Biomea Fusion Inc Aktie

Good day, and thank you for standing by. Welcome to the Biomea Fusion BMF-650 (GLP-131) Phase I Top Line Results Conference Call. [Operator Instructions]. Please be advised that today's conference is being recorded. [Operator Instructions].

I would now like to hand the conference over to your speaker today, Ramses Erdtmann, Co-Founder, Chief Operating Officer and President of Biomea Fusion.

Thank you, operator, and welcome, everyone, to this conference call. Today, we will discuss top line results from the Phase Ib, a multiple ascending dose study evaluating BMF-650, our investigational oral small molecule GLP-1 receptor agonist, which we developed alongside our menin inhibitor, icovamenib.

Before we begin, I'd like to remind everyone that today's discussion contains forward-looking statements. I direct your attention to Slide 2 of our presentation and our SEC filings for a full review of the risks and uncertainties that could cause actual results to differ. The development of oral GLP-1 therapies has advanced substantially.

Across the field, multiple programs have demonstrated that all incretin therapies can deliver clinically meaningful weight loss and glycemic improvement. At the same time, the category continues to confront a practical challenge. As exposure rises to levels intended to produce meaningful efficacy, gastrointestinal tolerability frequently becomes the limiting factor.

The challenge is straightforward to describe but has been difficult to solve. For example, in a real-world 2025 study of more than 125,000 overweight or obese adults who initiated a GLP-1-based therapy, 65% of them discontinued within the first year. To date, no oral program has conclusively demonstrated that potent clinical activity can be fully separated from a meaningful cumulative gastrointestinal burden.

Across programs, the most consistent development response has been to primarily adjust and manage the exposure, which includes lower starting doses, slower escalation, additional intermediate steps and a longer time before patients reach maintenance exposure. BMF-650, however, was designed differently. It was designed with the intent to separate weight loss from GI tolerability and thereby allow patients to stay on treatment.

With that, let me turn the call over to Thorsten, our Head of Research and leader of the BMF-650 development program. He has overseen this program since inception and will review the design rationale and our early nonclinical results, which provided us a first proof for the emerging 650 profile. Thorsten?

Thank you, Ramses. I will begin with orforglipron because it provided an important scientific reference point for our work. Orforglipron established that a potent orally available non-peptide small molecule can activate the GLP-1 receptor and produce meaningful clinical activity. We admire the rigor and success of that program and the insights it delivered.

That brings me to the central objective behind BMF-650, which is captured in the title on Slide 8, the potential to separate GI side effects from weight loss in the oral GLP-1 receptor agonist space. A successful oral GLP-1 receptor agonist should capture the convenience of oral dosing, while addressing some of the limitations of the class. With BMF-650, we specifically designed the molecule for less acute GLP-1 receptor agonism in the GI tract with the goal of improving GI tolerability. If successful, that could enable fewer titration steps, ideally just one and ultimately support greater persistence with chronic therapy.

Slide 9 takes you into the molecule design behind that hypothesis. BMF-650 is a selective and biased GLP-1 receptor agonist with no off-target concerns identified in our counter-screening assays. Importantly, BMF-650 has approximately 26-fold lower agonist potency than orforglipron. This reduced potency is an intentional element of the design and part of our hypothesis for reducing acute GLP-1 receptor activation in the GI tract.

Slide 10 shows another aspect of the design, bioavailability. In nonclinical PK studies in both monkeys and rats, BMF-650 demonstrated high and prolonged exposure following oral dosing. Importantly, bioavailability was approximately two to threefold higher than orforglipron in these experiments. So conceptually, the design is quite straightforward.

Lower receptor potency, coupled with high and sustained systemic exposure. The nonclinical PK gave us confidence to take that hypothesis into humans, and you would see the human PK data in the clinical section that follows. But before entering the clinic, we wanted to know whether this profile could translate into meaningful weight loss.

We, therefore, evaluated BMF-650 in obese cynomolgus monkeys using once-daily oral dosing. As shown on Slide 11, we observed significant dose-dependent weight loss of approximately 12% and 15%. The response was consistent across animals within the different treatment groups and showed no apparent attenuation towards the end of the study. Importantly, any such emesis events were relatively limited despite dosing without titration.

On Slide 12, I bring together these nonclinical observations to highlight 3 key elements of our design. First, BMF-650 uses a relatively higher oral dose and was designed for broader intestinal absorption with the intent of reducing localized concentration peaks within the GI tract and supporting absorption across a broader intestinal surface and time window. Second, BMF-650 demonstrated high order bioavailability with low variability in our nonclinical studies. Our hypothesis was that this should translate into consistent and predictable exposure in humans. And third, BMF-650 was designed to produce a gradual increase in systemic exposure with a relatively low peak-to-trough ratio providing a more even exposure profile over the dosing interval.

Taken together, this was the design hypothesis going into the clinic. Lower acute receptor activation combined with sustained systemic exposure could potentially achieve meaningful weight loss activity while improving GI tolerability. We sometimes describe the intended distinction as a blow torch versus a radiator, concentrated intensity versus a more gradual and sustained delivery of the biological signal.

Against this background, let's now turn to the Phase I clinical data and see how BMF-650 behaved in humans. For that, I will turn the call to Dr. Juan Pablo Frias, who leads our Scientific Advisory Board supporting the BMF-650 program. Juan Pablo is a recognized clinical investigator in diabetes, obesity and metabolic disease with extensive experience evaluating incretin-based therapies. Juan Pablo, over to you.

Thank you, Thorsten. Today, I'll review the top line results of the Phase I study of BMF-650 and I will focus on 4 areas: the study design, weight reduction, safety and tolerability and pharmacokinetics. I will then briefly summarize what we believe these findings support as the program moves forward.

Let's begin with study design on Slide 14. This was a randomized, double-blind, placebo-controlled Phase I study in overweight or obese participants. The first part evaluated single ascending doses of BMF-650 primarily to assess safety, tolerability, pharmacokinetics, pharmacodynamics and the effect of food. The second part was a 28-day multiple ascending dose study. This part was primarily designed to evaluate co-primary tolerability measures, including adverse events, vital signs, EKG measures, like QTcF interval and safety labs.

The secondary endpoints included percent change in body weight at study end along with pharmacokinetic measures. We initially included 4 active dose cohorts and corresponding placebo participants. The dose regimens increased across the cohorts. The first 4 cohorts evaluated different weekly dose escalation schedules.

Now let's turn to the baseline characteristics on Slide 15. Overall, demographics and baseline characteristics were reasonably balanced between BMF-650 and pooled placebo groups. Participants had a mean BMI of approximately 34 in the active group and approximately 36 in the pooled placebo group. Mean baseline body weight was approximately 100 kilograms in the active group and 110 kilograms in the pooled placebo group. Each cohort included 8 active and 2 placebo participants for a total of 32 active participants treated with BMF-650 and 8 pooled placebo participants in the first 4 cohorts.

Turning to the clinical activity findings on Slide 16. This analysis examines the incremental weight change during each weekly dosing interval of cohorts 1 through 4. Here, we observed reductions across all 4 BMF-650 treatment cohorts through day 29 compared with essentially no change in pooled placebo; mean reductions range from 1.5% to 3.2%, with cohort 3 achieving the greatest mean reduction of 3.2% in this key secondary end point. While these are short duration Phase I data from small cohorts, the consistent direction of weight reduction across the active cohorts provides encouraging early evidence of clinical activity for BMF-650.

On the next slide, you can see that across these first 4 cohorts, 14 of the 16 weekly dosing observations showed additional weekly weight reduction and the magnitude of the weekly weight reduction generally increased at higher administered doses. Across these cohorts, the mean weekly weight reduction at doses of 200 milligrams once daily or higher, was approximately 1 kilogram per week. In cohort 4, we observed an increase in weight during the first week, which was unexpected. Closer inspection of the pharmacokinetic data raised concerns that some participants may not have taken the study drug consistently.

We, therefore, introduced cohort 5 under confinement to ensure dosing compliance. We also evaluated a simpler titration schedule in this additional cohort starting at 200 milligrams once daily and increasing after 1 week to 400 milligrams once daily for the remaining 3 weeks. At that point, we had observed only limited safety findings and importantly, no clear increase in gastrointestinal adverse events in the earlier cohort.

Turning now to the results of this additional cohort 5 on Slide 20. We can see that the confinement allowed close assessment of safety and tolerability, but it also appears to have influenced eating behavior. All participants were provided 2,100 calories per day. The 2 placebo participants consumed approximately 33% of the presented food and may have been sensitive to the food choices. They experienced weight reduction similar to the active participants, which complicates the interpretation of weight loss under confinement.

cohort 5 participants receiving BMF-650 lost an average of approximately 1.55 kilograms per week for a total weight reduction of 6.2 kilograms or 6.1% after 4 weeks with no observed attenuation over the treatment period. Because cohort 5 was small and the 2 placebo participants consumed less food than active participants, the results of this cohort should be interpreted cautiously.

We, therefore, view cohort 5 as an exploratory analysis and consider it together with the dose response pattern across the complete data set, the pharmacokinetic findings and the observed tolerability profile. Taken together, these findings support potential meaningful pharmacologic activity.

Turning to safety and tolerability on Slide 21. Overall, BMF-650 was generally well tolerated across the 5 active dose cohorts. All treatment-emergent adverse events were mild or moderate. No severe or serious treatment-emergent adverse events were reported. There were no dose modifications and no study discontinuations related to treatment-emergent adverse events. We also did not observe a clear association between treatment-emergent adverse events and dose escalation, dosing cohort or time at a given dose.

On the next slide, we show selected gastrointestinal adverse events. Across the 40 participants treated with BMF-650 in the MAD cohort, nausea was reported in 7 participants, constipation in 4, vomiting in 3 and diarrhea and 2. In the highest dose cohort, the selected gastrointestinal events were all observed to be grade 1 in severity. Only 1 of 8 participants in cohort 5 reported nausea and 1 reported a single vomiting event. There were no reports of diarrhea in this cohort. Two participants reported constipation.

Slide 23 provides post-hoc descriptive context relative to selected Phase I disclosures of other oral GLP-1 receptor agonists that have progressed to late-stage development. At the highest BMF-650 dose regimen, the observed incidences were 12.5% for nausea, 12.5% for vomiting, 0 for diarrhea and 25% for constipation. No head-to-head studies were conducted, and these cross-trial comparisons should be viewed cautiously. The studies differed in size, duration, dose escalation schedules and adverse event collection and reporting. Nevertheless, we believe the observed gastrointestinal profile of BMF-650 supports further evaluation at the 400-milligram dose.

Slide 24 shows selected changes in liver enzymes, fasting glucose and heart rate. Mean ALT and AST values decreased from baseline in both the active and placebo groups and no adverse events involving ALT or AST elevations were reported. Fasting glucose decreased across all BMF-650 dose cohorts with a mean reduction of 9.2 milligrams per deciliter in the pooled active group compared with 3.5 milligrams per deciliter in pooled placebo. Mean heart rate increased by 6.4 beats per minute in pooled active group compared with 0.8 beats per minute in pooled placebo. No adverse events involving heart rate were reported.

Turning to pharmacokinetics on Slide 25, which were key secondary measures, BMF-650 achieved the target exposure predicted from the nonclinical studies. In cohort 5 on day 28, the mean exposure over 24 hours was approximately 79,000 hour nanograms per milliliter. The observed peak-to-trough ratio was approximately 1.7, indicating relatively limited fluctuation in exposure over the 24-hour dosing interval.

The observed human exposure was also consistent with the efficacious exposure observed in the relevant nonclinical weight-loss study. The pharmacokinetic analysis remains preliminary, but these results support once-daily administration and confirm the clinically relevant exposure was achieved.

Turning to Slide 26. In summary, BMF-650 was designed to separate weight reduction from GI safety risks. Across the 5 active cohorts, we observed that with increasing dose and exposure, participants achieved greater weight reduction while maintaining a very well-tolerated profile with comparatively low GI effects.

Bringing these findings together, the Phase I results support the original BMF-650 design hypothesis in 3 important respects. First, participants reached the target dose of 400 milligrams once daily through a single titration step after week 1, supporting a potentially simple and practical dosing paradigm.

Second, cohort 5 demonstrates sustained and meaningful weekly weight reduction of 400 milligrams across 3 consecutive weeks, reaching mean weight reduction at day 29 with no evidence of attenuation over the observed treatment period.

And third, the GI tolerability profile was very encouraging across the active multiple ascending dose cohorts: there were no serious treatment-emergent adverse events, no treatment-emergent adverse events leading to dose modification and no treatment-emergent adverse events leading to study discontinuation. Biomea plans now to continue with longer-term toxicology studies to support Phase II clinical evaluation and advance the Phase II planning, including the assessment of whether participants can initiate treatment directly at the highest dose without titration at all.

With that, I will turn the call over to Mick, the company's interim CEO.

Thank you, Juan. I am very pleased with the results BMF-650 demonstrated in this first clinical trial. In the highest dose cohort presented today, we observed meaningful weight reduction together with an emerging safety and tolerability profile that we believe supports the design objectives we established for BMF-650. Our goal was to create an oral GLP-1 receptor agonist while modifying its properties to improve tolerability and support sustained use over time.

When we look at BMF-650 in the context of the Phase I results reported for other advanced oral GLP-1 receptor agonists, we believe the combination of clinical activity and tolerability data we observed is encouraging. Importantly, we are not looking at the clinical activity or tolerability data in isolation. We believe the opportunity is to deliver both profiles and ultimately to provide a treatment experience that can support long-term use.

Based on the results presented today, our intention is to continue advancing BMF-650 towards Phase II development. The next steps include completing the additional nonclinical work required to support longer duration dosing, manufacturing clinical supply and preparing the program for the next stage of clinical development.

At the same time, I want to be clear about how we think about capital allocation. We intend to invest in BMF-650 through the stages where we believe we can further establish its clinical profile and maximize the strategic value of the program. We do not currently envisage Biomea independently funding a large global clinical obesity program.

Our objective is to advance the BMF-650 and position the program for a strategic partnership, which could include a licensing arrangement for late-stage development and commercialization. We believe this strategy allows us to continue building the value of BMF-650 while remaining disciplined in how we deploy Biomea's capital. At the same time, icovamenib remains at the core of Biomea and represents a major potential value driver for the company.

Our focus now is on validating the highly encouraging clinical signals we have observed to date and advancing the program through a series of important milestones over the next 18 months. Over the next 2 quarters, we plan to initiate 2 Phase II studies in type 1 diabetes. Here, we are expecting to get a first set of 6 months response data from 36 type 1 patients within the next 18 months. Then in the first half of next year, we expect 2 additional important Phase II readouts.

The 26-week primary endpoint for icovamenib in insulin-deficient patients, as well as the primary endpoint from our study in patients with inadequate glycemic control on GLP-1 therapy. And towards the end of next year, we also expect results from our study evaluating icovamenib in combination with semaglutide, where we are investigating the potential for additional weight loss together with preservation of muscle, bone and physical health.

Taken together, these milestones are designed to help us organize end of Phase II meetings with the FDA for type 2 as well as type 1 diabetes and move icovamenib to late-stage development.

We thank you for your continued support and appreciate your interest in the work we are doing at Biomea. Operator, we are now ready to take questions.

[Operator Instructions]. And our first question comes from Jon Wolleben with Citizens.

Congrats on the day. Wondering if you could talk a little bit about the timing to complete a tox study. And then it sounded like you guys would be open to running a Phase II program. Wondering how you think about some initial thoughts given the freshness of this data?

And then maybe a question for Dr. Frias. Wondering how you think about or differentiation and how many oral drugs the field may need and what actually constitutes a clear differentiation between these molecules?

Jon, it's Mick. In terms of the Phase II, I think given where we came out on the Phase I, we want to do another dose in the Phase I, possibly 400 directly and figure out what was going on in the short term with that. That would lead us then to potentially a Phase II design where we would have no uptitration. We just started the dose that we were going to use and see how well that works over time.

I'll pass the other question over to Juan.

Yes. So I think -- I mean, the answer is quite similar to what you said. I think the differentiators would be, one, the tolerability if this pans out as we look further in the clinical development program. But then also either having a very short escalation, basically one dose step or if the tolerability is there to be able to initiate and just have one dose. So I think that would be a fairly important differentiating feature. So I think there certainly is room for a drug that has those characteristics.

What's the minimal amount of weight loss you want to see for a drug to be worthwhile to use?

I think probably somewhere in the range of 10%. I think would be -- it could even be a little lower than that. But I think 10% is still, on average, very good weight loss for a lot of patients. I would also say that the patients who would benefit from less weight gain, particularly if we're trying to prevent obesity-related complications and other cardiovascular risk factors. But I think somewhere in the range of 10% as a minimal.

Maybe, Jon, I just want to add one more comment because I found it so profound when I looked at the data that in the highest dose when we went into the -- where we put the patients up in confinements and we added the highest dose with one-step titration, the safety profile was upheld. And if you look at the safety profile and the tolerability that the drug has shown, it's so comparatively superior in my mind, and this is a personal view.

But I was amazed that if you just do 1 step titration going from 200 to 400, you're not incurring more safety issues. One, it stays fairly benign in comparison to all the other players in the field. So if you were to ask me what is the key differentiator between us potentially as we validate our signals in further studies and others, it could be that the safety is the key point of differentiation. One, we can go faster there. And two, we're just unusually safe based on the design.

And we spent quite a few slides on explaining the design and Thorsten's section goes into the reason for why we designed the drug we did. But I would argue that is for me the key differentiator, trying to give somebody weight loss without all the GI tolerability issues they have to go through. Anyway, next answer -- next question. Operator would you mind?

And our next question comes from Joe Pantginis with H.C. Wainwright.

Very nice start to the data. So I have a couple of broader questions looking forward here. First, can you give sort of the profile you would be looking at with regard to a BD partner and that also links to the profile of the drug you might want to see in the future. Obviously, as Ramses, you just said, a better safety profile, but would you look at maintenance therapy, frontline therapy? What kind of options would you potentially see for this drug? And so that's number one.

And then number two, what would you consider to be -- and you touched upon this a bit during your presentation, the open questions with regard to finalizing the dose and the quicker titration.

Yes. Thanks, Joe. So if you look at the field, and that was sort of in my section, persistence is the problem, meaning we have a great backbone here as in the GLP-1 strategy on how to address obesity, yes. So we understand that part, but we haven't fully figured out as a field on how to really do it in a way that we can get patients to stay on drug. And that's why we quoted that recent survey from 2025 in our slide deck. So if 125,000 users, 65% are not staying on drug after -- within the first year, something is wrong.

And the way we designed the drug, and that was evident already 5 years ago, the way we designed this compound was to achieve persistence. And that's where I think a partner would find potential entry into the space. If you look at everybody was going for maximum weight loss, and that's great. And now who's staying on drug and who can achieve persistence with patients potentially wins in the long run.

Our goal was not to achieve maximum weight loss. Our goal was to achieve a good weight loss over time. You can step into this compound from another drug. You can -- you don't have to up titrate, you can easily just switch if you're unhappy with what you're currently on. Those kind of aspects, I think, could potentially add value. And so a BD partner would be somebody who has a failed program, it could be somebody who has a program but hasn't gotten this aspect in his own drug or it could be somebody who hasn't entered the space and wants to come in the space was something new.

We're looking at all 3 of these categories. We're pursuing each one of them. And as a small biotech company that is surviving on good data and also nondilutive funding from pharma. That's where we are seeing opportunities, particularly with 650.

Now you asked another question on finding a dose. And Mick alluded to that, we think another cohort 6 in a nonconfined setting, so in an open setting where people have these choices for eating as much as they want to would hopefully -- not hopefully, we think actually that would be a great setting for us to show the key difference between placebo versus us. We already know the safety because in confinement for sure, the physician sits right next to the patient and picks up on every AE profile you may imagine.

So safety-wise, we feel really certain that this is what it is. Efficacy-wise, yes, the placebo were a little bit behaving quite abnormally. And that can happen if you have a small n, and it did happen to us here. So what we're thinking of doing is initiating another cohort 6 potentially with a partner where we would go in, add another, whatever, 10, 15, 20 patients with a larger placebo setting, not in a confinement situation and run that cohort. That would more or less clarify the signals we have seen and allow somebody else very likely to take this drug into Phase II.

I appreciate that, Ramses. And if I could just set a quick 1 in there. Have any discussions started yet? Or are these data the impetus to go ahead?

So I can't really comment too much on it, but you can imagine that we don't want to wait for pharma to approach us. We're doing everything we can with what we have to engage conversations like every company should do in our situation. So you can assume we've done the same.

Our next question comes from Cha Cha Yang with Jefferies.

I was just wondering if you can speak a little bit to the dose response that we see or specifically about cohort 3 performing better than cohort 4? Do you think it's mostly a small end issue? Or what other things are we thinking about here?

Cha Cha, this is Mick. I think the thing that's important to see, and I mean, this is the reason we've broken it out is the dose response is pretty good if you get rid of that first point in cohort 4. So we think something went wrong there, which is basically changing the starting point for the rest of the line to go down.

And I think, again, it is small numbers. There's only 8 in each active cohort. And so that probably has something to do with it as well. But I really think it's the fact that it went up on the first dose -- sorry, on the first week, and that sort of changed the starting point for the line to come down.

Yes, anything else to add, Thorsten?

When you look at the cohort from compliance. Yes. So it is true the cohort 4 generated the most question marks towards compliance because the PK, as we've shown, is very reliant when you can measure it for participants. So the -- essentially, the T0 value on certain days is a good indicator of drug compliance on the day before. And so some of the analysis we did in cohort 4 points towards there may have been a problem along those lines. The patients didn't take the drug because they didn't have sufficient exposure, right? And you would have expected more exposure.

And that kind of led us to the conclusion to get into cohort 5 because some patients haven't taken the drug. It would be false to conclude that cohort 4 is reality, right? And so that's why we said, okay, let's do cohort 5. cohort 5, if you put them next to each other, is obviously under confinement; when everybody takes the drug, it is a beautiful response line. But we think a cohort 6 would -- in a nonconfined setting will probably help clarify that.

Our next question comes from Yigal Nochomovitz with Citigroup.

So I had a few here. The first one is when you look at the NHP data, which showed the 15% reduction at a month, can you just explain a little bit more what the -- how the exposure on the AUC and the Cmax compared in those -- in those control -- in those animals versus cohort 5 in the confinement experiment? Were those similar? Or was the exposure higher in the monkeys?

And then can you just explain a little bit more on the confinement? These patients were essentially in confinement 24/7 for the entire month? Or was it just at certain points during the day when they were eating or taking the drug?

I'll start with the answer. So with respect to the exposure in the monkey study, the 400-milligram titration target dose, either cohort 4 or cohort 5, they align very well. Actually, the exposure that you see is the area under the curve on day 28 and cohort 5 is essentially what the high-dose cohort of the monkeys had as a daily exposure. And then it's approximately two to threefold less in the monkey for the low-dose cohort, which aligns approximately between 200 and 300 milligrams titration target of cohort 2 and cohort 3. So everything kind of came out nicely.

And personally, I'm actually a fan of cohort 3. The weight loss placebo-adjusted, resembles almost orforglipron actually. So that's that. And then addressing your question about the confinement. So cohort 5 was a complete confinement study for 30 days actually in the unit. So participants didn't leave the unit. Everybody had their room and it was kind of staying there, sleeping there, taking their meals under supervision, getting the protocol assessment and dosing under supervision for the [ entire ] time.

Okay. So do you have a hypothesis as to why in the animals, you saw mid-teens percent versus what looks like about -- I guess, 6% in the cohort -- in the cohort 5? Is that -- how do you reconcile those?

Yes. So thank you for the question. So for us, as a medicinal chemist, I always am faced with translating animal data to human data and every animal almost has a conversion factor for PK parameters. I apply these for almost everything else. So for monkey, generally, that's 3. So if you divide what you see in the monkey by 3, you actually almost really get to the human numbers. So I would think a monkey with high metabolic rate and the smaller species altogether, more heart rate, everything just comes together to just adjusting it downward by approximately this factor. So I'm actually not surprised. In fact, that's what I would have expected.

Our next question comes from Michael King with Rodman & Renshaw.

A couple of follow-ups. Just to focus on -- like if you look at cohorts 4 -- cohort 5, I'm sorry, and compare the placebo-adjusted weight loss, you're same in the almost identical ballpark as Carmot did some time back with CT-996. So this does look like an active drug. I'm just wondering if there was any explanation from the site about why these individuals kind of starved themselves. And were any other -- were food logs kept for patients in any of the other cohorts 1 through 4 to see if eating behavior was modified or how much it was modified?

Yes. So maybe the truly easy question first. So the -- for cohort 1 to 4, it was an outpatient setting, so there are no food logs available for those patients. But for cohort 5, every meal has been traced against presented how much was consumed. So we have this for every patient for every meal in cohort 5. Obviously, we looked at the placebo patients who behave this way. So one of them truly is 50% less than the next nearest consumer. This was apparently a very committed person who had weight loss very much high on their personal agenda and did it from day 1 to the very end. So this person very much.

What does the 50% mean?

They've got much more power than I have.

So they consumed 33% of the 2,100 calories that we presented, and they presented versus those that were on active drug 60% of what they ate, meaning they ate less than the ones that were on active.

Yes.

That is they are doing...

And Ram just now went more for the average of the 2 versus I had peered out the one particularly noticeable.

Yes. So it's -- that's the tough part, Mike, if you have only 2, right? If one is a dedicated and what you asked for a response from the investigator, we interrogated them and they said, yes, that's kind of what happened. And they may have been sensitive to the meal that we presented and said I don't want to eat it or they may have just wanted to lose weight. But they use this opportunity to achieve both.

You think that the site would encourage them to -- everybody eat everything right? Eat up because if you're on....

They did it with all of them. And they didn't know who was on drug from placebo. So they try to encourage everybody to eat.

But I think I would like to take an optimistic perspective and compare it to the pooled placebo.

of course, it's a little unfair. That's why we put the press release out the way we did.

Yes, I understand. The other question I have -- well, a couple of questions. Number one is we're talking about safety and dose response. It seems like another thought is instead of just titrating directly to 400, why not go to, say, 600 to see if you can get even greater weight loss given the tolerability, it seems like you've got a lot of room to play with on the tolerability side that you might even go higher than 400. What are your thoughts?

So Mike, the reality is, obviously, we could do that if we wanted to see more weight loss. However, the real objective here is to think about what we want to do for the longer term. And having a greater weight loss in a short period of time isn't necessarily the goal of the program overall. So I think we've already seen an amount which you wouldn't want to take forward into, for example, a 6-month study because they'd be losing already, what, 36% of their weight in 6 months.

I think that will be pretty much over the top. So I don't really see the value in going forward with a weight loss program that sort of tries to force fit a higher amount of weight loss than we've already seen.

Okay. Fair point. And then just finally, I just would like to get your thoughts on -- well, there's 2 things. On the -- the cardiovascular effect on Slide 24, there is a fairly high -- if you're, let's say, baseline of 72 beats per minute normally and cohort 3 goes up to 82. Is there any concern about that? And is that -- was that measured over time? Is that at the end of study? And was there any -- I assume there was no tachycardia or shortness of breath that's associated with these increases in heart rate.

So the quick answer is none of the observations were called adverse events by the PI. So no. Everything was fine.

This is Juan. I would add that, I mean, this is in line with what's seen with the class. So I wouldn't be concerned. Generally, over the longer term, the heart rate will start coming down...

Will return to normal.

Several months. So I mean, this is very short term. And again, no AEs from it. And actually, I don't think there was anyone symptomatic from it, you wouldn't expect it. So I think class effect, and I wouldn't be concerned about this at all.

Okay. And then finally, just on Slide 25, where you show the PK curves. I just want to tie this back to the discussion that the others have had with you guys about persistence, which I think is the right way to look at it. Is there an ideal goal of the nanogram per ml levels that you'd like to maintain in a maintenance setting to get that balance of continued efficacy as well as persistent weight loss?

So based on everything that we've learned about the compound so far to this 4-week dose, this would be at the moment, the approximate exposure that we're shooting for. I would give it a twofold arrow on maybe on the lower end. But yes, this is approximately where we want to be even in the long run.

Our next question comes from Kumar Raja with Brookline Capital Markets.

With regard to the GI adverse events, at what time points are you seeing that? And what data do you have in terms of gastric emptying delay?

Sorry, I didn't understand your first question, but...

Time points when these GI events occurred.

So there is no correlation to any event during the study, meaning it's not day 1 first dose or the uptitration dose. They occur essentially spread out over the study for -- among the group. So no pattern emerged from this.

Also interestingly, in cohort 5, they were all mild, right? All -- the GI tract. I should have started maybe...

And we did not perform any gastric emptying studies. So we didn't do any [indiscernible] that's sometimes used as a probe. So we didn't do anything of this. We anticipate the gastric emptying is also slowed by this compound very much with the class, but we have not investigated this in the course of the study.

[Operator Instructions] Our next question comes from Anupam Rama with JPMorgan.

Just a quick clarification question. In the press release, it notes that the long-term toxicology studies need to be done before the next study. Can you outline what exactly needs to be done from that perspective?

So we had the correct tox study to run this clinical study. The next tox program would generally be of 23 -- of 13 weeks duration. That would be the subchronic tox program, which is the one we would initiate to be able to run a 13-week weight loss study than in the clinic.

