Mereo BioPharma Group plc Sponsored ADR Stock

All right, everybody. Let's get started. Welcome to the 44th Annual JPMorgan Healthcare Conference. My name is Priyanka Grover, and I am part of the JPMorgan Biotech team. Today, our next presenting company is Mereo and presenting on behalf of the company is CEO, Denise Scots-Knight. Denise?

Thank you, Priyanka, and thank you to JPMorgan for inviting me to speak here today and to host us. So I just want to move quickly through the disclaimer and the forward-looking statements. And on to Mereo. So Mereo is a rare disease company. And the 2 young gentlemen that you see here on the photograph are Martin and [ Frey ], and they both have osteogenesis imperfecta or OI. And Martin, who you can see smiling away, actually has Type 3 OI, and he's in wheelchair.

And they both came to talk to us about the impact of OI on their lives. They're both students at university and Martin is studying to be a medical student. So Martin, Type 3 OI, and he's been on bisphosphonate since he was 6 months old and he's had hundreds of fractures. He's now in his 20s, early 20s. And OI has had a huge impact on his disease -- on him, but as you can see, he's doing relatively well. Now we have individuals like Martin and [ Frey ] who come to talk to us about the disease and about the impact on them. And this is something that we do very regularly at Mereo. So we have 3 clinical programs, 2 of them are late stage, setrusumab for OI, we just reported out the Phase III results with our partner, Ultragenyx, and I'll be going through some much more detailed data on that program in a minute. Alvelestat for alpha-1 antitrypsin deficiency, we're focused on the lung disease. And this is now a Phase III-ready program, having agreed the endpoints with the FDA and the EMA.

And then finally, vantictumab for osteopetrosis or bone overgrowth. And this is a program that we've partnered with ashibio. We have retained EU rights, and this will be entering the clinic for a Phase II study, hopefully, Phase I/II study in the second half of this year. We have around $41 million in cash as at the end of '25, and that gives us runway into mid-2027, having revised our runway guidance. So here are the 3 programs. And what's interesting about all 3 programs is they're all large patient populations, as you can see on the slide. And they all are high unmet need. So setrusumab for osteogenesis imperfecta, our anti-sclerosing antibody, which is both the bone building as well as prevention of bone resorption antibody.

And there are no EMA or FDA-approved therapies, although, as I mentioned, bisphosphonates are used off-label. For alpha-1 antitrypsin deficiency, we have alvelestat, our oral neutrophil elastase inhibitor. And this targets the unregulated neutrophil elastase, which destroys the lung tissue in these patients. Augmentation or AAT replacement therapy is used to treat alpha-1 antitrypsin deficiency, although it hasn't really demonstrated clinical outcomes. And as a result, it's not reimbursed in many countries in Europe, and it's not reimbursed for many earlier-stage patients. And finally, osteopetrosis. So we have vantictumab, an anti-frizzled antibody. This targets the Wnt pathway. Again, a rare genetic bone disease with a relatively high prevalence and again, no FDA or EMA-approved therapies.

So I'm going to move on now to talk about the data that we just reported out with setrusumab, but also go into a lot more detail around the data. So to our surprise and disappointment, we had 2 Phase III studies, Orbit and Cosmic, and neither of them hit their primary endpoint, although Cosmic, which was versus bisphosphonates, did show a difference in terms of reduction in annualized fracture rate. Both studies, as we expected, demonstrated very robust changes in the bone mineral density, statistically significantly improving bone mineral density in both studies.

And what I'm also going to show you now is -- which is really important is that additional data analysis showed that we have a reduction in vertebral fractures. And things that are very hard to do, we have statistically significant changes in PROs, particularly focused on pain and daily activities. And we know that these are 2 particular symptoms that have a huge impact on individuals with OI. So now we're looking through the data further, doing further -- very detailed data analysis with a view to potentially going to the regulators to talk about the data package. So as I mentioned, there are 2 randomized Phase III studies. So very unusual for a rare disease like this to have 2 randomized Phase III studies.

