C4 Therapeutics Inc Stock

Good day, and welcome to the educational KOL webinar Alliant. [Operator Instructions]. Please note, this event is being recorded.

I would now like to turn the conference over to Leah Gibson, Vice President of IR and Corporate Communications. Please go ahead.

Good morning, and thank you for joining our educational webinar to discuss the multiple myeloma landscape, including the role of IKZF1/3 degraders and the emerging profile of site. We will be making forward-looking statements today, and Slide 2 contains our legal disclaimer on this matter. Those presenting on today's call are Andrew Hirsch, our President and CEO; and Nisha Joseph, Associate Professor in the Department of Hematology and Medical Oncology at Emory University School of Medicine; and Len Reyno, our Chief Medical Officer.

Andrew will begin with opening remarks and then hand it over to Dr. Nisha Joseph, who will go over the multiple myeloma landscape and IKZF1/3 degraders Foundational biology. Len Reyno will discuss some Cemsidomide's potential best-in-class profile. We will end today's call with a Q&A session. Andrew, over to you.

Thank you, Leah, and good morning, everyone. Thank you for joining us. As you know, C4 Therapeutics is a leading clinical-stage biopharmaceutical company advancing the novel modality of targeted protein degradation to treat patients with cancer as well as inflammatory neuroinflammatory and neurodegenerative diseases. Our lead asset, Cemsidomide, is a next-generation IKZF1/3 degrader in development for relapsed/refractory multi myeloma, where it has demonstrated a potential best-in-class profile in a Phase I study recently presented at EHA.

There has been exciting data recently presented on next-generation IKZF1/3 degraders, bringing the importance of this mechanism in multi-myeloma into focus. As the next-generation IKZF1/3 degrader, Cemsidomide is designed to be highly potent and deliver a wider therapeutic index, which was reinforced by the updated data that we presented at EHA last week. We're very excited to have Dr. Nisha Joseph on the call with us today, an investigator on the Cemsidomide program and a recognized expert in relapsed/refractory multiple myeloma from [indiscernible] Winship Cancer Institute.

The multiple myeloma landscape has evolved rapidly with a focus on immune-directed agents like T cell engagers and CAR-Ts across different lines of treatment with potential for various combinations. In our view, the question that many are asking, given recent shift is what anchors combination therapy and what therapies will remain relevant as the landscape evolves. Given that context, we felt it was critical to bring in a leading clinician to provide an independent perspective on how the landscape is evolving, what's resonating in clinical practice and where IKZF1/3 degradation fits.

Dr. Joseph brings deep experience in treating multiple myeloma patients and a strong understanding of IKZF1/3 degraders in clinical practice. So with that, I'll turn it over to Dr. Joseph to walk through the evolving landscape.

Thank you so much, Andrew, and thank you so much for the kind invitation to speak to today. So to get going here, I thought I'd start by walking you through really what is my Lamont and talk you through a little bit about the very rapidly evolving treatment landscape in multimyeloma specifically relapsed and refractory myeloma. So for those of you who are not as familiar, multi myeloma or myeloma does that get most common hematologic malignancy.

So even though it's overall a rare disease is still the second most common key malignancy that we see and it is classified or defined as a clonal proliferation of plasma cells, and that manifests clinically in the patient's body with 4 main symptoms. So elevated calcium, kidney dysfunction or renal failure, anemia analytic bone leases. And in addition to these symptoms that patients can present with, they're also often prone infection because they have a disorder of their immune system, they often have decreased antibodies in their system.

And so it's very common for these folks to either present at initial diagnosis with infection or to develop infection along the way. So that's a really important piece of myeloma therapy is to also make sure that we are supporting patients so they did not get life-threatening infections while we're attempting to treat their myeloma. So myeloma, we expect around 30,000 to 40,000 new cases of myeloma each year. And even though things are getting markedly better in terms of outcomes and survival. We still expect roughly 10,000 to 11,000 deaths in 2026, and we still are seeing about 40% of patients that are not surviving beyond 5 years. So even though we have a significant we've had significant advancements in treatment.

We have a lot of new treatments and classes of drugs. There's still a large chunk of patients who are not experiencing the significant benefit that some patients are. Sometimes these patients have high-risk disease, so whether that is defined cytogenetically. So if there are genetic changes that we know signal more aggressive myeloma, sometimes we're able to detect that at the onset. Sometimes they develop or require some of these genetic abnormalities every time they relax or the longer they have myelomas.

But there is also a class of patients who might not even have any of these high-risk features of diagnosis. But they are functionally high risk. They don't respond to therapies the way that we expect them to. So there's still an ongoing need to find safe and effective therapies for many myeloma patients who still relapse and need effective treatments in the relapse setting. So here, you can see really kind of the evolution of myeloma therapies across the last, what, 70, 80 years. And so before -- long before I was trading myeloma, there really wasn't a lot happening. If you look there in the 60s and 70s really into the early 2000s, there was a few drugs that we had and patients had very limited survival. When I was in medical school, we learned that myeloma survival was 2 to 3 years.

The therapies we had were toxic, and it was just not a diagnosis that you want it. And you fast forward now in 2026 and looking ahead, we have so many effective and well tolerated there. So not only have we had now the proteasome inhibitors, so portezamib and carfilzomib, ixazimib, we have several monoponal antibodies in daratumumab and etuximab with ilium. But now, more recently, as I'm sure you're familiar with, we now have more of these T cell redirecting therapies.

So there's 2 FDA approved CAR-T cell therapies in myeloma, iDose and sites really to cell is the CAR-T cell therapy we have access to in the relapsed setting, early relapse setting that target something called BCMA or B-cell maturation antigen that's highly expressed on the surface of malignant plasma cells. And then we have several bispecific antibodies. So we have several bispecific antibodies that target BCMA, so limboseltumab, [indiscernible] and we also have one bispecific antibody that targets something called GPRC5D which is also another antrigen that's highly expressed on the surface of malignant plasma cells.

And then with that, there are other classes like selinexor, which is an XPO1 inhibitor and other drugs in clinical trial development. that offer different mechanistic approaches to myeloma death. And what we are learning is how to best sequence and combine these agents to be the most effective. So even though we have these drugs, patients will relapse. So vast majority of patients relapse. So how do we make sure that when they relapse, we still have really effective options for them that are safe and well tolerated and how do we know which one to use and in what combinations?

So there's a real explosion of not only clinical trial activity with new classes of drugs that are still very much in need but also with the drugs that we already have, either in combination with each other or in combination with some of these novel therapies to try to make them even more effective at each line of treatment at each time the patients relapse. So here, you're looking at just examples of some of the drugs that we think about at each time point in the myeloma patient journey.

So for a standard myeloma patient, when I meet a newly diagnosed myeloma patient, I tell them unfortunately, we have not yet cured this disease. We're working on it, but the silver lining is we turned this into more of a chronic disease. The natural history of this disease is we're going to treat you. We're going to try to get the longest remission possible, but for most patients, this disease, unfortunately, will come back.

And so my role as your physician is to make sure that I'm selecting the most appropriate treatment at each relapse to maximize your depth of response, which will correlate to your emission time. And I want to take into account not only the disease factor, so that would be genetic factors, high risk factors, how the disease is presenting. But also what therapies that patient or that myeloma -- excuse me, has seen previously because that will affect how we respond to this next slide, and we have to take into account patient direct factors. So for a vast majority of myeloma patients, the average age of diagnosis is 67 to 69. So many patients in my clinic are in there are 70s and 80s. They might have other health problems and may have other comorbidities.