It's in 2 animals, right?

In 2 animals species, yes. So one is rat and the other one will be the cynomolgus monkey, as we have done for this enablement as well.

That's all, Anupam. That's -- and then we would be able to go into a Phase II once we have that data in hand.

I would now like to turn the call back over to Mick Hitchcock for any closing remarks.

I think what we've presented to you today gives you a clear picture of the information that we have generated from the GLP-131 trial. We're very pleased with the outcome. We're excited about the possibility of the drug moving further along. And as we said earlier, it's something we would like to do with a partner because we are very focused on icovamenib program for diabetes type 1 and type 2. So thank you very much for your attention today, and we'll close the call. Thank you.

Thank you. This concludes the conference. Thank you for your participation. You may now disconnect.

All right. Good afternoon, everybody. Thank you for joining us this afternoon for what I believe will be an informative and lively discussion with our guest KOL, Dr. Alex Abitbol. We're going to cover a number of topics in the diabetes space concerning both type 1 and type 2 and with a particular emphasis on icovamenib from Biomea Fusion. We also find our call to be particularly timely as we are exactly 1 month today from the start of the ADA conference, which takes place this year in New Orleans.

Before I ask Dr. Abitbol to introduce himself, we want to point out that we have a research coverage of Biomea. We rate the shares a buy, and I hold an $8 price target. Neither I, nor members of my household own shares in the stock. The firm does not own greater than 1% of the stock. The firm has not received investment banking compensation in the past 12 months, but it may seek compensation in the next 3 months.

Finally, if you have questions for Dr. Abitbol that you would like me to anonymously ask on your behalf, please shoot me an e-mail at [email protected], and I would be happy to put that in front of our guests. So with that out of the way, Dr. Abitbol, can you would like you to introduce yourself and tell us a little bit about yourself, where do you practice, what kind of patients you see? And then tell us about any conflicts or disclosures that you want to mention.

Certainly. Thank you for having me, everybody. I'm Alex Abitbol. I'm an endocrinologist and Assistant Medical Director at LMC Healthcare, which is the largest single specialty group of endocrinologists that practice together across 11 sites, mostly in Ontario, Canada, centered mostly around the Greater Toronto area as well as a site in Calgary, Alberta that we have as well.

As part of my role, I see patients with general endocrine disorders, of which about 50%, 60% are affected with diabetes. And within that breakdown, about 80% or so, 80%, 85% have type 2 diabetes, and then about 10% to 15% are affected with type 1 diabetes. I'm also an investigator for centricity research. And so my relationship with Biomea is that I met them initially as we were being considered as an early phase site for their Phase I single ascending and multiple ascending dose trials. And then we were also selected for some of their early phase type 2 diabetes and type 1 diabetes trials after they had initially started in the States and then we got started in Canada.

My interest certainly have anything to do with wide-ranging clinical implications for patients. And I have received investigator fees as part of the clinical trials that we supported Biomea. I'm also an adviser and consultant for Biomea as well as all of the major pharmaceutical companies that have anything to do with GLP-1s, SGLT2 inhibitors, DPP4s and lipid-lowering medications that we use in type 2 diabetes and cardiovascular disease.

Great. Well, thank you for that thorough overview. To set the stage, LMC -- you gave us a bit of a tease there, but your role at Centricity Research, what is your typical patient flow look like on a day-to-day basis between type 1, type 2 and then those that are participating in clinical studies?

Yes. So it depends on which day of the week. But if I'm booked for clinic, then usually my patients are booked at intervals that anywhere between 10 and 15 minutes. I work with the physician's assistant. So I'll probably see between about 30 and 35 patients per day, mostly follow-ups, but between 5 and 8 new patients that are referred to me. The breakdown, as mentioned, is the majority, I would say, 50%, 60% are affected with diabetes. The other remaining have general endocrine disorders, like thyroid and lipid and pituitary adrenal disease. And then in that diabetes cohort, it's about 80%, 85%.

The flow-through is most of them are referred by their family physician. In general endocrine care, it's pretty rare to see people who are only on metformin or on no therapy because they're often managed by their family physician. And when they're referred, it's either because we're in an urban region where there are good access to specialists and they want access to dietitian support. They want access to injectable medicines like GLP-1s earlier on in the disease course. And so fundamentally, they refer them earlier, or in some of our more remote locations or suburban communities like Oakville and Brampton, the family doctor is traditionally managing them until they're out of options and referring them either for an insulin start or when the management becomes too complex because of comorbidities like kidney disease, and they don't know how to adjust the medicines anymore.

And what proportion of patients are new to treatment versus follow-up?

I'd say about 10% to 15% are newly diagnosed with diabetes. 50%, 60% are probably on more complex insulin management or either on or recently started on GLP-1s. And then the remaining might come from referrals outside of GPs, like internists, cardiologists or nephrologists, with either a specific question or a diabetes patient who's also managing for something else, like a lipid disorder or a kidney disorder or happens to have a general endocrine disorder that also needs to be managed.

Does that flow changed at all in the era of GLP-1s at all? Or is it -- has it really not bent the curve at all?

Yes, I would say it has. When I started practice, we would say that when specialists start prescribing a new agent, it takes on average between 5 and 7 years before family doctors will jump on board, and you'll see them start referring to this to specialists, and they'll actually start prescribing it for themselves and feeling more comfortable. And then you see sort of the uptick in primary care matching the initial uptake that you see in early adopting specialty care.

But I would say now it's faster. And people are asking their doctors for the therapy that they see advertised on the Internet or that their friends are on or that they see Oprah taking. And so fundamentally, they're asking. And so the GPs are having to be a bit more receptive to newer agents and newer technology a bit faster than before. But it's still messaging to specialists and then messaging to primary care, depending on obviously how it's doing in specialty care.

Got it. Okay. I do want to start diving into the mechanism of action of icovamenib, but I also want to explore this discussion about the patient population because they're obviously not all monolithic, and I'd like our listeners to better understand the potential commercial opportunity for icovamenib. I think it's a given that a large preponderance of type 1s would be eligible for treatment with icova. But clearly, there's a large population of the type 2 diabetics that could also benefit.

So my question is 2 parts. First is, what is -- I think we -- I didn't ask you specifically, but what proportion of your type 2 diabetic patients are already on a GLP-1 and failing to get benefit? And what proportion of type 2s are on insulin? And even further to that, what proportion are of this brittle form or this SIDD form?

Yes. Good question. So I would say that for the proportion that are on GLP-1s in specialty practice, you're always going to see higher proportions. So we sit around 35% to 40%. And it's a lot higher where we reside in Ontario because of better public access to GLP-1s for those over the age of 65. When you look at primary care rates or sort of the overarching rates just amongst all people affected with type 2 diabetes, we're somewhere between 15% and 20% for those affected with diabetes. Across the lifespan, somebody with diabetes will need insulin 50% of the time. In specialty practice, we see about 50% to 60% that are treated with insulin currently. And of that, about 20% are treated -- or sorry, of that 60%, 20% is treated with multiple daily injections. The other 40-or-so percent is on basal insulin only.

In primary care, it's always going to be less. They see a diabetes patient every 40th or 50th patient. I see every second, every -- or 2 out of 3 patients with diabetes. So in my practice, I'm always going to see more insulin. In primary care, they're seeing those patients, but they're either not really managing the diabetes because they're followed by a specialist or they're seeing a much lower proportion, usually 10% to 20% that are treated with insulin.

Right. And are they coming to you -- or type 2s coming to you on GLP-1s and not getting an adequate response? Or do you not see that patient in your clinic?

It varies extensively, but I would say that when I -- when semaglutide launched and maybe in the 5 years that followed, the majority was being started in my office. And people were being referred for GLP-1s. The same as before GLP-1s, they were being referred for insulin. Now we're still getting the same, if not more patients, referred for insulin, but more are coming to us already on GLP-1s, looking for the next GLP-1, looking for what to do when they failed GLP-1 therapy and either need more weight loss or more glycemic control to a much greater degree.

I'd say it's probably about 50-50 only because in my Toronto office, we get referred them earlier on. So there, I'm probably seeing about 30% referred to me on GLP-1s. In Oakville, where I practice, they have a very savvy GP population. They're about 60%, maybe 65% are coming to me on GLP-1s.

Why would it be higher if the GPs are savvier?

Because they have to manage the diabetes for longer. They're coming metformin than an SGLT2 than another agent and they're out of option, I'm going to refer. I'm an executive health physician and I'm newly diagnosed with diabetes, I want to see a specialist right away. And I have access to one because I'm in Toronto. So different.

And what type of failure -- not necessarily failure rate, but relapse rate or inadequate response rate are you seeing in that population? Do you have any sense of that?

It depends what you mean.

Well, I mean the patients that are type 2 diabetic, that have been on a GLP-1 for 6 months, 12 months. Now the slope of their weight loss is either plateauing or coming back or because of tolerability challenges, they are -- they've gone off and now have to have some other alternative.

And we'll talk about this when we get into the mechanism of icovamenib. Fundamentally, diabetes is a progressive condition. So if you manage a patient for long enough, whether they are being treated with 1 agent or 2 agent or 3 agents, they will eventually need another agent because none of the agents we utilize right now outside of those that cause profound weight loss and can mitigate to a certain extent the course of the disease, there is the unfortunate consequence that eventually, you're going to need another agent, or you're going to want more weight loss after achieving good glycemic control.

Got it. Okay. All right. Since you brought it up, let's switch to the mechanism of action of icovamenib. I did cover this in detail, and this is for our listeners. I covered in detail several weeks ago with a call I did with the company in late April, but I think it bears repeating that icovamenib operates by a mechanism that is unique in the diabetes space and derived from human biology. Dr. A, I like the way you described it during our prep call yesterday in the expert in the space. And we'd like to understand how you view the science and what may -- what you found captivating or compelling about it?

Yes. So I think that for me, what captivated me is that whenever you get an underlying disease process that leads you to have something that intervenes with the pathway of the disease, then you're able to consider it at any point in the spectrum of diabetes. And that means not just when someone is diagnosed, but somebody who might have prediabetes, somebody who might have risk factors for diabetes, somebody who might have more advanced disease and is looking to lessen their burden of medicines. But the real fundamental key with this is that most people who are diagnosed with diabetes are under the impression that their disease just started at that very moment.

The way it works is your pancreas is usually making a lot more insulin for many years without you being aware, and you only become aware when you've reached that maximal capacity. And why it's progressive is because you're not at your maximal insulin production forever. Eventually, you come down. And when you go on to metformin or other agents, all you're doing is lessening the glucose, either by telling the liver to make less, to let the kidneys pee more out, to make more insulin in response to meals with older and newer agents. But the beta cells and the loss that happens over time in both function and number is what eventually leads people to say, "I'm doing the same thing. I'm taking the same medicine. Why does my sugar get higher and higher? And why is it that I need another agent?" What's heterogenous here is that everybody may respond to medicines differently, may have different durability of these medicines, and they may be heavier, leaner. They might have more family members affected.

And so when we get at something that can actually prevent the next medicine, something that may lead to essentially what protected you from high glucose for many years before you're getting at the disease is what excited me in the type 2 space. And as we get to it in the type 1 space, well, that's where I'm even more excited as a clinician. We've had nothing new in type 1 in over 100 years. It's just been insulin. But to make insulin in someone who no longer makes insulin for someone who's type 1 begets millions of questions as a clinician because there's an immune-mediated process by which they destroy it. But we're talking about groundbreaking research there if you can give somebody who has not made insulin for many years and all of a sudden allow their beta cells to not only come back, but to be regenerative and allow hopeful an insulin reduction or a reduced rate of complications.

Yes. It definitely is fascinating stuff. So I want to just talk about the sort of the initial observation by Karnik in 2007 in his paper at Stanford. It's rooted in the observation that menin is naturally suppressed during pregnancy and lactation -- expressed in pregnancy and lactation and it enables the beta cell to expand and increase insulin output. As a clinician, how intuitive is that biologic rationale? And do you think the field is ready to embrace a short course of therapy that aims to restore the underlying cellular machinery rather than simply managing glucose on a day-to-day basis?

So the way I understand it is that menin is essentially one of those ubiquitous processes that's involved in essentially putting the brakes on cell growth and proliferation. And so by inhibiting it, as we see through a prolactin-mediated process in pregnancy, you see obviously that the cellular expansion and growth can allow it to restore or even enhance what you're seeing in the case of a pregnant female pre-pregnancy levels and hopefully in somebody with diabetes to the state by which they had before they ran into the problems of high blood sugar and needing more medicines. And that's why ultimately, when you were looking at a ubiquitously present process that was involved in cell growth, that's why I think the oncologists had it for longer than we did because it was a unique target to consider an acute myeloid leukemia for ultimately inhibiting the cellular growth process that leads to cancer formation.

So if you were to -- let's say, a icovamenib is approved and it's whatever, 2029, 2030, when you explain it to a patient, they progress to either type 1 or type 2, you find them to be a suitable candidate. Do you think this is a -- the narrative of what icovamenib does is easily understood by the patient and would be embraced by the patient?

So the narrative today, based on the trials they've done so far, could look like -- and you mentioned the SIDD patients because I'm sorry, I didn't cover that before. But amongst the ADA framework, they define different patient subtypes. But I can't say that when I'm sitting in my office, I'm actually thinking of these patient subtypes, especially not if I'm not thinking in the paradigm of this is somebody who might have insulin deficiency, I should start them on insulin. I'm not really thinking of other subtypes.

But the narrative today could look like you're on three or three agents, you're needing a fourth agent or if you don't do well on that, you might even need insulin to protect yourself against kidney disease or eye disease or heart disease. But instead of me giving you a medication that you're going to have to take for the rest of your life, I'm going to give it to you for between 12 and 24 weeks. We're going to allow the subcellular process by allowing your pancreas to regenerate and make more beta cells. And then you'll be able to stop that therapy and have durable improvement in glucose where maybe we prevent the need for more agents, reduce your risk of complications and in the best case, can even reduce your background medicines. In the case of the studies they haven't done, then someone on insulin could be put on this therapy and then ultimately remove the need for their background insulin.

Or at least reduce the dose, correct?

Yes, or reduce the dose or reduce the fast-acting doses and maintain them with just a lot of people who go on semaglutide or someone with prediabetes who's being told about lifestyle factors and weight management and all of that very, very important. But instead of inevitably staring down the problem of eventually developing diabetes, taking a short course of treatment and thus preventing many more years before they develop the disease.

And the other study that they haven't done is the before metformin study. So when you reached a threshold, I've tried my hardest for 3 to 6 months, I've done everything I can. I've told my family doctor to just give me another chance 3 or 4 times, and I'm still in a range where he's recommending therapy, then okay, I'm not on lifelong therapy. I'm on a 3-month or 6-month course of therapy and then I stop and then I don't need to worry about taking long-term medicine and have similar control to those who take regular medicine.

Right, right. Well, yes, it will be very interesting to see how long that effect does last, and we'll come back to that in a minute. I'm just -- yes, for sure. So I was just -- I'm just curious, were you familiar with this work by Karnik before? Because it seems like such a fundamental, and for me anyway, who loves drug targets that arise out of human, either human genetics or human physiology, it seems so physiologic. I'm surprised that it didn't sort of open the floodgates to more work on it, but I don't know if you can comment on that. I was a bit surprised that there weren't a whole host of papers following that.

It was -- so I'll say 2 things. It was a new mechanism for me. And if I'm giving my opinion, as I mentioned yesterday, I don't think it's the only mechanism that protects against the insulin resistance that happens through placental-mediated processes when you're pregnant. I think it's one of the few different protective mechanisms. And I was shared this mechanism by Biomea in full disclosure, and I sit on a few of the advisory panels where some of these experts did speak to the mechanism, and it was not only palatable to me, but through global experts in the field.

But I will say that general endocrinologists also treat high prolactin in a pathologic process. They're usually from pituitary tumors or background medicines that have the side effect of raising prolactin. And I am not familiar with any protection that, that has ever been demonstrated in people affected with insulin resistance prediabetes or diabetes where they naturally see improvements like pregnant women do through an only prolactin-mediated process. So I think it's one of the explanations and maybe the uncoupling of menin as the partial response for Y beta cells. But I think there's other things going on as well that are also preventing hyperglycemia pregnancy.

Okay. Well, it's good to know. There may be further work to be done there. What -- one thing I do think is interesting, and again, as a clinician, what that means to you is that this is -- the menin regulation is context dependent, it's glucose dependent. So how does that give you comfort as far as treating your patients with a menin inhibitor?

Well, I think my main concern is menin is also known as ME1, which is a gene that's coded in humans that when it's mutated, can actually lead to tumor genesis that affects pituitary, pancreatic and other neuroendocrine tissues in the body. And so my worry was that by inhibiting it the way that they're doing it, that you may see neuroendocrine tumor growth. Now fortunately, they did a robust job of tracking every possible subcellular signal, and we didn't see anything remote to that. But it was also explained to me better thereafter that it's very different when you're inhibiting it thereafter in the context of hyperglycemia in a pathologic state than when you're born with this genetic mutation and, of course, never had the ability to encode any of the protecting factors that prevent that from happening, which is why when they did in leukemia, they also didn't see any new tumors forming or inhibiting the cancer. That also provided me with a lot of reassurance.

Okay. And then the glucose dependency, is that protective against hypoglycemia or...

So that's the distinct advantage of when you're using endogenous factors, you're not going to have a high risk of hypoglycemia. We didn't see much hypoglycemia, although the full disclosure is that they excluded people who were on background agents that could cause that or insulin. So we weren't going to see a lot of hypoglycemia. But certainly, we didn't expect that a beta cell response that heightens the amount of insulin led to low blood sugar. That only happens with sulfonylureas and background insulin because there's no way to turn that off endogenously when it's happening.

Right, right. Okay. One more mechanistic question, and then we'll move on. I often get asked about what -- to what do we attribute the durability of the effect. So if you take a GLP-1 and take it away, you'll regain your weight. You take most medications, your heart, your blood pressure, your cholesterol, you take the medicine away, and you return to your baseline. We don't see that yet with icovamenib. You would think that the beta cells could proliferate, get healthier, but do you think once the medication is taken away, they would probably regress. Any thoughts on what changes? Is it creating some kind of effect internally? Or what do you think may be responsible for the durability?

The mechanism of action and the fact that all of the other agents you mentioned, CPP4s, MET, SGLT, they're all reliant on their half-life. Once the medicine is gone, the effect on whatever tissue it's operating on to reduce glucose, nothing to do with beta cells or insulin resistance, but just to reduce glucose, is lost because about 1.5 days after not taking an SGLT2 inhibitor, glucose will stop being urinated out. You don't take your metformin for about 18 hours or so, and you're going to see more production of glucose from the liver in a disordered process that it's not happening. But none of that is, in essence, intended on allowing the pancreas to regrow or expand the beta cell mass. And then by withdrawing the therapy, you accept that, okay, this is now my regenerated and regrown...

This is my new...

Which is functioning at a higher level than before. I'll withdraw the therapy. I know I will probably lose these beta cells again in the future as I don't know how long that will be, but the same process is still going on in the background. It's just giving me more time and more beta cells to thus prevent the need for more medicines. And fundamentally, diabetes is a high glucose factored over time. So the higher your glucose and for longer, the more you'll damage eye, blood vessels, kidney blood vessels, heart blood vessels. So any means that reduces that and ideally by preventing the need for more medicines and insulin and thus reducing the rate of hypoglycemia is going to put that patient in a better situation.

Okay. Wonderful. I want to -- I'm going to kind of work in reverse order here because the most recent data was in type 1. But in terms of your type 1 patients, what remains the hardest problem to solve? Even those that are on the best-in-class glucose monitoring, automated insulin delivery, what other challenges do you face with them?

Yes. So that's a good question. I mean I live in a very spoiled closed-loop system world with a lot of technology, but these are all just insulin delivery mechanisms that are algorithmically adjusted. And still, there are obviously operator dependence, wear dependence, skin issues, hypoglycemia that even in the most savvy of closed-loop system remains an important complication. And even the best closed-loop systems, you still have to announce meals, you still have to count carbs, you still have to warn the pumps before you're exercising. So we're certainly not in a perfect setting of managing type 1 diabetes. We're just in a much better setting than when people were using injections and obviously, the older injections and the animal injections from 50 years ago way worse than before.

But type 1s today are surrounded by technology, but they still fundamentally only have insulin to utilize. And many of them now are plagued with similar weight issues that are, of course, affecting the general population. Insulin is a growth factor. So the more they use for their condition, the more resistance they may ultimately develop from it, and then there's weight issues. So absolutely, if we can get at a process here as well that reduces or limits the amount of insulin they'll need, which, of course, doesn't change as much as in the lifespan of somebody with type 2, then you may fundamentally move beyond the technology that we're providing them.

Right. Now are you seeing -- speaking of that the weight gain and the growth factor aspect of insulin, are you starting to see these type 1.5 patients?

Yes, yes. Yes, it's always been the case. People are becoming resistant to the exogenous insulin. And there are great papers by Shaw, by others in the field that have demonstrated that. Even in people on closed-loop systems that have type 1 and high BMI, they do better when you also add in GLP-1s, weight-wise and glucose-control wise. So there's certainly something to be said about weight management, even in those that need it for type 1, and the insulin requirements they have often exceed the pump reservoirs that we have today. So it's even more complicated in managing some of these type 1s with insulin resistance.

Yes, yes. Interesting. Very interesting. All right. So let's -- as I said, we're going to run in reverse chronology here. Just interpreting the COVALENT-112 type 1 data that the company put out, it's a 52-week data from COVALENT-112 that came out last week, showing a 52% increase in mean C-peptide at week 12. In the patients that are on 200 milligrams, you saw a 7% decline from the peak to week 52 following that 12-week course. So what's your clinical reaction? We had sort of 2 arms, groups of patients in that study? What were your reactions to the data that you saw there?

My reaction was generally positive. I'm missing a little bit of data to really kind of uniform it in my brain, that we're seeing endogenous C-peptide production in type 1s who've been inside of 15 years since their diagnosis. So obviously, you're super excited. You try to put it next to the early [ teplizumab ] data and some of the other ones that we're not looking at Stage 3 type 1 but Stage 2 and before type 1 and really trying to wrap your head around a lot of what this means. I would have liked to have seen sort of the PK/PD with the response to C-peptide since as we discussed yesterday, some of the nonresponders here, I'm curious why we didn't see always a response. And yes, type 1 diabetes is also a very heterogeneous condition, but still fundamentally did it match with the exposure that they got to the dose? Was it something else that might explain it? And 52 weeks, I think, is a long time frame to obviously have given the dose for as long as they did and then see a decline thereafter. But we're dealing with an autoimmune form of diabetes.

So great that we've demonstrated that it works and that we can make more C-peptide. What this means clinically is still an important piece because we didn't look at insulin doses and certainly complications long term is the most important thing to be looked at for a type 1 because even if they don't come off of insulin, more C-peptide is also tied to less complications for that person for many, many years to come has been demonstrated by all of the big type 1 registries.

Yes. Now how do you -- not to interject, but how do you look at that C-peptide and an improvement in the AUC over that period of time versus the relative or absolute reductions in A1c? Are they equally as important? Or if you had to choose one versus the other, would you choose a C-peptide or would you choose the A1c reduction?

I would choose the C-peptide. Yes. Because in the long term, the A1c with a type 1 has so much to do with how they titrate insulin and how good they are and obviously adjusting, but the C-peptide is the biggest predictor of complications. It means that even if you manage somebody with type 1 perfectly, if their C-peptide is 0, that person is still, at some point, maybe 40 years, 50 years, going to see complications at a higher rate than someone who might have similar control and it's still making some C-peptide.

I analogize it for my patients like a parachute. If you don't have anything left in the pancreas, then when you're not calculating perfectly when you're seeing hyperglycemia, there will be no response whatsoever from your pancreas. But if you're making a bit of C-peptide like we see in our honeymooning type 1s who are newly diagnosed and new to insulin and they still have a lot of endogenous pancreatic production before they really run out of it completely, they're a lot easier to manage. Their insulin doses are a lot more liberal, and that's what we hope to see with this as well.

Right. And now that you mentioned the honeymoon period, I would ask you to comment about -- you said -- you may have mentioned that the patients had been less than 15 years with -- from diagnosis. But also, these were all Stage 3 type 1. So how does that impact your perspective on the data versus the patients that might be earlier or still in the honeymoon period?

So the honeymoon period is still Stage 3 because you're usually honeymooning when you have high glucose, but you still have detectable C-peptide. We usually find other antibodies or they're very young, and so it's clearly not type 2 diabetes. It's a juvenile form. But the idea is that in this stage, you are clearly antibody positive, clearly having hyperglycemia may have presented in DKA, but your doses are not quite at 0.3 to 0.5 unit per kilos yet. You're usually well below that because there's still some endogenous production. But within a year, 2 years, 5 years in the best case, that person usually becomes C-peptide negative or near undetectable, and then you see their doses move up to the conventional.

When we talk about earlier stages of type 1, this is when they have antibodies and have no discernible hyperglycemia. And even if we challenge them with the juices that we give in pregnancy, they still are normal, but they have positive antibodies, which means we have to watch out that they might develop it. And in Stage 2, they have positive antibodies and they are beginning to have hyperglycemia, they either only have it on challenge like the juice we give in pregnancy or they're in like the prediabetes or at-risk zone, where they're not quite meeting the definition for type 2 diabetes, but we have antibody positivity and they are close to it. It's very difficult to find those people.

So I'm very excited about something for Stage 3 type 1 because that's what I see. That's what we detect. That's when the patient usually becomes aware of the disease. The type 1 detection programs that are going on are fantastic, and they're a little further along in the U.S. than we have in Canada. But success is not a lot of patients. The number of people that have been infused is a few hundred. And that's because to find somebody with earlier stage than Stage 3 type 1 diabetes, we're really nowhere near there clinically. And outside of research registries, even there, it's rather slow in my opinion.

Right. And when you say infused, you mean with teplizumab or...

Teplizumab, that's right.

Yes. Okay. You did touch upon this, but I want to come back to it and ask you, again, we're very close to ADA. Biomea's data will be presented on the 5th. The things that you'll be looking for or asking about are what...

Yes. So this is an early phase trial. So like I get excited by glimpses of data that show me C-peptide and hopefully improvements in A1c and robustness of rates of hypoglycemia and insulin doses as all of their endpoints kind of outline. But early phase trial, I need to see the treatment-emergent adverse events. I want to look at liver, I want to look at kidney. I want to make sure there are no surprises with any of these neuroendocrine hormones that I mentioned. And that's because I'm actually worried about the mechanism actually leading to it, but with a novel molecule in a new space amongst endocrinologists that have never heard about it before, you're going to run into skepticism. And so you really have seen data early on to get anywhere outside of the effect that largely we're excited for in later Phase II and early Phase III data.

Right, right. Okay. Well, maybe we'll book an appointment with you to come back after ADA and let us know how the audience reacted. Going forward, company outlined a very interesting trial in the T1D population where they're going to give an upfront placebo-controlled regimen for 6 months with icovamenib monotherapy versus placebo and then rerandomized either off therapy, continue with icova, immunosuppressant baricitinib or -- sorry, yes, and then the JAK inhibitor alone. Comments about the study design, does it make sense? Do you worry about combining with a JAK, which tends to have their own idiosyncratic side effects?

I'm not an expert with immunosuppressant. I've been involved in a handful of the interferon-based ones with GLP-1s in my early days as a sub-investigator with older mentors, but I find it interesting. It's a 4-arm comparison. So they're going to need a lot of patients to get enough statistical power to show differences in those groups. So the methodology of the trial is very challenging and a huge undertaking because I worry they'll see small differences after they cross over the groups, but it's what we want to see. We want to see if the drug beats out placebo and then thereafter, how long it persists for with or without immunosuppressant. So kudos, if they can pull that off because that's the trial everybody will want to read.

Right. Are they -- I mean, obviously, you could do lots of different -- you could do a study like this with teplizumab. You could do it with -- well, SAB-142 is investigative. But one could think about other -- and the insulin -- sorry, insulin, the IL-2 agonist from Nektar. I mean there are lots of different immune suppressants immune modulators that you can think of. Would you want to start to see further development there as well?

I review that data, and I really thank you for sharing it with me. But I really think the distinct difference here is that they are different populations of patients. If I'm thinking about infusing somebody with teplizumab, if I'm thinking about using Nektar's molecule, this is in Stage 2 type 1 diabetes. So this is to prevent the development of type 1 diabetes as a onetime treatment that I can never do again allegedly. And then that will buy me between 4 and 6 years before I'll go on to develop the disease.

When I'm treating Stage 3 type 1 diabetes, and I am either using a short-term treatment to lessen the burden of insulin, hopefully reduce doses and come off, but that's very presumptive at that point. But also, I know that if I use this medicine for long enough, continuously, I have no idea yet that by making sure that I have more C-peptide than I started with, I can bank on having less complications long term. And all the better if it's a short course or a continuous course that's paired with an immunosuppressant that works because that's the worry of endose. You can make -- you can show me that I can make C-peptide in type 1. But if my immune system is just going to come back and wipe it out really, then that is unfortunately not as advantageous as it will be in a type 2 patient.

Yes, yes, for sure. Okay. Great. Well, let's transition then to the type 2 population. 1 in 3 patients in the U.S. will eventually progress to insulin use. Is that consistent with what you're seeing in your clinic?