And obviously, that's going to be helpful given potential discussions with the regulators given that we didn't hit the primary endpoint, but we'll be doing a lot of subgroup and post-hoc analyses. To have 2 studies like this is really going to help us with those. As you can see, Orbit, which was setrusumab versus placebo, 2:1 randomization, enrolled 159 subjects. And you can see here the balance between the 2 arms. Just to highlight there are more severe type 3s in the setrusumab arm than the placebo, about twice as many. And on the flip side with the type 4 patients, there are more in the placebo arm. We typically think of the Type 3 patients as the most severe patient population. In Cosmic, the 69 patients enrolled, a 1:1 randomization with setrusumab versus bisphosphonates.

And as you can see here, the arms actually are quite well balanced, although there's slightly more severe patients in the setrusumab arm. And the box -- the red box here is highlighting the fact that if you look across the 2 to 12-year-olds across both studies, we have a lot of patients in that age group to compare across both of the studies and to focus on the pediatric population aged 2 to 12. So here are the baseline characteristics from a fracture perspective. And what you can see, they look relatively balanced between the arms. A thing to hone down on is these are the fractures over 2 years prior to enrollment. They're both radiographically confirmed as well as suspected fractures. So if you divide the numbers involved by 2, that's the AFR.

So we have a mean for the Orbit study of around 1.6 and around 1 for the median and the placebo, very similar. And again, you can see that in Cosmic, these younger patients are actually higher fractures. So we have an AFR of around 2 going into the study. In the Orbit study, we actually had a rescue arm. And so because these are high fracturing patients, and it's a placebo-controlled study, we wanted after 12 months of being in the double-blind period to have a rescue arm so that if patients are having a lot of fractures, they're able to go into an open-label extension where they would receive setrusumab.

And what was very interesting about the open-label extension patients -- as we expected, most of the patients were the severe type 3 and 4 patients. However, there were half as many of those patients in that rescue arm on setrusumab versus placebo. So a kind of indication of efficacy here. As I mentioned, the BMD data were very robust. You can see that they're highly statistically significant versus placebo and statistically significant versus bisphosphonates, demonstrating that we are increasing BMD much higher than bisphosphonates, the current standard of care. And also clinically meaningful. So these are looking at the Z-score changes. And you can see versus placebo, we've got around a 1-point score increase in the Z-score. So that's really clinically meaningful.

So here are the fracture data, the primary endpoint. And on the right, you can see the event -- fracture event rate curves. And you can see that there's no separation of the setrusumab arm from the placebo. And you can see when you put all total fractures into the mix, there's no difference between -- essentially no difference between the 2 curves. So why is this? The first thing to look at is the placebo median AFR on treatment. And if you remember, I mentioned that it was around 1 in the -- at the enrollment in the baseline characteristics. And you can see here, it's actually 0. And so what this means is in that placebo arm, we had over 50% of the patients did not have a single fracture during the course of the study. And what you can also see is that the mean is 0.8.

And if you remember, I said that the mean at the baseline was 1.6. So what we're seeing here is that this placebo arm is around in the mean a 50% reduction in the AFR. And so it's very hard, obviously, to show a difference if you have that in your placebo arm. Nonetheless, the other perspective we were concerned about, we've been hearing all these anecdotes that patients are doing very well. We've heard of children on bicycles and they've never written a bicycle before. So we had a look at the PROs, and we're wondering, could that explain some of these data. And when we look at 2 different PRO instruments, so the PGIS, which is a global impression score and the POSNA-PODCI, which is actually a validated pediatric PRO instrument.

These are the data that we see in the pediatrics and the teenagers in the Phase III Orbit study. So those represent around 135 of the 159 patients. So you see a very large representative patient number from the total study. And what you can see here is we have a statistically significant impact on OI pain across both instruments, which is usually very hard to show in studies. And we also have a statistically significant impact on daily activities in the PGIS and a strong trend in the sports and activity in the POSNA-PODCI. So we're really showing what is happening with these patients. They're feeling better. They've got less pain and the overall symptoms are improving when they're treated with setrusumab.