They might have limited mobility, limited social support transport. Many of the folks that I see in Georgia, in the Atlanta area, we have a large case area they were very far from the center. So a vast majority of my patients, I don't actually treat on a day-to-day basis. I check in with them, but they have local community oncologists several hours away that I coordinate with and they receive their care there. And so I have to take all those things into account every time they relapse, every time we're selecting therapies. So here's an example showing you of some of the drugs that we use or classes of drugs that we use exciting.

So in the newly diagnosed setting, what really is standard of tariff for both transplant eligible and transplant ineligible patients. is a quadruple therapy with a monoclonal anti-CD38 antibody. So that's either daratumumab, isatuximab, often in combination with what we call an or a KRD backbone. So lenalimide, bortezomib and dexamethasone. So you can see their lenalidomide, which is a trader or an amid is very integral and very important, really, in all lines of therapy, but particularly in combination with PI, the combination of an IMiD with the PI and then adding that monoclonal anti-38 has really revolutionized responses in newly diagnosed myeloma.

It's such an important component of that quadruple regimen. And then when patients relapse, depending on how they relapse and manner in which they relapse, the time at which they relapse, we start thinking about what would be best at their -- for them next. And so for example, if I have a standard-risk patient, I treat them with a quadruplet, they have a transplant, they're on maintenance therapy. And then 1 year later, they relapse. That's not what we would expect, right?

When we look at the pure colo patients who get their RVD, transplant and maintenance, we're expecting remissions. I don't know if I believe some of the projections of 17 years, but I would say it's reasonable to say over 10 years. That's very impressive. But again, that is clinical trial data, that is not real world, and that's not what we see. I think it's an effective argument, but we often have folks relapsing a few years after transplant. So then we start thinking about things like should we do another medical therapy-based combo with some of our standard therapies. So using another anti-CD38 using it again, daratumumab perhaps with another image like pomalidomide or maybe lenalidomide if they weren't online maintenance-based therapies, should we combine that dara with carfilzomib, so that's data from the IKEMA or the CANDOR trials looking at a monoclonal antibody with proteasome inhibitor.

And those are often regimens, particularly for folks who are in the community that are very effective because those are all drugs that community oncologists are very familiar with and they're able to deliver them. They have a lot of experience with those kinds of drugs. We also have things like anti-SLAMF7, which is ilituzumab, the XPO1 inhibitor selinexor and then the anti-BCMA antibody-drug conjugate is belimataolanzumab acidian which we have no access to an early relapse in combination with bortezomib. And that's also an option, I think, that is reasonable in the community setting but it still can be challenging with some of the ocular toxicity or eye toxicity that they're seeing with the drug.

I think for community really, they have more familiarity with those combinations of monoclonal anti-CD38 with either an or a PI. And then certainly at an academic setting, where I am, particularly after some of the data, of course, with CAR T cell therapy in early relapse, if you're familiar with the CARDI trial showing efficacy of filters in early relapse and now kind of the newest excitement in the myeloma world, particularly in the U.S., is the Majestic 3 data looking at teclistamab in combination with daratumumab or even as monotherapy and early relapse, that's certainly an interesting option to use T cell engagers or bispecific antibodies and CAR-T cell therapies.

But as that's a small portion of patients, 20% to 30% of my patients who are able to receive those therapies with me here in an academic setting. Those patients were thinking about even clinical trial, right? That's a smaller subset of the patients. Many of the patients were talking about some of these other therapies that they can receive closer to home. And then as we kind of look forward, what's on the horizon, certainly some came a novel class of drugs going really high potency, particularly what's really interesting about [indiscernible] contrast to the image and even the [indiscernible] is we're looking a lot of the post BCMA. Many of the patients enrolled in the early trials had received BCMA and T cell redirecting therapy.

There's a novel cost of drugs that I think are really interesting with P300 inhibitors in development, either in really more in combination. There is some single-agent activity, but in combination with -- there is some development of allogeneic CAR T cell therapies. I think there's been some limited efficacy there, but certainly an interesting concept and being further explored. And there's also, I think, interestingly, in the CAR T space, ongoing investigation of dual-targeted CAR T cell therapy. So looking at BCMA and GPRC5D or BCMA and CD19, which so far in early trials are showing really interesting efficacy. And then, of course, ongoing work looking at bispecific antibodies in a late relapse.

So there are specific -- there is a bispecific, for example, called savoimab, looking at FcRH5 and then price specific. So now using -- we had bispecifics, now we have trispecifics, looking at CD3 and 2 targets on the myeloma cell surface. So a lot of really interesting and exciting novel classes of drugs. That we absolutely need to make sure that all patients matter their disease type or no matter where they're being treated have access to really effective, well-tolerated drugs.

And not only are these drugs in clinical trial development but they're in clinical trial development in combination with other drugs, whether those are other novel agents or other standard myeloma therapy. So really a lot happening in the myeloma space is moving very rapidly, which sometimes can make these questions of sequencing and what to do challenging, but it's a good problem to have.

Okay. So now a little bit on some biology at a very high level. Why did IKZF1/3 degradation matter? SP-6 So when we think about IKZF1/3, but we're talking about our cross -- and then subsequently, IRS 4, which is a downstream transferation factor. And basically, what all we're saying here, these are very important transcription factors or components of minicell survival. They're needed to make sure that, that myeloma cell lives and lives and lives. When you cut those things off at the needs, when you degrade those proteins, you are enhancing myeloma cell death.

Without those important transcription factors, the myeloma cell has a hard time surviving. And so that's why these drugs are so affected, whether it was done with IMS or CAM when you degrade these proteins, and that's what Cemsidomide can do or any of these degraders can do, they target these important transcription factors for destruction, and once you start decreasing or destroying the amount of crisis in the cell, that leads to enhanced myeloma solid death. So it's a very critical component of myeloma therapy using these types of drugs.

And not only what we have learned with these classes of drugs, whether it's MD or AMoD or Cemsidomide, is this very interesting T cell activation data as a byproduct. So you're leading to a personalit degradation. You have enhanced myelomas. But as a byproduct, you're actually seeing increased cytokine production, you're seeing less T cell exhaustion and so you're having T cell stimulatory effects just by using the drug in the first place. It's not necessarily what's happening to the myeloma, but it's a nice side effect. It's a nice byproduct. And I think this becomes particularly rather than an important in a field where we're using so many T-cell redirecting therapies or we're seeing so much T cell redirecting use in clinical trial development.

Not only can we potentially pair these types of drugs, the IT degraders with T-cell redirecting therapies to enhance their efficacy. I think that's one really important pathway, but we can also use them in between T cell redirecting therapies. That's another really interesting place to put them. So for example, after someone receives a bispecific antibody, you feel a lot of T cell exhaustion or dysfunction. It's challenging to move directly into another T cell redirecting therapy. You need to give time for their T cells to recover essentially.

And so potentially, that's a space for these classes of drugs. Their T cell simulatory -- they don't require functional T cells to work, but you see really nice efficacy and nice safety profile, and you're positioning that patient well in case they do need a next-line therapy. So here is showing you examples of how IKZF1/3 degraders are incorporated across the myeloma treatment landscape. So you can see here for patients in the second and third line and then patients in the fourth and fifth line. And you can see here, there's multiple options in these spaces.

But ICFI and 3 degraders are integral in many different combinations. So you can see them in combination with CD38 and proteasome inhibitors or monoclonal antibodies. And moving forward, we're seeing more and more combination with those in clinical trial development in combination with bispecific antibodies or even as a maintenance therapy or even before T cell apheresis for CAR T cell therapy. So they're really a critical component of relapse across every sector from second to fifth line, we can use is in combination with our standard agents. We can use them in combination with our more novel T cell redirecting type therapies or bispecific antibodies or CAR-T cell therapies or we can use them in between.