The rates are higher as far as I know, the type 2 diabetes lifetime risk, although they're a bit outdated in an emerging world of these potent GLP-1s, where you're not going to insulin next, you're going to GLP-1s. But 2018 data would have said about 45% to 50% eventually need insulin for type 2 diabetes. And that can be for different reasons, right? We always think of the person who's maxed out, on 4 agents with a GLP-1 and needs insulin. There's also very lean people who don't go to a GLP-1, they go to insulin first. There's a lot of younger people, like those pregnant, they go to insulin first because none of these other agents are approved. And then your comorbid patients with more advanced kidney or liver issues, some of these agents weren't studied there. So there they often get more insulin too.

Right. Okay. And I think we touched upon this a little bit earlier, but I want to come back to the population that's been on a GLP-1, not getting any further benefit or still on the drug coming back? How much of that are you seeing now? And to that population, what do you have to offer them?

It's a great question. So yes, we see a lot of that now. I mean, even in my own practice, like when we look at the registry of GLP-1 users, there are still about 30%, 40% that are either treated with insulin or got started on insulin after they were treated with the GLP-1. In my own practice, we know that a lot of the people that would have been either treated with GLP-1 early on still will be started on an SGLT2 inhibitor, see problems of glucose control. It's not always as quick as it used to be. But when we have a registry that follows these people because these are our patients for many years, but the 2- to 3-year rates are very different than when you were looking at the 1- to 2-year rates that were looked at in the clinical trials and treatment failure, if you follow somebody for long enough, is inevitable.

So what do we do? Well, the GLP-1s now have higher doses, so we consider them. For many of them, there is poor access to things like Mounjaro or Tirzepatide. So we would love to transition even though there isn't a lot of data for switching. But many of them eventually get started on basal insulin and progress from there in order to manage their glucose control. It's just that it depends on your frame of reference. It's that we're starting them maybe 2, 3 years after a GLP-1, whereas it was maybe 6 months to a year after DPP-4 because the durability is way better, but it's not permanent. It's when you look at a patient statically in a clinical trial and you say, wow, 79% of people on Mounjaro reached a target of A1c, that's robust data. It should not be discounted. But 2, 3 years later, that percentage will have whittled down, and you're going to need to be doing something with that patient after.

Right. All right. And do you -- I mean, do you routinely look at -- does anybody look at in any systematic way about C-peptide in the type 2 patient populations that require insulin? And what does that look like?

It won't work well either because the different calculators like HOMA-V, HOMA-IR are fraught with discrepancy based on the glycemic control and body weight tends to make it very discrepant. But you can't look at a C-peptide as a static measure in type 2. It's really just to answer a clinical question. It's, okay, wait a second. This person is referred to me for type 2 diabetes, but they're lean, and they're telling me they've lost a lot of weight, and they're being managed with therapy that doesn't look like it's actually made an improvement. Let me take a second here and make sure this person is actually type 2 diabetes and not type 1 diabetes. And so that's how we diagnose autoimmune forms or type 1 forms in the adult population where they're often mistakenly think -- thought of as people with type 2 diabetes.

But if I were to track somebody's C-peptide, well, it might look at first in type 2 diabetes like they're actually making more C-peptide, or their glucose control might improve. And so it might look like they're making less C-peptide. But really, it's just that they don't need to make as much because their glycemic control is better. So that's why we can't look at it as a measure over time.

Got it. Got it. One of the things that intrigues me, and it's clearly a leading question, but it's been shown that menin inhibition increases the number of GLP-1 receptors in pancreatic beta cell that makes for a very intriguing experiment, I guess or hypothesis generation about wouldn't it be great to -- in a type 2 diabetic who was on GLP-1, to put them on a menin inhibitor in order to get more out of the GLP-1 as well as to stave off them going to insulin for as long as possible. I mean is that a reasonable future scenario?

You hit the nail right on the head there, Michael. To be honest, that is I mean, I'm a clinician, so I can't put on my marketing hat or my financial forecasting hat like probably the people on this call, but we're about to enter a world of generic semaglutide. And so that looks very different than a world where you're paying a lot more for Ozempic or Wegovy because you're right, not only if I'm failing therapy, would I be more reluctant to go to the more expensive branded product? And of course, I never want to go on insulin. So if my only option to pay a lot for a branded product or to go on to basal insulin, then to enhance the effect of my background medicine or to augment it if I was initiating that over the more potent branded products, is a very strong message for clinicians because it's not changing therapy. It's enhancing therapy in the short term and then seeing obviously the effect that you might see with GLP-1s.

And so in a generic semaglutide world, it's truly what a lot of the competitors would fear, to essentially even augment the penetration of generic semaglutide, which we're seeing in Canada start this summer, and you'll be seeing in the United States probably in the early part of next year. So that's a very, very important message because it doesn't augment too much today if you're paying the same for different products, but it does if there is a price advantage for augmenting your generic medicine.

Right, right. Yes. And I would -- I think we've seen sort of the prototypical type 2 patient who is going on insulin is probably -- is usually overweight, obese and you're giving them the insulin so they don't get the complications, but at the same time, you're pushing the rock up the hill in the wrong way because you're trying to -- you're losing control of their weight. So it might be...

And ultimately, the same thing that happens with the progressive disease of diabetes, well, weight management often follows the same course. You even see it in a lot of the weight loss trials that go to 78 weeks, because inevitably, even on the most potent therapy, people plateau, and weight regain is seen in a high percentage of people that ultimately even are very successful at approaching 20% and 25% body weight. And that's because of biology. That's left-mediated and appetite regulation centers that have no idea that you're trying to lose weight, and it thinks you're starving in the forest, and it's trying to keep you alive.

So you touched on diabetes, but as I always say, diabetes and GLP-1s, that's old news it's obesity and GLP-1s that now 1 in every 8 person, I think, in the latest survey in the U.S. mentioned that they are either on or considering being on a GLP-1 for weight management. So if you can enhance even though that's not really what they're putting forth in clinical trials yet. But if you can show that you enhance GLP-1s in diabetes, why couldn't you do that same thing for weight management shortly thereafter?

Right, right. Okay. COVALENT-111, this was a study of type 2 patients. We saw A1c reductions between 1.2 and 1.5 percentage points, C-peptide 24% to 35% at the end of 52 weeks. Is that a meaningful outcome? Obviously, smaller studies, but we have to replicate that in Phase III. Is that a meaningful outcome?

Same story for that one. It's early phase, TAEs looked clean to me. There were no grade 3s. I really love seeing that data. I was happy to be a part of that clinical trial. 1% to 1.5% A1c, if replicated in a Phase II or Phase III trial would be on par with some of the GLP-1-based medicines. Now we're seeing obviously dual and triple agonists now pushed to a mean reduction of 2%. So this would be a little bit more with the early GLP-1s that we see but clinically meaningful. We approve agents that have a 0.4% A1c reduction, hugely clinically meaningful. And again, differentiator is short term versus continuous treatment. That you really can't put these agents together when one is being given continuously and one is being given spurts in treatment, and then we're monitoring for this A1c reduction off treatment.

Right, right. One of the things that I found a bit curious on COVALENT-111 was that the -- I could actually even share my screen on this. But I found that there was a lot of noise in the system, as you can see here. I mean, obviously, major reductions in A1c and with the Arm B is the continuous for 26 weeks. But bouncing -- these A1c numbers bounce around a lot. And I know they're relatively small, but not so small numbers, and A1c is measured over 90 days. So any thoughts about what's going on here?

Same thing. Yes. It's an early phase study where you're seeing the improvements not matched to the exposure. So did Arm A, Arm B, Arm C, did they see the same exposure to the medicine as tracked by their PK and PD or because Arm C had a higher dose, but they took it on an empty stomach, they actually didn't see as much exposure as Arm C that had a lower dose, but took it with food and therefore, saw a greater response. So I don't know. I don't love noise, and I agree with you. That would be an eyebrow raise for me, too. But I need to see that next to the area under the curve for the PK/PD. Otherwise, you see negligible A1c reduction that have high exposure, then I'm a skeptic. If they see no exposure, then it's formulation. You got to go back to figuring out how to get that drug into the bloodstream so it can augment the effect.

Yes. I'm not sure that's a concern at this point, but it's a good point. Okay. Just real quick, I guess, looking forward that the readouts, I think we've covered this pretty thoroughly. Let me ask a different question because I think we've touched upon this already. When you think about type 1 versus type 2, the drug is clearly exerting a strong clinical effect in both type 1 and type 2, although the etiology of the underlying condition is different. I mean they're losing pancreatic beta cells in type 2, but it's not an autoimmune reaction. So does that -- I guess it doesn't surprise you that it works in both patient populations.

Yes, it does, but it's because of how it works. So the same way SGLT2 inhibitors, we studied them in type 1 because you can pee out sugar and still see improvements in how high your sugar goes after meals even if you're not making any insulin from your pancreas, the problem was ultimately the risks of you glycemic DKA, which we didn't really consider at the time in type 1 and why the FDA and only a handful of European countries ended up actually approving it outside of North America. So if the mechanism makes sense, then the only thing that's common between type 1 and type 2 diabetes is that they both share high glucose. But when you have no beta cells and an autoimmune component, then regenerating beta cells is likely to be favorable, but how much you can regenerate and at what point you can still regenerate it with type 1 diabetes and how long it is the most important question.

In type 2, the effect is less important. As long as you can do something and it's of a reasonable clinically meaningful improvement in A1c or allows you to buy time until your next agent, then a short-term treatment is welcome in the field of any chronic disease because it's unlike anything that you see in diabetes, cholesterol and hypertension management. You're on those medicines, you're on them forever because it's not really being about on those medicines, it's about preventing heart disease, preventing stroke, preventing blood clots, preventing microvascular complications. So you accept that if I have this disease, I'm going to manage it by staying on this medicine to improve my numbers on my lab, but also to prevent the diseases that follow.

But people don't want to be on medicine forever. That's why they don't go see their doctor. That's why we give them prescriptions, and 40% of them don't make it [indiscernible]. And then 50% get stopped within the first year. So that's the huge potential of a short-term treatment that affects the underlying disease process and not Dr. DeFronzo's ominous octet that tells you the 8 different ways we have high glucose and tries to give therapy to match those different processes, but none of them regenerate beta cells.

Very good point. All right. I did have a question. It does not concern menin, but it is in the type 1 space, and that is, there has been some recent concern about teplizumab T Shield safety. And I don't know if you could comment on that in the Stage 2 population.

Specifically, like just the concerns like [indiscernible] with some emergency?

No, no, with the side effects. It was just -- there was -- they got a CRL from the FDA before they got their approval for prophylaxis. But I don't remember. [ Sima ], do you...

I remember seeing things related to immune side effects. I remember that the initial paper, which was New England Journal had an appendix that was not immediately available for some of the lymphopenia, cytokine syndromes and some of the infections that everybody was wondering. Now I don't remember hearing much of that after like 2021, 2022 and having spoken to physicians in the states that have much more experience with teplizumab than I do, because I think we're at like 5 or 6 people infused in all of Canada, is that a lot of that has been very well tolerated and had to do [indiscernible] that weren't given and now better of premedication...

I see. And I know there's concern about serum sickness and the like of that. But sure. You're saying it is...

it's mediated disease.

Right.

Like others.

Like if you premedicate and do what you're supposed to do, it should be well tolerated?

From what I hear, having never prescribed it myself, yes. And for my colleagues in Toronto who prescribe it within the University of Toronto system, the couple have done very well, and there was no immune-mediated reactions. But that's the prevailing thing that you're getting a daily infusion for, I think it's like a week or a week.

Yes, for 8 hours a day, something like that.

So you're vigilant for that 5 days for the same thing you would get with a blood transfusion or a platelet transfusion, like any serum reaction you might see.

Exactly. I did get a question through the chat. It says, in your opinion, what would it take for icovamenib to stand out in a space crowded by GLP-1s?

Well, firstly, if they can show in that trial that they enhance the effect of GLP-1, then their entry is for those failing GLP-1s. I think the key is going to be when you're managing a patient that has -- okay, so we didn't touch on this, but their most robust effect in type 2 was in a SIDD patient. So if you can demonstrate in either an insulin using type 2 that you can still replicate that improvement in beta cells or in a lean type 2 that we wouldn't really consider for GLP-1s, then you'll have certainly differentiated yourself as a new molecule with consideration.

But being short term before GLP-1, long term or short term after a GLP-1 or ultimately, when they're either failing a GLP-1 or considering insulin, I'm okay with the entry at any point there because I don't necessarily have to consider it before my GLP-1. In fact, the way the landscape is moving is we're going to start to get referred people with type 2 diabetes that have probably been on GLP-1s for weight management and are now dealing with high glucose and need something else. So I think that the order of entry is an important question, especially for market penetration, but clinically before or after is very suitable for this agent.

Right. And I would think that the population large enough to...

Absolutely.

It'll come out in the wash. Okay. Well, we're just at time. So I'm going to wrap it up here and thank everybody for participating. And obviously, we want to thank Dr. A for his participation and his candor. We look forward to seeing you down at ADA, and we can catch up again after.

Looking forward to it. I hope it's been helpful, and I appreciate you mentioning the candor. I speak from the heart here as an investigator and obviously, as a clinician, excited about new molecules and patient care.

Sounds great. All right. Thanks again. All right. Bye-bye, everybody. Enjoy the rest of your day. Take care.

Good day, and thank you for standing by. Welcome to the Biomea Fusion conference call. [Operator Instructions] Please be advised that today's conference is being recorded.

I would now like to hand the conference over to your speaker today, Ramses Erdtmann. Please go ahead, sir.

Thank you, operator, and welcome to this conference call. Today, we will be discussing top line results from the COVALENT-112 clinical trial to assess the safety and tolerability profile of icovamenib, along with exploratory efficacy endpoints in people with type 1 diabetes.

Before we begin, let me remind you that today's presentation contains forward-looking statements about the business prospects of Biomea. These statements are subject to a number of risks and uncertainty that could cause our actual results to differ materially from those expressed or implied in this presentation, depending on the progress of Biomea's preclinical and clinical development activities, actions of regulatory authorities, availability of capital, future actions in the pharmaceutical market and developments by competitors and those factors detailed in Biomea's filings with the SEC, including its most recent 10-K and subsequent filings. All forward-looking statements made during this presentation are based on the beliefs of Biomea as of this date only, and future events or simply, the passage of time may cause these beliefs to change. Please be aware that you should not place undue reliance on the forward-looking statements made today.

With that, I'll turn the call over to Mick Hitchcock, our CEO, who will kick off the call with some opening remarks.

Thank you, Ramses, and thank you, everyone, for joining us today. This morning, we are pleased to share top line results from our COVALENT-112 study evaluating icovamenib in people with type 1 diabetes. These data represent an important milestone for Biomea as we continue to expand our menin inhibitor platform into metabolic diseases.

Type 1 diabetes remains an area of profound unmet need. While advances in insulin delivery and glucose monitoring have improved daily disease management, there are still no approved therapies in clinical Stage 3 disease that address the progressive loss of endogenous insulin production. Our goal with icovamenib is to explore a fundamentally different approach, one that targets beta cell biology itself.

Today's presentation will walk through the biological rationale underlying menin inhibition in diabetes, the clinical design of COVALENT-112 and the top line results we are reporting. Importantly, these findings are early and exploratory, but we believe they provide encouraging biological signals that warrant continued and more rigorous evaluation.

With that context, I'll now turn the call over to Dr. Juan Pablo Frias, Chair of our Scientific Advisory Board, who will place these results in the broader disease and clinical landscape and review the data in detail.

Thank you, Mick. Let me start with the disease context shown in Slide 4. Type 1 diabetes represents a large and growing global health burden, with approximately 9.5 million people living with the disease worldwide and more than 0.5 million new diagnoses each year. In the United States alone, approximately 1.8 million people live with type 1 diabetes, with around 64,000 new diagnoses annually.

Biologically, type 1 diabetes is driven by autoimmune destruction of insulin-producing pancreatic beta cells. Once patients reach symptomatic Stage 3 disease, beta cell function declines rapidly. In fact, natural history data suggests that C-peptide declines by almost 50% per year in the early years following diagnosis. Importantly, beyond exogenous insulin replacement, there are currently no approved therapies in Stage 3 type 1 diabetes that address the progressive loss of endogenous insulin production or restore beta cell function.

Turning to Slide 6. I'll briefly review the biology underlying our approach. There are well-described physiologic states such as pregnancy and lactation in which menin levels are naturally reduced, enabling beta cell expansion and increased insulin production and secretion. Across multiple preclinical models and human islet studies, reduced menin signaling has been associated with increased beta cell mass and improved function. Icovamenib is designed to pharmacologically replicate this biology. By reducing menin levels, our goal is to support and potentially restore beta cell function rather than simply slow its decline.

Turning to Slide 7. We see the first preclinical validation in a partial beta cell ablation streptozotocin rat model of insulin-deficient diabetes. In this model, icovamenib significantly reduced blood glucose levels during oral glucose tolerance testing. This is notable because meaningful glucose lowering in this model is typically achieved only with exogenous insulin administration.

Slide 8 provides an important translational bridge to humans. In ex vivo human islet studies, icovamenib reduced menin protein levels and promoted beta cell proliferation. Importantly, this proliferative effect was conditional. It occurred under hyperglycemic conditions, but not under normal glycemic conditions, supporting a disease-relevant and conditional mechanism of action.

Turning to the treatment landscape on Slide 10. Most investigational approaches in Stage 3 type 1 diabetes focus on immune suppression, immune modulation or preservation of remaining beta cell function. As a result, clinical success has largely been measured by slowing the decline in C-peptide, which is why most studies enroll patients as early as possible following diagnosis. To date, however, no investigational therapy has demonstrated a durable increase in beta cell mass or function in Stage 3 disease outside of cell transplantation approaches. This is the gap we are trying to address.

Slide 11 summarizes representative results with other investigational T1D therapies. There are essentially 2 dominant investigational treatment paradigms, immune-directed approaches and beta cell-focused approaches. Broadly speaking, immune-directed therapies aim to stop or slow the underlying autoimmune attack in pancreatic beta cells. Prominent examples include teplizumab, an anti-CD3 antibody that modulates autoreactive T cells and promotes immune tolerance. Other approaches include: [ rapid ] antithymocyte globulin, ATG, which induces broad T cell depletion; cytokine pathway inhibitors such as baricitinib, a JAK1 and 2 inhibitor; [ anyuates ] inflammatory signaling; and agents like [ ustekinumab ], which targets the interleukin 12 and 23 pathway. Emerging approaches, including polyclonal human antibody therapies such as SAB-142, are also being explored to modulate immune pathways implicated in disease progression.

Beta cell-focused approaches, by contrast, aim to preserve remaining beta cell function rather than directly targeting the immune system. Examples include: verapamil, which reduces beta cell stress and apoptosis; rituximab, which indirectly impacts beta cell preservation through B-cell depletion; and GLP-1 receptor agonist, which provide beta cell [ rest ] and may offer protective effects over time.

While many of these programs show relative preservation versus placebo, the long-term trajectory across studies remains continued C-peptide decline, as you can see in the small images showing the individual study results. Durable restoration of endogenous insulin production has not been achieved. Importantly, most approaches aim to preserve what remains rather than restore what has already been lost.

What's notably absent for most of these approaches is regeneration. The ability to restore beta cell mass has already been lost, where we believe icovamenib could occupy a generally differentiated position. Icovamenib, Biomea's menin inhibitor, is designed to target the regenerative capacity of beta cells through epigenetic reprogramming, driving proliferation of residual beta cells rather than simply protecting the remaining beta cells or dampening the immune attack.

With that context, I'll briefly touch on the study design on Slide 13. COVALENT-112 was designed to be a proof-of-concept study to assess beta cell function as measured by changes in stimulated C-peptide and metabolic parameters in patients treated with icovamenib plus standard of care insulin. The study included patients across a range of disease durations, those who were diagnosed within the last 3 years and also those who were diagnosed up to 15 years ago to better understand icovamenib's effect across different stages of the disease.

Patients were treated for 12 weeks and followed through 52 weeks to assess both on-treatment effects and durability. Two dose levels, 100 milligrams and 200 milligrams once daily, were evaluated to explore dose response. Study enrollment was interrupted in May of 2024 due to the clinical hold, but the data we're presenting today reflect approximately half of the number of patients we originally intended.

Now turning to the data. Slide 14 shows what we believe is a strong on-treatment signal. In Cohort 1, patients diagnosed within 3 years, treatment with icovamenib in the 200-milligram group resulted in a mean 52% increase from baseline in stimulated C-peptide mean area under the curve, AUC, at 12 weeks during the dosing period. This magnitude of increase has not previously been observed in type 1 diabetes studies and stands in contrast to the natural history expectations of progressive decline.

Slide 15 focuses on durability. Week 52 C-peptide mean AUC remained largely preserved in the 200-milligram group with only a 7.1% decline from baseline. This compares very favorably with the approximately 50% annual decline reported in third-party literature for untreated patients.

Summarizing these findings on Slide 16, we observed a statistically significant increase in C-peptide from baseline during dosing in the 200-milligram group, encouraging durability out to 1 year dose response favoring the 200-milligram group and a generally favorable safety and tolerability profile with no new safety signals observed through 52 weeks. We look forward to presenting additional data at an upcoming scientific conference.

Looking ahead to Slide 18, we now have greater clarity about both what we understand to date and what remains to be addressed. We have observed stronger activity at higher doses and greater benefit in patients treated earlier after diagnosis. We also see signals suggesting that longer treatment duration may further enhance beta cell function. At the same time, important questions remain, including the impact of continuous dosing, the interaction between beta cell expansion with immune modulation and whether combination strategies may further improve durability.

Finally, turning to Slide 19. This leads directly to our proposed next study. The next trial will be an investigator-led Phase II study, which we plan to conduct in collaboration with leading U.S. type 1 diabetes centers. The study is currently designed to enroll adults within 3 years of diagnosis who retain measurable C-peptide. The design includes extended icovamenib treatment duration, placebo control and comprehensive immune and metabolic assessments with the potential incorporation of a JAK inhibitor to explore combination strategies. This study is designed to more rigorously evaluate both the magnitude and durability of the effect while also beginning to assess beta cell targeted approaches may be combined with immune modulation to potentially impact disease progression.

Stepping back, our goal is to build on the biological and clinical signals observed to date and more definitively understand the potential role of this approach in type 1 diabetes. I will now turn the call over to Mick, Biomea's CEO, who will provide final remarks.

Thank you, Juan Pablo, and thanks to the entire Biomea team for the work behind these data. To step back for a moment, we are very encouraged by the results from COVALENT-112. Although this was a small exploratory study, the magnitude of the on-treatment C-peptide response, along with the observed persistence after treatment cessation, stands in clear contrast to the natural history of type 1 diabetes. We believe these findings provide important clinical validation of menin inhibition as a therapeutic target in diabetes. Seeing evidence of improved beta cell function even in a limited number of patients reinforces the biological hypothesis that underpins this program and supports further investment in this approach.

At the same time, we are appropriately cautious. These data come from small cohorts, and important questions remain around optimal dosing, treatment duration, durability and the interaction between beta cell regeneration and the underlying autoimmune process. That is precisely why we are enthusiastic about moving forward with the next investigator-led study, which is designed to more rigorously evaluate these factors and to further define the role icovamenib may play in type 1 diabetes. We are grateful to the investigators and clinical sites for their interest, collaboration and commitment to advancing this work, and we are excited to get the next study up and running in the near term.

Finally, I want to thank everybody on the call today for your continued interest in Biomea. We look forward to updating you as this program advances and to sharing additional data in future scientific forums.

Operator, we are now happy to take questions.

[Operator Instructions] Our first question is going to come from the line of Edward Tenthoff with Piper Sandler.

Congratulations on encouraging results. This is really exciting in an area that needs new therapeutic development. Question, based on the mechanism and -- what percentage of T1D patients are on a JAK inhibitor? And can you kind of get into a little bit more detail about the potential synergy or additive mechanism of action between the two things?

Thank you, Edward. I'm going to turn that question over to Juan Pablo.

Yes, it would be extremely small, and it would be -- as far as [indiscernible], it would be investigational use only at this point. But as I mentioned previously, I mean, they're really complementary mechanisms by which we feel that icovamenib through inhibiting menin is going to be replicating beta cells and any other adjunctive therapy such as a JAK1 inhibitor would be providing -- or helping not have these cells, if it is an issue, have an immune attack, if you will. So really, it's using the two as complementary rather than synergistic.

And are there other mechanisms that make sense too, Juan Pablo?

Yes. I think theoretically, it would be any of the mechanisms that we discussed that are more focused on the inflammatory response that may -- again, we don't know. That's why the study will be conducted. That may certainly help the cause here.

Our next question is going to come from the line of Roger Song with Jefferies.

This is Cha Cha Yang on for Roger. Congrats on the data update, and also agree with the last speaker that this is definitely an area of great unmet need. So I have two questions, one is just to confirm. For your Phase II, will patients need to be on immunosuppressants during the follow-up period or just the treatment period? And without the immunosuppressants after the treatment period, how are you going to work to overcome the immune-mediated attacks on the new beta cells? And then my second question is, can you just confirm, Were patients on exogenous insulin for this trial? And were they able to stop using it at any point?

Juan Pablo, I'll let you take that one.

So let me start with the second. These patients were all on exogenous insulin throughout the trial period, so in the COVALENT-112. With respect to the proposed trial design -- and this hasn't been finalized yet. I mean, the participants would receive icovamenib only for the initial 6 months, and then some of those patients would continue with icovamenib only. Some would come off of therapy, and then others would either have the immunosuppression with continued icovamenib or after icovamenib is discontinued, have the immunosuppressive therapy.

So we'll really test what icovamenib alone would do for 6 months and what icovamenib alone would do for the entire 12 months or 52 weeks and then also what the combination of icovamenib with immune modulator would do in combination through the 52 weeks or stopping the icovamenib at 6 months and then going on to the immunosuppressive therapy. That will be answered there.

Maybe one more point for you to make, if you could. All these studies that we are presenting here are -- every patient is on background insulin because that's the standard of care. And if you wouldn't have them on insulin, they would have severe side effects. I mean, that's a standard. And when -- could you describe the mixed meal tolerance test that we do with the 4 hours so that people understand that is a standardized format that people use to measure C-peptide?

Yes, absolutely. So to measure the C-peptide as we did in the 112 [ and ] other studies is having a mixed meal, which stimulates the pancreas to secrete insulin, and C-peptide is what's measured to look at insulin secretion and beta cell function. So during the 4 hours subsequent to ingesting the meal, C-peptide is measured at specific intervals, and that's how we measure beta cell function and the change in beta cell function over time.

And the others do the same in their study. So when you look at all these study results, it's a 2-hour or 4-hour test. You can cross reference at least to a degree that they are all treated or they're all tested in a similar mechanism to understand what does the pancreas do for any of these patients.

Correct.

Cha Cha, does that answer the question?

Yes. And then one more question, if I may. Can you just tell us what are the baseline C-peptide levels required for insulin dependence, so somebody not on -- somebody who [ doesn't ] have type 1 diabetes? And then also, do you foresee icovamenib potentially reaching up for patients?

Yes. I think potentially, it could. But the levels that we're looking at here, I mean, are certainly very low in this study would be -- it would have to be over 0.2 nanomolar. And that's already -- even over that is extremely low at that point as you're getting below 1, for example. So these will be patients that absolutely would require insulin and more than likely be symptomatic and have Stage 3 type 1 diabetes.

Our next question will come from the line of Michael King with Rodman & Renshaw LLC.

Just a couple of questions again on the Phase II study design. Can you just walk us through the dose titration schedule? I see you started at 100 and gradually move up to 200. How will that be gated? Is it time gated? Is it tolerability gated or otherwise?

I'll pass that one to Juan too, please.

Yes. So that has not been fully worked out yet. But what we've generally done has been -- it will be probably -- likely 4 weeks at 100 milligrams and then escalating. But the idea will be to start at the lower dose and then escalate to 200. So exactly how that will be done and the timing is not yet fully decided.

Okay. I'll follow up on that in a second. But just as far as the patient's insulin regimen, are they allowed to be on any insulin regimen? And are they being counseled to not adjust their insulin regimen? Or will they adjust it dynamically depending on their blood glucose? I mean, are all of them on continuous glucose monitoring?

Yes. Again, I'll say a lot of those details are still being worked out, but they absolutely will be able to, and hopefully, they will need to make insulin dose adjustments to maintain euglycemia or not have hypoglycemia, certainly. So there will be adjustments. I imagine most of these or all of these patients will be on continuous glucose monitoring.

And again, the final eligibility criteria is still being worked out. But I would say, yes, most of these patients will be on CGM, and they absolutely will be allowed to make insulin dose adjustments.

Okay. Great. And then -- so I guess a bit of a compound question about the 200-milligram dose and the combination with immunosuppressants. We did see a clinical hold in the first -- in the Phase I at 200. So is there any concern about combination with immunosuppressants? Are any excluded from the second half of the study because of potential interactions? And just from a high-level standpoint, is the company concerned about -- just the possibility of confounding or complicating the safety attributes of icovamenib because of the combination with immunosuppressants?

