All right. Hello, everyone, and welcome to the H.C. Wainwright 4th Annual BioConnect Investor Conference. My name is Lander, I'm a VP of Equity Research at the firm, and here with me are Ramses Erdtmann, COO, and Steve Morris, CDO of Biomea Fusion. Thank you for joining us.
Thank you for having us.
Of course. Before we start from a disclosure standpoint, we currently cover Biomea with a buy rating. Maybe Ramses, at a high level, can you briefly frame how you're approaching obesity and diabetes, and how is Biomea uniquely positioned?
That's a very loaded question. I assume in my answer that you may not know much about the company and that I don't bore you with my answer. If you look at diabetes in particular, you will see we have. This is not an exaggeration. We have over 60 approved agents in diabetes, and we have a disease where the numbers of diabetes patients is growing, and the number of controlled patients is not changing, meaning 50% of the patients that have diabetes are uncontrolled. Their sugar level is above normal, which is weird. You ask yourself, "I have all these agents, why are they not working?" If you just go one level deeper, you will realize what all these agents are doing is they're trying to address sugar in the blood, and they're doing this in various ways.
You've all heard about metformin, you've heard about all the various mechanisms we're doing in addressing diabetes, meaning high sugar levels, how do we get them down? At the end, about 1/3 of patients to have end up on insulin, which is your last resort. You can't make enough insulin yourself. You take an outside agent, forget all the other agents you're on, you need insulin. What we have found is that in pregnancy and obesity, the body has a mechanism to address the need for more insulin naturally. That is phenomenal, but only under these two stress conditions. In both conditions, the body upregulates prolactin, which is a hormone, which then downregulates a control valve or control mechanism called menin. It's a protein.
It's a scaffold protein that sits in the position of, you gotta get rid of me, otherwise this mechanism is not working. By upregulating prolactin, this downregulates, and now these cells can act in the function they should be, meaning they either restore themselves to produce more insulin. In pregnant women, you see they have an enlarged pancreas. There are more beta cells, and they produce more insulin. The more women go through pregnancies or breastfeed, the less chances they have for diabetes. When we saw that research, we thought to ourselves, if I could address this mechanism with a drug, I would help a diabetic person in the most root cause way. We're addressing the reason why they have diabetes, which is the depleted pool of beta cells.
We started with animal experiments. We did cell experiments, human cells, and we saw this mechanism is working exactly the way academia had described it. We reproduced the same results. Once we confirmed that it's only happening under glucose toxicity, meaning the body, even if you take menin out, does not produce more insulin if it's not needed or doesn't reproduce beta cells. We said, "Okay, this is a self-regulating mechanism. We should not induce too much insulin," which you always get when you try to tamper with insulin in the body. You overdose or you underdose. We shouldn't have that. Let's go into humans. We did an all-comer study. We had to isolate, does it work in humans?
Those are the results you have covered so well with all your reporting, where we had seen there are segments of patients where this mechanism was beautiful, and in others it doesn't. Why not? Well, if you're obese, you already have this mechanism engaged. If I give you more menin reduction, you make more insulin, but your problem is resistance. That's how we defined our segments. Now we're in patients that are insulin deficient. They're not obese typically, and where we see, and now go into a phase II study to repeat the results.
If we focus on the COVALENT-111.
That's the study. Yeah.
That's the study. Focusing on the SIDD patients.
Yeah.
As you move to a potential commercialization, how are you thinking about working with regulators, payers, and prescribers in terms of defining an SIDD type 2 diagnosis?
Yeah. It's actually, he uses an acronym which is a little unfair. SIDD means severe insulin-
Insulin.
deficient diabetes, no problem. The FDA doesn't like that. They don't like us as industry to come up with new terms that they haven't blessed.
They want us to define patients with inclusion, exclusion criteria. We have used those inclusion, exclusion criteria to go after the quote-unquote "severe insulin deficient patients." It's a very close proximity to what these criteria mean to academia. That's how we defined it earlier. We're now in agreement. We submitted our protocols. The protocols were released, we are now enrolling patients in standard inclusion, exclusion criteria. However, the way you define them also to payers and insurances, if your patient is on metformin, SGLT2, all these agents, and his A1C is high, meaning he's uncontrolled, what do you do? You give him insulin. Once he's on insulin, he becomes insulin dependent, once he's there, he loses, in average, do you know the number? 10 years of life. 80% of those die of a diabetes related disease. That's the problem.
