kind of why I want to get involved because of such the track record of that agent. So I think for other physicians, it's about the company messaging that to them. And also, as we get further and further away from when those studies were done from Iowa, there'll be a role to educate newer physicians about especially the data from Japan, because that's a little more recent.

And then Jackie will answer your second question, Leland, because it's a good one.

So, as far as how do we plan to spread the word. There are specialty conferences such as SUO that we are -- now that we have data that we're submitting to that individuals like Dr. Jones will be presenting the data to his colleagues. We're doing symposiums. We're obviously going to publish. And I think once we have an understanding from the FDA how OK-432 data may be able to be utilized from a supportive perspective in our regulatory filings, that will give us an opportunity to think about how we might be able to start to disseminate a combination of the 002 data with OK-432 data to kind of put that more substantial set of safety and more substantial set of efficacy findings out there.

I do want to say, though, that majority of RPIs that we have now had someone in their history of training that either was part of the University of Iowa study and knew about OK-432 and either they were residents or they were early physicians when those studies are being conducted and they had experience with it or they knew about OK-432 just because to earlier to Dr. Jones' point, there was such a -- this drug is very effective, very safe, why don't we have access to it.

So, I think there's already awareness out there, Leland. I think it's just now we need to get the awareness out there that the 002 data is consistent with what has been seen for the last 30 years since the drug was approved.

And maybe just to put a final note on that. Leland, you've been following the company for 5 years now, right? And I think so much has transpired. Taking you back to 2020 when we were first sort of bringing this product -- or this program into everyone's field division, the only reason that we call this product, TARA-002 is because there was sensitivity on our partner's behalf that what we were doing was introducing an investigational product into the U.S., while they were marketing a approved product in Japan.

So, their view, Chugai, our partners view was, your product has to be called something different because we can't have a Phase I, Phase II product in NMIBC in the United States being called Picibanil because that then creates problems for us in Japan.

Just a reminder, this every batch of 002 is manufactured from the exact same master cell bank as every batch of OK-432. And in fact, our agreement with Chugai is that we will eventually, from our modern facility in Winston-Salem, North Carolina, supply commercial Picibanil for the Japanese market, which means Japanese authorities are looking at Protara essentially as a site transfer of the manufacturing of OK-432. That's how very alike, in fact, exactly alike 002 is to OK-432. And again, in 2022, the FDA deemed us comparable to OK-432.

Now as a biologic, we know there's no such thing as an exact replica of -- from one batch to another even. And so comparability is the terminology utilized to sort of say, "Look, these are functionally the same thing." So, that has already been established. The reason FDA wanted us to kind of be as methodical with the safety sentinels of the study is because, a, it's pediatrics; and b, a reminder, you are involved in some very sensitive architecture in the head and neck area. And so this, in our view, and in the FDA's view is backfilling further reference back to OK-432.

That's really very helpful. And then just a follow-up for the company. Jesse, could you just remind us on your eligibility for a priority review voucher upon approval, given various timelines and steps to that program?

Yes. So we have been granted RPDD, yes, Rare Pediatric Disease Designation, which effectively means that we would be awarded a PRV on approval. Now we know that the sort of the legislation that back that PRV program under which we were designated sunsets on September 30 of this year. But what we know is that the commerce department, which oversees PRVs and their designation has agreed to extend or is proposed to extend the PRV program out to 2029. That language left the commerce department and is now in Congress. We understand that there are 50 co-signees of the bill to push out the PRV program and those congressional co-signees, span both sides of the aisle.

And so we feel pretty confident that as the government comes out of shutdown and we get ourselves to a place where legislation is making its way back through the house and then the Senate, it's a high likelihood that this program is going to be renewed again. But it's -- these are strange times in which we live. And so, this program has got to stand on its own two feet with or without the PRV. And we're very, very confident that there is a significant return available here with or without the PRV.

Sorry, Operator, that's all the time we have. If it's okay, I'd like to just wrap up real quick.

Great. So listen, this is an -- you tell me? Right. Okay. This is an exciting day here at Protara. We are committed to enrolling and completing the study as expeditiously as possible in service of the patients and families that are impacted by this condition.

We'd like to thank Dr. Jones for his participation today. And more broadly, we'd like to thank the patients, the families, and all the investigators that have made this data possible. We are working tenaciously to get this product into the hands of patients that desperately need it. We thank you for your attention and wish everybody a great day. Thank you.