Biomea Fusion, Inc. (BMEA) Earnings Call Transcript & Summary

Hello, and welcome to Biomea Fusion Investor Call and Webcast. [Operator Instructions] I would now like to hand the conference over to Ramses Erdtmann, the company's President and COO. Sir, you may begin.

That's great. Thank you, Towanda. Good afternoon, everyone, and thank you for dialing in. We are very happy to announce that FDA has lifted the clinical hold placed on Biomea's ongoing Phase II clinical trials of the company's investigational covalent menin inhibitor, BMF-219 in Type 2 and Type 1 diabetes, our study COVALENT-111 and COVALENT-112. Some quick introductions. My name is Ramses Erdtmann, I'm the COO, President and Co-Founder of Biomea. With me on the call today from our team and available to answer some questions at the end are our CEO and Chairman, Tom Butler; also Co-Founder of Biomea as well as our CMO, the renowned leader and expert in diabetes research and patient care, Dr. Juan Pablo Frias. Before we start, let me remind you, during this conference call, we may discuss forward-looking statements about the business prospects of Biomea Fusion, including expectations regarding Biomea Fusion's clinical trial and preclinical study results and potential future product candidates in different areas of therapeutic research and development. Results may differ materially from those expressed or implied in this presentation depending on the progress of Biomea Fusion'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 Fusion's filings with the SEC such as 10-Q, 10-K and 8-K reports. All forward-looking statements made during this presentation are based on the beliefs of Biomea Fusion as of this date only and future events or simply the passage of time may cause these beliefs to change. You should not place undue reliance on the forward-looking statements made today. I will now turn the call over to our CEO, Tom Butler. Tom?

Thank you, Ramses. Patient safety is paramount and our top priority. We greatly appreciate the FDA's review of our data and the swift resolution of the clinical hold. The in-depth review of the clinical data to date reconfirms our confidence in BMF-219, as a novel first-in-class agent for the treatment of diabetes. We are encouraged from the safety review of the ongoing Phase IIb Expansion Study, where the concerning safety signals seen in the Phase IIa Escalation Study did not translate over to the larger Expansion Study. And most importantly, none of the elevated lab values translated to confirmed serious liver injury or liver impairment. We see the clinical hold as serving 2 important roles: one, an opportunity to ensure the safety of our patients as we advance BMF-219 into late-stage clinical development; and two, advance our understanding of how to best deliver a profile that maximizes efficacy while maintaining safety for all patients who receive BMF-219. I believe the outcome of these 2 roles is an increase in the probability of success for our BMF-219 program in diabetes. We took the clinical hold very seriously, which is why we conducted not only an internal but also an independent external investigation using world-renowned liver experts to carefully examine the safety signals. Let me walk you through the key observations from our safety data review. The liver enzyme elevations are predictable, dose-related, transient and return to baseline. High-grade elevations occurred in the first 30 days and were seen in patients with the starting dose of 200 milligrams. These patients typically had high baseline blood glucose levels and experienced a rapid drop in their blood sugar, in the first 30 days. Patients who received 100 milligrams throughout the dosing period and patients who start at 100 milligrams during the first 60 days and then escalate to 200 milligrams, do not experience these high-grade elevations independent of baseline glucose levels. During our call today, Juan will provide a bit more color on the findings and our plan moving forward in Type 1 and Type 2 diabetes. As previously announced, we are on track to review our top line results from the Phase IIb portion of COVALENT-111, the expansion phase with approximately 200 patients with Type 2 diabetes in late Q4 2024. We will also be able to review before year-end early top line results from the Phase IIa of COVALENT-112 with approximately 20 patients with Type 1 diabetes who completed at least 8 weeks of BMF-219 dosing. Both studies are on track for the readout and the planned time lines have not been materially impacted by the FDA review. With our study readout coming by year-end, we believe we will significantly increase our understanding of BMF-219's unique mechanism of action for the treatment of diabetes. As we continue to investigate BMF-219 and Type 2 diabetes broadly, we are particularly excited to see the impact of longer dosing in patients whose disease is primarily driven by beta cell deficiency or dysfunction compared to patients whose disease is primarily driven by insulin resistance. The upcoming data will help us to confirm the optimal dosing scheme and the patients who respond best to BMF-219, both of which we can then be utilized for our Phase III study design. We are very excited for the upcoming data sets in Type 1 and Type 2 diabetes. Let me also address the advancements in our metabolic portfolio. We have made really great progress with this third program, which we also developed in-house with our Biomea Fusion system. This third program is a potent, selective, oral small molecule, GLP-1 receptor agonist candidate. We plan to press release the formal announcement of our third program and host a company call in Q4. It will include data from our non-human primate study, including glucose lowering, insulin secretion and appetite suppression. I will now turn the call over to our CMO, Juan Frias.