What we're doing is we're saying, "Give me that patient before he goes on insulin. I'm gonna help him restore his function, so he doesn't have to go on insulin". Meaning, we're taking a huge burden out of this healthcare system by restoring a functional response in a human the way it should be. Mother nature doesn't allow beta cell growth outside of those two conditions just willy-nilly, meaning they don't grow, and beta cells live for decades. It's a, it's a very unusual opportunity to do something in this disease setting, which costs $0.25 of every healthcare dollar goes to diabetes.
If we could win this, I think we can win over insurance companies without a problem, but also the regulators. We work very closely with them to understand how would they define a phase III study. The way we're designing our studies COVALENT-211, COVALENT-212 are in with that in mind. We think this is registrationable once we show results.
Okay. Okay. The second subgroup or subtype, it's the GLP-1 non-responders.
Yeah.
For this population, maybe, Steve, do you think that the mechanism is still beta cell restoration, or do you think that maybe icovamenib can upregulate GLP-1 receptor expression and somehow resensitize patients to the background therapy?
Right. We did identify in our initial type 2 study a subset of individuals who were on a GLP-1 receptor agonist, but were not achieving glycemic targets, specifically an A1C of 7% or below. When we added icovamenib on top of the GLP-1 receptor agonist to that subset of patients, we saw a phenomenal reduction in A1C to the tune of about 1.5%, roughly. What is the mechanism underlying that response? We think, to answer your question, in part, it is an increase in the beta cell pool.
In addition to that, we and importantly independently others, for example, in the academic peer-reviewed literature, have shown that if you inhibit menin, not only do you increase the beta cell numbers, but you also modulate the expression of the GLP-1 receptor as well as GLP-1 as well as GLP-1 itself. You add icovamenib, you increase the receptor expression, you increase GLP-1, you convert a type 2 patient who is failing a GLP-1 receptor agonist now to a responder.
Mm-hmm. Makes sense. Yeah. Maybe changing gears into icovamenib in Type 1D. You recently announced exploratory data from the open label COVALENT-112 trial. Can you guide us through the C-peptide results and comment on how icovamenib may overcome maybe limitations from other beta cell-oriented approaches for Type 1D?
Yes, definitely. In our type 1 study with icovamenib, we showed actually an increase in C-peptide levels. Now, that is essentially unprecedented. Just to level set that statement, the other agents that are under investigation for the type 1 population seek essentially to blunt the autoimmune destruction of the beta cells. They do not, they're not focused on increasing the number of beta cells, increasing overall beta cell function. Rather, their goal is to decrease the rate of decline of the beta cell given the ongoing autoimmune destruction of the beta cell pool. By contrast, as mentioned, our icovamenib in those type 1 patients, we saw an increase after only 12 weeks of dosing 52% above baseline. Really, as I indicated, this is essentially unprecedented with other agents in type 1.
Yeah. Considering that the effects were greater in Type 1D patients with recent diagnosis, how?
Right. Yeah
How do you think that how important do you think this targeting this specific patient population?
Great question. The other agents, the agents that I mentioned, seek to decrease the rate of C-peptide decline. They enroll patients very soon after the diagnosis of insulin-dependent type 1, specifically typically within 90 days, sometimes even less. The reason they do that, because of the ongoing destruction of the beta cell pool, if they wait too long, there are no beta cells to protect from that ongoing destruction. By contrast, we enrolled in our Type 1 study individuals who were up to three years post-diagnosis. We also enroll patients longer after diagnosis. The patients who were within three years of diagnosis, the mean was 2.1 years post-diagnosis. We saw the 52% increase in the C-peptide that I mentioned to you earlier. Again, it speaks to our mechanism of action.
We're not just protecting the beta cells that are there. We're adding to the pool.
Yeah. Awesome. Thank you for that. As you move to our randomized phase II study in Type 1D this year, hopefully, what magnitude of effect would you consider clinically meaningful in a larger trial? How are you thinking about duration of dosing and combination with immunosuppression, maybe to boost or enhance beta cell function?