So they're really -- they maintain a really important role in the treatment of Myeloma. So as we look ahead to the future of multiple Myeloma treatment, again, things are changing and moving so quickly, but there's still a significant unmet need in the late-line setting, particularly not only for an effective, well-tolerated treatment. And I'll point out, particularly in late relapsed, these patients can be a little up. They've seen a lot of therapy.

So it's important to have not only an effective therapy, but one that they can tolerate, one that they can be consistent with and does not negatively impact their quality of life. And then I think another really nice aspect of these types of drugs is that they're oral. And so particularly for older patients, particularly for patients who don't live near a large city or near an academic setting. Having an oral option is really convenient and really allows them access to effective drugs that wouldn't otherwise have access to if they're all going to be T cell redirecting therapies that have to be delivered in academic.

The other thing we think about when we think about what to select and relapse is we want to make sure there is a known attrition in myeloma therapy, meaning. As you look at first-line patients, second-line patients, third-line patients, there's a drop off. Even though patients are doing better, there's a drop-off. So there's side effects, there's ability to continue with treatment, et cetera. So we really want to make sure each relapse for using absolutely the best, most effective therapy that we have, the most potent.

We want to use that early, and we want to use that in combination in a way that's effective and against seeing for these patients. We're seeing a huge shift in these novel immune therapies into earlier lines of therapy. But these therapies are not curative. So even though we're using these therapies earlier, the vast majority of patients are relapsing, they often have T cell dysfunction or exhaustion, and it's important to still have regimens that are effective for those patients.

And as we think about CAR T cell therapy, I think there's another really important unmet need and how do we make CAR T cell therapy even more effective? How can we add maintenance therapy there's ongoing trials not only with maintenance post CAR-T, but even using these types of drugs that have T cell simulatory effects in patients who might have an exhausted T-cell phenotype to use these drugs prior to apheresis. So there's a lot of work, and I think interesting ideas but how can we use these important class of drugs to make CAR T cell therapy even more effective to help with persistence and help with duration of response.

And so I think what I tried to talk about in the last few minutes here is this is a really effective cost of drugs. And it might be easy to think that moving forward, we have all these novel immunotherapies. Is there a role for these therapies? And there absolutely is, okay, the therapies that we have that are using T cells, the bispecifics, the CAR T cell therapies, they're not curative, there is room for improvement. These drugs can potentially fill that space.

We're seeing in its predecessors and in some of the early data, there's a real mechanistic advantage combining these classes of drugs with other standard myeloma therapies and some of the new novel therapies are seeing enhanced potency, enhanced myeloma cell death without a significantly worse safety profile. We're seeing that we can use these drugs across multiple different treatment lines. So again, in combination in between in really each setting, there's a specific role for these drugs to make sure that we're getting good myeloma depth of response and long-term remissions.

So I think this is a really important cause of drugs. I'm really excited about some of the clinical trial data that we're seeing and looking forward to seeing more data as we start to combine these drugs with some of the T-cell redirecting therapies and novel therapies in our field. And so with that, I will conclude. I thank you so much for your attention, and I'll turn it over to Len, C4 Therapeutics Chief Medical Officer to discuss Cemsidomide's profile.

Thank you, Dr. Joseph for the excellent summary, and we appreciate you joining us today. With the context just outlined, I'm excited to discuss Cemsidomide's potential best-in-class profile as a next-generation IKZF1/3 degrader for multiple myeloma. To start, it is helpful to understand how IKZF1/3-degraders have evolved low time. IMiDs, CELMoDs, and Cemsidomide all have the same mechanism of action. Lenalidomide and pomalidomide were first-generation IKZF1/3 degraders, i.e., IMiDs and they have been clinically relevant for over 20 years.

However, when IMiDs were developed, their mechanism was not understood and there's a clear need for next-generation IKZF1/3 degraders because of the limitations in terms of potency, selectivity and durability. Mechanistically, these original drugs primarily block proliferation and did not drive multiple myeloma cell death, which ultimately allows resistance to emerge. But they did very effectively establish the importance of the pathway.

Next-generation agents, iberdomide, mesignamide, also known as CELMoDs and Cemsidomide were designed to address these limitations by not just inhibiting proliferation but actively driving myeloma cell death and overcoming resistance. Importantly, Cemsidomide is built on novel chemistry with a well-understood and validated mechanism, and we believe it is uniquely positioned as a potential best-in-class IKZF1/3 degrader as we move into later-stage development.

Let's think about Cemsidomide as a molecule and its potential for best-in-class in multiple myeloma. [indiscernible] was designed from the bench up as a highly potent and selective IKZF1/3 degrader. In this regard, it has uniquely highly targeted specicity. It does not degrade off-target neo substrates, including CK1 alpha and GSPT1. Important for patient care, where 50% of patients with myeloma have some degree of renal impairment. Subside has no renal clearance. It also has low protein binding, which maximizes the availability of free circulating drug to deposit deep in the tissues, including the bone marrow. In patients, Cemsidomide has a 2-day half-life. This 2-day half-life is important because it sustains free drug at therapeutic concentration while maintaining efficacy and allowing neutrophils to recover during a break in dosing. In this regard, Cemsidomide is uniquely dosed on a 14-day on, 14-day off dosing schedule.

This break in dosing allows the potency of Cemsidomide to maintain anti-myeloma control, but also enabling full neutrophil recovery. These features make Cemsidomide an ideal backbone for combination regimens. We've taken this information and launched it into a differentiated label-enabling strategy from other IKZF1/3 degraders. We are particularly focused on how to incorporate the potency of Cemsidomide with its class-leading safety and efficacy into the evolving multiple myeloma landscape.

Now let me take a moment to walk you through the data that has demonstrated some Cemsidomide potential for a best-in-class profile from our first-in-human Phase I trial. This Phase I trial, which is schematically illustrated on this slide, completed enrollment in September of 2025. And last week, we presented further analysis from the trial at the European Hematology Association. In total, 73 patients were enrolled on the study across multiple dose levels, including stand expansion cohorts. 100 micrograms was declared as our RP2D.

Patients enrolled in this trial were extremely heavily pretreated with 7 median prior lines of therapy and important in the current evolving context, 75% of these patients had prior CAR T or T-cell engager with therapy. The fact that we've been able to show an impressive response rate in this population confirms that the mechanism of action of targeting IKZF1/3 remain foundational regardless of prior treatments. Cemsidomide was extremely well tolerated across the dose levels tested.

There were no discontinuations related to Cemsidomide and minimal dose reductions, well-tolerated safety profile also included manageable neutropenia. It should be noted that all drugs in this class require a break in therapy to allow neutrophils to recover. On this study, Grade 3/4 etropenia rate was 22%, and the grade 40-ton rate was 36%. But more importantly, there were very low rates of neutropenic complications, including low rates of federal neutropenia across all dose levels with only 4% at Grade 3 and 1% at Grade 4. Equally importantly to patient care, there were also incredibly limited Grade 3 or 4 nonhematology side effects. It's also important to note that the risk of neutropenia did not increase over time on this study. there was limited G-CSF use.