Yes. All I'll say to that is that we'll be monitoring this, obviously, extremely closely during the 6 months when the patients are up or dose escalating from 100 to 200 and beyond that. I don't think theoretically, there's no concern above and beyond what we've seen with icovamenib. So all I would say is we're going to monitor it extremely closely.

And certainly, patients who have issues, if they have them with aminotransferase elevations or any issues with liver during the 6-month period would not continue therapy. But again, we're very confident from what we saw with 100 and then escalating to the higher doses that we shouldn't have a problem that clearly, this will be monitored very closely through the trial.

Steve...

Sorry, go ahead.

Steve, do you have anything further to add? We've looked at significantly higher doses.

Yes. Thank you, Mick. First of all, we do not, as Juan Pablo mentioned, anticipate any drug-drug interactions between icovamenib and immunosuppressant agents. These agents are metabolized and have an impact on various metabolic pathways that are not overlapping. So again, we don't anticipate any issues with DDI.

With regard to the liver safety profile, based on our type 2 study, COVALENT-111, we did in one cohort in that study, do this ramping up from 100 milligrams daily to 200 milligrams daily. And with that ramp up, we did not observe any clinically significant LFT elevation. So we don't anticipate that being a limiting issue with the planned type 1 study.

Congrats. It's a great group, a great cooperative group you guys are working with.

Our next question comes from the line of Joe Pantginis with H.C. Wainwright.

So first on the Phase II. So can you define the enrollment criteria a little better? Is it just a focus of [ time ] for diagnosis, similar to now? And then also, as you said and as we believe this is a very rigorous design that you're looking at, but from an IST standpoint, what is the potential that you've been discussing internally to have higher numbers in the cohorts?

So Juan Pablo, I'll let you take that one, too, please.

Yes. I mean, what we're disclosing now is with respect to the entry criteria, diagnosed Stage 3 type 1 diabetes diagnosed within 3 years at the time of entry and then with some residual C-peptide, so C-peptide greater than 0.2 nanomoles per liter. That really is what we have at this point.

I don't know what the discussions have been with respect to increasing the numbers, but I think this is quite robust and will give us an idea of where we would move forward, particularly with respect to the need for adjunctive immunosuppressive therapy. And I'll add that it has a placebo arm as well. So I think these numbers are quite reasonable.

Can I make a point, Joe. Every study that you see, if you do a little bit of digging, over 90% of them try to find the patient very early on, 0 to 90 days, 0 to 100 days from diagnosis. And that is where most of these therapies need to be because of this progressive decline, just to have an impact and to move that curve a little bit over. And you can see in all the charts, they're all trending down, or most of them, if not all of them.

And so we -- when we approach the investigators with the study design, they said, this is unbelievable that you're targeting a patient population between 0 and 3 years. It's unheard of, actually. And so we see not really a problem in finding those patients because they're very much available because they're not picked up by the other studies.

And then two, to have a pathway or a drug that potentially works in patients that have been so far into their disease is a very welcoming fact for these investigators. So we found great response with them. It's a great group of professionals there. And if we were to enlarge the numbers of patients, it's an IST. If they want to go higher, for us, time is of the essence. The more patients we enroll, the longer it takes to read out.

This is 40 patients. We can do 40 patients with 4 centers fairly fast. But if we increase the numbers, maybe we do it in a secondary study. But the intent is go in, understand the signal, really confirm all these points we made in the script. And once we have that data, come out with results very quickly so that we know this pathway is fully -- is actually valid for a Phase III design theoretically.

No, that's helpful. And then if I could just switch back to today's data, which are very encouraging signals. I guess I want to focus on the C-peptide concept. So first, what do you potentially attribute the initial drops in C-peptide? Is this a potential for patients on their current trajectory continuing before icovamenib can engage its mechanism of action, first? And then second, how would you define, for these patients, the clinical relevance in the changing of the slope positively to say, only seeing a 7% C-peptide decreases or even potential increases over time? Can you discuss the clinical relevance around that?

[ Do you want ]?

Yes. So I mean, it's very small. I would say that going to the decrease you mentioned, there really doesn't -- with the 200-milligram dose, there's really no change. And then at week 8, you start seeing it go up. So I think any very small decrease, maybe at week 4, there just all has to do with the end. I mean, these are 3 participants in that group, in the 200-milligram group in Cohort 1. So I really think it's no change until we see out to week 12, where we're seeing this 52% increase.

And I think it's highly relevant, even maintaining C-peptide, but certainly the increase in C-peptide. We know that these patients do better overall with less hypoglycemia likely will, and this is something we'll look at further, would have a reduction in insulin dose as well. They're much easier to treat from a clinical perspective if they have remaining C-peptide secretory capacity. So I think they're very clinically relevant.

But again, as we mentioned, the numbers are very small here, and that's why we want to explore this further. But I would say that even no progression in the decline of C-peptide is clinically relevant. But certainly, the increase in C-peptide really hasn't been seen before, and that's what we're striving towards.

And a little bit of color because I've talked to all these investigators. And when you show them these graphs, you hear comments such as this is provocative data or never -- I've never seen anything, any drug that would increase the C-peptide that patients are using so fast.

And I refer you to the quote from Alexander Fleming in our press release. We put that there because we found it was just so telling of what we're trying to do and the excitement around what we think is potentially there. And just read that quote, and then you can see what professionals think about what we're doing here.

Our next question will come from the line of Yigal Nochomovitz with Citigroup.

I just had a question on the Phase II strategy. Over the years, you've talked about doing a short course of treatment as you did in this study, the 12 weeks to boost the beta cells and then take a pause. And obviously, acknowledge that this is a small study with low end. I'm just wondering if you'd considered basically repeating this type of study with the 12 weeks for a larger set of patients to sort of further anchor these conclusions before moving to change variables and do a longer study and then add the immunosuppression? I just wanted to get your thoughts on that first, please.

Yes. This is Mick. I think all the investigators that we've talked to look at this data and say, "This is great, but we want to do more." And so this is part of why we want to go to a longer term of treatment. In addition, we now have the preclinical data that would support us to go into a longer treatment paradigm.

So I think it makes sense for us to go after 6 months. If we saw any concerns about 6 months, we could go back to 3. But I think what we're looking for now is this is a great response, but if we can do better, then we certainly want to see what happens there.

Okay. And then can you just comment on the -- just the inherent variability of the C-peptide, the glucose tolerance test assay and whether -- and how much of that variability is being reflected in this data set or whether it's well beyond that inherent variability of the assay?

Juan Pablo, can I get you to take that one?

Yes. You know what, I think -- obviously, the higher end will help with that. There clearly is some variability, as with any assay. So there is variability there. So although we're seeing this improvement with the 3 patients, which is consistent in each of the patients. I think that's why we absolutely need the bigger numbers to confirm this.

Okay. And then Juan Pablo, just kind of getting your thoughts on the slope. You get to the negative 7% after 52 weeks versus the 50% for a year. But I'm just getting your thoughts in terms of whether you're pushing out the decline because you're getting a bump at 12 weeks, and then you kind of resume the original decline because the slopes are very similar. You know what I mean? So like, does that -- how do you think about that in terms of possible redosing to kind of keep that slope from returning to that natural history decline?

Right. Well, I think it goes to your first question and the need to potentially go out further. So I think we'll see that with the 6 months. And I think what the trial provides as well, the upcoming trial provides 6 months of therapy and see what happens, and then also then coming off of therapy at 6 months versus continuing the therapy.

So I do to your point, and the slope was the same. In a sense, you need to buy in time, if you will. But I think that was the rationale behind dosing for a longer period of time, seeing if we can have a more sustained reduction and then also seeing what the immunosuppressive therapy, adjunctive immunosuppressive therapy does, whether that improves that slope or not.

Okay. And then just one other thing. On the Cohort 2, that data is coming later at the meeting?

Yes.

Yes. Our next question comes from the line of Anupam Rama with JPMorgan.

This is Joyce on for Anupam. Maybe just as a follow-up to the previous set of questions, regarding your next Phase II looking at extended dosing out to 6 months and also 12 months, as you mentioned. I was just curious if there's anything in your work so far to help inform what the right duration of treatment might be here? At 12 weeks, it seems like there's no plateau yet. Obviously, small end still, but just wondering if there's anything in your modeling work that might suggest when the max benefit might be reached here?

I think at this stage, it's all hit and hope. We're really trying to sort of figure this out in real time. There's no precedent for this. So I think we need more experimental data to come to the conclusion about what the best dosing period is going to be.

That's exactly the purpose of the study, right? The purpose of the study is to answer all these questions quickly, not overload the study with too many questions. But the question you're asking is our question. We couldn't answer that question before because we didn't have the tox data. Now that we can continuously dose patients, we can actually get an answer to your question well. And with 12 months of dosing of icovamenib, we will see how far reaching this increase can be and how durable it then is.

Another theory that we heard from investigators was if you have a buildup pool of beta cells, could they survive better? Meaning, is there a mass that you have to reach or overcome in order to have a sustained effect? Those are all the things we will find out in the study.

Okay. And then if I could just follow up with another question. At ADA, I understand you'll have full data from both cohorts. I was just wondering if you'll have any additional analyses specifically from Cohort 1 relative to today's top line update that you would have us focus on as we look to that upcoming presentation?

That's a good question. I -- the reason why we put this here, this is the top line. This is the big update that we wanted to give everybody and that we took out of the ADA because it's important for you to know and to have.

The ADA will provide further details. But as you can imagine, if you go to Cohort 2, 3 to 15 years, the effect is not as impressive as you see here. It's sustaining, yes, but you can debate that, meaning, don't place undue importance on the ADA as if we come out with another set of data. This is the data here that you see that is most important.

[Operator Instructions] We have a follow-up question from the line of Michael King with Rodman & Renshaw LLC.

Mike, we can't hear you.

Sorry. What I was going to ask is on the cooperative group study. Is this only going to be in patients -- it looks like less than 3 years as well as 3 to 15 years. Will they be analyzed in a stratified manner? Or will they all be pooled? Do you know the answer to that?

Yes. It's only 0 to 3 years.

Only 0 to 3. Okay.

And just not to get into -- obviously, there is a chance and that we have an effect in these other more burdened patients where type 1 has just decreased the pool too far. But that would be so much work for us to do now. We're a small company. We want to find -- we really want to solidify what you see here today very quickly and then see how far this can take us.

If you look at the teplizumab results that they have with the FDA right now, look at the results and see the lasting effect of their drug and compare that to ours, and then draw your conclusions of the potential of what icovamenib has in the bag potentially for 0 to 3 years. They go after 30 to 90 days. And I think when you compare just what we show here with what's currently at the FDA, you can see that, one, we can potentially -- and that's the goal -- achieve a lot more just with this study design to show that there is a greater effect size potential, one.

And two, later on, we can look at 3 to 15 years. We can look at all these other patient subsets because then, we understand the signal. But we want to get out and fast and show that we are actually -- we could have a dominant role in type 1.

Thank you. And I'm showing no further questions at this time. And I would like to hand the conference back over to Mick Hitchcock for further remarks.

Well, thanks very much for being on the call today, guys. We appreciate your interest, and we're really excited about the data. And if anybody has any further questions, please feel free to reach out to us. And thank you for your interest, and that's all we'll do today. Thanks. Bye-bye.

This concludes today's conference call. Thank you for participating, and you may now disconnect. Everyone, have a great day.

Okay. All right. So then we can begin. Sorry about all the confusion everybody. We're going to kick it off right away in the interest of time. So we're pleased to be joined by the management from Biomea, including a welcome late addition Mick Hitchcock, Interim CEO; Ramses Erdtmann, Founder, Chief Operating Officer and President; and finally, Steve Morris, who is the Chief Development Officer.

So I'm just going to make a couple of opening remarks, and we'll kick off the discussion. But let me just start by saying that we really like to buy me a story for a variety of reasons. In addition to the management team that's got a documented track record of value creation by the de novo development of a novel agent for the treatment of a condition. And in this particular case, CLL, Chronic lymphocytic leukemia that had seen little in the way of novel agent -- sorry, innovation prior to the advent of ibrutinib, which as you all remember, was the first of the BTK inhibitors.

The company's Biomea that is the lead program, icovamenib, is the first in the category of menin inhibitors directed to the treatment of both type 1 and type 2 diabetes that holds the potential to preserve and potentially increase the function of pancreatic beta cells and therefore, could redefine how the world looks at the treatment of diabetes with a relatively minuscule market cap, but with a tremendous market opportunity in front of it, we believe the stock is poised for significant upside.

So welcome, gentlemen. We're pleased you could join us today for this discussion. I just want to remind everybody, if you do have questions for the team, you may e-mail me directly at [email protected], and I will ask your question anonymously, please do not put it in the chat box.

So with that, let's get started. And as we discussed prior to this call, I really want to focus on the mechanism of action of icovamenib in respect to menin inhibition in the contact disease context of diabetes in the context of elevated glucose. So I feel like folks are very familiar with the menin inhibitors from both Kura and Syndax, which have been marvelous drugs for our genetically altered acute myeloid leukemia, but I think there may be this intellectual disconnect, if I may put it that way, with regard to how could a drug that treats hematologic cancers be a usual drug for diabetes.

So maybe we can step all the way back and look at the Stanford -- the initial Stanford University publication and talk more about this and how menin plays a role in the life cycle of the beta cell.

I'm going to hand that to Ramses.

Okay. And I'm going to pitch it to Steve in a second. So Mike, great intro. Thank you. Thanks for hosting us. So when we started, and there is -- if you want me to show slides, I can show them to you, when we started to work on menin and we actually were just like the other 2 companies for oncology. However, the preclinical information showed in a first 2005 paper in PNAS paper from chronic, the same gentleman you just quoted for the Stanford study, menin regulates pancreatic islet growth by promoting, et cetera. But he had isolated menin as a target in the pancreas.

And when we saw the work that was done on menin, we thought, wow, wouldn't it be cool if we're safe enough in oncology to move and sort of migrate over to the diabetes space. And as we learned over time, we were safe in oncology. We've dosed quite a few patients over a year. So we knew what menin does and how our drug has an impact on menin and we can go into all of that in part of this discussion here, but just to answer your question, menin is a scaffold protein that is being used either way. And in the pancreas, menin has the function of control. And if the control is no longer there, a restoration effect can occur that we see in obesity and we see in pregnancy. And that's the paper you just quoted. We saw that as well, and it was an aspiration at the time in 2017.

If we end up developing a drug that is safe enough, which we now have and have evidence for, and if these effects can be replicated in animals, in cells then we may potentially go into humans. We've done all the animal work. We've done the cell work, and now we are in humans. And the effect that these papers described is exactly what we see. We see that by down regulating menin, the restoration of the pancreas or the beta islet cells occurs, beta cell mass expands.

Insulin is increased and you have the residual down effect into the glucose in the bloodstream than in the human. And the islet work is phenomenal when you look at -- it's all in our deck, but we're like at the forefront of something new. Nobody has done it before. They've only crispered out menin and then...

Right, well, maybe you can -- I mean that's a good segue. I mean talk about those knockout experiments and what...

No, it's cool. I mean, let me show it to you because -- let me see if I can -- yes, I can share. Look at this right here. So this is the paper you just mentioned, which is the original paper on the right-hand side from 2007. And this is in our deck. But if you -- in this slide here, what we're showing here is something that...

Ramses, can you just slide it over a little bit because we're only seeing about 3 quarters on the slide?

Yes, is it better?

Yes. There you go, much better.

Okay. Yes. You can see here, this is the work that I had quoted earlier. This was done, I believe, in 2010. Here, they excised in diabetic animals. They excised menin. And they basically said, let's look at a knockout model. If you don't have menin what happens. And you can see the control group under conditions of hyperglycemia, the glucose cannot be absorbed.

But in the menin excised animals, the glucose is absorbed. So something is occurring. That was sort of the first giveaway. And when you look at that, we then look at it, we asked, well, what if a drug could do this effect safely versus crispering out the menin.

And so we ended up doing this exact experiment, I can show it to you what we found is this. I mean this is our work. The red line is our drug and this is 2022 when we publish that. From there, we went to cells, from there we went into the early human data, did an all-comer study, and now we know where exactly the effects are most pronounced.

Right. I'm just surprised that it didn't get picked up sooner, but you would have thought that this paper would have had replicate studies and a flurry of drug development, but kudos to you guys for picking up on that. I don't know, if you wanted to show any animal data, rodent data primate, but I mean, I think it's pretty clear.

No. No. This is the only slide I've sort of in the deck summarized everything.

Okay. Maybe you can talk -- you mentioned pregnancy, prolactin, that's another thing. You have a nice chart in your deck, one of the decks that I've reviewed that shows how you get this prolactin bump in pregnancy. And I know that there's been -- that was, again, where the insights is at the biology first came from in pregnancy. Maybe we should explore that a little bit more.

Steve, do you want to go into that because it's more of a physician's viewpoint.

Happy to do that, Ramses. So Mike, it's been known for at least 50 years that women avoid pregnancy associated diabetes by actually increasing their beta cell numbers and the insulin secretion. But the mechanism by which that occurs has been unknown until this Stanford paper that was published in Science in 2007, as shown on this slide. And what the standard investigators show that in pregnant mice, as pregnancy proceeds and prolactin levels normally increase, prolactin actually downregulates the expression and function of menin.

Now normally menin serves as a break. And when prolactin decreases menin function, it takes the foot off the brake and allows the beta cells to increase the number. So -- to avoid diabetes is -- yes, I'm not sure when I lost you but what I was saying is...

We lost you for about 10 seconds before when you're talking about the increase in beta cells. Why don't you pick up from there?

My apologies. What I was saying is that the Stanford study showed that prolactin downregulates menin. Menin because it normally inhibits beta cell proliferation, once it's inhibited, it allows the beta cells to increase in number and avoid pregnancy associated diabetes. It's also interesting that epidemiologic studies have followed women and segregated women who had live births, those who did or did not breast feed. So -- prolactin levels if those women are followed for a prolonged period of time, up to 30 years after giving birth, the incidence of type 2 diabetes is reduced by 50% in when you had live births and breast fed. So it's quite remarkable.

Steve, if I may ask you, it might be better because we keep losing you. Why don't you turn off your video and just stay on audio, please, if you don't mind. Apologies for that, but I think it's going to be a lot smoother if we go that way.

Maybe I don't know if Ramses or Steve want to take this question, but also talk about that glucose-dependent beta cell proliferation because I think that's important from a clinical standpoint. You guys have shown that, but maybe we can talk -- explore that topic a little further.

Yes. I have to show you that graph for that. This is this slide here. Can you see it?

Yes.

Yes. And so the experiment we've done here is we've used human -- pancreatic human islets, which are from a person that is about to die. And so they're live, they are resembling the pancreas most closely. And you can see on the left-hand side, the amount of menin protein through the use of icovamenib has been down regulated by about 50%, depending on the donor.

On the right-hand side, you can see as icovamenib is increased, on the bottom, you can see we use higher levels of icovamenib, meaning more menin inhibition, understanding glucose condition doesn't have an effect. However, with high glucose when there is a need for the beta cells to respond, then you can see that there are more menin inhibition leads to a higher replication of those beta cells. That was profound, right? It's controlling itself. You need glucose as a stimulus. But once you have the glucose, we have a dose-dependent effect, more menin inhibition, more proliferation.

Right. Okay. Great. And obviously, there's -- maybe I don't want to jump to conclusion, but the correlation between menin expression and beta cell function is sort of one-to-one relationship? Or does it plateau out at some point?

I have -- yes. You mean the more we reduce, the more we get and it just keeps going. We don't -- we haven't done all the work yet. We -- I mean, this is very early work. So what we found at first is we studied 4 weeks of dosing versus 8 weeks versus 12 weeks, and we saw that 12-week inhibition gives enough beta cell restoration that over the course of 52 weeks of observation you can see up to 1.5% A1c reduction, which is order of magnitude, this is a very functional diabetes care, like Ozempic, right? It's in the upper 75 percentile of reduction in glucose if you just use 12 weeks of dosing, we feel that's completely sufficient and the trend is still going down.

So from our perspective, if we were to dose longer, could we achieve more or dose harder or higher, maybe, but we didn't really see much more improvement when we went to 400. It cause safety concerns versus it actually has a beneficial effect. So that's why we don't need to.

So Mike, I think one of the things is it's self-limiting, right? So once you get the glucose under control and the glucose level falls, then you've got nothing to facilitate the response to icovamenib and so you -- for example, we don't see any cases of hypoglycemia in our trials.

Yes. I do want to talk about the clinical results that Ramses just referred to in terms of durability of effect. But is there -- was that anticipated based on the preclinical work because you would think that once, let's say, prolactin, let's say, in the pregnant women or in the animals when you take the inhibitor away, you would think that would return to sort of the normal relationship once again. So what have you -- what's the hypothesis behind why this produces such a sustained effect?

This is the hypothesis behind it, and it's us creating an understanding of this mechanism. This is something, obviously, which will be explored further, but companies who've done stem cell transplant have seen this that when you -- that the maturity of these beta cells, these newly created cells take time until they're fully functioning. So we see an effect, for instance, what I'm showing you here is the beta cell mass decreases, you use icovamenib right before you become insulin-dependent, that's the spot where we think we're best utilized. You enhance the mass, you build a pool and now the beta-cell pool matures, meaning cells come online and become active.

You can -- what does this translate to? If you see here in these particularly insulin-deficient patients, you can see during the dosing period that is indicated in green, we have an effect but the continuation of the effect is because we believe these beta cells are maturing and coming online. You can see it even more if you look at just C-peptide, which is the output of these cells. You can see that the C-peptide improves and it even improves further as you are off drug.

Right. So do you -- you think you create sort of a beneficial do loop, so to speak? Are you kicking off a positive domino effect where you restore beta cell health and function and now you've got a healthier pool. And even if there's gluco-toxicity, still hovering around, you've got a healthier population of beta cells that can deal with it.

Unfortunately, you can't look inside, right?

I know. And the animals can't speak.

But we do know is that this pool that we are sort of restoring at first is not fully functioning, meaning it needs time to mature and become a fully functioning beta cell. The other interesting fact is we don't know how long this effect lasts. So we've seen -- if you see here in this slide, 52 weeks, but the trend is still going down. There is still toxicity to be worked through in these patients that we have dosed. So we're exploring it. But so far, very exciting.

Okay. Yes, indeed. I share your enthusiasm. Let's talk a bit more now about the clinical development aspect of the story. One thing you say in your slides that icovamenib is synergistic with GLP-1-based therapies. Where is the proof for that? What kind of data can you point to, to show us what that means?

Yes. This is -- here's the proof. This is work we've done, and it kind of goes along with all the ideas around pregnancy and obesity that these pathways need to be -- if menin has a control function, then if menin is no longer there, there should be sensitivity to these pathways. And you can see here that the GLP-1 receptors are more expressed. They sit on the surface of the beta cells. And when the hormone GLP-1 receptor agonist, the GLP-1 comes along, to ask of the beta cell to produce insulin that this whole aspect should be improved in a pregnant women or in obese individual.

And you can see that we saw the same thing in our own pilot studies, we see receptors more expressed, insulin heightened and now the combination of semaglutide, which you -- we've tested it at higher levels of semaglutide, we see more impact through icovamenib and at higher levels of icovamenib, we see more impact of semaglutide.

So the pathway of having a GLP-1 receptor agonist on board is sensitized to the use of menin. That's why we see in patients. And this is -- I mean, think about it, patients are enrolled -- they are on semaglutide, A1c is rising, the GLP-1 is not working. They're diabetic.

Okay. So what do we do with them? Their next option would be insulin. And what we're saying to this patient, try icovamenib and that's what we do, and you can see it here. these patients here, there were 11 in our study, and this is a post-hoc analysis. This graph I showed you earlier was prespecified. Here, we asked the question very generally of all patients enrolled who was on a GLP-1. Literally, that's a question we asked. And there were 12 patients on icovamenib. We pooled them and we saw this pathway that we had explored preclinically earlier does have a profound impact on these patients.

We enroll them as the A1c goes up. They have this benefit, again, the same benefit as we described earlier. And over time, the effect is even more pronounced here from 0.3 to 1.2 in absolute reduction in A1c. That's strong. While you are on background GLP-1 that didn't work for you earlier because you have more GLP-1 natively expressed and you have more receptors.

So you're having -- yes, so you're having more GLP-1 express, more GLP-1 receptors, healthier beta cells and possibly more data cells as well. So it's an additive or synergistic effect.

Think about 2 aspects that are important to note. One, how easy it is to identify this patient. Well, you're overweight or obese, you're on a GLP-1. That's it. and GLP-1 is not working. I mean we want to find a patient where the FDA and we, and the patient, we see a need for a drug. Once you're not working on a GLP-1 and you are unfortunately in the position of being overweight or obese, there's not much more you can do. You will then become insulin-dependent.

And what we are proposing, you don't need to become insulin dependent. Look at the amount of HbA1c reduction, I can -- you can achieve with icovamenib. This is if I -- if these cells keep on working for you, you may not -- we may push it out over years. And if we can push it out over years or redose over time, what benefit can this do for you, a patient, not in one insulin.

Right. Exactly. So that -- you anticipated one of the next questions I had, which was novel mechanism, does it matter? Does it need to possess best-in-class benefits like A1c, cholesterol, inflammation markers, weight loss, what's a win and just from a regulatory, we'll get into the specific COVALENT studies in a minute. But just in general, what's a win for icovamenib as far as a novel mechanism of action in a disease state that's got 50, 60 different options that patients can be on, including GLP-1s, either oral or injectable?

You can see here, there's a little line that we drew in there, 0.5 threshold for clinical significance, CMS clinical endpoints review, blah, blah. This is us looking at when did the FDA consider an agent. And by the way, all chronic, we're not a chronic agent. This is a chronic agent that has obviously, through the chronic use of a drug, you have more side effects just by the nature of being chronic. They were approved at 0.5 improvement in A1c. That's our hallmark of a win. If I can achieve and surpass...

As a single agent.

Yes, as a single agent in addition that is given for a 12-weeks period, we believe that's enough for the FDA.

All right. Well, that's enough for the FDA, but what about from a commercial standpoint?

This is kind of important because we've looked at where do we fit in. On the left-hand side, you can see all these agents, you're going to adjust your lifestyle, you're going to take metformin. You're going to use all these drugs, but at some point, they fail. 1 in 3 patients move over to the right. And we would be in between that. That's the benefit we give to the health care system. Once you're over on the right, the way your body responds to exogenous insulin is heartbreaking, meaning you're going to have -- you've got to be uncontrolled because the exogenous insulin does not -- it works to a degree, but it does not control your HbA1c either up or down as we know.

So you get these "side effects" that are core mobilities, now you're going to die potentially of coronary artery disease, chronic kidney disease, et cetera, et cetera. This is -- you don't want to be insulin independent. That's on the right-hand side, and we will prevent you from getting there by using icovamenib. That's the best.

Yes. Now -- well, 2 questions. Number one is, do you think GLP-1 will shift the curve? I would imagine they have to, but that's just intuition. There's no proof yet on that.

GLP-1s are in there, meaning they are on the left-hand side.

Right. But I mean, they're relatively new agents, and they're doing an amazing job at reducing weight. There's more to come. So I would imagine that...

Menin shift the curve over the last 20 years. Look at...

Well, that's the kind of answer, I was looking for.

What it may do, Mike -- can we go back, please, Ramses.

Yes. Sure.

What it may do is slightly reduce the number of patients who are going into that middle bucket. But our expectation is that this is where we get our foot in the door, and this is where we start the process. we are going to sit between all the other agents when they fail, we will be the opportunity that you take rather than go on injectable insulin. We will be 3 months of oral who knows how long value. And so we think that's a good place to start, and we have evidence that, that's already shown by the studies that we have to date, and we just have to sort of redo those to make them more credible.

But we think eventually that icovamenib based on its mechanism, it should probably be the first thing you think about using. And so we can move further back up the line there. And you've seen this with a lot of other drugs where you start at the back end of therapy and you move up the line as long as you're safe enough, you can go down that pathway.

Well, again, just I guess 35,000-foot question, I'm trying to get your answer to and hear your thoughts on is that what you're saying is true, and I agree with it, but the question is in the clinical community in order to do that, will you eventually need things like outcome studies or impacts on other metrics of diabetes beyond just the 0.5, even not that 0.5 reduction, A1c is a bad thing. But again, in the crowded marketplace, lots of options, higher demand from payers, et cetera. Will you have to show some of the outcomes on these elements that we see here on the chart? Or will you think it will be taken as a given, based on prior studies of anti-diabetic agents?

Yes. I think none of us will know firmly until the FDA votes on it. But at the end of the day, if you can -- if you enroll patients that otherwise would have gone on insulin. Everybody agrees on the need, ensure everybody. And so if I can make that part of the enrollment criteria, and get closer to that statement. Right now, it's inclusion/exclusion criteria, and you could potentially argue. But from what we're seeing in our studies, these are -- most of these patients will end up on insulins if they wouldn't be on our drug. So if you can firm up that thought, that argument further, I think that would be sufficient in my mind.

Yes. It sort of reminds me a little bit, I hate to make the analogy back to cancer, but if you can -- in the early stages of cancers like breast and prostate where progression takes a long time. If you can have a therapy in the early stages that prevent someone from going on chemo or going on something more aggressive or deleterious, then you can get a regulatory approval on that end point, but that is -- we haven't tested that yet.