So pain is actually the #1 symptom that is cited by OI patients in terms of the impact on their daily life. And what I've shown here is the impact survey. This was a survey that we carried out in collaboration with OIFE in Europe. We had over 2,500 responses to these questionnaires. And you can see the output here for peds and adolescents. And what you can see is pain is by far the #1 symptom. That is what impacts them. And we're clearly with setrusumab treatment having an impact on OI pain. So that [indiscernible] now move onto setrusumab -- sorry to Cosmic, so here is Cosmic, and again you can see the event right curve, the fracture of the right curve on the right hand side and what you can see here is what we expected to see, which was a separation of the setrusumab arm from bisphosphanate arm and you can see that happens relatively early around the 3 months period and you can see the clear separation. This input was not statistically significant. However, it was around a 21% difference in terms of setrusumab reducing the AFR compared to bisphosphanate.

What was actually very interesting as we start to dig into the data are the vertebral fractures. And you can see here bolded in red are the vertebral fractures. So all vertebral fractures, so both the morphometric and the clinical vertebral fractures, we see a 59% reduction in the setrusumab-treated patients compared to the bisphosphonate-treated patients. And then when we look at just the non-morphometric vertebral fractures, so the clinical vertebral fractures, we almost eliminate those in the setrusumab arm.

So we have 1 fracture on the setrusumab arm and 18 clinical vertebral fractures in the bisphosphonate arm. So we're really reducing these vertebral fractures in these patients. And vertebral fractures are the key cause of these patients having spinal deformities, being bound in a wheelchair, leading to scoliosis. And also, it's a major driver of the OI pain. So as we put together the BMD, which is measured -- increases measured at vertebra, a reduction in pain and then this substantial reduction in the vertebral fractures, you can see that this all fits together.

So the safety continues to be consistent with what we've seen in all the other studies. We now have patients who've been on study -- on drug for over 3 years and this has been a very, very consistent picture with a relatively clean safety profile. So the overall data, we're still -- obviously, there's still lots of data to analyze, but the overall data suggests that setrusumab is having an impact on these patients with OI even though we missed the primary endpoint. And so as I mentioned, we have the substantial BMD changes statistically significant, leading to reduced vertebral fractures versus the standard of care and then improved functional outcomes with decreased pain, improved functional ability. And actually, this is probably the reason that we have seen patients who were in a wheelchair and can now -- are now mobile and walking independently. And we've heard many such antidotes -- anecdotal, sorry. So what we're doing now is doing further data analysis and then looking for a potential path forward to go and talk to the regulators.

Another important thing about the study, all the patients had the option of going into an open-label extension study where they would receive setrusumab and virtually all of the patients have opted to go into that open-label extension study. So we have over 200 patients now in that study. And so the setrusumab patients opted to continue on setrusumab. The bisphosphonate patients went on to setrusumab and the same for the placebo patients. So that will also be generating some longer-term follow-up data. Moving on to alvelestat. So as I mentioned, this is Phase III ready, and we're focused on the severe patients, the PiZZ genotype. The study design is around 220 patients, 18-month study. We have 2 independent primary endpoints, SGRQ total, which is a validated PRO instrument that's used in COPD studies. And then that's with the FDA. And then with the EMA, we have lung density by CT, where they have said that a p-value of 0.1 may be acceptable to allow us to do an 18-month study rather than a 3-year study.

So with alvelestat, we're planning to enroll much earlier-stage patients that have typically been enrolled in the augmentation studies and who are also being enrolled in the editing studies as well. So a partnering process is underway for alvelestat. And to broaden the scope of that partnering process, we've also designed a Phase IIb for bronchiectasis. Alvelestat has shown reductions in exacerbations across a number of indications in Phase II studies. And so we've designed this bronchiectasis study with a target of showing a reduction in the exacerbation rate. It's a 6-month study, 2 different doses and around 250 patients.