And in fact, there was a minimal impact of the neutropenia on the patient's clinical experience and patients did not come off drug for side effects of [indiscernible]. Across all doses, only 45% of patients ever receive G-CSF. And in fact, most of the neutropenic events occurred in the first 2 cycles, where in later cycles, when the disease was controlled, the patients enjoyed excellent tolerability. The exciting safety profile of Cemsidomide is supported by an equally and more exciting evidence of anti-myeloma activity. On this slide, we summarized reductions in serum-free light chain levels across the doses tested in the first-in-human study.

What you can clearly see on the graphic that we had deep degradation of serum free light chains across all doses, but most especially at the 2 highest doses. Of course, serum free light chains as a prerequisite to demonstrate IMWG responses. And on this slide, you can see that our highest dose level 100 micrograms that in 19 patients we had a 53% response rate. We had two patients who achieved the [indiscernible] and the CR also achieved MRD negativity. From a drug development point of view, it's also important to note that the drug is active at all doses studied. And in fact, we had a 40% response rate at the next lowest dose level.

And in fact, over all those levels enteritated for Cemsidomide plus dexamethasone, the response rate was 36%. It's important to put this anti-myeloma activity for Cemsidomide in context. On this slide, we compare the Phase I results of Cemsidomide against the other next-generation IKZF1/3-degraders currently in development. let's first consider the population studied. The populations are not the same in that the Cemsidomide first-in-human study enrolled patients where 75% of the patients received prior BCMA-directed therapy.

1% of patients had BCMA-directed therapy for mesignamide, and none of the patients had BCMA-directed therapy on the abertamide first-in-human study. Notwithstanding these differences in the pretreatment populations, Cemsidomide across all dose levels has the highest overall response rate of 36% and at the dose level of greatest interest, the RP2D, our response rate of 53% compares favorably with mezignamide and is almost double the response rate of Iberdomide. As you can see from the available data, Cemsidomide has the potential to be a foundational treatment across multiple lines of multiple myeloma therapy.

Based on this emerging profile, we've designed a development strategy that is both differentiated and aligned with how the treatment landscape for multiple myeloma is evolving. First, in the late-line setting, there remains a clear unmet need for safe and effective therapies, highlighted by our Phase I trial that despite new emerging therapies, patients are still progressing and seeking disease-modifying care. We're enrolling the Phase III MOMENTUM trial now with the potential for accelerated approval. This is a setting where other IKZF1/3 degraders, including next-generation degraders are not currently pursuing label-enabling strategies. Second, in the earlier line setting, we're focused on combination strategies.

Our initial development strategy is in a combination with the BCMA. The rationale for this combination to combine Cemsidomide T cell activation with deep anti-myeloma activity which should drive higher and more durable responses. We've initiated a Phase Ib study with elranetinab with plans to advance into a Phase III trial. This Phase III trial has the potential to support accelerated approval based on MRD-negative CR rates as well as confirmatory for the broader program. And third, we're exploring ways to include Cemsidomide as a possible broader image replacement strategy.

These activities include a Phase Ib trial with a proteasome inhibitor in CD38. The trial is expected to initiate in the first half of next year. The goal here is to establish a consistent predictable dose of Cemsidomide that can be combined with agents that are used frequently to treat multiple myeloma in standard of care regimens. We are currently not planning to use this data to embark on a registrational trial, but rather to increase the body of knowledge of how to combine Cemsidomide safely with other drugs.

Overall, these three strategic paths are designed to maximize both near-term and long-term value by addressing unmet need in late-line disease while building toward broader use in earlier settings. With that, I'll turn it over to Andrew for closing remarks.

Thank you, Len and Dr. Joseph for this highly informative session regarding the evolving multiple myeloma landscape. As you heard this morning, despite the rapid emergence of new therapies, IKZF1/3 degradation remains a foundational mechanism that continues to underpin treatment across lines. At the same time, the limitations of first-generation agents create a clear opportunity for next-generation degraders that can deliver improved tolerability, deeper and more durable responses and better address resistance mechanisms.

Based on the data we've generated to date, we believe Cemsidomide is well positioned to deliver on that opportunity with the potential to be a best-in-class IKZF1/3 degrader. Our goal is to establish Cemsidomide as a foundational backbone therapy across multiple lines of treatment and believe Cemsidomide is well positioned to play an important role in the future multiple myeloma treatment landscape. We're encouraged by the progress we've made and remain focused on advancing this program through later-stage development.

This year, we plan to provide additional commentary on how our Phase Ib trial with elranetinab is progressing, and data is expected mid-2027. Our Phase II MOMENTUM trial is on track to complete enrollment by the end of Q1 2027 with initial ORR data expected in the second half of 2027. With that, we're happy to open the line for Q&A.

[Operator Instructions]. Our first question comes from Tyler Van Buren with TD Cowen.

Thanks very much for the presentation. I thought it was very well done. A couple for you all. The first is, as we think about the higher the 75 and 100-microgram doses, what do you think median PFS and median duration of response might be trending towards?

And then for the second question, just can you discuss the significance of the successor to data at ASCO for the class as well as how we should benchmark the control arm for the successor 1 trial reading out some months from now, which could be even more important for the class.

Yes. Thanks, Tyler, for those questions. I'll have Len address the [indiscernible].

Thanks, Tyler. Obviously, they're good questions and yet they're difficult to answer. So let's start with first principles, though. Obviously, we have small cohorts right now at any given dose level and they do not represent or anything remotely as a randomized comparison. But I would say the following: we know overall in the population that we have a PFS that's around 4 months, and we also know and not be irrespective of response rate irrespective of dose you received.

We also showed in the webinar you just saw that as you increase the dose, you get deeper degradation of the transcription factors, and better response rates. So one would anticipate that we have an opportunity at the highest 2 dose levels in particular, to improve on that. I think it's really difficult would be pure conjecture to try to say what the size of that improvement is.

But I would suggest that overall, the data supports that we have a compelling signal to start with, and as we optimize our dosing of patients at the RP2D and/or 1 dose reduction, if necessary, I think we'll see improvements there. The second piece of the puzzle that you alluded to in terms of XR2 data. So just to align with everybody on the call, that represents a randomized trial where mezigtimide was added to a 2-drug regimen and has an incredibly compelling hazard ratio.

And we are really happy to see that hazard ratio because it provides an initial read through on the class, meaning a potent degrader can be done in a global Phase III trial safely and successfully can be associated with a high efficacy signal. And we congratulate the patients who enrolled on the study and BMS for conducting it. However, what we also see there is an important read through to how it fits to symptom.

What's unique perhaps about this class of drugs, IKZF1/3 degraders is how well early first in human data predicts future outcomes. And so if we think about where gas mezignomide was at the time of its original first-in-human data, which we summarized briefly in the webinar. -- we're at there or better. And the part where we're better is actually on not having fewer dose reductions and less need for supportive care.

Well, why does that matter? They had a positive study? Well, because in that positive study, what's really important to note is it was positive despite the fact that 40% of patients had dose reductions, and we don't know what they were dose reduced, too. In addition, there was evidence in the study that some patients on study, the cause of death was actually not myeloma, but we don't know details for. So we think Cemsidomide can do at least as well or better. in that.

And then finally, to your next question with respect to the successor 1, which is comparing a 3-drug regimen and swapping pomalidomide foreside. Again, we would anticipate as the positive study. I would anticipate the effect size is smaller because you're actually just augmenting a class of drugs. And we wait to see that data with interest.

Yes. And I'll just add, I think the two comparative sort of points we can point to for what that kind of Palm KD arm is going to look like? Or is this IT called the SELECT study of 52 patients where there was an 11.1-month PFS. And then if you look at the comparator arm to the Majestic 9 study, which is a very similar patient population. We saw that have about an 8-ish month PFS. So that's another way to handicap success or 1 to see what is that palm triplet arm going to do versus the doublet that was in success or 2.