Okay. That's to me? Okay.
Yeah.
When you look at what Steve just said, it is really profound. In Type 1 diabetes, there is no agent, period. Now you're dealing with a disease where there is no therapy other than insulin.
Yeah.
Anything that you can show that improves the disease characterization is a benefit. If you delay the onslaught, which Steve just mentioned, that's a benefit. It doesn't really solve the problem. The problem is the onslaught happens, these cells die, and that's it. Meaning then you're insulin dependent for the rest of your life. What we're trying to do is we're trying to dose for six months.
Yeah.
Now that we can chronically dose, we've passed all the tox work. We dose for six months, we stop, we check. Did we trigger a T cell attack? Did we trigger the autoimmune system? If so, at what rate? One arm goes and continues for another six months. Another arm says, "Let's just stop and see if we can hold those responses for longer." Maybe six months is enough, maybe we need 12. Let's just look at if the protection of those cells through an immunomodulation agent, so you're modulating the immune system, could benefit this patient. We're looking for a strategy when we do this next study that would solve a potential problem not just as a patch but more profoundly. The goal is to come up with a strategy for a phase III.
Yeah.
This data informs us we can now go to phase III. We can either go against placebo, go against teplizumab, go against whatever then may be the standard of care, but do all that by next year.
Yeah.
That's, that for us as a company is incredibly rewarding because there the need is clear. We can still debate until the cows come home that there is a need in type 2. Everybody knows there's a need, but we have so many agents and so many other companies are trying to take the attention off the problem. Look, metformin. Look, GLP-1. There, it's a confusion for a lot of people, but it costs the healthcare system a tremendous amount of money to care for these patients. In type 2, the need and the overcoming of obstacles is greater than in type 1. Type 1, there's nothing.
Yeah.
Yeah.
Maybe, in terms of the potential combinations with immunosuppression, do you wanna comment anything on that?
Yeah, of course. I mean, they add safety issues. That's why we have six months lead in without them. 'Cause we didn't wanna mingle.
Yeah
And have that safety be on top of us. The first six months will tell us how good is our agent, and then we have one arm combining with them and one arm without. I wanna compare against them to see, do I really need them? Right?
Okay. In terms of the plans for a potential phase II, anything you wanna share?
Well, that is a phase II.
Yeah.
The data that comes out of that.
A confirmatory phase II.
Yeah, exactly. The question is this now detail, but can I start my own study? This study is actually we had inbound interest. If you look at America and you say, "Which are the top centers in America?" Well, there's the Barbara Davis Center in Denver. That's the guy who's gonna run this study. Oh, there's the Joslin, the largest type 1 diabetes center in the world. Oh, there's the sub I, our sub-investigator from there. Oh, there's the center in Miami where Jay Skyler is. Well, there's another investigator from there. There's San Antonio, where DeFronzo is. You have the four premier investigators in America that have an interest in this study.
Okay.
That we hope to bring into this protocol. Once this is up and running and we see the signals, we're gonna do our own study.
Okay.
Yeah. The minute we see the six months data.
All right.
That would be a confirmatory study.
Perfect.
Yeah.
That was very insightful, yeah.
Yeah.
I also wanna touch a little bit on your obesity asset.
Yeah
BMF-650.
Yeah.
With phase I weight loss data coming up anticipated this quarter.
Yeah
How are you thinking about the differentiation profile and potential advantages versus other oral GLP-1 receptor agonists?
Yeah. For those who have reviewed the phase I data of the other guys, take orforglipron as an example. Orforglipron is the lead compound currently. Orforglipron had a pretty good safety profile in the phase I and had really good, I think, efficacy data in phase I, but now they're in phase III. From there the titration from 2 mg- 36 mg took them four weeks, and now here in the commercial setting or in a commercial study for approval, it took them six months. Why did they change their titration schedule? Because they needed to. Nobody wants to add titration.
First problem is orforglipron is super, super potent, and it hits a long intestinal tube with 1 kernel of sand. How are you gonna distribute that?
Okay.