And finally, vantictumab. So vantictumab binds to specific receptors on the surface of osteoclast and increases osteoclast activity, resulting in bone resorption. So increasing bone resorption. And this has actually been demonstrated in some oncology trials. So when the program was owned by OncoMed, they were running some oncology studies. These were Phase Ia, Phase Ib in around 100 patients. And as a side effect, what they saw is they saw evidence of increased osteoclastic activity and actually fragility fracture in some of the patients. And actually Bio has now replicated this in a mouse model of osteopetrosis. And as I mentioned, they're looking to take this into the clinic in the second half of this year. So as we look forward to milestones this year, for setrusumab, we have potential regulatory interactions once we've completed further data analysis.

We have the partnering activity on alvelestat and vantictumab going back into the clinic in the second half of this year. Thank you very much.

Thanks so much for the presentation. So what I'll do is I'll ask the first couple of questions, and then I'll ask the audience. So feel free to raise your hand when I do. So looking at the totality of data that came from Orbit and Cosmic and talking to people about the data itself, what do you believe are the most compelling, let's say, 2 or 3 data points that you would take from Orbit and Cosmic and provides you with confidence of the path forward?

Yes. I think -- so the BMD change -- the story fits together, right? So the BMD changes are highly significant. And so we've already demonstrated in Cosmic that versus the standard of care, which is being used today, we statistically significant improved BMD over the standard of care. We improved vertebral fractures. We're improving pain. We're improving independence. I think the whole storyboard fits together. And the pain, as I mentioned, is the #1 symptom.

So as you mentioned, like the bone mineral density is such -- it was an interesting data point, especially in Cosmic with the younger patient population. So how should we think for that younger patient population, the BMD increases in the context of OI?

Yes, I can take that. I'll step in here. But -- so in OI, and I think everyone or most of you are aware of this, the bone is really of poor quality. There's a collagen mutation and the bone forms poorly. So it's of poor quality. And that's really demonstrated by the fact that there's a markedly reduced bone mineral density in these patients and also the increase that we see in fractures, right? It's all a consequence of that. So in Cosmic and in Orbit, setrusumab treatment led to statistically significant increases in BMD. And that surely underlies both with respect to placebo and also bisphosphonates.

And that surely underlies the decrease in vertebral fractures that we're seeing, the increase in -- you can see something -- no, the decrease in placebo fractures, the increase in -- the decrease in pain and the increase in activity. So those are all connected.

Yes. I mean I think the thing to remember about these patients is they start with an incredibly low Z-score.

Yes.

So they can be as low. We've seen some patients who have a Z-score. And the Z-score for everybody who's not familiar with Z-score, so it measures your BMD relative to someone of an age matched -- so gender and age matched. It measures your BMD relative to that. And so we've seen patients with Z-scores as low as minus 4, minus 5. And so when you start seeing changes which are plus 1, plus 1.5 in your Z-score, that is very significant for these patients.

And just to add one thing to that, Denise, because in a lot of these patients, what we're actually doing is we're normalizing the Z-score. So we're bringing it up to those of an age and gender matched general population. So they start really low. We're bringing them up to normal. It's really pretty remarkable to think about it.

You know in osteoporosis, as I'm sure you're aware, Priyanka, they have now -- the FDA has now said that it will accept BMD as a surrogate marker for fracture in osteoporosis patients. Obviously, they have a lot of data that underlies that, but that's the approach they're taking with osteoporosis.

I think that information came out a week before the data readout.

Yes.

So it'd be very interesting to see how conversations go with the regulators. Another aspect that I found rather interesting was the pain scores for these patients that pain for them is something that they're very concerned about and aware about. But also you showed that with setrusumab, you're having a decrease in pain that is reported. Can you guys go a little bit more into that detail?