Thank you, Tom, and good afternoon. As everyone on the call is likely aware, a significant unmet need remains for our patients with both Type 1 and Type 2 diabetes. Despite very important advances in pharmacotherapy for diabetes and diabetes-related devices over the past decades, most patients remain poorly controlled with hemoglobin A1C levels above the generally recommended target of less than 7%, putting them at increased risk of diabetes-related complications. There are many reasons for this poor control, with one of the key reasons being the fact that today's agents do not specifically address a root cause of diabetes which is a progressive decline in beta cell mass and function resulting in impaired influence accretion and hyperglycemia. In Type 2 diabetes, even if a patient can attain adequate glycemia control, it is very difficult to sustain, given this progressive decline in beta cell function. In patients with Type 1 diabetes, exogenous insulin administration is not even near physiologic and frequently leads to dangerous hypoglycemia, which often limits appropriate insulin dose titration, resulting in some optimal glycemic control. In addition, all of today's currently available agents for the management of diabetes require chronic daily or weekly therapy. This, along with the fact that most patients with diabetes, particularly Type 2 diabetes are on multiple other medications contributes to poor therapeutic adherence and persistence, worsening glycemia control and increasing the risk of poor long-term outcomes. Even with today's most potent glucose and weight lowering medications, the GLP-1 receptor agonist based therapies such as f, real-world clinical practice data demonstrate generally poor adherence and persistence with therapy, which may ultimately impact short- and long-term outcomes. There is an important global need for an agent such as BMF-219 that is designed to specifically target the beta cell, augmenting beta cell mass and function in that potentially disease modifying and could significantly enhance glycemic control and improve the outcomes in persons with diabetes. BMF-219 is an investigational oral covalent menin inhibitor, which has been shown in preclinical studies to increase beta cell proliferation, thereby increasing beta cell mass and function. Clinical data to date have demonstrated significant and durable glycemic control in some patients with Type 2 diabetes, 22 weeks after a short 4-week course of therapy. BMF-219 has several characteristics, which we believe differentiated from currently available anti-hyperglycemic agents. It is an oral small molecule with a mechanism of action that is complementary to today's agents, including GLP-1 receptor agonist based therapy and SGLT2 inhibitors. Importantly, we believe that it may not require chronic dosing given its mechanism of action and the lifespan of a beta cell, which is measured in the order of decades. As such, the population of BMF-219 has the potential to address includes many persons with diabetes, including Type 1 and Type 2 diabetes. In Type 2 diabetes, particularly those patients with significant insulin deficiency has the primary pathophysiologic driver of their disease. Let me now turn to the FDA review. Over the years, in my roles in drug development and as a clinical investigator, I've had many interactions with the FDA, participated in advisory committee meetings and I have a great appreciation for the FDA's oversight of patient safety. In our case, the clinical hold was based on elevated liver enzymes, ALT and/or AST lab results. Elevation is higher than Grade 2 or of concern to us, the sponsor and to the agency. FDA specifically reference cases of elevated liver enzymes observed in the completed dose escalation phase of COVALENT-111, our Type 2 study, during which we assessed higher doses up to 400 milligrams and various food intake regimens. We provided FDA all of our safety data and all patient narratives including medical history and concomitant medications to allow for a full assessment of all the factors that may have led to the concerning elevations. Diabetes is a multi-organ disease with the liver playing a critical role, rapidly changing glucose and insulin concentrations impact multiple organs, which need to adapt to these metabolic changes and achieve homeostasis. Many patients with diabetes of metabolic liver disease and excess of liver fat, which can affect the organ's ability to efficiently adapt to the changing environment. Based on the data collected to date, all elevated liver enzymes of concern occurred in the earlier escalation phase of the study, where we assess starting doses of 200 milligrams. No Grade 3 or higher elevations were seen in participants who initiated therapy with a dose of 100 milligrams or lower. During the expansion phase of our phase -- of our Type 2 study, COVALENT-111, we dosed over 200 patients with this lower starting dose and did not observe any grade 3 or higher liver enzyme elevations. A very low incidence of grade 2 elevation and no dose interruptions or dose discontinuations. And most importantly, none of the elevated lab values translated to confirmed serious liver injury or liver impairment. Given these findings, FDA has recommended and we have implemented a single step escalation from 100 milligrams to 200 milligrams and increased monitoring designed to support patient safety in our ongoing trials. These measures include a BMF-219 starting dose of 100 milligrams once daily in all future diabetes studies. Dose escalation only after the initiation of 100 milligrams and an increased focus on liver safety surveillance, enhance more pronounced interrogation and observation of the patients enrolling in our studies as concomitant medications as well as the patient's own medical history are potentially contributing factors to their safety profile. The FDA review and interactions related to this clinical hold have provided helpful guidance for us as we plan our Phase III trials. I will now pass the call back to the operator and open the floor to questions.