All right. Why don't we talk about some of the studies that have been conducted already. You've done COVALENT 111 in the type 2 diabetes, you did COVALENT 112 in type 1, the 211 and 212 are enrolling now, correct?

Yes. Correct.

Okay. And so let's talk about a couple of things. First of all, I'm curious to know when you -- and I was looking from the demographics of your previous study, it doesn't seem to influence it. But given women's prolactin and such, do women have different baseline levels of menin they respond inhibition. Do they respond to menin inhibition differently than men do? Do you have to account for that as you...

I didn't -- I checked the statistics on all the various parameters of the biomarkers that go in, I didn't see that. I did not.

Okay. And do you -- do we know if any different levels of menin based on adiposity or BMI or anything like that? Or is it more -- do you feel it's more uniform?

I don't know if it's more menin, but BMI is a huge criteria for success or -- I mean for defining a patient population that is insulin deficient. When we look at severe insulin deficiency or insulin deficiency overall, the higher your BMI, the more you potentially become insulin resistant.

So the reduction of weight versus your production of insulin just by reducing the weight, you could create a benefit for a patient, and that benefit could be enough to control your sugar. That we see as we go in our study and we look at our patients, we do see that BMI is a driver, that if you're above a certain level of BMI, the drug doesn't work as well for you unless you're on a GLP-1.

Interesting. I mean -- but have you tried to play with a dose based on whatever body mass index of 35 or above or...

That would be interesting, but I think it's too complicated. Right now we know anything less obesity is better for patients who are just on icovamenib and back on their own.

Got it. All right. I want to ask a couple of specific questions about -- this was from -- I think this is from COVALENT 111. You had A1c at the 800 -- so A1C at 800 -- sorry, 8 weeks at 100, a modest reduction, Arm B, 12 weeks at 100, very nice reduction. Arm C, where you had 8 weeks at 100 and 4 weeks at 200 sort of in the middle. And can you address that? Why do you think that A1c was less impressive in that thirdly Arm C regimen?

Do you want to do that, Mick?

Yes, sure. I think -- we're -- we've got a limited number of patients here, and I think it's small numbers that are probably having the major impact in terms of why we don't see a dose response. But when you think about a dose response and you can think about what do you look at generally to find a dose response with any drug, you've got to do at least twofold or sometimes a fourfold increase in the drug to actually see a difference.

And so I feel here that where, if you take the 100 milligrams as being a dose of 1, then the lower dose is sort of 67% and the higher dose is, I think, 150%. So it's only a little bit more. So I think the doses are somewhat close, I think it's the time that's probably the difference in terms of 8 weeks versus 12 weeks, and so that's why we've concentrated on the 12 weeks for our future studies.

And one more aspect, Mike, just to add to it. This is -- the number one thing we learned from this all-comer study, we had to run an all-comer studies. We didn't know the difference in dose concentration that is needed, we found that out 100-milligram works. We didn't know the dose duration, whether 8 weeks or 12 weeks, 12 weeks is better than 8. We found that out in this study. And we also -- and this is a key component. We didn't know the diversity of type 2 diabetes patients.

What you see here in this graph is they're all together. And we just organized them by one got 8 weeks, the other got 12, one got 200, one got 100. That already is confusing by itself. But if you think through what we learned from the study is, these criteria are not the drivers. The drivers are BMI. The drivers are the subtypes primarily. That's why our inclusion/exclusion criteria in 211 is 12 weeks is what you need, 100 milligrams, we learned that from this study. But underneath what you see here are subtypes that are grouped together. They actually need to be not grouped together. And that's why we say BMI in the obesity range, you should be in a different segment when you're...

Right. And you're doing that in 212, right?

Exactly. And 211, lower BMI, they work. And there, we saw over all these arms perfect results.

Okay. I want to do a little bit more exploration of 111 just because I want to set it up to help us understand what we might expect from 211 and 212. But on slide -- let's see, one question before I do that. The one question I wanted to ask about this was this -- was Arm C impacted at all with adverse events or tolerability issues. And I know you hit a COVID problem as well. I don't know if these A1c numbers were thrown off by that.

We did not have that as an issue. And think of the 100 milligrams, it's not really 200. It was 100 milligrams twice. This is PID, right?

On the last 4 weeks.

Yes, 4 weeks, right.

So we do it here and you do it there, right? Do you do it twice daily, but one in the morning, one in the evening, are you really generating 200 milligrams of drug? Or are you just putting it in twice when the drug is no longer there. You can run a lot more experiments trying to figure this out. We don't think it's necessary. We think 100 milligrams does beautiful.

Okay. And then on Slide 22, you had 12 weeks of dosing of Arms B and C, but the numbers are quite a bit smaller. They're 10 and 12, 10 of icovamenib, 12 pooled placebo, why is there such a big reduction in the numbers analyzed here?

I can show you the -- well, it's not a mistake. But at the end of the day, the definition of what is an insulin or severe insulin deficient diabetes patients. We left that up to -- we took all 160-plus patients, and there's an algorithm online that you put in 5 inputs, and it says, this is now segmented as a subtype, and we did all that together with the FDA. We showed them the algorithm, the inputs and how we're subtyping. So it's predefined, meaning before the readout, these are the 4 groups, and this group, in particular, and we were very keen on looking at this group because we knew the less amount of insulin production you have, the greater potential effect could be. So these are the severe insulin deficient patients.

But dosed at 8 weeks, they're not quite as good. The 1.2 is 1 roughly. So since we're dosing for 12 weeks, we wanted to look at what would that look like if we replicated these patients. And you can see here, 1.2 is what these patients that are insulin characterized as severe insulin deficient from Arms B and C because Arm A was at 8 weeks arm, what they were -- what the results were. This is 10 patients because that's all we enrolled. These are not selected by any other criteria.

Okay. All right. Just -- yes, just don't want anybody accusing you of...

I know, I know. And it's a lot of information. I agree.

We had to look at the patients who've got 80% of dosing because if they got less of that, it didn't really make sense to include them in the efficacy analysis.

Right. Okay. And then one more quick question. Sorry to be so nitpicky, but on Slide 28, you show that you've got short treatment of icovamenib delivered A1c reductions comparable to chronic injectable and orals. But can we -- are we comparing like-to-like here? Or are we comparing better to worse? Or maybe talk a little bit about this.

Wherever we could, and you can go to the study SUSTAIN 8, SURPASS-1 blah-blah-blah. This is not handpicked. What we're trying to find is where did Ozempic show 52-week data. And sometimes they go with 48, sometimes they go with longer and here, we took -- we tried to get as close to our readout as we could find. And you can see 1.5 Ozempic, 1.9 to 2.1 depending on what study is Mounjaro at 40 weeks. So that's pretty good.

But I'm not even trying to compete at -- this is a chronic agent with side effects, et cetera, et cetera, given every day and in this case, an injectable. And I'm comparing myself as an oral dose for 90 days only, and we're looking at 52-week data readouts. It's an unfair comparison. We're doing it anyway just to show order of magnitude. That's it. We're also...

I'm just -- but are the patients as healthy, worst off, your patients healthier, worst off?

That's a good question. In this case, these are all failing these drugs, you could argue they are one row behind, and we didn't even look for that. They are all -- we only have failing patients on our study.

Okay. Good. All right. So the next 2 studies that are going on right now, COVALENT 211, 212. You're still using 100 milligrams. Do you think the food effect is going to influence compliance at all? Or do you think people are pretty adherent to having, let's say, having breakfast and then taking their drug at 30 minutes after.

What we're actually asking is the major meal. That's kind of what we wanted because we really needed to figure this out, and we now figured it out. We actually spent quite a bit of time understanding what is the impact of food on the drug before, after, without food, fasted. And these are the instructions we come up with that, we feel consistently give us less variability. You can't predict everything. But this is fairly -- we think we're going to increase exposure with that. We should have better exposure in our next study because of it. And it just allows making it all the same versus some guy in the morning without food, the next guy after a heavy meal. That is different exposure, and we needed to learn this, and now we know.

Right. Okay. And then typically, the FDA likes to see multiple dose exploration. Any thought to -- I mean...

We've done that. We've done higher, we've done lower, and we can show that this is -- we think, with a safety profile that we didn't want to jeopardize a very, very good dose. And when we go lower, we can achieve the results.

And the GI tolerability is good enough that you can get one for the therapeutic dose.

I mean the dose is our safety profile. I want to show you the upper combined arms. And if you look at combined arms icovamenib, in the bracket is the percent, we're like equal, except liver Grade 1, primarily Grade 1, these are -- because you have a drug, the liver says, hey, something go off...

Yes, sure. First pass.

First pass. And so we have 3% and 2%, grade 1 liver. That's it.

The important thing on the liver is that these effects disappear while we're continuing to dose and so they go back to baseline and so we don't believe it's a serious issue. It's more of an adaptation than a toxicity.

Right. Okay. Let's see. All right. Let's talk about the patient enrollment criteria. I think it's worth spending a bit of time because we've used this 2 terms a number of times in our discussions here. One is an inadequate response to insulin. How do you quantify that? Also tell us how you define severe insulin deficiency. And what's the difference between -- there's a nifty slide in your deck that talked about patients who are insulin deficient versus insulin resistant and you're going into the insulin deficient population. So maybe talk about the choice that you made there.

So you want to discuss the enrollment criteria. So to create a new category for a body that is governing all of us is really difficult, the FDA, I understand that completely. We needed to find a standardization that we could use that people could reference that we not willy-nilly come up ourselves with. So that's why we use criteria and academia had agreed on, there are 4 different types of diabetes. And if you read the literature, you can see, in general, people agree with that. The algorithm we used was the most quoted algorithm on how to identify those patients.

That is not the way the FDA wants us to run more regulatory-oriented studies. They want standard inclusion/exclusion criteria. As you can read them here. Now they bring us very close to those patients. It's not a perfect landing, but good enough that we feel this is a path forward. If you have a BMI that is not in the obesity range, less than 32, if you have HbA1c that is elevated, 7.5 to 10.5 and you have been -- you have -- you're failing your current therapies, which puts you further into the disease progression. We don't want you early...

And failing -- and Ramses, failing, it means what? Increase in hemoglobin A1c, reduction in CRP. What are we measuring, is it the constellation?

It's typically your A1C is above 7 and it can't be controlled.

Criteria of 7.5 and above. So anybody who's 7.5 and above is by definition poorly controlled.

We want you to have failed a prior agent where the physician says, look, this agent had an effect, no longer has an effect. They got to find another one. that's where we define ourselves. And you can go up to 3 failing agents. And sometimes they get stacked on top of each other. And so that's 211. This is characterized as a severe insulin deficient patient. You could argue, are there other criteria? Yes, you could look at other criterias. But in the bulk of the definition of where we saw the response was statistical analysis. This explains 70-plus percent of the responders in a very a predictable way, easier predictable than other criteria that are too specific, and you can't find the patient.

This enlarges the pool quite a bit and it makes things -- it smoothens out the curves, at least from our perspective. If you look at 212, the criteria is fairly simple. You are either overweight or obese, okay? That's defined by BMI and 25 to 40, and you have high HbA1c above 7.5. And that's kind of where -- that's the patient that we saw in the study 211 -- 111 and that we're now enrolling in 212, pretty simple.

Right. And it's interesting to me, 212, the body weights are relatively low for that population.

Yes, that's true. Very true. And I thought the same thing when I looked at all the data sets and I thought interesting, it's the driver -- the GLP-1 is the driver that allows together with a menin inhibition to create this response even in somebody who is not necessarily obese, just overweight.

Right, yes. Okay. And just as far as 212 is concerned, you have a much wider range of BMIs. And to your point about the greater the obesity, the lesser the response, do you -- are you concerned that you may not see the same kind of impact on clinical outcomes with a heavier population than you would in 211?

Well, you see that 212 has -- I mean, I don't think it matters much. We could have gone at 10.5. I don't think it would be necessarily much different to tell you the truth. But the higher you go, the more placebo will be failing. And if placebo is failing, then you can't use them because then they're on rescue and if they're on rescue the patient has gone for you in the database past that point.

But you want to have patients that you can follow down a year, if a patient doesn't want to come back because he's on placebo and he's failing and he's on rescue, you -- one, you lose them on rescue and two, can you get them back? And it's a dance 10.5, 9.5. I tell you, I don't -- personally, it's an opinion of mine. I don't think it matters much, either of those 2 studies.

Okay. And just time lines, when are we expecting readouts for 211 and 212.

So we are -- we said publicly, we -- one, we initiated the studies, that means you have to get the sites identified, you've got to sign contracts, you've got to negotiate all of this. We're in the middle of this and we are starting enrollment very, very soon. You should see press releases coming out soon. And that means up on clinical trials, there is a heavy push then on enrollment, which will last very likely for the next 3 months when we hope to have 60 patients in both trials enrolled.

Why is that important? Because our goal is to finish the 26 weeks data readout of the last patient enrolled before year-end, so that could be data in before year end. And that's...

Okay. It could be easier or both.

No, both. I mean, I tell you the goal.

That's the goal.

I mean, we're all humans, but that's the goal.

Yes, yes. Okay. Wonderful. Can you -- I had always thought that icovamenib was also a really interesting drug for type 1 diabetics, and that's -- there's a real unmet need there, not a lot of novelty. We've got Teplizumab, We've got the SAB-142 to preserve beta cell function. We've got the transplant from Sana, from Vertex. But what -- where is your attitude? Where is your head at on Type 1? Is it going to wait for the data to read out in the second quarter?

No. So we're going to have data readout in the second quarter of this year, meaning the next couple of months.

It's a 52-week data, right?

Yes. So we've done a proof-of-concept study in patients that were 3 years from disease identification and patients that were 3 to 15 years from disease identification. Now if you look at every one of them, you just quoted, except maybe the stem cell transplant. If you look at all, everybody is trying to get a patient within 90 days of the disease identification because there is still enough beta cells there. We asked a different question. We asked a question of even if there are no beta cells there are very few sporadic patches, can we have an effect there? What would that look like?

So it's a proof-of-concept study at 2 dose levels with 20 patients over 2 big cohorts, 0 to 3, 3 to 15 and in different dose ranges. So very little data, but it will be directional hopefully. And the direction that we hope to see is, can I -- and this is kind of what everybody is trying to do. C-peptide is the hallmark of your betas cell health. And as C-peptide goes down with the attack of the immune system on your beta cell, how quickly does it go down? And the literature, if you read up on it, it says about 47% per year, and it goes down that 47% every year.

And by year 3 or year 4, you are so low, then it's mostly gone. That's why everybody is shifting up front here. We said 0 to 3 years for a reason because we think within that time frame, we can still have an impact on that depleted pool of beta cells. That will be, for me, the most important update in the 0 to 3 category and thus those 100 or 200 have an effect on these patients. That's what we're going to show in the second quarter, very exciting.

And the companies you just mentioned, SAB-142 is the one who just came out last week with 4 patients, and they saw at 2x dosing, right? And -- but it's the AUC that they looked at this patient over here, which had been on drug for -- had been identified 4 years ago. very interesting data, very interesting pathway. So that's one that is making a headway. But other than that, there is nothing really in type 1 diabetes.

So Teplizumab is stage 2. They're not Stage 3, which means you have the disease. When you have the disease, you have insulin as your only agent. So there, I believe, from our planning perspective, the FDA and we are both -- or the whole community is in need of an agent. And so we hope that we can show efficacy there and collaborate with everybody on getting something.

Yes, because it would seem to me if you're expanding a pool of beta cells or even keeping them in stasis while you still have an immune attack, you're going to need both components of it. So anyway, that's down the road, but we're going to -- we're running short of time and I know we started a little late, so I'll run a couple of minutes over, but not much.

I want to shift real quick to BMF 650 in Phase 1 initial readout in second quarter of '26. Give us your thoughts where you think it fits in? And I don't know that there's another crowded space like GLP-1 agonist. And is it sole purpose to be an adjunct to icovamenib or do you think it has its -- the chops to stand on its own?

Yes. I think that's going to be a great deal dependent upon what data we find from this trial. Now the molecule was designed and we have at least preclinical evidence to suggest that -- it has better pharmacokinetics. It may be a bit less potent, but it seems to work very well in the monkeys, and I think you've seen that data before. And so we think from this particular trial, we'll be looking for a couple of things. Number one, I think to be in the game, we're going to obviously need to have a similar type of weight loss. It doesn't probably need to be any better because I think all the things that you're looking at out there now that are potentially oral have a similar type of weight loss, 3% to 5% after 4 weeks. So we'll see what comes out of that.

But our main thing in terms of where we think we might go forward is if we've got a better safety profile and if we can titrate up in a more patient-friendly way, some of the drugs that are out there at the moment, they take a long time to titrate up to the dose where you actually are...

Mick, you -- speaking of that, do you want to show your titration because I know that's something that you put in your deck. Show your titrate -- there you go.

Yes. So what we're doing there on the right-hand side at the bottom there is the uptitration. And you can see we're uptitrating to 100, uptitrating to 200, 300, 400, those are the 4 doses in the multiple ascending dose group. On those data are the data that will be available at the end of the second quarter this year. And the important thing will be, as I said, the side effect profile, we think that we can probably uptitrate a little faster. And that if these are well tolerated, they could be a very useful way of getting to a weight loss dose very quickly.

And then longer term, we think that within this space, everybody has sort of tried to go after massive weight loss. And people lose weight and they go off drug and the weight comes back on again. And we think with an oral drug, a better strategy would be to drop the weight and then back titrate so that you maintain the weight and basically sort of kept at whatever way you were trying to get down to. And so our expectation is that, that will be something that will be more feasible with this type of drug.

Right. Can you also talk about -- I know in theory, I think there's the opportunity to combine 650 with icovamenib but have you done anything further to try to elaborate on that? Or are you waiting for the results to come out to see...

We want to see what goes on here. But I mean, again, while there is always the possibility of combinations, especially with 2 orals. The reality is there's a lot of GLP-1s out there at the moment. And so what we've done with icovamenib is looked at the combination data with semaglutide. And we'll be including that obviously in our 212 trial. But in animal studies, we've been looking at it not only in terms of the antidiabetic effect, but also weight loss.

Okay. And just a quick question before we wrap up on IP. How do you feel about your IP position? We saw that Roche paid $100 million to Structure Therapeutics to get access to their IP? Do you have any thoughts about whether your 650 reads on their IP or not or anyone else's for that matter?

We feel very confident that we have a selective patent, and that we will be able to keep others out of the space.

Okay. Great. Anything I've missed that you want to mention in closing, I don't see any questions pending in my e-mail. So if there's nothing, any concluding remarks you guys want to make before we close it?

If you ask that invitation, Mike, you're going to get a long answer, but...

What I'll say, first of all, it looks like you've got like some nice milestones coming up. You got the second quarter where you have the type 1 diabetes full 52-week readout, you have your initial data from 650. Then by the fourth quarter, let's see, knock wood, we got 211 and 212, so you certainly have a list of maybe identifiable...

There is a great need. Just remember that there's a great need in diabetes. We have a lot of agents, but they're not serving the need properly. Because of the depleted pool of beta cells, we're trying to go with the symptoms, but the symptoms management failed at some point, you need insulin. So there's a great need, one. And two, we have identified the biologics through others, there menin has a role in the pancreatic sort of functioning, menin controls. We have then isolated in animal experiments that, that is actually, if you take out menin or you inhibit menin function, you have a beneficial effect.

We then went to the human islets, and we identified it there as well. And now we're in the humans then we see, gee, there as well, in particular, in patients that are insulin deficient, we have a very beneficial effect and then also in patients that are failing the GLP-1 therapy.

Now that's very, very clear from us as developers. I got my bread crumbs, I figured it all out. Now I'm in the clinical. And now I go to Phase II to validate those early signals in a larger study. So that study reads out by year-end. We feel very confident that we can replicate the results we've seen. And then -- and this is what I'd like you to think forward with when I have my end of Phase II meeting, and I can show the benefit that we create with no or limited risks, then if I can move this into a Phase III, do I need big brother or big pharma to help me? No, it's not a 5,000-patient study, meaning we as developers can do -- we've done many Phase IIIs. We can do a Phase III of 300, 400 people. No problem.

If I can then move the value creation into the Phase III, and we have this conversation in a year or 2 years from now, and I'm ahead of becoming a commercial asset then you should do the modeling and ask the question what value does icovamenib have to the industry? I can be thrown into any drug. I can be thrown at any point of the journey in diabetes because I don't add toxicity. I'm not a chronic agent, et cetera, et cetera. That's the future story that we're trying to sort of accomplish.

All right. Well, we will certainly stay tuned and we urge investors to take advantage of the modest valuation that shares present right now because that's not going to -- yes, it's not going to stick around forever. Anyway, guys thank you so much for taking the time. I appreciate the willingness to go deep on the science.

Thank you, Mike.

Bye-bye.

Welcome, and thank you for standing by. I would like to inform all participants that this conference call as well as any Q&A may be recorded and made available to clients of JPMorgan. Where a company is presenting any recording may also be posted on their website. Views and opinions expressed by any external speakers on this call are those of the speakers and not of JPMorgan. Parts of this conference call may also be reproduced in JPMorgan Research.

Participants are prohibited from posting, sharing or distributing any part of this call or its content on social media platforms or any public forums without prior written consent from JPMorgan. If you have any objections, you may disconnect at this time. This call is intended for JPMorgan clients only. Plus participants are not permitted on this call should disconnect now. Unless otherwise permitted by internal JPMorgan policy, members of JPMorgan Investment and Corporate Banking are not permitted on this call and should disconnect now.

I would now like to turn the call over to Anupam Rama to begin. Please go ahead.

Thanks, operator. Thanks, everyone, for joining the call. My name is Anupam Rama. I'm one of the senior biotech analysts here at JPMorgan. I'm joined on the call by Joyce Zhou, Rati Pinge and Priyanka Grover from the team.

Today, we're continuing our 2026 JPMorgan Biotech Conference Call Series with Biomea. We have Mick, Ramses and Thorsten should be joining here in a second from the team.

Guys, we have a lot to get through here in the next 30 minutes. So maybe we'll just hop straight into the Q&A. So the Phase I data for BMF-650, the oral GLP-1 receptor antagonist is expected in 2Q, which is technically tomorrow. So just to set the stage here for 650, this is a compound that's built upon the orforglifron scaffold. What are the key attributes of the molecule itself that translate to potentially addressing the unmet need clinically and commercially in obesity?

Thanks, Anupam. I would turn this question over to Thorsten in a minute. He was the guy who actually was responsible for putting this molecule together, and he's running the program. But what we're trying to get out of this molecule is, number one, oral, which is similar to orforglifron; but number two, better pharmacokinetics, which could lead to better tolerability, and we are testing that in our Phase I program. Is Thorsten available?

We are currently trying to make Thorsten a speaker, so that they can speak.

Should I go on?

They can go ahead and talk. Their lines are open.

Okay, Thorsten, are you on?

Yes , Thorsten, you can unmute yourself.

So thank you very much for letting me in and let me be part of this discussion. Yes. So BMF-650, the upside of the molecule. So when we looked at the chemical space, we believe that in the orforglifron chemical space, the PK of that lead compound really wasn't optimal. So a key attribute of BMF-650 is very good, smooth PK and a high oral bioavailability, which leads to less interpatient variability down the road. That's what we designed into the compound. So we are hoping for this. We're seeing this.

And we also looked at the intrinsic potency of compounds of this chemotype, and we believe that this 1 milligram starting dose in a 2.7 meter intestine, we never distributed well. So we took a little bit of potency out, so that the edge when people are being introduced to the compound for the first time is off. And I think this is a very good design, better PK and slightly less intrinsic potency at the beginning of the titration phase.

So we believe that people will very quickly get to a pharmacologically relevant dose and that the titration is not such a drawback for a compound of this class. So we have -- yes, we believe that's an asset and the design feature of the compound.

Can you remind us what is the size and scope of the Phase I update that we're expecting here in 2Q for 650. And just remind us of the key tenets of the trial design.

Yes. Thank you very much for this question. So any compound that goes into the clinic first will actually have an SAD, so a single ascending dose phase and will have a multiple ascending dose phase. So our single ascending dose phase essentially has 5 cohorts where we dose titrate up single dose-wise from 10 milligram to 200 milligram single doses who they are already then establish safety tolerability for the compound and also the PK that we wanted to see for the compound. So this phase has actually already concluded.

The MAD portion of the clinical trial is ongoing. Here, we are dosing in 4 cohorts, 10 individuals per cohort. It will be 8 and 2 active versus the placebo. And we have here healthy individuals that are overweight or obese, so nondiabetic, and then we will track the weight loss in what in the end amounts to be a 6-week single daily dosing strategy, where we have essentially a 2-week up titration phase and a 4-week hold as a titration target.

We have titration target of 100, 200, 300 and 400 milligrams. So we'll be able to read out essentially the normal 4-week weight loss period when you titrate. And we also have essentially the weight loss when we hold for 4 weeks titration target. So this will be giving us multiple dimensions of data readout. So how does the titration look and how good is 4 weeks a titration target already with respect to weight loss. So we believe we will be extracting a very good amount of data out of our very first-in-human study for BMF-650 with this design.

With all that being said, Thorsten, can you -- how many patients we're going to be getting in this initial 2...

Yes. Okay. Sorry, I may have run past this. So in the SAD portion, we will have 40 individuals over the 5 groups. So a split of 6 who get the drug and 2 placebo. But more importantly, for the MAD in our 4 cohorts, overall, we will have 40 people. So every cohort has 10, which we will be splitting into 8 on active and 2 placebo. So sorry if I ran past this too quickly.

What is a win scenario from your perspective in this initial kind of Phase I update for 650? What are the reference comps that we should be considering in the competitive landscape?

Yes. Also a very good question. And I feel people sometimes think about this one dimensionally, just how much weight loss do you get over the time. This will be a key feature. But I think there are 2 other features that needs to be in this triangle of balance. One is how quickly can you dose up titrate, right? And how much GI disturbances do you see on your way up to the titration target. So those 3 things need to be looked at then in [ red ] balance.

And I do believe, though, that orforglifron in its original reported 4-week up titration and weight loss study will be a good reference point. There, the placebo group lost essentially 2 kilogram. We never know how much percentage it was, but it was only reported absolute and then the highest dose lost 5. So you could argue either you are looking around 5 kilograms or 3 kilograms placebo adjusted.

So in this range, I think one should look, but then very much have an eye on the side effects observed towards generating these weight loss numbers.

You'd point us to the actual absolute magnitude versus a percentage.

Yes. So I have pointed in this direction because there is this paper that one can easily point to and is essentially on very solid ground saying, please compare to this. The field has certainly evolved to a degree multiple GLP-1 small molecule receptor agonists are out there.

And essentially, the 5 kilogram, 5% weight loss mark is kind of where you have your eye on, but I think it's not the only parameter to look for. You kind of need to be in that range. I mean weight loss need to occur, but really check GI side effects largely. And how quickly could you get there? And how quickly -- how high was your entry point of your titration versus target because this will, in the end, unfold to either 6-month titration strategy like orforglifron has it or potentially just 2. And if patients essentially see the weight loss earlier because they didn't need to titrate so slowly, they might be much more happy with the product that they are actually using.

I think the key element is patients with more weight tend to lose more weight. And so this is why people have generally moved towards percentages. But in terms of a comparator, we only have the orforglifron study in which they did not give percentages. They only gave actual kilos.

Yes. Okay. Okay. And then the other way to think about a win would be just did you titrate faster? And I think you said GI AEs.

Yes, exactly.

And then let's say, pending positive data here in the initial Phase I study for 650, how are you thinking about the potential range of next steps in studies?

Yes. There's a lot of pieces, and we have obviously to go into a longer-term trial. I think if we can uptitrate quickly, you can look at the longer-term effects fairly quickly. I think the goal ultimately, however, is to sort of not just look at how much weight can you lose over time, but maybe how you can keep it off because most of the studies that have been done so far, you go on the drug and then you stop it and all the weight comes back.

And I think what we want to do is think about more sensibly how do you lose the weight at an appropriate weight at an appropriate rate and then think about how do you back titrate in a way that keeps people at the weight they want to be rather than taking them off drug and seeing them jump back to where they were in the first place.

Okay. Maybe switching gears then a little bit. Broadly speaking, what would you say are the top 2 or 3 most misunderstood aspects of the icovamenib program by the Street?

Yes. I'm going to turn this one over to Ramses. He's put a lot of thought and effort into this, and there's a lot of moving parts, but I think he can address them nice.

Yes. So 2 to 3 is difficult. Let's start with -- but I'll go fast. Let's start with the space overall. Does the space need a new agent? We have a lot of agents out there. They're all chronic. Every agent that you take in diabetes is a chronic agent. They all address one way or another, the over -- the effect of too much glucose in your blood.

None of them are addressing the functional or the dysfunction your body has in conquering this problem in a healthy person. A healthy person has a sufficient pool of beta cells and the beta cells produce insulin and they take up the glucose. That's how it should be. We're doing symptom management and half of the patients out there are uncontrolled, meaning they're on these drugs, but their HbA1c is too high.

So about 1/3 of all patients move into insulin dependency as the last resort. So first point that is misunderstood is that this diabetes care is leading to an insulin dependency for 1/3 of the patients. And we, as a new mechanism of action are addressing exactly that. We don't play into the initial treatment phase, but we try to help a patient not to get there when all standard of care fails, icovamenib steps in and takes your pool of beta cells, and that's the goal of the drug, improves the dysfunctional pool of beta cells and enhances them, restores the capacity so that you do not have to end up on insulin.

