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

Good afternoon. My name is Michael Choi, and I'm a member of the JPMorgan Health Care Investment Banking team. Thank you all for joining today. It is my pleasure to introduce Tom Butler, who is the Founder and CEO of Biomea Fusion. As a reminder, you may submit questions through the Ask a Question feature under the presentation. With that, I'll hand over to Tom.

Thank you, Michael, and to the JPMorgan team for hosting Biomea. Starting on Slide 2, Biomea Fusion is a precision oncology company with an irreversible drug discovery and development platform. We have 3 very exciting and innovative programs, all pursuing novel cancer biology. Our lead program currently in IND-enabling studies is focused on the novel target, menin. We are pursuing both liquid and solid tumor indications with defined gene alterations. We are -- our mission is to design and develop small molecules with a superior efficacy to safety profile, resulting in more effective and safer medicine for cancer patients. On Slide 3, we are now discussing the history of the company. Biomea Fusion was founded in 2017 by a team of medicinal chemists to explore novel targets and novel mechanisms of action such as menin. In the beginning, it wasn't known that you could target menin with an irreversible inhibitor. But after almost a year into the program in 2018, the discovery of a key cysteine in the active site and observing the deficiencies of the reversible menin pathway, we advanced into irreversible drug design and development. In 2019, we identified our lead candidate, a third-generation irreversible covalent inhibitor, BMF-219. We were also lucky in the transition between 2018 and '19 to be admitted to the Johnson & Johnson Innovation and JLABS, where we could literally get our feet wet. In 2020, it was really a transformational year for the company. We completed key translational studies and raised over $60 million to continue building out the company and advance our very exciting menin inhibitor 219 towards the clinic. The next slide is the Biomea team. We are a group of experienced and accomplished biotech professionals who have designed and developed blockbuster irreversible drugs. I've been lucky enough to be able to handpick these incredible people, all folks that I've worked with in the past, whether at Gilead or Pharmacyclics. The team also has a recent addition, Heow Tan, to support large-scale manufacturing and preparation for the clinic. The pipeline on Slide 5 highlights our lead program targeting menin, which will complete IND-enabling studies in the first half with an IND filing and a first-in-human clinical study in the second half of this year. We have 2 additional programs, which are complementary to the menin pathway and represent novel, but validated biology. We will disclose these programs once we have a lead compound that has been identified with the support of animal data. These programs have been built from scratch by our research team. Moving on to Slide 6. I'd like to describe our Fusion system. We leveraged this system, which is a proprietary Scaffold Construction method to build novel irreversible inhibitors. But our advantage truly lies in the many years of experience and success in designing and developing novel irreversible inhibitors. It starts well, though, and a very key aspect of it is the biology. You need to select the right target, one that can benefit from irreversible engagement. That way, it leads to a superior drug candidate profile. We spend a lot of time vetting these processes. We also use Crystal Structure based drug design, of course, which complements our Scaffold Construction methods. Our fusion process, to be clear, is an iterative process. And I'm now on Slide 7, where we design, test and optimize until we have a scaffold that meets our requirements for further development. This is where we spend a lot of time. Here, you can screen out scaffolds that may not be hitting the mark on selectivity or specificity as well as timing for irreversible binding. Slide 8 covers some of the irreversible drugs in history. There are many examples of novel and successful irreversible drugs, some of which may not be well known that they are indeed irreversible. Common drugs like aspirin and penicillin are commonly mentioned, but also antivirals like SOVALDI, Viread, remdesivir and, of course, cancer therapies like IMBRUVICA and tipifarnib. These drugs have had a dramatic impact in the lives of patients. On Slide 9, I'd like to take a moment to describe the benefits of an irreversible inhibitor and targeting menin represents a perfect example. The traditional sense of reversible drug comes on and off the desired target, which needs constant exposure to maintain its effectiveness. This may be difficult with larger molecules, especially when trying to disrupt a protein-protein interaction. So you can see at the top of this chart that the scaffold can engage with the target, but is in competition with natural substrates. Conversely, down below, the irreversible drug needs a short period of time, fused to the target and form a permanent bond. Here, the effectiveness is maintained without the need of additional drug. It is a much more elegant way of disruption. And on Slide 10, this is a perfect example of that elegance. The precision to disrupt the target while minimizing exposure is highlighted here. I'm showing you a PK/PD curve of a commercial drug and irreversible BTK inhibitor. And just to orient yourself, on the X-axis is time post-dose in hours. On the left Y-axis, in green, is occupancy of the active-site in BTK by the irreversible inhibitor. On the right-hand side on the Y-axis is plasma concentration. And you can see here within 4 hours, you reach maximum target engagement, and it's maintained through the 24-hour time point. Conversely, the exposure comes up and comes down within 4 to 5 hours so that you don't need to have untoward concentration through the rest of the day unnecessarily. Less exposure means less potential off-target effects. This gives you an optimal effect to exposure profile with maximum target engagement and a better selectivity and drug-like properties because you get to leverage a lower molecular weight small molecule. I'd like to take a moment to describe menin the target. When