[Operator Instructions] Our first question comes from the line of George Farmer with Scotiabank.

Congratulations on getting this hold lifted, that's great news. Wonder if you could talk about the ongoing study a little bit more. And a little bit about what you've learned as far as who are the best responders in this Type 2 population? And then perhaps elaborate on other cohorts that you might be contemplating. And then secondly, can you go higher than 200 mg in this titration phase? Or is 200 mg going to be the maximum you think that you can dose up to?

George, this is Tom. Thanks for your questions. It was a little hard to hear you. So please correct me if I didn't cover all of your questions. So for the ongoing COVALENT-111 Phase IIb Expansion Phase, that study is still blinded. So the analysis from a responder perspective will be done as part of the statistical analysis plan at the time of the readout. So, to your point, we will greatly increase our understanding because the end has greatly increased compared to the escalation phase, and we've also are now treating patients out to 12 weeks versus just 4 weeks of treatment. And we'll get to basically bifurcate and look at how patients are responding based on kind of a beta cell deficiency characteristic versus insulin resistant characteristic. And so we're quite excited to see that. And so for COVALENT-112, obviously, we will continue dosing patients in the open label. And as we continue the open-label portion, it will give us a really good understanding of who are the right patients from a year since diagnosis perspective, from a dose level perspective to then weave into and start up the randomized placebo-controlled portion of the study. And I'm sorry, the last question?

I can address that, actually, George, this is Juan, here. You mentioned whether we might go beyond the 200-milligram dose. And I would say that in the expansion cohort, as you know, we're studying 100 milligrams for 12 weeks, and then we have the 100 milligrams for 8 weeks, escalating to the 200-milligram dose. And again, we did not see any Grade 3 elevations in the expansion cohort. Now we will need to -- we will be starting future trials of 100 milligrams and we'll need to see these data from the expansion cohort to see if we even need to go beyond 200 milligrams. But if we do, we would do it in an escalated fashion, always starting with the 100-milligram dose. But I think it remains to be seen at this point, again, based on the data we'll see at the end of the year.

Right. Yes. That makes sense. But again, how about other cohorts for 111, have you contemplated any other designs beyond what you've been evaluating now and say these first 200 patients?

Yes. no. We will -- clearly, based on these data, have additional studies as we move forward, but not further cohorts in the 111 study.

Our next question comes from the line of Yagal Nochomovitz with Citi.

8 This is Ashiq Mubarack on for Yagal. Congrats on getting the lift holded. I just had a few -- I think you touched on this, so I apologize if I missed it, but could you discuss a little bit what you believe the root cause of the liver signal to be? I know you were considering a few major theories as to the ideology, but I'm wondering what you've learned at this point and what you feel was the exact driver? And then a follow-up on that is besides the step dosing component, are there any major changes to the protocol moving forward that you'll have to implement, especially as related to patient selection strategies or exclusion criteria related to patients on any particular type of concomitant medication? Any color there would be very helpful.

I'll just take the first part -- this is Tom, and I'll pass it over to Juan. But Juan, I think described it quite well that, look, you have a disease setting where the liver is greatly impacted by -- and with rapidly changing glucose and insulin levels with high dose exposure is leading to these elevations. And that hence is why we would start at 100 milligrams. And Juan for other questions...