Thank you. The next question comes from Brad Canino with Guggenheim.

Great. Thanks for the question and for the overview this morning. question for me is how do you think about the ability for these next-generation IKZF1/3 degraders to be more effective than pomalidomide and earlier lines of therapy. And really the question behind the question I'm thinking about is why a T cell engager combination in second, third-line therapy might be better with a drug like Cemsidomide instead of a generic drug like pomalidomide?

Thanks, Brad. Nisha, I'm actually going to ask you to address that.

Sure. everyone. Happy to be here this morning. So I think the question was why would we think that Cemsidomide might be more potent with T cell engagers than the classic image that we have currently, is that correct?

Yes. Yes, roughly. Yes.

Yes. I mean I think we don't have the data, but I mean my answer to that would be an extrapolation from what we're seeing in the late line. So when we look at pomalidomide in this -- if we looked at that in this combination or we looked at Cemsidomide in this late relapse population, the Cemsidomide data looks more potent. So the depth of essie were not supposed to do cross-trial comparisons, but we do all the time.

And the depth of response, particularly in a much heavily pretreated population looks so much better. And so when we compare them, we're expecting to see better efficacy than them is that we have currently. And I think it's encouraging the data that we see with them is that we use IMiDs in combination with bispecific antibodies, both on trial and really in the rural world practice all the time, and we see those preclinical effects in patients all the time. There's immune stimulatory effects able to really deepen the responses that we see with bispecific antibodies in late relapse and even in early relapse in several clinical trials that we have here.

So I mean, for me, again, we have the Phase Ib open here looking at [indiscernible] in combination with Densan we're enrolling the first patient on [indiscernible] looking forward to see that data. But for me, it's just a very simple answer of it looks more potent than the late relapse. And we're seeing that efficacy with in so we would expect to see at the very least the same, but I would imagine improved efficacy given what we're seeing in the late relapsed population.

If I could add to that, at. Just 1 other point that is embedded in what Nisha said, so it's not different, but just as more illumination, if you will, is for us, our starting dose with our L recombination is 75 micrograms. And what's unique about that dose is we obviously know it has T cell enhancement features, and that's great. But that dose has a 40% response rate. And if you think about the first 2 cycles, in particular, when you're giving a bite, you're trying to get the patient into response.

So we're hoping -- and the data will be the data. And I want to make sure I'm clear on it. I'm hypothesizing, but at the end of the day, we're hoping what Cemsidomide can bring because we can give it at a dose that has its only independent anti-myeloma effects that it will really help drive getting the patient into a really clinically important response quickly. as well as the T cell enhancement effects than sort of supporting the back end for long-term durability and increasing depth of response over time. So we're really excited about the trial.

And certainly, we have great investigators participating on it.

And I'll add one other comment is what's really also important is the selectivity of Cemsidomide. When you think about the first gen, right? No one do the mechanism so they can't be selective. They -- they rate a number of other NeOsubstrates like GSPT1 and CK1 alpha. And when you think about combining them with a bite, you really want to do the safest, most tolerable one because there can be overlapping toxicities and bites alone have some toxicity.

So to be able to maximize the anti-myeloma effect and give the maximum dose possible, you want the cleanest sort of broad on target and really based on kind of the data that's out there, that's really subside.

Yes. On that aspect, if you could hear Dr. Joseph's perspective on how much TCEs can actually get out into the community and penetrate that patient population over time as the community continues to learn how to give them. And then also the feasibility of combining with a drug like EMC and the potential for overlapping neutropenia. Is that going to be a challenge? Or can that be administered there as well?

Yes, of course, happy to address those. And I think really good questions. I think at least in our region of the country, we have been seeing bispecific uptake in the community. At a slower rate, maybe than other regions, but it's definitely happening. And I think what's also been really helpful recently is Tecan Tech, and I think it's kind of becoming unavoidable that community physicians need to become familiar and learn how to get bispecific antibodies, and they want to, right?

They want to keep patients. So what they don't want to do is having to send patients to us often, right, even with CAR T cell therapy. They don't want to lose the patient. And they're worried that they come to an academic center. They won't get the patients back. So they want to be able to give BCMA therapy. They have belantamab, that can be a trickier 1 for them to give because of some of the ocular toxicity. So they want to be able to give a drug in their clinic that's effective and they can keep their patient. And I think given some of the data looking so effective in early relapse, I really think we're going to see even more shifts.

I think another thing that we've been working on here at Emory, we've been doing this now across the country. is how do we make administration more feasible for the community practice. And so right now, what we're currently doing is we do the ramp-ups for them. There's a lot of anxiety about CRS and IgAN. But we've also started, I'm sure we've heard and we started doing this in clinical trial practice now is just routinely using prophylactic cola we've made folks have published on this, it markedly reduces the rates of CRS and we're not seeing a lot of ICANS.

And so it's really a lot of education that we all do about the role of prophylaxis, how to use it and how limited those effects are into the first cycle in terms of CRS and ICANS. I think that is getting better. I think community doctors are becoming more comfortable. At the very least, we did the ramp-up and we send it back. That's -- it won't be forever, but that's what we're doing. And I'm seeing more people comfortable picking up with cycle 2. So I do think that's going to continue to shift just because it has to sets are coming in earlier line trispecifics are coming. I mean they just are going to have to start making this shift.

This is becoming standard of care for myeloma patients in early relapse, and it's going to become I think, standard in newly diagnosed, at least for certain populations. So that's just an inevitability, I think. And then in terms of the feasibility piece, about neutropenia, right, in combination with Cemsidomide. And again, let's see the data. I mean, certainly, when we look at CELMoDs in combination with bispecifics we saw a good amount of neutropenia, but with some dose finding, I mean that's certainly improved.

I think the thing you have to remember is even with community docs who are giving these regimens, they are hematologists. So there are side effects that are not good that we really can't tolerate and then there are side effects that we can, and those tend to be hematologic. And so hematologic even with significant rates of neutropenia, that's very familiar community [indiscernible]. So giving GCSF holding drug or doing dose reductions, I'm not particularly worried about that. I mean I think it's on us to make sure we find a dose that is appropriate and that we're not seeing high rates of federal neutropenia or opportunistic infections and things like that. But outside of that, I think it's quite manageable, certainly for academics but even for the community.

Okay. The next question comes from Etzer Darout with Barclays.

Great. Thanks for conducting this webinar. A couple of questions for Dr. Joseph. Just again, if these data hold, I would love to hear your thoughts around how you would use instead? And would you use it ahead of other IKI, the greater image or Cemsidomide? And then also, are you seeing patients that have progressed on BCMA modalities and how you're currently treating these patients? And maybe the success or lack thereof you're having with those patients?

Sure. Yes, happy to. I'll start with the last 1 first. meaning the question about, are you seeing post BCA how those patients are doing. So we have -- that's the most rapidly growing population in our practice as post-BCMA. We're giving so much more sale in early line starting to get more bispecifics.

So not only are we seeing a post-BCMA population, we're seeing a post-PC growing post GPRC5D population, and that's going to grow as we start using trispecifics and other dual-targeted CAR T cell therapies in early line, which are coming also. In terms of how they do or what I do currently, I mean that's -- that depends certainly on the case, but I think that really highlights the efficacy or the role of these classes of drugs because often coming off, certainly of a bispecific antibody, as you know, we tend to have a dysfunctional T cell phenotype, going to another bistate isn't going to work going into CAR T cell therapy is usually not the ideal.