It's a nonchronic agent, very, very key. You don't have to be on the agent. We restore the healthy or the functioning pool within 12 weeks. And you end up with a benefit that you otherwise can't achieve, right? So we're basically giving you a new lease here that you could -- if your lifestyle changes could potentially lead to a long-term benefit.

Now many people will not do that. They will need another dose of icovamenib over time, but the drug is designed for complete restoration. And we're designing studies right now where the endpoint is 26 weeks primary, 52-week secondary endpoint. And with that body of data from those 2 studies that we're doing right now, we go to the FDA for an end of Phase II meeting, and we are planning to go into Phase III next year. That's not easily understood that's how far we are along in this.

We have biologic clarity that this is happening in the pancreas, not from us, since about 20 years, you can read up on papers where people see menin is the culprit or is the checkpoint. We have evidence in animals that we can show to you. And we have the islets, the human pancreatic islets where we've done the experiments. Now we're in the humans, and we see the same effect. So we feel very -- we have a very solid base of why we're doing what we're doing, and we can predict the outcome.

I'm going to turn it over to JZ from the team. She's got a few questions.

Thanks, Anupam. So digging deeper into icovamenib, 52-week follow-up data from the COVALENT 112 study in type 1 diabetes is expected in 2Q. What would you have us look at within that update?

Yes. That is sort of a program that comes out of nowhere, right, because everybody is looking at type 2. This is a proof-of-concept study that we started. And we have 2 cohorts there. We're looking at patients 0 to 3 years since diagnosis and 3 to 15. There is hardly -- you will not find any study out there that looks at patients 3 to 15. They all look at early onset.

And what we wanted to see is what benefit can we give to these patients in general in type 1 at various doses with these 2 different subsets of patients. And it's about 20 patients overall, meaning these increments where we hope to see responses likely in the 0 to 3 and likely at the higher dose is a handful of patients. But overall, we will show you 20 patients.

Got it. And then -- going back to type 2 diabetes, how is enrollment going in both COVALENT 211 and type 2 diabetes and COVALENT 212 and type 2 diabetes in patients not controlled on a GLP-1. Where are you in terms of site activation on both? I believe your guidance for data from both studies is 4Q this year.

Yes, that's correct. So all that is correct. We are still holding on to that guidance, which is a tough one, but we do think because of all the understanding we have of the market, of the investigators of the sites, we will achieve this target. So right now, we have engaged with about 20-plus sites. They're all up and running, and we're now getting site initiation visits, all these workflows done so that we will start enrolling in Q2 and hope to finish enrollment of these 2 studies in Q2, so that we have a readout by year-end. Everything is going per plan at this moment.

Great. I will hand it back over to Anupam.

Sure.

Ramses, maybe you could expand a little bit about outlining what a win scenario looks like for COVALENT 211 and 212 programs in this 4Q update.

Yes. So we have quite a few updates that are really meaningful. It's one, the type 1 update coming in Q2. Then it's the 650 that we talked about earlier also in Q2. And then at the end of the year, we will show those 2 Phase II studies that are now going after type 2 patients, those are identified to go into Phase III.

And so those studies, typically in type 2 diabetes, your endpoint is reduction in HbA1c. And when you look at what FDA has approved in the past, they have approved 0.5 as one of the benchmarks. And our studies have shown 1.5%, 1.8% placebo adjusted in an all-comer study.

If we hit anything above 0. 5, we're good, meaning we feel that's a win. Now how far can I get it? It depends on the patient, it depends on the numbers, on the type, et cetera. You can't get it as precise as you want it. So 0.5 and above for an agent that is not chronic would be a win for me.

The other part of that, I think, is really we've seen in the 2 patient populations that we've showed today that we have a reduction at 26 weeks and then there's a reduction at 52 weeks, which is even bigger. What we don't know is how long that persists for.

And I think that's part of what we want to show as a follow-up study to 211 and 212. So the win will be ultimately, if it's still coming down at week 52 weeks, which would be a sort of recap of the data that we've just produced in our 111 study, then we think that that's a win too because then there is a very strong probability that this is going to be utilized significantly instead of injectable insulin to sort of bridge that gap between when you're failing on all the other agents that are currently out there and when you have to go on to insulin.

Just to clarify, so the 0.5 that you're talking about as a win scenario, that's for 211 and 212?

Each one. Yes, either one.

Yes, that type of...

Above. I mean, 0.5 is your bottom hurdle that you have to clear. DPP-4 was approved for that. They look at risk and they look at the -- what do you give to the disease and what do you take from it. So if I truly keep somebody off insulin, right?

And this is your next step, meaning I take the last line, and I say this patient, standard of care has failed him, HbA1c is rising. We can bring that down by 0.5 and continuing over time, not being on a chronic agent. It's a win. I mean it's a win for the patients, it's a win for the FDA. But obviously, our goal is that this trend continues and improves even further. But my minimum hurdle would be 0.5, yes.

So can you speak to that? -- sort of you talked about your -- I think recently in your press releases talked about data from some of the chronic toxicology studies, right?

Yes.

Pending the data that you see in COVALENT 211 and 212 and Mick has kind of alluded to this, how does your chronic tox work evolve your thoughts on development program?

Yes. And it's an interesting question because you kind of -- you're hinting towards now that you can do longer-term dosing because we were limited by the tox we had. Now we have shown in 2 species that longer tox is okay. We don't see signals there or we think we don't, and the FDA will probably agree with us, do we need it? And I think there will be subsets of patients, not the 2 that we have in our Phase II studies right now. We feel 12 weeks is fine.

The results are stellar if you just look at those subsets. But there could be subsets where, for instance, in type 1, where longer dosing does make sense or redosing does make sense or there are patient subsets where it could be beneficial to have longer dosing.

But like the focus that we're currently on is not limited by the tox, but it's the outcome that we're achieving, we think, is sufficient. It's continuing and it's beneficial to a large degree for those 2 subsets in type 2. In future patient populations, particularly like type 1, I believe a longer-term dosing could make sense, and that's in the discussion.

Okay. To round out the call here. Can you remind us of your cash runway and position? And just remind us what key milestones are assumed?

And Anupam, you have it in your report as if you're one of the star criticizers of our cash position. There is -- it's always a balance, right? Over raise, under raise and you don't want to dilute too much. You still want to produce good valuable data for everyone, and we're all shareholders. So our cash today that we have is $56 million at the end of last year, and it will last into 2027. What does that mean? Somewhere in Q1 based on what our auditors have identified as our spending plan, we were running out of cash. But what do I buy for that cash? I buy type 1 data readout, which could be transformational.

I'm not saying it is. I'm just saying it gives a new potential, which is big, and there is nothing approved in type 1, as we all know, at least not in Stage 3. So type 1, can we open a door there? Yes, no, we will see. Then we have 650. It's an oral agent. It has new PK. And Pfizer has just paid for an Asian compound that is also oral, over $100 million as an upfront, not just now, but recently.

Preclinical.

Preclinical. So we have to see what the value of that is. But that's an interesting update, which is coming at the end of Q2. And then you have the 2 updates coming before year-end in our Phase II, which are 26 weeks primary endpoint data. All that is part of the current cash.

Now the cash is always tight in biotech companies. We've reduced the size of this operation from spending a lot to spending really only for those programs I just mentioned. We're not doing any more groundwork research. We think we're done with that. We have released those former employees just to focus on clinical development, quality, CMC and all those those key departments.

So we're right now running lean at 40 people. The spend is really focused. And when do we raise is probably one of your next questions. And the question is always, it depends, right? We have enough power to get to where we need to get to. And if things work out the way I think they will, we will raise along the way, obviously.

Mick, Ramses, Thorsten, I want to thank you guys so much for taking the time. You guys have got plenty of updates coming here imminently in 2Q, which is -- and we look forward to the updates. And I hope you guys have a great rest of the week.

Thank you. Very good. Thank you.

Thanks, everyone, for joining.

And that concludes today's call. Thank you all for joining. You may now disconnect your lines.

Welcome to the 44th Annual JPMorgan Healthcare Conference. My name is Anupam Rama. I am one of the senior biotech analysts here at JPMorgan.

I'm joined by my squad, Priyanka Grover, Joyce Zhou, and Rati Pinge. Our next presenting company is Biomea Fusion. And presenting on behalf of the company, we have CEO, Mick Hitchcock.

Yes. Thanks a lot. Good afternoon, everybody. Thanks for coming. I want to thank JPMorgan for putting on the conference and for inviting us to give a presentation so that everyone can see what we're doing.

Also, just for context, my name is Mick Hitchcock. I'm CEO of the company. I've been on board since about March, and I'll jump right into the presentation.

First, of course, is the legal disclaimer. And I think you've probably seen enough of these after 3 days that I don't need to dwell on it.

I think everybody knows what it says. So in terms of what Biomea Fusion is working on currently, we are developing 2 assets, and we believe that they're both significant contributors to our new focus, which is diabetes and obesity.

Icovamenib specifically at this point is targeted at diabetes. It's an oral small molecule. And what I'll talk to you about is some data that we got out of this Covalent 111 study and then tell you about the 2 patient populations that we have significant activity in and then talk about where we're going next.

On the other hand, more recently moving into the clinic is a program with an oral GLP-1 receptor agonist, and this is called BMF-650. It's targeted for weight loss. It's an oral, again, oral small molecule, and we're in a study, a Phase I study now called GLP-131, and we are looking at enrolling obese patients so that we can study weight loss.

So just in terms of giving you some background in terms of what we're looking at, the existing type 2 diabetes treatments tend to address the symptoms and not the disease progression itself.

And what we have here is a plethora of names, different drugs that have been developed over the last 30, 40 years, and they all address the symptoms, but not the root cause of diabetes. And you've seen all these things like metformin and dipeptidyl inhibitors, DPP4, I can't even say it, thiazides, et cetera, and GLP-1s.

And I think there's a lot of drugs out there. There's been 60 that have been developed, but they all address symptoms. Icovamenib, on the other hand, is a selective and partial menin inhibitor targets a pathway that has not been addressed to date.

Now the root cause of diabetes is driven by progressive beta cell failure. In this graph, what we show is that your beta cells that you you're given after you get to about age 2, they increase maybe a little bit up until your age 20 and then they go into a decline.

And you can see this number going down over time. By the time you're diagnosed with diabetes, you've usually lost about 50% of the cells, and you will continue to lose them even when you're on these particular therapies.

Now diabetes itself is a big health problem. In the U.S., about $1 in every $4 is now currently spent for health care of diabetes patients.

So there's about 35 million with type 2 diabetes. And of those 7 million are considered insulin deficient, and they are one of the targets that we'll be looking at in this presentation.

So let's start with the results, and this is really where I want to sort of engage you and get you excited about what we're doing. You can see the green bar at the left. This is the treatment period.

We actually treat orally once a day with 100 milligrams just for 3 months. And then we follow the A1c over time. You can see it goes down over the 12-week period. But then when you stop dosing, it continues to go down.

Now every other drug that I showed you previously, if you stop dosing, basically the A1c will return to baseline in no time, certainly within a month or 2. So the fact that it goes down by 26 weeks was pretty special, and we announced that data earlier in the year.

Of course, the expectation was then, well, okay, if you follow them for longer, it will either flatten out or go back up. But in fact, as you can see here, the 52-week data show that it continues to go down and that you get overall about a 1.5 reduction when you consider the placebo-adjusted rate.

So that's pretty significant, and it's pretty similar to many drugs that have been approved. And we feel that for that reason, this gives us a lot of credibility around dosing.

Now what you'll notice here is that there's not a lot of patients, and these were pulled out of the trial that I showed you earlier.

And so I'll show you later how we're addressing that particular criticism. Now why does it work? Well, this is a measure of insulin production. It's called C-peptide.

It's the piece that gets cleaved off of insulin after insulin is made. Insulin gets used up, but the C-peptide remains. And so it becomes a measure of how much insulin has been secreted.

You can see it goes up over time, and it continues to go up after we finish dosing. And so we believe that, that is based on the fact that we increased the number and the productivity of these beta cells in the pancreas.

Now obviously, it's a great theory and all the rest of it, but what leads us to have credibility around that is actually a couple of things, and I'll talk about them in the next slides.

Menin, which is the target for a drug, it suppresses beta cell proliferation and function. And so if we inhibit menin, what is going to do is to lift that break on the replication.

And a short week -- a short 12-week dosing period is good enough to allow beta cell regeneration and that continues post treatment and drives the sustained A1c picture that we show.

Now there's also the question of, well, does this work? How does this work in normal situations? Well, one of the situations that we looked at in terms of where menin controls the beta cell proliferation is in pregnancy.

And you can see this particular publication that was put out talks about how when you have a pregnancy because of the extra mass in the pregnant woman, we do get occasional cases of -- sorry, I'm blanking on the neck.

We do get diabetes in pregnant women, but it's not very often. And the reason it doesn't happen mostly is because menin is being suppressed and we get the extra cells being produced.

This has also been showed by studying in cadavers of pregnant women, and you can actually see in the pancreas that there are more beta cells.

So icovamenib has been shown to directly inhibit menin. And so what it's doing here is essentially recapitulating what happens in a normal pharmacologically relevant process and it enables us to give us a sort of rationale for why our drug is working.

Now obviously, in the people, we can't go in and pull out their pancreas and look at their beta cells. But what we have done here is in 2 studies that are shown in this slide.

On the left-hand side, you see the studies in rats, where you can show that if you give icovamenib, you increase the number of beta cells. And unfortunately, I don't think you can see the little red dots on the bottom right-hand corner of that 4-panel block.

But insulin production is increased in those situations when you give icovamenib, and that's because you're actually causing proliferation because you're inhibiting menin.

On the right-hand side, what we've done is a similar type of experiment, but these are with human isolated islets. And what we can see there is from 2 different donors. If you just add the solvent, you get a certain amount of insulin production.

The insulin production is shown by the green stain. On the right-hand side, when we've treated the cells with icovamenib, you can see much more insulin production.

So while we can't actually show that these cells are replicating in the humans, we have enough preclinical data and evidence that, in fact, that's what the situation is happening and that's why when we give the drug for 3 months, you see an increase in production of insulin and then it's maintained going out through 52 weeks, even 9 months after you've stopped dosing.

Now within the study that we did COVALENT-111, there was another group of patients where we found a significant effect and this is a different group of patients, but these patients came into that study on a GLP-1 agent.

In order to get into the study, they were considered failing their regimen because the target dose that you're trying to get to is 7% A1c, and these guys came in at 7.5% or above.

So they're all failing the GLP. We found these 12 patients, who were on GLPs. We kept them on the GLPs, and we gave them 3 months dosing of icovamenib.

You can see again, there's a decrease in terms of the A1c in the icovamenib group compared with placebo. And then again, once the drug is stopped, the effect continues, and it goes down at 26 weeks and it goes down at 52 weeks.

And again, a significant drop, minus 1.2 there. And when you look at other drugs in this therapeutic area, if you can get anything greater than 0.5 effect over 6 months, that's usually considered enough for registration.

If you look at some of the other drugs, they might have a 1 or 1.5, but I think we're in a similar ballpark to some of the other drugs in terms of potential registration.

Now again, the rationale for why does this work? Icovamenib, you can see on the left-hand panel there, if you give icovamenib, you increase the amount of GLP-1 receptors on the pancreatic beta cells.

And on the right-hand panel, you can see that it also increases insulin production. Now what about the safety? It's all very well to look at the efficacy of the drug, but it's safety also that's required to get you on to the commercial front.

So if you look at the first 2 columns here, this is looking at the whole study. We had 267 patients, 66 on the placebo, 201 on the icovamenib, combined arms.

And you can see here that the adverse event rate is pretty similar between placebo and icovamenib. There's nothing there that would suggest any issues.

When we get to the next slide, what we're looking at now is not necessarily AEs, but specific events. And in this case, looking at ALT and AST increase, we do see some ALT and AST increases.

These are monitors of liver function. And what we found with those is that they do increase a little bit while on therapy. But if you continue therapy, they go away.

And you can see the bottom line there, resolution of those without interruption of study treatment, 100%. So they all resolved over time.

So we feel pretty comfortable that we have for 2. So looking at the overall effects, we have a durable treatment effect in severe insulin-deficient type 2 diabetes. That was the first group I showed you.

What I haven't shown you is higher icovamenib exposure leads to improve responses. What we did was we actually segmented the patients into groups of A1c reduction and the ones with the higher A1c reduction had higher exposures to icovamenib.

So we thought about that and decided, okay, we need to do another study to figure out how we make sure that all the patients going forward get a higher exposure.

And we've just finished a study. It's called 121. It was a study looking at food effect. And we showed that if you give the drug without food, you get a certain exposure.

But if you give it with food, and it doesn't matter whether it's a high fat meal or a low fat meal or half an hour after or 1 hour after the meal, then you get twice the exposure.

And so for our future studies, we now have dosing instructions that will require the patients to be dosed with food.

On the third bullet point, icovamenib increased insulin secretion as measured by C-peptide. I showed you those data. The treatment effect in GLP-1 failures continue to improve.

And those, again, going out to 52 weeks, and we have a favorable safety profile through week 52. Now somebody asked me before the talk, what is the most underappreciated fact, and I think this is it. COVALENT-111, the 2 studies -- the 2 patient populations that we showed, we have an effect.

It highlights the potential to restore endogenous insulin production capacity in patients who would otherwise progress to chronic insulin therapy.

And anybody who knows anybody who does insulin therapy knows that, that's not a great thing. So we are now offering with this treatment, the possibility of short-term oral treatment, i.e., 3 months daily oral pills rather than lifelong injectable management.

And we think that's pretty significant. So we're moving forward with 2 studies to take these populations forward and make sure that we can repeat the outcome of these 2 studies.

The first one is called 211. This is the insulin-deficient patients. And you can see there, we're taking patients with HbA1cs between 7.5 and 10.5. The BMI is not massive. They're a little bit obese or a bit smaller.

So anything under 32 we're taking. And then it's basically by looking through the data, we found that the effect is better in patients who've been pretreated with 1 to 3 antidiabetic medications.

They'll come into the study. They'll be randomized to Arm A or B. It's 40 patients versus -- 40 patients on treatment versus 20 on placebo, and we'll get those enrolled and then followed up for 6 months.

And so the primary endpoint is at week 26 and secondary endpoint at week 52. Now the parallel study, which we'll be doing at the same time, is COVALENT-212, and this will take the patients who come on with a GLP-1-based therapy.

We're restricting it in this case to I don't know if you call it semaglutide or semaglutide. I'm not sure what the correct pronunciation is. But these are larger patients tend to have a BMI in the 25 to 40 range, and we bring them in with A1cs greater than 7.5, i.e., not meeting target.

And they will stay on their GLP-1 therapy through the trial. And we have the same makeup in terms of 40 patients on treatment and 20 patients on placebo.

And so these 2 studies will run in parallel, and we're in the process of getting those going right now. So what we've showed you is mechanism of action of icovamenib.

There's a dual effect on beta cell function, increase in beta cell mass and increase in insulin synthesis and secretion and then the GLP-1 receptor expression, which is increased expression and increased release of the enhanced incretin effect.

We also get enhanced weight loss, but we are not exploring that further at this. Now the second product I wanted to talk to you about is the GLP-1 receptor agonist, BMF-650.

It was designed for better bioavailability and so that with better bioavailability, you should get more consistent efficacy. I think one of the problems with the orforglipron compound that's also an oral GLP-1 receptor agonist, it tends to have a lot of GI side effects, and so you have to titrate up slowly.

Now the data that we produced around the midyear was a monkey study. And what I've shown you here is the results from the monkeys in terms of body weight change over time. There's 5 monkeys in each group.

The gray group at the top is the monkeys get in the vehicle. Then there's the orange group, which get 12 -- sorry, 10 mg per kilo and then the green group, which get 30 mg per kilo.

And you can see after a 28-day dosing period, and this is significant in terms of the reduction in body weight is associated with a reduction in food intake.

By the time you get to the 28 days, the top dose has given you a 15% reduction in body weight and the mid-dose or the lower dose has given you a 12% reduction.

So armed with these data and all the associated toxicology, we looked at how to get in the clinic. We have a chemotype, which is similar to the Chugai chemotype orforglipron.

And so that drug has known -- not shown any LFT signals, and we've not shown any LFT signals. And as you know, the other Pfizer chemotype has had a number of LFT abnormalities that have led to discontinuation of development of those drugs.

So daily oral dosing in cyno monkeys, healthy and obese, for up to 6 weeks has led to no ALT and AST elevations. And the first-in-human study, which is ongoing, I'll show you in a second, also to date has shown no ALT or AST elevations. This is the design of the Phase I study.

On the left-hand side, you can see the single ascending dose, the SAD, and we go up 10 milligrams, 25, 50, et cetera. And you can see where we are now by the red arrow.

In each of those dose groups, there are 6 of the blue patients. They are the ones getting the active drug. The 2 gray ones are the placebos. And so for us to go through the rest of the cohorts, we'll end up with 40 patients getting single doses.

And then we'll move into the multiple ascending dose. And in the multiple ascending dose, we will have overweight or obese patients, and they will have to come into the trial with a BMI of 30 to 45.

So we will have some extra weight to be able to see them lose it in the study. We are in the process of getting ready to start the MAD first cohort that should be in the next week or 2, and then we'll escalate from there.

And the outcome is body weight, and we'll look at reduction in body weight over time. We'll get both a 28-day normal type of outcome, but we'll also get a day 42 because we -- during the toxicology, we decided we would do a 6-week toxicology study and the FDA allowed us to translate that into a 6-week in-human study.

And so we'll be hoping that we get good results from that. We've got 8 patients there who are on active and 2 on placebo, and we'll get -- we'll get the data shortly.

So the overview and the key milestones, I think, are presented in this part of the program, the COVALENT-211 insulin deficient first patient enrollment planned in 1Q, 26-week readout expected in 4Q this year.

COVALENT-212, which is the GLP-1 patients who are not meeting target. The first patient, again, will be enrolled in 1Q and the 26-week data readout in 4Q.

And then for the GLP-1 study using obese otherwise healthy volunteers. We're still in the up-dosing for the single ascending dose, but we expect to have the 28-day weight loss results in the second quarter of '26. So that's my presentation. Thank you very much for your attention.

Yes. I'll ask the first couple of questions, but there's an opportunity for others in the audience to get their questions in, just raise your hand when I prompt.

Just wondering, for both COVALENT-211 and COVALENT-212, first patient enrollment is in this quarter in 1Q. So what are the final kind of gating factors to getting that first patient enrolled?

So we've done most of the preparation. We've got the protocol approved, we've got a CRO on board for both studies. We've got the place that's going to look at all the blood work.

And so now what we need to do is to do a final selection on the sites and send them drugs so that they can start dosing patients. So we're pretty close.

And just -- I know the data is in 4Q, but broadly speaking, for each study, how would you kind of define like a win scenario?

I think a win for both studies would be to come up with the data that's similar to what we saw in the 111 study. Anything above a 0.5 reduction at week 26 is considered approvable.

So from 0.5 up, we see 0.5 as good because it was approvable, but we'd like it to be better so that it's more competitive with what type of reductions have been seen with other agents, maybe in the 1.8 to 2 range.

Questions from the audience? So let's say you get kind of your win scenario and it's compelling enough to move to the next stage. What does that look like from a clinical perspective but as well as a strategic perspective?

I think from a clinical perspective, once we get the 26-week data, we'll be pursuing discussions with the FDA to build out a Phase III program. And the big issue that everybody talks about with a Phase III program is how many patients are you going to need and how long is it going to take you to enroll them.

And we had discussions with the FDA early on about the 3 months of dosing. And they basically said, if you do 3 months of dosing, you will not be considered a chronic agent and you will not have to put in thousands of patients and do all the long-term work studying cardiovascular outcome, et cetera.

So we feel it's a smaller subset of patients that we would need to put into a Phase III. And obviously, we'd like to have those discussions and get that nailed down after we get the Phase II data.

Then maybe a quick one on 650. Just thinking about the MAD portion and the efficacy portion, what would you be looking for in terms of weight loss? What's a win scenario given the competitive landscape?

Yes. If you look at the other things that are out there at the moment, the general perspective is you need after 28 days, a 5% weight loss. If we get a 5% weight loss, that will be great.

If we get a little less than that, then it will be, well, how well is the tolerance, how well is the up titration dealt with. One of the challenges with the GLP-1s currently is that they do take a long time to up-titrate.

And I think we've seen recently some of the drugs take as long as 6 months to actually get up to the weight loss dose.

I don't know about you, but if I want to lose weight, I don't want to wait 6 months. So I think having a faster up-titration period would be beneficial.

In terms of the general development, provided the safety is good and we do see weight loss, I think what we're looking for as much as anything is not just how to maximize the weight loss, but how to give somebody weight loss that's maintained over time.

And I think a better strategy than what we've seen clinically from the agents so far is to actually use a dose that gives you a slower weight loss. But then when you get to the weight you want to be at, maybe back off on the amount of drug so that you go into a maintenance phase rather than going off the drug and gaining all the weight back again.

Any final questions from the audience? I have one more. Can you just remind us of your cash position and runway?

Yes. Right now, we don't have the 4Q numbers yet. But if you look at 3Q and you add on the $27 million that we raised, we were about $70 million at the end of the third quarter, and we're spending somewhere around $12 million, plus or minus a couple for each quarter. So as we lay out the runway right now, it gets us sort of into early '27.

All right. Thank you.

Thanks.

All right. Hi, everyone. I'm Yigal Nochomovitz, biotech analyst at Citi here in Tribeca in Downtown Manhattan. So we do this virtual C-suite fireside chat periodically. We've had many over the summer. We have many on the schedule. You can check your e-mail if you want the full lineup. Today, we have the pleasure of having the senior leadership from Biomea here with me. And I have Ramses Erdtmann, who is the Chief Operating Officer and President; and I have Thorsten Kirschberg, who is the Head of Research at Biomea.

If you are listening and you want to ask questions, then you got to e-mail me please, [email protected] and I will line up. I will [ pass it ] over to Ramses and Thorsten.

So with that being said, Ramses, I think it would be good if you could start with an overview, please, of the company's pipeline. What is the key objective in the short term and maybe highlight just some of the upcoming catalysts?

Okay. You go straight to the heart of it, okay. So -- and Yigal, we know each other since a long time. The company was started in 2017. It went public in 2021. We're about 40 people here in California. We have a focus on 2 key areas, and these are very, very relevant areas. It's diabetes and obesity. There is a program in each area that we're pursuing. The size of this problem is of magnitude because what you're thinking of when you think of diabetes, you say, "Oh, there's a lot of solutions out there that you can get in the public markets. The doctor has over 60 available therapies."

But at the end of the day, half of the patients that are diabetic today in America are uncontrolled, meaning their HbA1c is above the marker of toxicity, meaning they are now in the range where there is a problem that is occurring over time. Their HbA1c, the level of glucose toxicity is not controlled. And that's something we've seen over the years, even though therapies have come on and new therapies have been sort of created.

And what we're focused on is we're focused on the root cause of the problem, which is in the pancreas, you have cells that are depleted over time. And as they hit a low mass of about 50%, that's when the function and the mass together is not capable of managing the toxicity of glucose in your system and the insulin production that you have has been reduced to a level that you now have what we call an HbA1c that is uncontrolled, meaning above 7. That is the problem in diabetes.

What we have done is we've created a drug -- and that is -- just think about the idea that we would be the first company that is addressing the reason why you have this problem is because of this depleted pool of beta cells. We've now created the drug that takes away the control function, meaning there is a protein that controls the growth of these beta cells. When you inhibit this protein just like a pregnant woman does or an obese person does, when they do not get diabetes in both instances, they over -- their hormone called Prolactin is down regulating this protein called menin. And when it's down regulated, these beta cells are allowed to grow again.

And we've seen it in cell experiments, we've seen it in animals, and we're now doing clinical studies. And that's the study that just read out a few weeks ago, where we have shown that we did control this function, and we have seen reduction of this glucose toxicity from above 7 all the way down post dosing, there is a period of where we dose patients for 12 weeks, and then we have seen it I mean, literally dramatically go down 1.5%, 1.8% versus placebo. And that's that is severe and that is significant and that people have to recognize. This is a pathway.

We're the first to do it, which is the menin inhibition pathway in diabetes program, one that has now been in my eyes, validated to a point where we're now starting a study Phase II just designed for patients that have what we call insulin deficiency. It's about 1/5 of all diabetic patients in the U.S. that are insulin-deficient, and they look like you and me and their pancreas is not producing enough insulin, those are the patients we would enroll in the next study.

We're also focused for the second program on obesity. And we all know obesity is the biggest pharma market today it's not resolved. 36% of the U.S. is obese. 25% of -- in the world, patients or people are obese. And if you look at that, it's the fastest-growing segment. We're going to hit $100 billion in sales sometime 2030-plus. And we are focused on a program there where we also looked at it strategically when we asked the question, what is needed here.

At the time we started, all drugs were injectables that were going after obesity. So we're looking at a noninjectable, an oral agent. And the pathway that people have sort of validated is called the GLP-1 receptor agonist pathway. And we are using the same GLP-1 receptor agonist-based sort of drug structure. And we're looking at, in this case, a chemotype that is similar to Lilly's and we have improved it to a point where one of the side effects you can see in the GLP-1 space is people are having a lot of nausea and adverse events, while on drug.