Yes. So we've used 2 different measures of patient global impression of severity score and also a pediatric outcomes data collection instrument. And basically, what we see is a statistically significant reduction in pain in both instruments. Actually, the global impression score is predictive of what would occur with the PODCI, the pediatric outcome data collection instrument. So that data was very consistent, statistically significant with respect to both of those. And the other thing to mention is the PODCI score, it really goes from 0 to 100. 100 is normal, 0 is most severe. And probably you can imagine that a lot of these patients are in the 20, 30, 40 range. And as you can see from the slide, we have a 10-point change relative to placebo, which from a clinically meaningful advantage point is pretty significant. I mean you're changing the score, you're reducing pain quite substantially in these patients.

Are there any questions from the audience?

Firstly, thank you so much for a fantastic presentation. And albeit from an AFR point of view, that endpoint wasn't met. You've just shown some fantastic slides around clinical relevance because actually, these are kids whose life and quality of life is enormously reduced. So actually, the data and this is really quite astonishing. Two sort of observations to me. The fact that you've actually managed to shift that bone minerality as well as the pain score indicates that there's much less inflammation.

And obviously, there is that bone density increase, which means that probably that AFR reduction might come later -- so it's almost you need like a follow-up 6 months down to 12 months. So that's the first part. And the second thing to say is that very often when you've got that reduction in inflammation and some mineral density, but particularly the pain going down, you get these patients who are much more mobile. And with more mobility comes greater fractures. So that sometimes gives it a noise that actually obscures the fact that you're having a highly relevant clinical outcome.

Yes. I mean the combination of the placebo effect, I mean, we don't -- we need to understand how did that happen with that placebo arm. But the combination of that -- and you're right, combined with the kids on the setrusumab arm, we know that they're feeling really, really good. We hear this all the time from the KOLs, my patient is doing really well on setrusumab and we do hear kids going on climbing frames [indiscernible] before, mountain bikes that they have not met before, so is happening in background, so that combination could have led to this outcome.

Just to add one thing maybe, because you made a comment about how AFR might come later and take longer, actually we see the changes in vertebral bone and vertebral bone is very rich in trabecular bone. Trabecular bone is porous. It has a large surface area. The osteoclast and osteoblast can attach to it and turn things over quite quickly. So the vertebral bone tends to respond quite quickly. And that was manifest in the changes we see in BMD in the lumbar spine. Whereas cortical bone, more rigid, it's really structural for the bone and it turns over much more slowly. So the comment you made about the fact that AFR may come later is actually spot on.

Right. That's for the long bones rather than the vertebral, yes.

There have been some really interesting points made, especially about the anecdotal stories of patients riding bikes or going on climbing equipment or whatnot. Are we going to have any additional data being presented later in this year? There's going to be more additional data analysis occurring possibly at a medical conference or any press releases or webcast scenario?

Yes. I mean there are plans later in the year to present more data. So one of the analyses we're interested in looking at is, is there a correlation with AFR and BMD in these OI patients as we've seen in the osteoporosis patients. So that's going to be interesting to see. But yes, there is a plan -- there will be presentations of more data later in the year.

And you had mentioned that patients have gone on to an open-label extension study. Is there a time lines regarding any additional data from that cohort of those?

So we haven't sort of decided on when those additional data might be presented. They are being collected. I mean we've already seen with some of the patients, they've gone off the bisphosphonate arm into the setrusumab arm, and we've seen a very quick uptake in their BMD increasing. So it's going to be great to see when these placebo patients crossover and they have crossed over, but it's going to be great when we're collecting the data to see the impact of that crossover, both from the bisphosphonate arm and also from the placebo arm.

Are there any final questions from the audience? Just one final question for me. How are you guys thinking -- I know you guys have talked about meeting with the regulators about setrusumab and OI. So are there any thoughts on time lines? Or are you guys going to first gather as much data as possible before going to them?

Yes. I mean -- so obviously, we're working with our partner, Ultragenyx on this, and there's a lot of data analysis to do. So that's going to take some time. I can't really comment on regulatory time lines. What I can say is if we were doing it, it would be in the second quarter. So I can answer it that way.

Got you. Thank you so much. And thank you, everyone, for coming here.

Thank you.

Thanks very much.