Yes. With respect to the protocol, I mean there are some changes, but I would not call them really major changes. So we're going to increase surveillance, particularly during the dosing of BMF-219. We were actually measuring safety labs quite frequently, but we will increase that formation of hepatic toxicity, the monitoring committee as well that's an important change, not necessarily great to the protocol, but again part of the increased safety surveillance. And then just being very careful, measured -- you mentioned concomitant medications. The patients that are taking, particularly new drugs that are potentially hepatotoxic such as recently started antibiotics, for example, that they either be excluded or we wait until the course of those -- of that therapy is completed and the patient is stable, those really are the major changes. So increased surveillance and again, just making absolutely certain that patients aren't initiating any way, have had a potential hepatotoxic medications, either a baseline or during the study without us knowing.

Got it. And if I could ask one last one. Is there any color as to when the timing as to when you can start reducing patients? And will that be within the context of a new study or starting a new cohort within the 111 or 112 studies?

Yes. So redosing can start today. And for us, the expansion phase is completed and all the patients are in follow-up. So that's why the study remains on track for readout. And then redosing for 112 will start as soon as possible.

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

Congratulations on your thoughtful discussions with the FDA here on releasing the hold. So my first question is, how would you characterize the types of follow-up you're going to have with the patients that might have been lost to the hold and the dynamics around them and how it could impact the data interpretation going forward. And obviously, 111 has -- does have a very large number of patients.

Yes. So at the time of the hold -- this is Juan. At the time of the hold, the vast majority of patients -- all of them have been enrolled in the study. And the vast majority had already completed dosing. So they're really a nonissue. They -- we needed to follow them for safety and they're being followed for efficacy as well. So there were some patients that were in the midst of dosing. Those patients also continued in the study. So depending on how much dosing they receive, we'll sort that out in the analysis. But over 90% of the patients had already completed their dosing. So we have adequate numbers to really look at this and have enough statistical power with the patients are completed.

That's very helpful. And more of a combined question, if you don't mind. When you show data by the end of the year for the Phase IIa, are you going to show any of the 400-milligram data for safety or efficacy or both? And for the patients that -- or for the studies that were placed on hold are patients with elevated liver enzymes during that time period, continuing on the study?

Yes. So those patients continued on the study that had elevated liver enzymes. And I'll tell you, the vast majority of those patients did not have to discontinue therapy and there was no interruption in therapy, even those that did have interruption of therapy, their liver enzymes came down and they continue in the study. And there was no one in that study. The highest dose was 200 milligrams. Again, when we're talking about the Phase IIb expansion cohorts on those patients were either dosed with 100 milligrams or started with 100 and escalated to 200 milligrams. So there are no 400-milligram patients in that cohort.

Next question comes from the line of Naureen Quibria with Capital One Securities.

I guess in your prepared remarks, you mentioned that the LFTs were transient and there weren't any liver injuries or toxicities. I was just curious, can you talk about the time or the fluctuation, the transiency that you saw this for? And like at what point in the treatment were these LFTs observed? That's the first question. And I guess another is just curious what gave the FDA comfort that these LFTs would be -- it shouldn't be expected at the current dose or 100 milligrams or 200 milligrams ultimately over time with increased drug intake?

Yes. So let me -- I'll address the last part of that question first if that's okay. And that's the fact that though it was blinded, we did have all the liver data for the expansion cohorts of the study. So the study was not unblinded. But -- and we saw in those 200-plus patients that starting with 100 milligrams, even if we escalate to 200, did not cause Grade 3 elevations, very few Great 2 elevations and no one had to come off drug. So that gave them comfort that, hey, using this dosing regimen that we're proposing now, starting with 100 milligrams really does not lead to clinically significant liver LFT elevations. And then none of them, whether it be in the prior escalation cohorts or in the expansion had increases in bilirubin. There were no increases in INR. So no indication that there was any sort of decrement in liver function. So these were isolated aminotransferase elevations that for almost exclusively were transient and almost all resolved what patients remained on medication. So that really is what I think at the end of the day, with what we mentioned also with the increased surveillance during the studies, I think that provided us and the agency with reassurance that there will be -- we will have good patient safety during the subsequent trials.