So I think that's a role for these types of drugs. In current practice outside of clinical trial, if someone was coming off of CAR T cell therapy, I might consider a bite, but if someone is coming off of a bit, I'm trying to scramble to find some other regimen that I think would be effective. So some kind of if they haven't had carfilzomib or even maybe selinexor, I mean we're kind of limited outside of clinical trial in that space. lineal trial, we go for things like this.

C4, sometime, excuse me, or other P300 inhibitors, things that don't require T cells. So I think that's 1 phase that these herbs are very helpful. In terms of how they do, it just depends. If this is an early relapse patient, I think there's so many options. This is a late relapsed patient. It does get harder and harder for these patients to find options. I'm sorry? Okay. And -- I'm sorry?

There was no one interrupting. Keep going.

Okay. I'm sorry. And then I think the other question was how do I see using Cemsidomide. Is that correct? Forgive me.

Yes. That's correct.

Yes. I mean I think, again, I guess I just addressed this. I think the role of these types of drugs are either in a post T-cell redirecting space, where you have. You don't need functional T-cells and you have this potential immune similar to our effect, or in combination. So I mean we were talking -- we've talked about [indiscernible]. I'm sure you all a familiar with CAR-T data. I referenced this in the talk. These drugs are effective, but they're not curative. There's significant room for improvement.

So to be able to not only improvement but improve safety, which was referenced early, and we're moving towards fixed duration also. To be able to give bispecifics forever and ever, is really not feasible. You saw the infection data in -- so if we can try to get deeper, more durable responses early and then back off on the bispecific and maybe continue an oral drug or whatever. I mean, there's so much earn there. But there's a significant room for improvement. In terms of efficacy, duration of response and safety. So I mean, in the current landscape, if you gave me [indiscernible] right now, I'd probably be using it in a post BCMA space.

I mean that would be the approval. But post CAR-T or post bispecific in between bispecifics. But I think there's a lot of potential as we learn about how to combine with bispecifics and other standard therapies, as you heard about, I would imagine it's coming earlier in terms of what would I do with CELMoD versus side that's all very hypothetical. I think certainly, we see activity with incentivized in the post-allo space and the sawlogs are going to move up and everything is moving up. So it's hard for me to kind of wax poetic on what's going to come.

But ultimately, the best drug wins. The most ton drug, the safest drug for patients. And I think particularly when you talk about an oral agent that we're going to be giving the community more safety matters, the amount of dose reductions matter, how much supportive care matters. Because community oncologists, I see motions today, they see 1 to 5 every 6 months. So we have to find drugs that are effective and easy to dose. So I hope that answers the question.

And the next question comes from Derek Cilla with Wells Fargo.

This is Jacob on for Derek. So just thinking about De step-up dosing, G-CSF usage and other approaches to mitigate some of the safety issues with this class in BCMA bispecifics, can you talk a little bit about the differences between your study with [ ELRA ] and then those of [indiscernible]? And then how might the differences affect the dosing intensity and reductions compared to the Cemsidomide.

I'll let Len answer address that one.

Yes. So the data that precedes us with ELRA, in particular with ibernomide, which was seen at ASH, if you remember that presentation, there was a learning curve, if you will, during that study vis-a-vis how to give the and, in fact, how to even define DLTs. And so we've been able to learn from how that trial was actually designed and try to mitigate the risks that we will get into a situation where were caught off guard by unexpected findings.

So we have proceeded to start the study with ELRA, which is in the dose of administration, the way it was finessed in that study. We've redefined the DLTs carefully and made it very clear how to use supportive care, in particular in the safety evaluation period to make sure patients all get maximum supportive tariff needed. Also a key feature is that, of course, we don't start Cemsidomide during the step-up dosing. So the step-up dosing, obviously, is there's a unique set of risks related to bite therapy to ELRA therapy.

And we want to make sure the patient gets through that safely, so that we don't contaminate our ability to understand any safety issues before we introduce Cemsidomide. So the trial is very well designed and it benefits from the knowledge that's been gained before us. We're super excited about it. And as I said, it's open and recruiting. But we have benefited from being second with this combination actually.

and this concludes our question-and-answer session. The conference has now concluded. Thank you for attending today's presentation. You may now disconnect.

Good morning, everyone. Welcome to Barclays 28th Annual Global Healthcare Conference. I'm Etzer Darout, Senior Biotech Analyst at Barclays. It's my pleasure to have C4 Therapeutics with us this morning to kick us off. I have Andrew Hirsch, CEO; Len Reyno, Chief Medical Officer from C4 Therapeutics. And Andrew, maybe you can just get us going with just an overview of C4 Therapeutics and then the upcoming milestones that you think are key and are worth noting to investors?

Yes, absolutely, and thanks for having us. It's great to be here. So for those of you who are not familiar with C4, C4 is a targeted protein degradation company. And we use our degradation platform with the goal of developing medicines in areas of high unmet need. We have 2 programs currently in the clinic. Our most advanced is Cemsidomide, and I'm sure we'll spend some time talking about that today. That is an IKZF1/3 degrader, that's targeting in development for multiple myeloma. Last year, we completed a Phase I study, and we've now started the next phase of development. We started a Phase II study called MOMENTUM. We started dosing patients last month, and that's underway and enrolling.

And then we expect to start in Q2, a Phase Ib study in combination with elranatamab, which is the BiTE from Pfizer, and we're excited to get that underway. And so that forms the basis of what we think is an exciting and differentiated registrational path. The other program we have in the clinic is a CFT8919 that's an EGFR L858R degrader for non-small cell lung cancer, that's in a Phase I study in China run by our partner, Betta Pharmaceuticals. And we expect to have data this month that will enable us to make a decision on the path forward for that program.

In addition, we have a robust discovery effort that combines both internal programs as well as collaboration programs. Our internal programs are really focused now on an area sort of outside oncology, we're focused on inflammation, neuroinflammation, neurodegeneration, we call out INN, and we're excited that really leverages some of the key elements of our platform as well as 10 years of learnings of degraders and what degraders can and can't do. And then in addition, we have collaboration partners. We're working with Roche, with Merck KGaA and with Biogen on developing degraders against targets of interest for them and more recently, Biogen has 2 molecules in Phase I that we've delivered as part of that collaboration.

And then we have a strong balance sheet. We ended the year with just under $300 million, which provides us runway through the end of 2028, which should get us though a number of important milestones, including an early look at data from the MOMENTUM study, which will be in the second half of 2027. And then through the Phase Ib and start-up of a potential Phase III with the BiTE combination. So lots of exciting milestones coming up is really a key year of execution as we get these studies underway and launch the cemsidomide development plan as well as pursuing our Discovery targets.

Great. Lots going on in multiple myeloma, obviously, even yesterday, we saw an update success 2 trial from Bristol-Myers Squibb. Just maybe give us some projective in terms of what cemsidomide could deliver to sort of the multiple myeloma disease armamentarium and what you believe is achievable with that molecule? And maybe highlight as well some of the data that you've generated to date there as well?

Yes. Maybe I'll start at a quick high level and Len get into some of the data. Look, I think the IKZF1/3 pathway for multiple myeloma is foundational. I think that's lost on a lot of people because these are targets that have been drugged through the IMiD class, which we've had for a long time. But if you remember, the IMiD class are not optimized degraders. In fact, when they were discovered we didn't know that they were degraders. And now that we've learned that they were degraders, we're able to develop and optimized degrader. And so we think that cemsidomide has a potential best-in-class profile based on the data that we shared last year. And that's based on the fact that we've really optimized both the catalytic activity as well as the selectivity and PK of the molecule. I think it gets lost on people that we're dosing in micrograms. People seem to forget that, which is incredible to me that we're able to do that. Len, I don't know if you want to...