About 7 out of 10 patients drop out of drug over the course of the first year. And we're trying to solve that with an oral agent that is more next-generation like that is more body harmonious. And Thorsten will go into that as we go through this Q&A. So the company is focused on these 2 areas with programs in the making there, we have a Phase I that is about to read out in Q1.

Okay. Well, let's see. So you mentioned the diabetes patient market that's the so-called insulin deficient. Can you tell us more about those people like how are they identified. And what did you see in the studies that made you believe that, that was the right place to focus for the later stage?

Yes. So when you look at diabetes as a segment, you will find very quickly that there is a large degree of heterogeneity. There's, on the one hand side, the heavy set diabetic who is obese, BMI 27, overweight 30, obese to 40 and higher. And those patients typically have an overproduction of insulin. So their body is trying to compensate and compensate and compensate. And what we're doing is we're giving you more insulin, meaning for those patients, the benefit of icovamenib is not as profound even though they will also, over time, have a failing pool of their beta cells.

But when you catch them in the early stages of their disease, we haven't seen such a profound impact on those patients. However, because the study that we just read out enrolled everybody, we found in patients that you can quickly identify just using BMI which is less -- typically not obese, and in HbA1c, which is the level of glucose in your system, HbA1c above 8. Those are indicators that show you're not resistant and you have a failing beta cell pool because you're not hitting sufficiently the glucose. And if that's the case, those are the criteria that we would go for. And we found in the readout of the study that those to a large degree, characterizes the severe insulin deficient patients.

There's other criteria you can use that are more technical, but we found those 2 plus having failed a prior agent, which is obviously, everybody who starts -- who goes to the doctor, the doctor says, "Look, use metformin, it's something that we've used for the last -- how many decades, and it's a very good agent we're coming after that. You have failed that agent, and that's where we come in and when we will apply our drug.

Okay. So you just had the recent 52-week data. What do you need to show then, having looked at that and understand that, especially in the segment you're talking about in the high HbA1c and I think it's the lower BMIs. What will be good enough additional reduction on top of all the prior therapies you're talking about in a pivotal trial that will convince the diabeticians across America and others that they should be adding the menin inhibitor to everything else to further push the HbA1c?

I think the number one thing or the number one problem, if you talk to an endocrinologist is persistence. Patients have to take these drugs every day, all day. Meaning you have to have drug on board every single day for the rest of your life. Well, 1, 2, all drugs have a shelf life. They all work and then they stop working. Oh, and then three, they get stacked on top of each other. And 1/3 of all diabetic patients end up on insulin.

Meaning ending up on insulin, which is now the thing that your body should produce that you're now giving yourself through injections on a day-to-day basis is the last thing you want to have. You are having to control your food. You're having to do all these things, and you're still not controlling the levels of glucose toxicity and it has huge side effects. Just...

We have a transmission problem. I think maybe Ramses had a freezing. I think we lost you there for a moment.

No problem. Can you hear me now?

Yes.

So when you get diagnosed with diabetes, that's the thing the doctor wants to avoid. So your question was, what is it that a physician wants from us? The physician wants the problem solved. What we believe is that we have seen first indicators that we're actually solving the core problem is we're rebuilding your pool of beta cells in 3 months. That's it. Then we stop dosing. You don't need to be on a chronic agent. You don't need to have icovamenib every day. We have rebuilt your pool. We have seen the effects of this pool now being active, your HbA1c is coming down post dosing. We have read out 9 months post dosing. There is not one drug in America that has been in a clinical study that has shown you can be on this -- you can have effects of therapy.

We're the first one. And we have shown these effects to a degree of 9 months post the last dose, and we have shown an HbA1c reduction in our best-performing arm of 1.5%. Compare that to any other agent and you'll see we're in the upper end of the spectrum without being on drug. So we believe the hurdle is much lower than what we have shown. The hurdle actually, if you look at FDA's approvals, is 0.5. I have threefold that hurdle, meaning at 0.5 DPP-4 inhibitors were approved by the agency.

Now I'm just looking at the benefit we're creating. And the benefit is you can be off drug. The persistence, meaning patients having to take a drug every day will stop because if we truly rebuild the pool of beta cells. Over time, you may not need other agents anymore. And we have to obviously prove these things out. We're an investigative compound. We are in clinical trials, but that's the goal. The goal is to reconstitute your pool of beta cells and you can be done. And we hope to show that with benefits as measured in HbA1c, we have shown huge benefits. And if we think our hurdle rate in a Phase II then going into III, then later on will be roughly around that 0.5 level. That's the comparator that we see in earlier studies. Obviously, we're targeting for above 1%. We as a company.

Okay. So what's to -- tell us a little more specifically, like so you finished this Phase II now, gotten the data and potentially promising results there. So then -- are you going to have a meeting with the FDA to discuss the next study, what will the next study look like? I guess you would -- and my guess is you would probably have to do another study just in these high BMI -- sorry, the low BMI, high HbA1c people. Is that the plan?

Yes. So there's 2 patient categories that we have identified. One are -- it's about every fifth patients in the U.S. So just 38 million have diabetes, roughly 2-plus-million have type 1. The rest have type 2. So it's about 7 million patients in the U.S. that we're targeting with the profound effect that we have seen in what we call severance and deficient patients. However, the study that we enrolled with all comers, we have also seen a subset of patients when we looked at the all comers and we looked -- we asked the question, this is another effect when you inhibit this protein, the body has -- the receptors in these beta cells are now more expressed, and we knew this from preclinical studies.

So we asked the question, if a GLP-1 is on board in a patient, would a patient have a benefit if these receptors are more expressed in the GLP-1 receptor agonist is now interacting. And we found out of 11 patients enrolled in our study that were on a GLP-1, they had a profound 1.1% on drug and 1.8% placebo-adjusted effect under HbA1c. So there are 2 subgroups that one was prespecified. The other one was a post hoc analysis. And in both subgroups, we're starting designated Phase II studies because they're both large patient populations. If you look at the one I just mentioned that are on a GLP-1, about 40% of all GLP-1 studies in type 2 diabetes have patients that are uncontrolled that are not reaching the 7% target.

That's a study, in the real world that number is bigger. So there's a lot of patients out there that are on a GLP-1 that don't quite get to 7%. Those patients, we would help and boost their responses because of these receptors being more expressed. And in both these groups we would do a Phase II study and we then with the study go to the FDA.

So -- they're basically like not overlapping populations. I mean the people that post GLP-1s are not the people that are the low BMI, high-HbA1c...

Actually it's the opposite. Patients who are obese are typically on a GLP-1. Patients who're insulin deficient are typically not on a GLP-1.

Yes. So this point I'm just making, so everyone understands is these are distinct populations.

Yes.

Okay. All right. So when these 2 studies are going to start -- are they going to run concurrently? What's the plan?

It's pretty clear. So we know the centers, we just enrolled a study. And just when you start something, obviously, the first hurdle is people are very skeptical. What is this doing? What is the side effect profile, et cetera, and the FDA as well. I think we've passed that point, we have hundreds of patients now on drug that we can point to from a safety perspective, look at the profile that we published, it's really, really good.

Meaning I have now a drug that is safe for the 3 months dosing that we have shown and that -- or in our eyes safe and that has shown tremendous benefits for patients in a desired -- in a very highly needed patient population. These patients that were dosing with icovamenib, both groups go on insulin as one of their next choices. That's the tough part. If you're insulin-deficient, within 5 years, you're insulin-dependent, those patients that we characterized early on in this conversation, their choice is insulin, s***, or, hey, I could use icovamenib.

So the enrollment, we don't see as a problem. These patients are typically looking for us. So there is quite a few centers in the U.S. that we know. We're starting both of these protocols right now. We're going to submit them to the FDA. We hope to have an FPI very early in the next year. And when these patients come on board, we anticipate 60 to 100 patients in each of these trials are sufficient and we're going to run through this fairly quickly with a 26 primary readout, and we're going to take that data to the FDA and the secondary readout will be the 52 weeks.

Then that's not -- that's still not quite the pivotal trial. That's a next...

No. It's -- Yes, true. But it's enough. For instance, we're doing something that is -- that hasn't been done before. So there is a lot of skepticism, as you know. One, not only from investors but also from pharma. And so the more data points we can show to this data is profound. So there is a lot of interest in looking at our data and understanding how did you guys do that? Because it hasn't been done before. Nobody has stopped dosing and shown this effect on HbA1c.

So as that benefit is better understood and people will come and help us to broaden our clinical pipeline. Right now, what we're doing is what we can fund ourselves. If you think about it, we should be in prediabetes. Truly. I mean you should prevent the disease right upfront. If we can -- if we would have more funds, we would be in prediabetes. We also have type 1 diabetes that you're probably going to ask about. That is another big area where we will initiate more work in because the study was disrupted last year the type 1D study. So there is more for us to do, but what I just showed to you or what we just discussed is what we're funding ourselves.

Okay. So you started the first patient in, you said, I guess, early next year, 26 weeks. You have to enroll. So the data then would be what if you said, so people can plan for their data calendars. When could we see....

Yes. So the 26 weeks readout, half a year later, take 1 to 2 quarters to enroll and then half a year later, you have to read out.

So like end of next year, early '27, maybe.

End of next year, yes. I mean...

What are they comparing to is -- everyday they stay on their background therapies and then you just do versus placebo, I guess? Is that how this goes? Or is it...

That's how it goes. And you have to really manage that they do not change anything. Otherwise, the signal is not -- you have to really control the study well and we know how to do that.

Okay. the GLP-1, so tell us more about that because that was a very interesting fine thing. I don't know whether the people at Novo or all the -- the Lilly, they even made this observation about what happens in the menin upregulation, like -- was this your observation? Like how did you come to even figure this out? And why -- do we even know why this happens, like why you get this receptor upregulation with the menin blockade, which would make it such that, I guess, your argument is you can have more GLP-1 receptor so you can lower the dose, I guess?

Well, that would -- that's one of the benefits that you could potentially lower the dose. So there's 2 categories where GLP-1s are used. One is diabetes, one is obesity. So far, what we have shown preclinical work in obesity, which is the poster that we showed at ADA and EASD. And there, in the poster, you can see the gene, the MEN1 gene goes up. The protein goes up when you introduce icovamenib. And these are cell experiments. And this is not our work. This is known in the literature that menin has that impact. We just put it into an organic environment like a cell or now a human, and we can -- obviously, we can't measure in a human as well as we can in cells. But we have validated what academia has identified prior.

So we knew what to hunt for. And as we read out, we thought, gee, we should check that because we know it should be there, but nobody knew the impact. And the impact is that with 3 months of dosing, so 12 weeks of dosing, patient is on a GLP-1 background, that GLP-1, which failed to control sugar, meaning, right -- I mean the HbA1c was going up in these patients. Now that GLP-1 is actually working again for this patient. And what could be -- the impact is not only that his HbA1c came down. That's what we measured because we know when you inhibit menin, the instant production goes up because of this effect.

So the GLP-1 works, good but what could it do in obesity? So we've done a study in obesity where we looked at rats. And these are ZDF rats. They look like rabbits and they come into the clinic. And what we did is we said half of dose of sema in this arm, half a dose of sema in this arm plus icovamenib. And you can see that this arm has a fourfold increase in weight loss, literally fourfold. If you look at the poster, and then you asked the question, what else happened? Well, insulin better controlled, da, da, da. So The things we already knew from the diabetes side, but also muscle preservation. Now that's a new finding, which you can read up in the literature. There is references for that, that when you inhibit menin, you have muscle impact, a preservative impact, and we have shown a little bit of that from other studies.

But at the end of the day, now the question is, can mean potentially be a combination partner to a GLP-1 therapy just for its benefits of the quality of weight loss. No question. And we have now -- we have more studies in the making that are preclinical that will fine-tune this finding further. And when it's further for us validated, then we'll take it into the clinic. And you get more updates from us throughout this year and beginning of next year with our experiments.

That's a true killer finding because the GLP-1 space is the background of obesity. You go to ADA, which is a diabetes conference, everybody is talking about obesity. And everybody is talking about GLP-1. And all of them have a problem. What is that? The quality of weight loss, it's the side effects of the GLP-1s, and it's the muscle loss and other negative impacts on the human body. And menin seems to have a natural way of dealing with these resistance problems, pregnancy, obesity where menin is by the body down regulated in order to overcome these 2 problems.

And when you ask the professors from Joslin and they do all these studies on beta cells, that's the first thing they've shown to us. They said, "Look, at obesity, look at pregnancy. This is where you can see a natural occurrence of what you guys are trying to do with your drug and look at the benefits that you -- that in both instances of being sort of upheld, no muscle loss in either one of them when there is no diabetes, right? When the body is able to overcome these 2 problems.

And that's why we think -- well, while we knew something was there and now we're exploring it further, and it's pretty profound, yes.

But that's -- so that idea of the combo, right, with the menin inhibitor and the GLP-1, that's 1 asset. But the fact that you're going into the post GLP-1 in the current study and the one we were talking about a moment ago, that's -- what was the -- what did you discover? Why did those people behave better in terms of response on the post GLP-1. What was the conclusion?

In diabetes?

Diabetes, yes.

In diabetes what you see is when menin is inhibited, these receptors are more expressed, and we know GLP-1 has an impact on the function of beta cells. It doesn't proliferate them, but it makes them -- it has an impact on their production of insulin. So when menin is inhibited, more insulin gets produced. And with more insulin produced to GLP-1 -- and the GLP-1 works better and more insulin gets produced. So I'd say, that was a cascade of effects we were aware of. And then as we interrogated our database, we saw that it had this impact on these patients.

We didn't quite know how much HbA1C to expect, but when we saw the effect and the continuation of the effect post dosing, it's not us who does that, it's the combination of us with the GLP-1 who does this. Because when we look at our obese patients, we don't really have that much of an HbA1c impact on obese patients per se. But when they're on a GLP-1, the impact is profound.

Because back many years ago, when you first made this observation, everyone was in -- everyone at the company and investors, we were all trying to understand this phenomenon of the beta cell mass and we were asking all the normal questions around, it's more beta cells, but maybe then they also -- the ones that were there that survived are working better, right, all these sorts of things.

So now it's -- part of that is a little bit -- you're saying part of that is a little clarified because by the upregulation of the GLP-1, the ones that are preserved may be working better...

And we have more.

And then -- but then that's the other thing. Like you've done a long, long time ago, you did all those cell spheroid models, and I remember those slides. But is there anything -- I think people would be very curious if you have like the -- it's maybe not possible to do to actually show the imaging, to show that there's more of the beta cells to prove...

We had a whole SAB. If you look at on our website, the SAB is pretty deep. And we had a whole SAB meeting with all these members trying to assess function, mass and how could I validate either 1 of the 2. And obviously, we've done all the preclinical experiments. And when it boils down to imaging isn't up to a point where it could -- one of them told me the whole pool of beta cells that you have is the size of your thumb. Go try to find them. Meaning the imaging technology in the pancreas is not up to a point where you could find the proliferative effect of an agent. You can only measure it by the outcome right now.

So we're measuring outcome, which is insulin production, which is transcripts of genes, which is those kind of things, but not -- we can't go into a human body as well as we can in an animal. But in animals, we've shown size increased.

You have. Okay.

We have. The other thing you can look at, which is super is when a woman goes to pregnancy where I said earlier during pregnancy, the mother downregulates the protein menin in order for the pancreas to enlarge and produce more insulin. Women who died during pregnancy have an enlarged pancreas, they -- we have those images. And I can send you that research where women who've gone through lactation, women who've had pregnancies have less probability of getting diabetes. 30 years out, meaning this effect is a known effect.

Okay. So you're going to do these 2 studies, the insulin deficiency and the low BMI, high HbA1c and then the post GLP-1. So you're going to get that data, I guess, like we said, end of next year, early 2027. What do you have from the -- in terms of the funding and the runway to go beyond that? And would you pick one of those to do the pivotal trial for the approval or what? Like how would you think about that? I know that's going to require more capital.

Yes. Okay. So the -- you need for both and for all the work that we're doing, obviously, we need agreement with the FDA and the need and the benefit needs to be clarified. That's why we're doing these studies so that the benefit and the risk that a person is taking when using icovamenib, which we think is benign at this moment. That's all that we can see in our clinical data, that the FDA is an agreement. And we believe that in both cases, the FDA with sufficient Phase II data will be an agreement for us to go into an end of Phase II meeting with the data and then see how we progress from there into Phase III.

We will try to pursue both. Why? Because the demand in both is very high. the identification of the patient is not that difficult in, one, you're on a GLP-1, your HbA1c is uncontrolled. pretty clear, meaning you're failing an existing therapeutic agent and your HbA1c is high. That gives rise for hey, what are we doing there? And there is no therapy. GLP-1 are the best therapeutic agents for obese patients. What do you do now? Well, there we have a solution for these patients.

That -- so the need in both is there, and we believe if we can show safety over time, then the agency -- and obviously, that needs a meeting and needs for them to look at the data, but we can find agreement with the agency that that's worth pursuing in both categories in Phase IIIs. And until that point, we have a few more updates that we will be doing. We will provide you more updates on the impact of menin inhibition in obesity, which could become its own clinical path because we would then look at how can we be an add-on agent to existing agents?

And would there be an interest to do a study that we've just shown in animals, semaglutide at half the dose, with semaglutide at half the dose and icovamenib. Is that a study that could entice people and investigators and potentially pharma. So we're working on all these things that we can support ourselves going to those Phase III studies with data points we will bring up in obesity, data points we will bring up in type 1 diabetes and data points we will bring up with our second molecule, 650 which Thorsten is on the line here, he can answer any questions...

We can talk about that in a minute. I just -- can we just finish on the type 1? I know you meant -- that one, you pursued it and then you paused. What is the latest update on the data?

Yes. So with the data that we came out with just 2 weeks ago, the interest really spiked from academia because we are showing that in a type 1 like patient, a severely insulin-deficient patient, is almost like a type 1. Your beta cell pool is depleted, and there is not enough production. Now we do not have an autoimmune attack, obviously, in severely insulin-deficient patients. But those -- in theory, what we were thinking of, and that's why we went into type 1 is that every type 1 patient still has some form of C-peptide production, which is a surrogate for insulin.

So we can still measure that instant production after a meal in a type 1. If the immune system of the person that has type 1 would have attacked those cells, there shouldn't be a production of insulin. So these cells are still alive and working. If I were to regrow those cells, what impact could I have on this patient. That was the question when we started the exercise. And unfortunately, were disrupted by the FDA. So the data that we have now that we read out this 1 study, we're going to look at this data and see is there anything useful in there.

And with the incoming interest from investigators, we need to do a study in type 1, which we, as a company, completely agree with, we will probably restart a study fairly quickly together with academic centers, and we will fine-tune the impact potential that we have on a type 1. And also an important data point for you is we believe by the end of the year, we should be allowed to do chronic dosing. So could it make sense for us to go into a type 1 study where we not only dose for 12 weeks, but maybe for longer because the pool could be so heavily depleted that it needs longer dosing.

In diabetes, we don't think so. In type 1, it may. Anyway, we will have likely chronic dosing ability coming next year, and then we could dose start a new study, chronically dose type 1 and have 1 arm, just icovamenib and another arm, icovamenib and an agent that suppresses the immune system so that we have a chance in case there is an attack to still have proliferation of beta cells. Those are thoughts that we have right now together with investigators and you will hear us engage further in the near future.

Okay. Well, let's bring Thorsten into the conversation a little bit. So do you want to -- you have a totally different program, the BMF-650, the oral GLP-1. And you mentioned it at the top of the hour, Ramses, just a little bit about the chemotype similarity to Orforglipron, but it's not Orforglipron obviously. So tell us what it is and what is different about it? And why is it interesting maybe for pharma to look at this one.

Thank you very much. I will just start then on BMF-650. Ramses is just giving me the floor. I can see this. So thank you very much. So yes, so BMF-650 is essentially a product of our internal program to discover a small molecule GLP-1 receptor agonist. We started the program now that we are at the doorsteps of the clinic, obviously, roughly 2 years ago. Two years ago, the landscape was still a little different. There were 2 scaffold types out there. There was a Pfizer scaffold type to just colloquialize it, and the Chugai chemotype.

We looked at the properties of both chemical worlds, so to speak. We believe that the Chugai chemotype offered the higher likelihood of delivering a very successful GLP-1 receptor agonist. So we focused our attention to this side of the world. We did analyze the data also for this chemotype for the Chugai compound as it was disclosed then already. And we felt the PK properties of the compound were not ideal. And before I go maybe into further detail, I mean, this is really a phenomenal molecule that, that group has actually produced. So as a medicine chemist, I really, really think that was a great effort.

But a few things are not perfect, and I think that is the PK. And one could maybe also argue that the intrinsic potency of that compound is actually a little bit too high. It is an oral drug. So the gut is immediately exposed to the drug. And it is a daily dosing. So you will have peak to trough, which is very different from a weekly dosing scheme in semaglutide. So we wanted to shallow out the peak-to-trough ratio, so have better PK overall and slightly less potency, resembling a little bit what happened when liraglutide actually was improved and it became semaglutide. So the compound had longer half-life and actually less free fraction that would have a sharp edge to really agonize and lead to side effects.

So this was the goal when we set out to have a compound in this class. And we tested the optimized compounds in preclinical species for PK properties. We saw that both in the cynomolgus monkey and in the rat. Our oral bioavailability is two to threefold better than Orforglipron when we compare it side by side.

And our intrinsic potency is essentially tenfold less than Orforglipron, which is easily adjusted for higher uptitration target dose, but it is actually an advantage when you start dosing the compound at the titration starting dose, where you do not hit the patient in particular parts of the GI with super efficacious doses versus other parts don't see anything just to try to distribute 1 milligram in the GI tract is almost impossible to get it homogeneously done. So we believe we have a much better titration entry point for the compound generated with these properties.

The program advanced to many steps to show that we have a very good incretin effect in cynomolgus monkeys. But at the end of the optimization program was our obese cynomolgus monkey weight loss study, where in a daily dosing regime for 28 days in a very nice and balanced group, we saw very significant and dose-dependent weight loss that showed no sign of plateauing at the end of the dosing interval, and we had 12% and 15% for low and high-dose group weight reduction at the end of the study.

And we believe these data because of the similarity of this receptor in the cynomolgus monkey and in human is very guiding towards what we're going to see in the clinic with this compound. And as a side remark, the amount of emesis that was seen for those monkeys on the studies without an uptitration scheme was actually rather minimal. So we are very happy that we achieved all goals that we had set out to achieve for this compound preclinically, and we are now truly at the doorsteps of the clinic to actually translate this now into human data.

So the goal is to have an equally effective but safer, more tolerable. Is that correct or not?

The more you condense -- want to condense, yes, that is correct. So the efficacy, we do not want to sacrifice anything that has been seen for Orforglipron. That is essentially handled by a slightly higher uptitration target dose. And we do believe that our uptitration time frame could actually be shorter so that you actually harvest in weight loss earlier in your titration. That we will need to see in humans, but it is a distinct possibility based on the data that we have generated.

Okay. So you said you're about to start a Phase I. What is the status there? You've got the relevant clearances and so on. When we see the data for that study?

Yes. Okay. So thank you for asking it this way. Yes. So the package has been submitted to the FDA. Has been cleared. We are ready to go. At the end stage, there's always a certain amount of CR optimization when can we dose. We are really at the doorstep. I don't want to give the date, but we are right there. The study will essentially be falling into 2 parts. There's the SAD, so a single ascending dose study and then there's the MAD, where we will really then measure the weight loss. The MAD is really scheduled to happen in the -- at the beginning of next year. So Q1 is a very, very important quarter for us with respect to BMF-650 data. And yes, Q1 to Q2 where we read out. And the additional information...

Yes, sorry, just to clarify, Q2 of '26, we would have...

Yes, next year, yes. First half of next year until we do the official data release, but we will be being in...

Our MAD that we will go into a Phase II with, it's a comparable...

How many people are going to be in this little -- in this starting study?

So the SAD part will have 40 and the MAD will also have 40. The group size is not the same for either one, but for the MAD, which is most likely the one you are more interested in, this will be 4 dose groups with 10 people each. and the ratio is...

What level of obesity are they going to be? Or are these just healthy volunteers for the first part?

So they are all healthy, overweight and -- overweight or obese. And for the -- yes, that's essentially the criteria. I'm not sure if you want the exact BMI right now.

We'll take it if you have.

I think it was 27.

27 to 30 is overweight, 30 plus is obese.

Yes. Okay. Okay. Now what about -- I mean, of course, some -- you've been asked about combining -- eventually maybe combining this with ivo -- with ico. I mean, is that something that's possible or you just don't know that yet?

So our long-term goal is that we do want to have a combo of those 2 internal compounds as well. But we will read out the beneficial additive effect first in this study that Ramses has described. But the long-term goal very much would be having a combo period as well.

Have you looked at it in the cell models and like combining the icovamenib with 650 preclinically in any sense or not yet?

Yes. We have pilot data where we have combined icovamenib and we have used Orforglipron and we have used BMF-650, and we see the anticipated beneficial effect of the combinations.

Okay. All right. And then after that, is this the type of thing that you would want to have more funding to do your own trial? If you get good proof of principle in the single ascending and multi-ascending, then what's the order of priorities for the company, Ramses? I mean you have to...

You need to create optionality. And that's the moment when you have optionality. And having a pharma partner and based on my experience with pharma partners is beneficial, is not as dilutive as people may think because it's a long way as we know. Icovamenib is -- we look as a non-chronic agent, meaning all the regulations for chronic dosing that we have in diabetes and in obesity, but in diabetes, in particular, there are very tough requirements.

Look at Viking, how much money they're spending to get through their studies. You got to raise a ton of money to get through. We feel this -- we would like the optionality at that time point to look at alternatives. And obviously, one route is to build up the company again and do all these things like others have done or go with a pharma partner who's just faster, bigger and more forceful. And those are options we would love to have, but I can't make a decision now on which one is the best. There are certain views I have because of my experience, but that may not be the best solution at that time.

Okay. All right.

Creating that optionality is -- we are drug developers. Our goal is to show the value that this compound may have. And you know from the BTK days, you can always improve a compound. We have looked at orpho over the last 2.5-plus years, and we believe it's a very, very good compound. However, as we now know from all the data they have published, there are deficiencies. And we will attempt to improve those deficiencies to show the next guy, this market opportunity that is there, it's $100 billion.

This market opportunity will be won with better patient-friendly compounds, no question. And it will be won by somebody who is willing to invest in that. And even though there is struggles at the top, you can get in there. And so that's kind of what we're doing. We're showing early on that this potentially is possible.

By the way, I was just curious, in the phenomenon you observed with the menin inhibition upregulating the GLP-1 receptor, you see that, that's not just like in type 2, like you would see that in the type 1s as well, right, I would think.

If there's something there, I mean the cells are much...

Is something there, yes. But I just -- that's what I was thinking about because you have such a less smaller pool, like is the biology somehow impaired in a different way that it doesn't do the same thing, but...

Very difficult for us to be definitive. But if there are cells there, which we know they're there, we should have the same effect. We couldn't yet measure it in the type 1s. We've measured it in other environments like cells and animals. We're now looking also at a type 1 animal model, which is not easy to get to, but we're on -- we're trying to get deeper into that space. And I tell you, just from our seat, where we are, you look at competition, you look at hurdles, you look at FDA, you look at all these things. If you look at type 1, there's not an approved agent really in type 1 in Phase III. Okay?

Well, what does that mean? That means there's very little competition. The approvable study of the last agents that got approved for Stage 2 is 75 patients in the Phase III, meaning the size of what you have to show, the benefits of what you have to show in type 1 are much different than the space over here in diabetes, where obviously, we're lucky because we're not chronic. We fall out of these huge demands the FDA has in terms of safety because the target population is so big.

But in type 1, I feel if we have -- if we can show C-peptide increase, which is the hallmark of benefit for a patient, that we can fairly quickly do that, meaning if I have the right investigator with a few patients, take 10 to 20 patients and I show you C-peptide increase, that would be game changing. And we're on that as well. It's not in our pipeline because we haven't secured the study yet, but that's one of the key goals of the company, show this proof of concept.

Okay. So just in terms of the funding picture, you have -- well, tell me, do you have the funds to -- presumably have the funds to get to the 650 readout, that's pretty soon. But then the funds for the 2 Phase IIs at the end of next year or early 2027, the post GLP-1 and the high HbA1c, low BMI people, that -- do you have the funds to reach that data?

Yes, we will get funding, we probably will have a public statement in our next quarter release where we will say funding will less and we have said that into 2027. It's just specificity of -- depends a little bit of how much spend do you have prior to 2027, and that changes the range, how far you get into 2027. But it is into 2027. And we have reduced the company. And just by the number, look at the number of 40 employees. We had over 100 at some point.

We really laser-focused now on those 2 indications, type 2 diabetes, obesity. We don't do any more sort of platform research. All these things have stopped. We have unburdened the company from a lot of expenses. We're now down to what we think is a very good operational level where you can't really cut further if you want to do the things we're doing. And you will see in our next quarter, it's one of the questions that you probably will have on, has the burn prediction stayed the same with the 40% we said in our last quarter. And yes, we haven't changed that guidance. So you will see us come down dramatically on expenses, and we will work on that further.