Yes. To your first question, these happened in the first 30 days, and it happened if you have certain characteristics of the patient with high dose level in the first 30 days. And that was the key.

Appreciate it. And just one quick follow-up. Speaking to the principal investigators, do they appear to have the same level of confidence that the FDA and you?

Yes, I think so. We've talked to many of the principal investigators, our Scientific Advisory Board as well. I mean this is a bit anecdotal. I haven't talked to every single investigator, but yes, I think they really do.

Yes, I agree with Juan. This is Tom. And we were at ESAD, we were at ADA, and I would say that the interest in what we're doing because it's so novel, so unique and so promising that the excitement encouragement for this to be a success is there. And the PIs and the patients on the study, really were there to support us as well. And I thought it was fantastic.

Yes, I completely agree with that.

Ladies and gentlemen, due to the interest of time, our final question will come from the line of Tony Butler with Rodman & Renshaw.

Two questions, please, and I really do appreciate the call. One is around concomitant meds. One, if I heard you correctly, you made a statement that, for example, we're a patient to go on say, a new antibiotic that being a newly dosed antibiotic. They may not be eligible for a subsequent trials, where you do, for example, do a new -- start a new cohort. The question is if that person is on study, and they begin to say that antibiotic for whatever reason. Do they -- is that a dose interruption or do they actually come off study? That's question one. And then question 2 is, does the -- is the interval between the starting dose, say, 100 to 200, which has been, if I'm not mistaken, 8 weeks or longer, can it be shorter, for example, 4 weeks per the -- what your agreement is with the FDA on follow-up trials?

Yes. Let me say something. This is Juan, about the antibiotic use. I mean, generally, these would be discussions that our medical monitor would have with the principal investigator or the investigator at the site. And they're always alternative antibiotics. So we're not saying any antibiotic. I mean, but there's specific antibiotics that have a higher risk of potential hepatoxicity. And we don't want to confound things. So there's always a discussion to be had, and we were choosing alternative antibiotic and the antibiotic in question was potentially hepatotoxic and the patient had to use it, yes, that would be a situation, and we would have to make a decision to interrupt therapy while they receive their antibiotic, make sure the patient was okay and then resumed therapy. I think that will be quite rare, but certainly could occur, but it would be in a very small percentage if it occurs at all since there are other options. And then with respect to the dosing interval, there was no specific instruction given to that. But I think, again, we'll need to look at the data at the end of the year and see how it goes with the arm, this arm so-called C that is dosing for 8 weeks with 100 milligrams and then escalating to 200 milligrams. And then we'll decide what we'll do always with very close monitoring the patients during the clinical trials.

Ladies and gentlemen, at this time, I would like to turn the call back over to CEO, Tom Butler for closing remarks.

Thank you, operator. We aim to bring diabetes patients back to a normal healthy state of glycemia control. With our Type 2 and Type 1 diabetes studies, we seek to evaluate BMF-219's potential ability to regenerate, preserve and reactivate healthy, functional insulin-producing beta cells and in doing so, potentially deliver the first disease-modifying treatment for diabetes, a therapeutic solution that tens of millions of patients in the U.S. and several hundred million globally need and deserve. With the data published to date, we have made important progress in understanding BMF-219's potential impact on beta cells and the underlying proposed mechanism of action of covalently inhibiting menin. With the continuous effort in progressing the clinical development by the Biomea team, we expect to have top line readouts from Phase IIb of COVALENT-111 with approximately 200 Type 2 diabetes patients by the end of the year. And also the top line readout from the Phase IIa open-label portion of COVALENT-112 with approximately 20 Type 1 diabetes patients before year-end. Plus, we will have a first readout of our preclinical data of our newest pipeline asset, our next-generation oral GLP-1 agonist. Lots of data coming. Stay tuned. In closing, I would like to thank the Biomea team and the FDA for working collaboratively and diligently, which led to a prompt resolution of the clinical hold. My teammates here are incredible professionals, they are executing at the highest level scientific excellence. When we started Biomea, we defined our mission as we aim to cure. Being able to address diabetes at its root cause impaired beta cell health, mass and function is an ideal manifestation of that mission. Thank you for your interest in our developments and for dialing in.

Ladies and gentlemen, this concludes today's conference. Thank you for your participation. You may now disconnect.