Yes, I don't know if I could build on that because, obviously, people are interested in the evolution of the myeloma space and it's undergone a fundamental disruption with the advent and the penetration of immune-based strategies. But it's a really important part to map back to what Andrew just said. IKZF1/3 degradation remains a fundamental mechanism of action. And it's really important to think about what that actually means in practice. And in that regard, our first-in-human study is incredibly informative because what we show in that study where we had patients who had a median of 7 lines of prior therapy.

In fact, 75% who have been exposed either to CAR-Ts or T cell engagers or both. We showed that at our highest exposure, we still had a 53% response rate. Why does that matter? It matters because what it tells you is notwithstanding all the other things the patient has been through, there remains a foundational role for targeting these transcription factors, mapping back to IRF4. So that's sort of the top line summary of the trial, but why are we positioned for success is, I think, really important to both patients and investors.

What's unique about our data set is that we were able to show really very elegantly that at every dose level we tested with dexamethasone, we had meaningful anti-myeloma responses with a very manageable and class-leading potentially safety profile. Why maps back to what Andrew just said, we were able to optimize the PK/PD relationships. We're differentiated in the class because we have a 48-hour half-life. That 48-hour half-life with the potency, we're the most potent drug in the class, more potent preclinically than Mezigdomide is with that 48-hour half-life we're able to achieve anti-myeloma effects over a range of doses, clearly goes up as you increase exposure, but we're able to release the break in time to allow for neutrophil recovery.

And so taken together, we have a data set that I would refer to as a broad permission slip that cemsidomide can be developed in really in the future in any line of myeloma care. And our plan moving forward is a very efficient plan to address 2 parts of that spectrum with MOMENTUM, late line, fourth line plus. And with the 1B BiTE anticipating further development in the Phase III earlier lines of therapy pivoting on the move to immune-based strategy.

Right. Great. Maybe with that, talk a little bit more about MOMENTUM of the trial, maybe the trial design there. And then maybe some of the nuances to relative to the Phase I/II, right, in a highly refractory population, if you can kind of talk...

Yes. So in some respects, the MOMENTUM trial mirrors almost exactly what we did in the Phase I first-in-human study with some important changes. One is simply operationally now that's going to be a study that we conduct both in the U.S. and Western Europe. So that increases us because obviously, in the end, cemsidomide should be and will be a global asset. That will affect the population we recruit. So I told you a few minutes ago that we had 7 prior lines of therapy. The eligibility criteria is fourth line plus. What that will map because of the 2 continents is that probably in the U.S., there'll be relatively more prior lines of therapy with more patients who have actually progressed after T cell directed therapy.

And in Western Europe, we anticipate they may have had relatively fewer lines of therapy. That's an important premise because, in fact, one of the things that we don't want to do is pigeonhole that patients have to have failed everything and anything to get value. Patients don't take [ end-line ] therapy that's approved for various reasons, including access. So it will find kind of trial on the high level. But I don't anticipate at the end that the median prior lines of therapy will necessarily still be 7.

The other thing, of course, that's different is now we've really understood how to give the drug, and so we can manage the drug in terms of dosing and decision-making vis-a-vis optimizing safety and opportunity for efficacy in a programmatic way, consistent with driving the drug forward for potential accelerated approval. And that's the other difference is the trial will be conducted with what I would describe as regulatory intent. Really, the main issue is we always follow the protocol, but we will follow the protocol and in addition, have the indices of safety and efficacy reviewed by an independent committee. And that will increase the potential rigor of the data set that we anticipate will support ideally an accelerated approval discussion.

Great. I guess with that, can you talk about what you view as sort of a hurdle rate for response rate for that, again, highly refractory population? And also maybe sort of coming to sort of quorum with the FDA around what sort of that bar, if you will, could be for success?

Yes. I think the FDA is always very cautious in trying to -- and giving an arbitrary bar for what success will be, especially if you are having a discussion regarding accelerated approval. And contextually, it's always how does the data look in the context of what else is happening in the space at the time you present the data, that's it. There are some principles that I think are reliable that we can think about. And one is we know from experience, most accelerated approval drugs are going to have to have a meaningful response rate with meaningful duration and also safety that's acceptable, manifested in particular, by not having patients come off drug for safety issues.

So we've modeled the study that with 100 patients we can reliably detect a response rate of 40% or greater. And we anticipate that the duration of that response benefit will be at least 6 months, more being better. We're higher than that in our IMS presentation and that the drug will be safe. And there, again, where we're really proud of and happy about from the first-in-human study, we have almost no discontinuations of cemsidomide for any safety-related events. So that's the sort of context of the study. Historically, it's compared against what the background rate of an effect might be. And we know that no off-label use in various lines is active. But typically, we statistically modeled that, that signal wouldn't be greater than about 25%. And with 100 patients we can distinguish between those 2.

Got it. Great. And I guess with the increasing use of anti-BCMA therapy, maybe you can also speak to how important is that post-BCMA activity we're observing with cemsidomide especially put in the context where the comparator IKZF1/3 degraders really didn't have that sort of -- that hurdle that you guys have with the anti-BCMA therapy. So can you speak to that...

It's a great question and an important observation that people obviously are always making comparisons with us in terms of emerging the class of BMS is calling CELMoDs, which are essentially optimized degrader. And that's a really important distinction. CELMoDs are nothing different in terms of mechanism of action than cemsidomide. What they are, are potent optimized degraders. And the difference is that when people talk about what folks have seen with those drugs, those drugs were developed. It's not a question of they didn't offer to include those patients. Those patients didn't exist. And in fact, when I joined the company 3 years ago, I had initial conversations with some investors saying, does this MOA even matter anymore?

And what our data just resoundingly showed that it does matter, that patients who get state-of-the-art care still progress and they still show up seeking disease-modifying care. And we are the only drug in the class that is actually articulated and defined and really impressive response rate with that exposure history.

Yes, I think that patient population is growing because as the CAR-Ts and the BiTEs move into earlier lines of treatment, what happens is patients are living longer, but they're still progressing. So if you look at the CARVYKTI data, I think 2/3 of patients kind of relapse around within 5-year mark. So for 1/3 of patients, it's close to a functional cure, but there are still 2/3 of patients who now have a great treatment option that can prolong keeping their disease in check, but they will progress too. And that just expands the number of patients available in this late-line setting as we see that migration of these newer therapies to earlier more immunocompetent patients.

Great. And between now and when you sort of get to the response rate, duration of response endpoint, are there any interim updates that you could provide on that trial before we get to that? Or is it just sort of heads down, if you will, until we get to that response rate?

No. I mean, so as Len said, we're conducting it for regulatory intent. And so we're blinded to the data. That's why we have the independent safety data monitoring committee. So we're trying to be as clean as possible. We don't want to bias the outcome of the study at all. And so we're not going to see anything so we won't really be able to provide an update until, as I mentioned, really that second half of '27, where we'll be able to share an investigator-assessed response rate. The regulatory endpoint will be that centrally assessed as well as some indices of durability, and that really won't happen until about mid-28, and we'll have that data set. But the first look that we'll be able to see and potentially share would be that second half of '27.

Got it. Great. Maybe we can shift to the second-line plus setting in combination with T-cell engagers. We've obviously seen data from Bristol there, from Iberdomide as well as mezigdomide. Maybe first, just your thoughts around where cemsidomide could differentiate from those combinations and I guess, relative to what...