And just to show you how focused we are, every contract I'm after, I just want to know from the vendor, did I have a 3-way bid? Am I at market with this price? Is this an old price? Can I do anything on this price? Can I get out of this agreement and get into a new agreement? So we're -- I'm very focused from an operational perspective on ensuring I have market rates and I have competitive and negotiated market rates for every sizable contract and sizable for me is actually at the $5,000 level and above.

That's why I get interested because my investment of time, one phone call to the vendor or a quick negotiation with the finance team is all that's needed to check out are we -- and we've made policy around it. So we're a steward of this money that we now have. We think it's very valuable. And obviously, we're thankful for that we can get this opportunity, and we're going to get to those milestones. That's our commitment to Wall Street.

Okay. Okay. Excellent. Well, we will certainly be following everything going on and watching for the next data card. So -- it will be an exciting journey.

Lots coming.

So thank you, both of you. Appreciate it.

Thank you. Okay.

Good day, ladies and gentlemen, and welcome to the 52-Week Results Conference Call.

[Operator Instructions] Please be advised that today's conference call is being recorded.

I would now like to hand the conference over to your speaker today, Ramses Erdtmann, President and Chief Operating Officer. Please go ahead.

[Technical Difficulty]

Ladies and gentlemen, please stand by. Ladies and gentleman, please remain on line, your conference will begin shortly.

Okay. Thank you, operator. Are we live now?

You are live.

Perfect. Okay. All the other speakers that have dialed in, we're going to go live. Maybe you can let Juan Pablo now.

Okay. Thank you, operator, and welcome, everyone, to this conference call. My name is Ramses Erdtmann, I'm the President and Chief Operating Officer of Biomea. Today, we'll be sharing the 52-week results from the COVALENT-111 study, a randomized double-blind, placebo-controlled Phase II clinical trial to assess the safety and tolerability profile of icovamenib along with exploratory efficacy endpoints in patients with type II diabetes.

Before we begin, let me remind you that today's presentation contains forward-looking statements about the business prospects of Biomea. These statements are subject to a number of risks and uncertainties that could cause our actual results to differ materially from those expressed or implied in this presentation depending on the progress of Biomea's preclinical and clinical development activities, actions of regulatory authorities, availability of capital, future actions in the pharmaceutical market and developments by competitors, and those factors detailed in Biomea's filings with the SEC, such as the 10-K, 10-Qs and 8-K reports.

All forward-looking statements made during the presentation are based on the beliefs of Biomea as of this date only and future events or simply the passage of time may cause these beliefs to change. Please feel aware that you should not place undue reliance on the forward-looking statements made today.

Okay. On today's call, you will first hear from me with introductory words. Then Dr. Juan Pablo Frias, Co-Chair of our Scientific Advisory Board, will walk you through the study design and key 52-week data. We are also joined by a very prominent investigator and one of the key opinion leaders in our field, Professor Ralph DeFronzo, who is an expert in the pathophysiology of type II diabetes. Finally, our interim CEO, Dr. Mick Hitchcock, will summarize our findings and discuss next steps before opening the call for Q&A.

Let me begin with a few remarks upfront. When we started our menin research back in 2018, we only had academic papers that indicated that menin has a control function in the pancreas. We then conducted animal studies and human pancreatic cadaver islet studies to validate the core assumption others had already observed that the select and partial inhibition of menin may lead to an increase of beta cells and the enhancement of their function. In these early studies, we observed similar improvements with the use of our menin inhibitor, an increase in the number of beta cells and increase in insulin production, better glucose control, which led to lower HbA1c values, and also an increase in GLP-1 receptor expression on the cell surface of beta cells, which potentially enhances the effect of GLP-1 receptor agonist.

When we initiated our clinical program and, in particular, our study, COVALENT-111, we wanted to identify which phenotype of patients will respond best to our menin inhibitor, icovamenib, and we also wanted to determine the appropriate dosage. Menin inhibition in diabetes is a brand-new modality for this disease. There were no references or prior clinical studies to lean on. So it was critical that COVALENT-111 helped us answer those 2 questions. I believe we have answers to both questions now that the study is completed.

With our 26-week primary readout, we learned that the strongest benefit from icovamenib occurred in those prespecified patients that were considered severe insulin deficiency and taking at least 1 antihyperglycemic agent. And we learned as well that patients already on a GLP-1-based therapy and not achieving their HbA1C target or another strongly responding subgroup. Now after 52 weeks, 9 months post the last dose for these patients, we will provide an update on how these groups have fared. We are confident today that we have isolated our responders and understand the mechanistic reasons for the responses in both of these type II diabetes patient groups.

I will now turn the call over to Juan Pablo, who will walk us through the results in detail. You may notice that the slides introduced Juan Pablo as Co-Chair of our Scientific Advisory Board. The reason for this title change is because Juan Pablo is heading back to clinical practice and research and will, therefore, have to reduce his role at Biomea. His support going forward will be more focused on assisting us in clinical trial-related questions, protocol reviews, FDA interactions, presentations and similar activities.

Juan?

[Technical Difficulty]

Please stand by. Ladies and gentlemen, please stand by.

Operator, are we live?

Yes, we are live. We're waiting for Juan.

Okay. Juan is traveling, and he is unfortunately in a position where he just lost cell coverage, and I hope he's getting back to us with the Q&A section. If everybody doesn't mind, I'm going to read his section, just assume it's Juan speaking, okay? He's going to come right back, hopefully, for the Q&A section.

Okay. So I would like to focus the majority of my prepared remarks today on the 52-week results of the COVALENT-111 study and what they mean for -- what they mean for endocrinologists and diabetologist like myself. During my remarks, I will not cover every slide that you'll find online but instead highlight the key takeaways.

Let's start with Slide 5, which is an important slide. It illustrates the 2 key effects we see with the orally bioavailable menin-inhibitor, icovamenib. These effects were first observed in preclinical studies, and we now have clinical evidence of this proposed dual mechanism of action. It's particularly important to understand the effect shown on the right side of the slide, which can be easy to be overlooked.

Icovamenib increases GLP-1 receptor expression on the surface of beta cells. Preclinical data demonstrating this were presented at the ADA scientific sessions in June of this year and again at the EASD Congress a couple of weeks ago. Clinically, we believe this may help people with diabetes who are not achieving glycemic targets on GLP-1 therapies.

Based on our preclinical data, we believe there may be potential for icovamenib to have an impact on body weight and, importantly, the quality of weight loss through preservation of muscle mass. The slide lays out where we are observing patient benefits and helps us understand the clinical development path for icovamenib.

Slide 6 to 10 summarize our trial design and patient enrollment. With this study, we aim to better understand icovamenib's safety and tolerability profile to assess for optimal dose and the durability of patients response to icovamenib. Additionally, we aim to identify the patient population most likely to benefit from selective and partial menin inhibition. Remember, before Biomea, no 1 had ever dosed a person with type II diabetes with a menin inhibitor. We had no benchmark for what to expect across different patient subtypes.

Slide 11 shows the 4 generally accepted and well-characterized subtypes of type II diabetes. The statistical analysis plan prespecified that our analysis include an assessment of HbA1c change within these subtypes for the readout at Week 26 and Week 52. When a patient with severe insulin deficient diabetes comes into my practice, I can usually recognize them. These patients are typically not obese, they present with a high HbA1c and they are often difficult to control on non-insulin therapies. They generally progress quickly to requiring insulin therap.

By contrast, from my professional experience, insulin-resistant patients usually produce sufficient insulin, but need weight reduction to lower resistance, enabling their own insulin to work more effectively. These patients often respond very well to GLP-1-based therapies, especially given the weight lowering effect. Roughly 20% of type II diabetes patients in the Western world fall into the insulin-deficient subtype, whereas in Asia it is closer to 40% or even higher.

Moving to Slide 12. At 26 weeks, we observed that icovamenib performed better when dosed for 12 weeks versus 8 weeks. In the two 12-week arms, arms B and C, icovamenib has particularly good efficacy signals in insulin-deficient patients. Importantly, this effect was durable with benefit persisting more than 3 months after the last dose. In addition, patients already on chronic GLP-1 therapies at baseline but who have not achieved HPLC below 7, also showed a notable reduction in HbA1c. Here, independent of dosing regimen, icovamenib's response persisted to Week 26 as well. This was a post hoc analysis. The key question was what would glycemic control looks like at Week 52, 9 months after the last dose?

In the severe insulin-deficient subgroup treated for 12 weeks in arms B and C, shown on Slide 17, we observed a mean HbA1c reduction of 1.2%, both clinically and statistically significant with a p-value of 0.01. That is remarkable.

Slide 18, focusing on RMB alone in the same severe insulin-deficient subgroup shows an even greater reduction of 1.5% versus placebo, also statistically significant. Overall, we saw durable HbA1c reductions to Week 52 in this predefined subgroup. We then asked whether response was related to exposure, if higher PK levels correlate with greater HbA1c reduction.

Looking at Slide 19, you can see that mean PK exposure in arm C was actually lower than in Arm B., which we believe helps explain why arm C not performed quite as well. As shown in Slide 20, greater exposure was correlated with greater HbA1c reduction patients with the highest PK exposure achieved the greatest improvement, a point also summarized on Slide 21. Our data suggests that readily achievable exposure levels may support HbA1c reductions of at least 1.5% in patients with type II diabetes. One additional observation, we believe that food type and timing impact icovamenib PK. We have started a dedicated food effect study to optimize dosing instructions and expect this to further improve exposure.

Turning now to a post hoc analysis, we also show -- which also shows some very interesting findings on Slide 23. Here we are showing the reduction in HbA1c for all patients that enrolled into the study while on a GLP-1-based therapy and who had not achieved their target HbA1C level of below the 7% range at enrollment. You can see the profound impact that icovamenib has on these patients with over 1.8% in placebo-adjusted HbA1c reduction 9 months post dosing, very impressive considering that these patients were on very potent agents at baseline that are not getting them to target.

We just presented more preclinical information at ADA and EASD this year, showing that when you selectively and partially inhibit menin, do not only achieve a regeneration of the beta cells and a recovery of beta cell function but we also observed an increase in GLP-1 receptor expression, which then led to a higher insulin release, glucose control and, in the preclinical models, also to enhance weight loss and muscle preservation. We believe that the increase in receptor expression is a key reason for the effect we are observing in this patient population shown on Slide 23.

Slide 24 provides context by comparing these outcomes with widely used therapies, which require chronic use and, in some cases, injections.

On Slide 27, our safety assessment is summarized. We observed icovamenib's safety profile to remain stable post dosing. The results here are consistent with earlier findings. Icovamenib has been generally well tolerated with no treatment-related serious adverse events or discontinuation. This is consistent with partial and selective inhibition of menin. In summary, icovamenib was generally well tolerated, demonstrated sustained reduction in HbA1c at 52 weeks in severe insulin patients taking at least 1 anti-hyperglycemic agent, and showed promising benefit in GLP-1 treated patients who are not at goal.

I would now like to turn the call over to my colleague, Dr. Ralph DeFronzo, who many of you know for his relentless work around the early pathways to address diabetes, which led to the approval of metformin, SGLT2 inhibitors and several others. Dr. DeFronzo, is a Professor of Medicine and Chief at the Diabetes Division at the University of Texas Health Science Center in San Antonio. He is also the Deputy Director of the Texas Diabetes Institute, which is one of the largest institutions in the U.S. They see about 10,000 unique diabetic patients annually. He has published nearly 1,000 peer-reviewed papers and has received lifetime achievement award from both the ADA and EASD, amongst many honors and accolades. Ralph? And I'm not sure if Ralph is able to handle his -- and you know what, I think it's up to me to continue reading. Okay? Operator, is that what we're doing?

Please continue.

Okay. I'm now going to the section of Ralph DeFronzo, and I'm going to read his section.

Thank you, Juan, for the introduction. Let me start with a bit of background before we put icovamenib's results in perspective. As you indicated, I've spent most of my career really trying to understand what causes type II diabetes and how we can address it effectively. Looking at the American Diabetes Association standards of care, they say very little about pathophysiology. To me, that is essential. If you don't understand what causes the disease, you're not going to understand how to treat it.

So very simply, we have 2 problems. On the one hand, we have insulin resistance, and on the other hand, we have beta cell failure, as Juan pointed out earlier. The epidemic of diabetes we're dealing with today is being driven by the epidemic of obesity, basically lipotoxicity leading to insulin resistance. But we tend to forget that there is also a large number of people who actually have primary beta cell failure. These are severely insulin-deficient patients. They are usually leaner patients, their A1c is fully controlled. They progress rather quickly to severe hyperglycemia. And for them, we really don't have the kind of medications that we need to stop this progressive beta cell failure.

The very obese patients with BMIs 35 to 40 are the insulin-resistant ones. In these individuals, type II diabetes eventually develops because of beta cell failure. And the leaner group progresses much more rapidly and they are the most difficult to treat. Most of them end up on insulin therapy. Yet insulin therapy for type II diabetes is very, very difficult and can be associated with serious side effects. For example, hypoglycemia, that interfere with effectively controlling blood glucose.

Let me remind you that 80% of people with diabetes will die from this disease and premature mortality caused by diabetes results in an estimated 12 to 14 years of life loss. So we are dealing with a real health care problem. As diabetes progresses, you initially start to lose beta cell function and then eventually beta-cell mass. When you lose a critical level of beta cell mass, about 70% to 80% of people become insulin-dependent. GLP-1 receptor agonists are actually very good at improving beta cell function, but they don't increase beta cell mass. If you have lost 70% to 80% of your beta cells, they're not going to regenerate them.

What we would like to have is a therapy that both increases beta cell mass and improves function. Menin inhibitors are a class that actually has the potential to do this. They also increased GLP-1 receptor expression on beta cells, which allows the body's own GLP-1 to work more effectively.

Looking at the data slides presented here today, I'm very impressed with -- by these results. The 52-week follow-up is rather striking in both groups. In the severe insulin-deficient group, which was prespecified in advance, the A1c was not just declining during the 12 weeks of dosing but continued from 12 to 26 weeks to now 52 weeks, even when there was no further treatment. This suggests an effect on increasing beta cell mass and/or function. These are very insulin deficient patients, the most difficult to treat. The drugs we currently have do not work for them, including GLP-1 RAs. And now we see an absolute mean A1c drop of 1.5% in Arm B and across all patients dosed for 12 weeks arms B and C when placebo is going steadily up.

This is an enormous positive effect. this is very encouraging because we know from animal studies that menin inhibitors markedly increase beta cell mass. They cause beta cell proliferation and likely also improve function by increasing GLP-1 receptor expression. So if we see a big drop in HbA1c in humans, that's quite meaningful.

Also looking at the trends of these graphs, the A1c is still clearly trending downwards, so we do not know how long the effect will last, likely until the beta cell toxicity is controlled in these patients. As I mentioned earlier, menin inhibition leads to an increase in GLP-1 receptor expression on beta cells, which, under conditions of pregnancy or obesity, makes good sense. In these natural occurrences, it helps the body to be more effective with its own GLP -- with its own GLP-1, to manage the stress and the demand for insulin.

So how did this GLP-1 effect help type II diabetes patients in this study? When icovamenib was used in combination with a GLP-1-based therapy, the data was equally striking, showing an improvement of 1.3% in A1c reduction. This effect was achieved in typical insulin-resistant patients where the menin inhibition alone without the use of GLP-1 is not working. But in combination with the GLP-1-based therapy, we see impressive diabetes control.

The effect started during dosing, as you can observe in these slides, and continued through the dosing and even 9 months post dosing. Striking, really striking. Menin inhibitors can give you more beta cells and GLP-1s can make those beta cell function better and likely promote weight loss. These 2 effects together combined show a huge effect. I would predict with a strong certainty that the GLP-1 plus menin inhibitor combination will be a very powerful therapy.

Let me also address safety concerns. At higher doses of 200 to 400 milligrams, there were some liver enzyme elevations, so the study was paused. But at 100-milligram daily, there has not been any meaningful liver signal. The side effect profile post 52 weeks looks quite manageable: some nausea and a little diarrhea, Grade 1 events. Menin mutations that cause abdominals are lifelong genetic defect. Here we are treating for 12 weeks, not a lifetime. The company is monitoring quite vigorously, and with further long-term observation, we will fully answer all these safety questions. But at this stage, I'm very pleased with the safety profile.

A question I get asked frequently is how this therapy will get approved. Here I can only say that good therapies typically find a way. I feel the company's approach of episodic treatment is quite reasonable: treat for 12 weeks and then the A1c stays controlled for the rest of the year. Whether it lasts 2 or 3 years or even longer, we don't know yet. But we'll learn over time. This would generally be the first therapy that is not chronically dosed and the first that would be addressing diabetes at the root cause level.

I've been involved with diabetes research for over 50 years, and I believe that having a medication that increases beta cell mass is a major advancement. If we can increase beta cell mass and function, that's a huge step forward for patient care. It is a game changer. For the severe insulin-deficient group, the most difficult patients to treat, who don't respond to basically anything, if we can normalize A1c for these patients, that is a huge step forward. Even in insulin-resistant patients, eventually, their beta cells will fail, and then they'll need the therapy as well. So in summary, I think menin inhibitors can become a major pillar for diabetes therapy.

Thank you, Ralph, for your insightful comments. Before we move to Q&A, I would like to reiterate the key points highlighted on the summary slide, Slide 33.

Icovamenib achieved clinically meaningful and durable HbA1c reductions out to 52 weeks. The effect was strongest in severe insulin efficient diabetes patients where we observed HbA1c reductions up to 1.5%. We also saw marked improvements in patients on GLP-1 therapy who had not achieved their HbA1c target, with mean HbA1c reductions of 1.3%. Importantly, icovamenib continued to show a favorable safety profile, with no treatment-related discontinuations or serious adverse events.

Turning to Slide 34, let me briefly outline the next steps. We are currently running a food effect study to optimize icovamenib exposure and defined dosing criteria, with results expected in December of 2025. Based on interactions with FDA, we believe the path forward is to conduct larger studies, specifically enrolling the 2 target type II diabetes populations that we have identified as responding to icovamenib therapy: patients with severe insulin-deficient diabetes and patients currently on a GLP-1 receptor agonist but not achieving their target HbA1c levels.

Given the responses to icovamenib's observed in the COVALENT-111 study, we believe these studies can be conducted in fewer than 100 patients each and will give both us and the FDA a clear understanding of the risk versus benefit profile of icovamenib. We plan to initiate these studies in the fourth quarter of this year.

Finally, on the obesity side, we are advancing BMF-650 an oral GLP-1 receptor agonist candidate. Preclinical data showed robust weight loss and appetite suppression. With IND clearance now in hand, we have initiated a Phase I study in obese, otherwise healthy, volunteers. We expect to report initial results from this program in the first half of next year.

This morning, you will also see that we announced the pricing of our underwritten public offering. This financing strengthens our balance sheet and extends our cash runway into the second half of 2027. With this additional capital, we are well positioned to advance icovamenib and BMF-650 through key upcoming milestones and continue driving towards our goal of delivering meaningful disease-modifying treatments for patients with diabetes and obesity.

I would now like to turn -- I would now like to turn the call over to the operator to start the Q&A portion of the call.

[Operator Instructions] Our first question will be coming from Matt Biegler of OpCo.

Everyone, can you hear me?

Yes.

Thank you, Ramses, for that nice presentation and, obviously, for dealing with the technical issues. But just maybe a quick one on COVALENT-111, the design and the eligibility here. Are you restricting it now just the severe insulin deficient patients? Or are you also seeking to include other insulin-deficient subtypes such as age-related deficiency like MARD? I know in the past you've kind of grouped both SIDD and MARD together, but it seems like now the focus really just is on SIDD. So I just wanted to clarify that.

Maybe, I don't know, Juan, how is your connection now? Can you speak, Juan? Is Juan on? Okay, no. And I'm really sorry that we had this technical difficulty. Juan one is traveling, he's presenting in Bangladesh. And so that may be the reason why we couldn't reach him. And then Ralph is on -- I know he's on. I talked to him earlier, but we couldn't get his script to him. So I apologize.

But to answer your question, Matt, yes, the purpose, as we highlighted in the prepared remarks, was primarily with the 111 study just to where is menin working, what are the patient subtypes where it is working. We identified that now. And so we are teasing -- we've teased it out and we're now going to the FDA with that certainty in a Phase II design study, primarily for severe insulin-deficient patients, as you indicated, the Study 211, and the study 212 is in combination with GLP-1. There the enrollment criteria is very easy. You fail the GLP-1 receptor agonist, your HbA1c is rising, you're a type 2 diabetic patient. That's very simple.

In the severe insulin deficiency, you could argue, well, what defines the severe insulin-deficient patient? And you can see that the criteria that are being used by the German group or the [indiscernible] group are very, very similar. And so the criteria will be a person that is failing, obviously, his current therapy, and that is of lower BMI and of upper end of the HbA1c, so above 8, below 30. So below 30 basically means you're not obese. Above 8 means you have a problem with your pancreas.

And the other criteria such as age very likely will not fall into it because we couldn't really see that as a signal. And lastly, probably the time or the duration of length since when you've had diabetes will also be an influencing factor. The longer you've had it, say, greater than 3 years, we've seen has an influence. So 211 is focused on these type of patients.

Our next question will be coming from Joe Pantginis of H.C. Wainwright.

Very nice to see the sustained data post treatment cessation. So a couple of questions, if you don't mind. I know you're doing the food effect study to look at the, well, basically see what you're going to find. But with regard to B versus C exposures that you were talking about, A, when did you measure your PK time point? And B, what anecdotes could you share right now with regard to what patients or some patients may have been eating or types of food at time point?

Thank you, Joe, for the question. Just a little background here on the way the study was done. The PK was taken like during the first administration and then a month later and then a month later, et cetera. So it's not systematic; it's periodic. And sometimes what we noticed was the exposure was very good. And sometimes we noticed the exposure was very bad. And we think that the issue ultimately relates to the solubility of the drug at low PH. We know it's much more soluble at PH. We know that the best way to get a low PH in the summer is to have food there. And food not only provides for low PH but also sustains the drug in the stomach for a longer period of time.

So the current study that we're doing is to basically look at what would be the best time to have the drug after we've eaten. And then we're also looking at things like high-fat and low-fat meal and half an hour after starting the meal versus 1 hour after starting the meal. We'll try and nail down what's the best approach is to increasing the exposure and getting it more consistent from one patient to the next.

No, it certainly does. And I'm just curious, would you wait for the results of the food effect study before starting various studies you talked about in your last slide?

Yes. We don't have to wait actually because of the way the timing is set up. The data will be coming out in cohorts, and we will assess the data all the way through food effect study. By the time we are ready to start 211 and 212, those data will be in the book.

No, that's helpful. And just lastly, if you don't mind, just curious, with regard to the dosing beyond the food effect impact that you're potentially looking at, are there any other dose learnings that you may apply or have seen for the next studies?

And then secondly, are you looking to disclose any C-peptide data from this data set?

From the current data set, we will have C-peptide data. Is that what you mean? Or did you mean...

Yes.

Yes, 52 weeks, yes. We don't have it yet but we should and we will probably publish that on the conferences. And then there was another question on...

Yes. The other question was about are there any other things we can learn about how to give the drug?

Yes, beyond the food impact.

No. It's -- we really think the food effect, based on what we've seen so far, will be the overarching effect. And once we nail that down, we feel like we'll be able to get consistent exposure.

And our next question will be coming from Yigal Nochomovitz of Citigroup.

Yes. Ramses, so with regard to this comment around the food effect and the better exposure at the 100-milligram QD for 12 weeks, are you saying that you're not going to look at 100-milligram QD and then 4 weeks of BID? Or is that still something you would consider, because if you solve for the food effect question and that Arm C regimen may, in fact, be something worth pursuing?

Yes. We didn't see anything outstanding in Arm C that would enable us to be excited about pursuing that at this point. We feel that the simplicity of keeping the dose the same all the way through is probably more important than getting a marginal amount of improvement in the PK. So right now, we're going to push forward with the 12 weeks of 100 mg QD. And we'll see what that provides us.

Down the road, I'm sure that other people will want to look at other ways of giving the drug. But I don't think at this stage it makes sense for us to go into many directions.

Okay. And then can you also talk a little bit about the GLP-1 up-regulation with the menin inhibition? How quickly are you seeing that in your preclinical work? What is the degree of up-regulation? If you could just explain a little bit more what you're observing.

Yes. Maybe let's see, Steve. Steve, are you on? Can you handle that question, Steve Morris?

Yes, indeed. I am, Ramses. Thank you. We do see it preclinically very rapid within minutes, an hour at most, you see up-regulation, the up-regulation occurs both transcriptionally and translationally, i.e., we see up-regulation of both the mRNA expression of the receptors as well as the protein. The up-regulation is multifold and it is sustained. By the way, this has been also described in the peer review literature by several groups. So it's not a finding that is unique to Biomea. Does that answer your question?

Yes. Thank you very much.

Our next question will be coming from Cha Cha Yang of Jefferies.

Can you hear me?

Yes.

This is Cha Cha on for Roger Song. I had 2 questions. One is I want to know if you're going to be continuing to study these patients in 111 and what future time points you'll be reporting.

And then my second question has to do with your Phase IIb and pivotal study design. If you could give some more color on your current thinking about this design, whether that's about patient population, endpoints or duration.

Starting with the 111 study. Because we haven't figured out exactly what was going on and we had to wait for the 52-week data to potentially get enthusiastic about how well the drug was working, we did not pursue the study patients beyond Week 52. So that trial is now finished and closed down, and we will not be getting any additional data from it.

However, the next studies going forward where we have a better idea of what we're likely to get out of it, whilst we will do a 26-week and 52-week endpoint, I would hope that we'll also keep those patients around and see how well they do over time beyond that and see how long this response ultimately is going to last for.

Could you repeat the second part of the question too?

Yes. Just about Phase IIb and pivotal study design.

So the Phase IIb that we're working on right now will give us a point to where we need to go, what sort of sample size we'll need, what sort of specification around the patients, et cetera. And I think that we'll have a good idea about how to design a Phase III once we've gotten even the 26-week data, if we can extrapolate to what 52 is going to bring us and set up meetings with clinicians and the FDA before the 52-week data comes in so that we have a good idea about how to move forward with those trials. And when the 52-week data comes in, we should be then ready to sort of kick them off fairly quickly after that.

Maybe a flavor, Cha Cha, if you look at the guidelines of FDA, the first question is, well, the guidelines are written for chronic agents. And if you look at the marketplace and I've done that work, you will find there are 60 approved agents or combination of agents, a lot of injections with a lot of side effects that are being used to treat diabetes. That's our landscape today.

So here we come along, and we propose to the FDA and the space, hey, by the way, there is this protein in your body that, if we inhibit it, it reacts almost like mother nature where mother nature when it addresses either pregnancy like Ralph DeFronzo mentioned, or obesity, it has this regulating mechanism. And if you take out or if you inhibit this protein, you may have the benefits of that mechanism. But we don't need to do it chronically; we only need to do it for 12 weeks.

And so what we asked the FDA and we feel and, obviously, you never get a perfect answer from a government agency that hasn't seen everything and where there's, obviously, large studies lacking but you get an indication, we feel comfortable with the understanding that we will not be treated under the guidelines of a chronic agent because we're not treating chronically. So the endpoints that were agreed upon for the study COVALENT-111 will likely be the influence that we think the protocol -- we already know that the protocols for 211 and 212, the 2 studies we mentioned in the deck, will have the same endpoint, 26 and 52 weeks, as Mick mentioned. But I also think that the FDA will look for those for a Phase III design, meaning you'll look at HbA1c reduction at -- your primary is 26 weeks and your secondary is 52 weeks with -- in concurrence with a safety review. And that -- those are the primary things we look for.

And if you take that into consideration, well, what does that mean? That means I may not have to do with the thousands of patient studies because I'm not having to follow the guidelines for chronic agents and chronic treatment of type 2 diabetes. So those large Phase III studies in -- that you are accustomed to, we think we will not need. We are more in the hundreds of patients for our Phase III design. Yet, obviously, we have to prove it in the Phase IIs that we're now embarking upon. Is that okay?

[Operator Instructions] Our next question comes from Edward Tenthoff of Piper Sandler.

Congrats on very compelling data. Just a quick follow-up and maybe a little bit more detail on this next study. You said you would follow patients up for 52 weeks and/or longer. Would -- and I apologize if I missed this but would these trials have longer-term dosing with icovamenib? And do you think that's even -- do you think that's even necessary?

Yes. Right now, I feel like we already know we're going to get good results with 12 weeks of dosing. And we're going to pursue that as a sort of strategy for registration at this stage. Whether we will need to come back later with additional dosing, obviously, we'll need to see what data happens over time. And I think right now, it's not, as I said before, it's not sensible for us to go into many directions. So I think we want to make sure that we can drive forward with a 12-week therapy, and then if we get a registration and we get on the commercial side, then we can investigate some of these other pieces.

Great. That's super helpful, and very differentiated profile.

Thanks a lot.

And I am showing no further questions at this time. I would like to hand the call back to Mick, CEO, for closing remarks.

Thank you very much for joining the call today. We appreciate your continued interest and support. This now concludes the call. Thank you.

And we do appreciate your patience. Thank you for participating. You may now disconnect.