we started this program back in 2017, we knew very little about the target. In the literature, menin is described as solely as a tumor suppressor, and it wasn't completely obvious to us, why would you want to inhibit a tumor suppressor. And so obviously, we needed to spend more time to really understand the biology of menin and its implications across the therapeutic landscape. Menin is a master regulator at the epigenetic level. We also know that menin can't act alone, it needs a protein partner. And whether menin sits in the neutral position, in the on position as a promoter or in the off position as a suppressor, it's more like a toggle switch. And the constant on position, as is the case with MLL rearranged leukemia patients is highlighted here in Figure A. I'd like to point out in Figure A, if you look at where the fusion is located on the MLL protein, it's happening at the tail end, not the business end where MLL engages with menin. This is what's so interesting. That engagement site is completely conserved across the different cell types and fusion partners. And whether the fusion partner is dictated that affects the affinity of MLL towards menin. In the case of this activation, you have homeobox series of A and B as well as mice 1 that prevent a white blood cell from differentiating and maturing as they should. Instead, they stay at this pre-incubation state and continue to grow out of control, which is the hallmark of leukemia. If you can build an effective menin inhibitor and act like a wedge to prevent this engagement from happening, you break apart the engagement and the whole homeobox mice 1 chromatin structure falls apart. Here, the leukemic cell can undergo rapid apoptosis with some differentiation. Menin also plays a significant role in solid tumors, really as a central node piece. And whether menin is engaged with nuclear receptors with MLL1 or MLL2 or alone with MLL1 or MLL2, what is known is that these tumors have high dependency to menin. And whether it's KRAS-activated pancreatic, lung or colorectal, metastatic prostate, ER-positive breast or triple-negative breast, you can see that the applicability is quite broad. But in order to achieve efficacy in these tumor models, you need a very potent and efficient menin inhibitor. Slide 12, BMF-219 rapidly shuts down MLL rearranged AML cells. And you can see here, what I'm showing you is Mom13, one of the most aggressive AML cells with the rearrangement. On the left-hand side, I'm showing you cell viability at 190 nanomolar. The X-axis is labeled in days, so T4, T7, T11 to T14 is day 4, day 7 to day 14. And the Y-axis is labeled with cell titer glow output. And right away, you can get a feel for how aggressive the cell line grows with the untreated in black taking off by day 7. You can see that this reversible in blue, a very low nanomolar potent compound has trouble controlling the cell line at 190 nanomolar. However, the irreversible inhibitor 219 does a fantastic job of controlling the cell line even at the earlier time point. If you increase the concentration by nearly tenfold, the reversible inhibitor is able to catch up and replicate what the irreversible inhibitor can do. On Slide 13, BMF-219 rapidly shuts down another subtype of menin-dependent AML, the NPM1 mutation. This NPM1 mutation represents about 30% of AML. A key subgroup within this NPM1 mutation is the FLT3-ITD. And here again, on the left, we've increased it now to 560 nanomolar concentration and the reversible inhibitor has very difficult challenge to maintain control; however, 219 does a fantastic job even at the earlier time point, which needs only a single concentration without continuous dosing. If we increase the concentration to 1.7 micromolar, you can see that it's still not enough to replicate the irreversible effect. Our in vitro data has translated into exceptional in vivo efficacy with just 2 weeks of dosing, significant separation between the placebo and the active arm can be observed. This potential gives us best-in-class opportunity. In Slide 15 now, the opportunity to leverage menin inhibition to disrupt cancer is quite large. There are well-defined patient populations that exhibit high menin dependency. We continue to validate these indications internally with our novel inhibitors. And so what I have here listed on the left side with the liquid tumor indications, we have the MLL rearranged leukemia, NPM1 mutation within AML, DLBCL and multiple myeloma, representing novel indications for menin inhibition. On the right-hand side, I'm listing the solid tumors with list Ewing sarcoma and examples of KRAS-activated tumors such as lung, pancreatic and colorectal, which have been validated with our internal molecules. Finally, on Slide 16, 2021 will be another big year for the company as we transition from a preclinical stage to a clinical stage biopharmaceutical company. We look forward to completing our IND-enabling studies in the first half and file our IND in the second half of this year. Our Series A financing raising $56 million over the holidays allows us to advance BMF-219 in the clinic and continue to build out an exciting pipeline. Thank you very much for your time, and I'll stop here for question and answer.

And I see some questions coming through. I'll start with the top of the book, when will you be in the clinic? So we'll be in the clinic with our lead molecule BMF-219 in the second half of this year, 2021. Where and which other indications ideally would menin inhibition have effect? This is a very interesting question. This is something that we've been pursuing and trying to understand internally. There are several liquid tumor and solid tumor indications available for menin inhibition. And really, what we've learned is that the reversibles and irreversibles can both target them. It's just that the irreversibles are more potent and more specific and driving down menin. This allows us to explore not only liquid tumors outside of the leukemic space, but also solid tumor indications. Another question. What is the difference between your menin compound and the other 2 out there? Another great question. I'm guessing the other 2 out there are the ones in clinic. Those molecules are reversible inhibitors. Our molecule is irreversible, which forms a permanent bond to a cysteine in the active site of menin.