Biomea Fusion, Inc. Common Stock Study result

Thank you, operator, and welcome everyone to this conference call. Today we will discuss top-line results from the phase I-B, 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 oral 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 non-clinical 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 molecular 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 non-clinical PK studies in both monkeys and rats, BMF-650 demonstrated high and prolonged exposure following oral dosing. Importantly, bioavailability was approximately 2-3-fold higher than orforglipron in these experiments. Conceptually, the design is quite straightforward. Lower receptor potency coupled with high and sustained systemic exposure.

The non-clinical PK gave us confidence to take that hypothesis into humans, and you will 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 study. Importantly, emesis events were relatively limited despite dosing without titration. On slide 12, I bring together these non-clinical observations to highlight three 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 oral bioavailability with low variability in our non-clinical 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 blowtorch 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 Frías, 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. I will focus on four 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 four active dose cohorts and corresponding placebo participants. The dose regimens increased across the cohorts. The first four cohorts evaluated different weekly dose escalation schedules. Let's now 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 eight active and two placebo participants for a total of 32 active participants treated with BMF-650 and eight pooled placebo participants in the first four cohorts. Turning to the clinical activity findings on slide 16, this analysis examines the incremental weight change during each weekly dosing interval of cohorts one through four.

Here we observed reductions across all four BMF-650 treatment cohorts through day 29, compared with essentially no change in pooled placebo. Mean reductions ranged from 1.5% to 3.2%, with cohort three achieving the greatest mean reduction of 3.2% in this key secondary endpoint. 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 four 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 one 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 one week to 400 milligrams once daily for the remaining three weeks. At that point, we had observed only limited safety findings and importantly, no clear increase in gastrointestinal adverse events in the earlier cohorts. 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.