Yes, it's easy. It's going to differentiate by being more effective. But you really want to know is what's the evidence for that. And I think it's important to think about why you're doing the combination in the first place. So you're doing the combination in the first place because we know that BiTE-directed therapy suffers from T cell exhaustion as well as lack of optimized T cell effect that does 2 things. It contributes to relapse, but it also reduces the depth of the response.

So if you think about the data we presented in our first-in-human study, there are 2 buckets that data that are important. One, we already talked about, and that is that we have the most active compound of the class. And then the second piece that we didn't spend any time on yet is that we also know from our translational data in that study that at every dose level we study. We have a beneficial effect on the T cell population and the concomitant related effect on cytokines that are associated with immune activity. So taken together, the promise of that combination is the following: that because we have at every dose level and every dose level that we have has anti-myeloma effects as well, we're hoping that we can both augment the anti-myeloma effects, which will appear very early in the first 2 to 4 cycles of therapy, and that would manifest with hopefully, higher quality, i.e., more CRs, deeper CRs, more MRD-negative CRs.

And then at the end, that will also manifest as prolonged progression-free survival and ultimately survival. Unique differences from the data that's already been presented for us. If you look at the data that was presented at ASH for Iberdomide combination with [ ELRA ] which is our combination partner. We benefit from that data because when that trial was started, the sponsor Pfizer was still figuring out how to give a BiTE with the combination and dosing schedule, as well as how to define the safety events and the response to the safety events. We have the luxury of learning from that and actually making sure that as we incorporate our combination strategy, that we're only really focused on the dose of cemsidomide and that we have appropriate indices of both safety and efficacy. And in addition, that we have optimized the support of care because, as you know, with BiTEs, there is a very real issue. The good news is it's manageable, but it needs to be optimally managed. So we benefit from that data.

Another key difference though is when I talked about the data that we had from our first-in-human study, that signature with the immune enhancement is with dexamethasone. So if you look at the Iber data from ASH, that was not with dexamethasone. And I think partly that's simply because the data to generate that hypothesis was lacking. So that's another key difference because we know dexamethasone does has augmented anti-myeloma effect, it will also reduce the side effects, risk of CRs. It also has an augmented safety benefit in terms of supporting neutrophil counts, especially in the first 2 cycles. So there's a lot of key differences.

We're excited about the data that was presented though because the data that was presented, notwithstanding, we think it's not the optimal combo is it did show a beneficial effect on a higher response rate. It really is a very small study and really doesn't have the ability to drill down into quality of CRs, et cetera. But as an out-of-the-gate data set, really supportive of our hypothesis and the design we have. So we're super excited about it, and it really enables us, I think, to move quickly because obviously, we need to be agile, and we need to move fast to get these trials done to get the data to the environment we need to get ultimately to design a Phase III in this instance.

And I think some people sort of looked at that data and said, well, like the bar is higher for C4. But actually, to Len's point, sort of derisked our hypothesis around can these classes of drugs be combined and managed safety? And the answer was yes. And you saw the increased ORR that really put it on par with CAR-Ts. But what it didn't do is increase the sort of CR and greater rate to be able to put that. And that's really the name of the game in myeloma today. It's not necessarily ORR because we think with these new combinations and these novel immune directed agents, you can get close to 100% response rate. It's really how you drive that MRD negative depth of response, and that's the opportunity for cemsidomide, which is, again, we think best-in-class in terms of both potency and tolerability.

And so we think that the potency of cemsidomide can actually drive that CR+ rate higher and maybe we haven't seen the MRD-negative rate for that study. And I don't know if they're going to present it at some point, but -- and then hopefully have a quality MRD negativity as well. So that's really the opportunity that, that data set opened for us.

Yes. And so as you think about the Phase Ib study that you're going to be this year? Is it really more around sort of the safety of the combination? Or are you going to sort of embed the ability to look at sort of the deepening of responses, the durability within that study?

So of course, by definition, it's safety, but obviously, it's got to be efficacious. And it's not going to be statistically powered to actually have a reported reliable response rate. But we will obviously look at and share the quality of response, the depth of response. And we'll be looking at that data and making decisions vis-a-vis how to design Phase III trial. So we anticipate that the regimen will be safe because we think we have the optimized drug vis-a-vis safety. It will be clearly very active. We won't be in a position to have 100 patients at a dose of interest quickly, but we will get data as quickly as possible at relevant doses.

And in that regard, I think what's really important to note we're starting with our starting dose of 75 micrograms of cemsidomide. A great question is why? And that reflects our confidence in the safety signal. We know the drug is safe across a range of doses. If we look at the data from our first-in-human study, we have a modest side effect signal at 75 purely manageable. When we look at the effect on neutrophils as well as the supportive care that would be administered with a BiTE, we're cautiously optimistic that, that dose will be clear safety hurdle. And that will do 2 things based on the design of our trial. It will allow us to go higher. We're not -- we have to define whether 100 is the right dose when you're using a combo partner that's not just [ Dex ]. But will also allow us to expand the 75 level and if need be an interest to look at 50.

So again, our job is to obviously do right by patients and to do safe regimens. But our job is also to bring efficacy to patients as fast as possible, and then, therefore, to bring data to who we need, which is our investor audience to give confidence that our plan is working and on our time line that's efficient to get the drug to market.

Yes. Great. I think one point I think that sort of maybe missed on folks to is sort of the innovation around the 14 days on, 14 days off that you ended up implementing for that versus sort of the legacy 21/7. Is that a moat, you think, in terms of for this molecule for this program? Is this something others can try to replicate? Or do you think that it's really the quality of the molecule that allowed you to do that?

They can. For a drug with a 24-hour half-life, you can give sort of a lower thing. But the question is I think I would frame back is our 14-day on, 14-day off schedule is pharmacologically optimized for this drug. And for a drug with a 24-hour half-life that won't -- anything less than the 21/7 if you're looking for the anti-myeloma effect, it's not going to be an optimal regimen. It will likely be safe and tolerable. But if you ask a different question, would it likely optimize the anti-myeloma effect, I think the answer would be it doesn't make sense. It wouldn't based on the understanding of how the drug actually works.

Right. Great. Maybe lastly on CFT8919, just your lung cancer program. And just the opportunity there and maybe the progress that the program is making currently?

Yes. So when we set out with this program, I think that we observed that when you look at osimertinib, which is a fantastic drug. There was really a gap in efficacy from [ DL19 ] versus LR patients. And we thought making a degrader against selectively against the LR segment, was going to lead to improved outcomes for patients with that LR driver mutation. And so that was the goal of the program, and we started a Phase I study in China with our partner, Betta. So we'll have the data -- some of the data from that Phase I study this quarter. And that will enable us to look at what does that mean and then kind of plug that back into our market assumptions the same.

There's been certainly some advances in that space that has shrunken the gap between the [ osimertinib ] data and in terms of [ DL19 ] versus LR. And then we will also, as we always do, will evaluate what does the development path look like to really capture the opportunity. The bulk of the opportunity we believe is in the frontline setting, and that will go into the calculus of what does that look like? How complex is that? And is that a study for us to do assuming the data supports it? Or is that something that may be better suited for a partner. And so we'll put all that together and make a decision internally this month and we'll communicate at the right time, but we're on track with that.

Right? So we're up on our time. Andrew, Len, thank you so much for this discussion. And then we'll be back with our next session. Thank you.

Great. Thank you.

Thank you.