What we're doing is we took that scaffold, which is an incredible scaffold, and we said to ourselves, "How can we make it better?" If we drag it out, meaning take peak to trough and lower it so the impact is not like a bomb, the impact is more.
Extended, yeah.
Effectively, extend the half-life, create more bioavailability, can we improve orforglipron? That's the goal.
Okay.
We wanna improve the safety. We wanna improve the titration schedule, which you can't really show in phase I, but we wanna try to show that we can. We wanna have a safety benefit, which is difficult to tease out in a phase I, but we hope to show something.
Yeah
that would help you understand we're there with the similar efficacy.
Okay.
That's the goal.
Yeah, because in terms of efficacy, would you like to highlight the data that you collected with
Of course.
animal models in the monkeys?
Yeah. Not really because it's for people who are in the know, they say, "Oh, that's great. Show me humans." What I can say is the GLP-1 pathway industry is seven out of 10 patients are dropping out of a GLP-1. Why? Typically, even if you give them insurance coverage, that's what the studies show, they drop out because of safety, because of tolerability, because of, "I feel uncomfortable." We all wanna lose weight. We all wanna look better. There's no question. Do I wanna take it with the burden of tolerability? That's what drives this market into, let's go from Ozempic to the next drug, to the next drug, to the next drug.
Yeah.
Now that we have orals, let's try. Patients are doing it themselves, and physicians are doing it. At the end of the day, what you want is reduction and then maintenance, and if we can add that maintenance piece to the industry, which we're trying to do, we've shown a little bit of that in the monkeys, but we can't really prove that in a monkey.
Yeah.
If we can add that maintenance piece, that's where we find a need for another agent like ours, and that's what we will then pitch also to pharma because these studies are very expensive. Raising money like Viking did is a strategy of the past. I don't think it's a strategy of the future.
Okay.
Yeah.
All right. Thank you for that. Maybe for the sake of time, would you like to summarize the upcoming clinical milestones?
Sure.
catalysts for the ongoing programs?
Okay. We have two assets, BMF-650 and icovamenib, which is difficult to announce. We can call it ico. The one is a menin inhibitor. We are currently in two phase II studies, which will bring us into hopefully by year-end, first quarter, we'll have readouts.
Yeah.
These readouts allow us to have conversations with FDA. They lead to an an end of phase II meeting. The FDA could say, "Show me longer duration. This is 26 readout. Maybe we have to wait another 26 weeks." In next year, we will have that FDA meeting, and the data is being produced as we speak. The sites are enrolling. Patients are enrolling. Those two phase II studies are up and running.
Sorry, those phase II studies, they go hand in hand, right? They're progressing together more or less?
More or less. One is faster than the other
Okay.
very likely because one is easier to enroll more patients. At the end of the day, we will have data fairly soon.
Okay.
That data reads out. It brings us to a phase III, hopefully. Number two is 650. 650, as we said
Yeah
will have a phase I sometime this summer. That one will then increase excitement around the GLP-1 pathway. We have type 1. You have to think of it as once I tell you that the phase II studies are finished enrollment, you can do the timeline. You can say, "We're gonna have data then.
Okay.
That's another update which we hope to bring you by this summer sometime. phase II study done. Type 1, first patient in. That's an important timeline because now you can see, okay, they have four sites, first patient in, they're gonna finish enrollment then. We'll likely give you a timeline then for that type 1 study. Now you can see type 1 is up and running. Type 2 is on the run.
We're gonna have data in type 2. Then you can predict type 1. BMF-650 in obesity is coming also this summer. There's quite a few things that are happening right now. Plus, we're working very tightly with investigators that are very interested in what can icovamenib do for an obese patient.
Okay.
We have seen in animal models that when you add icovamenib to a GLP-1, you get increased weight loss. You guys covered that, but it's an animal model, so we gotta get into human. We don't have the funding to do all these studies.
Investigators are coming into the mix and are trying to see the signal and identify those patients, and those things will be announced fairly soon as well.
Awesome.
Yeah.
Well, thanks again.
Yeah. Thank you.
Ramses and Steve.
Thanks for the great coverage, by the way.
Awesome. Thank you. Thank you.
Yeah.
Thank you.
Thank you, Joe.
Look forward. Yeah.
Okay. Thank you.