STIFEL 2026 HEALTHCARE CONFERENCE - BLACK DIAMOND THERAPEUTICS INC

All right. So I'm here with Black Diamond Therapeutics CEO, Mark. So Mark, anything new today? Lots new today. Really great to be here at the Stifel Conference after disclosing new data from our phase two trial and a really positive outcome from our meeting, our end of phase two meeting with the FDA. So, I'll enjoy chatting with you for the next 30 minutes. I'll just start real quickly with about Silivertinib and what it is. Yeah, summarize the update that you guys gave today, or the drug, and then briefly, and then we can get more into Q&A as well. Sure. So Silibertinib is what we believe a best-in-class fourth-generation EGFR TKI. I think everyone here knows the drug Tigriso Osomertinib, which treats about three-quarters of EGF-R mutant non-small-cell lung cancer patients quite well. Obviously, that drug does very well for AstraZeneca. But I think what we've learned in the space, in the EGFR mutant non-small cell lung cancer space, especially over the last three or four years, is that while EGF-R TKIs can control disease very well in the thorax, in lung cancer, most of these patients progress in the brain. And many of these patient present with brain metastases. So there's something about EGFR mutant, non-swell cell lung cancer, where it likes to go to the brain, and that's ultimately when patients progress on therapy, even with drugs like osomertinib. So our drug was designed from the get-go to be highly brain penetrant, and it is. We believe it is the most brain penetrating of any EGF-R TKI. And it also addresses not only these classical mutations that the Grisso goes after, but this other quarter of EGFR mutations, which is over 50 of them. They're often called atypical or uncommon, rare. But as a group, they're actually 25% of the population. Our drug very potently targets all of them, all 50-plus of those, unlike osomertinib, which does not have potent activity. So we've been developing this drug for the last two years in this frontline patient population. It's a phase two trial, 43 patients conducted primarily in the U.S., a few sites in Canada. We had an oral presentation at ASCO. And today we have now data, mature data, that I think we'll get into that led to a highly positive end of phase two meeting with the FDA where we now have a very clear path to accelerated approval and capturing that entire non-classical mutation population. So I think perhaps as an analyst, one of the most exciting parts for me about that was that we no longer have to break down all the atypicals into all these rigorously defined little subgroups. So it seems like if you don't have a classical mutation, if you have an exon 20 mutation, you can be enrolled in this trial. That's right. And I think there's been some confusion. Our chief medical officer, and he said this in our call this morning, calls it alphabet soup of mutations because there's so many of them. But if you think about a prescribing physician, they get the NGS report. The first page says you have a classical mutation, LA58R exon 19 del. Every doc knows what to do with that. You prescribe osomertinib. Exon 20 insertions, definitely some more treatment options like ribavit, but then they get to the second page and there's this laundry list of mutations and they don't have a drug. Now, there are a couple of competitors that are developing drugs in this space. They're focusing on a subset of those mutations called PAC, and that is confusing too, because what's PAC, what's not? Our definition, agreed to by the FDA, is any mutation that's not a classical mutation or an exon 20 insertion. Home run. Makes it a lot easier. Makes it lot easier to enroll a trial because all these patients are getting NGS testing. It's like, oh, you don't have a Tegrisov mutation? Come on to the trial. And as a prescribing physician, ultimately, when the label, very easy to understand. And as far as the phase three, in addition to having this broad group of EGFR mutant lung, you're focusing in on patients with brain metastases, unlike some of the competitors that you just referred to. You guys have discussed what the FDA potential for an accelerated approval path based on CNS-ORR. Competitors are focusing on systemic ORR. Can you speak to the de-risking involved with using a CNS ORR relative to systemic? Yeah, we can talk about why we're so confident that we can win in that patient population and still cover patients without brain metastases with this novel design. First, let's talk about CNSORR as an endpoint. It's been used for many primary CNS tumors. It's actually, well, it's not in the indication statement for Ducatinib. It's a breast cancer drug. They do use CNSORR for, is it in the label? The FDA issued guidance in 2020 for CNS active drugs. There are separate criteria to evaluate CNSAR called RENO-BM. It's more stringent criteria than RESIST. which is used for systemic ORR. So that's kind of the regulatory backdrop. So we walk into the agency, we've treated over 200 patients with this drug, 43 of them in the frontline setting. We have a CNS-ORR by Raynaud BM of 86%. 86%. Can you contextualize that? What's that? Can you conceptualize that versus the- Well, for Afatinib and Osimertinib, which are the only drugs available for these patients, it's in the mid-30s at best. And those data sets come from patients who have had, some of them, prior radiation. Our patients, that 86% came from patients who did not have radiation. So you walk in with that kind of data, combined with PFS data, that's now 16 months maturity, we have median follow-up of 16 months, our PFS in that patient population is 12.2 months. The PFS for afatinib and osomertinib, again, recent published data, big study, just published on osomertonib out of Memorial Sloan Kettering. Hundreds of patients. The PFF is 5.1 months for osomertenib. Yeah. 5.11 months. We're at 12.2. So it's very simple. Accelerated approval on CNSORR, full approval on PFS. There's your benchmarks. you're you're twice both of them you can run a relatively small trial 300 patients randomized one-to-one physicians choice we're ready to go yeah can you speak the powering like what kind of Delta you think you need to hit on the CNS ORR and also you know if you can comment on the PFS endpoint at this point yeah yeah so I could definitely I won't get into super details I will tell you that we talked at length with the agency in this end of phase two meeting about trial design, powering, number of patients, alpha spend, nominal alpha will be spent on the CNS-ORR endpoint. We believe it's adequately powered to pick up a difference of about 35 points. So even if we come down into the 70s and those controls go up to 40, adequately powered. What's really interesting in this trial and completely different than the trial that our competitors. Systemic ORR only has to be similar. No statistical comparison. As long as you're similar, which means your confidence intervals overlap with systemic ORR, that's fine. And now for PFS, again, we're at 12.2. Very recent data with osomertinib, which included patients who had radiation, which our patients won't. They're at 5.1, Afatinib's at 6.1. So even with somehow that control gets a little better, we're not quite as good. Even though our 12.2 isn't mature, our upper bound is still ending. So that 12.22 might get bigger. We're confident we're more than adequately powered for PFS with 300 patients, one to one. And can you speak to the control arm? I think Afatinab is pretty broadly believed to be not super CNS active. Osimertinib, yes, but not necessarily in this population. What kind of conversations did you have with the FDA regarding the selection of this control arm? Yeah, so FDA does believe, and it's true, it's the only drug labeled for these non-classical mutations, right? Osimartinib is widely used in the US because it has NCCN guidelines for those three mutations that Afatinib has. So this will be a global trial. You know, we have about 40 sites, about 30 sites in the U.S., another bunch in Canada. Most of the docs in the US will keep osomertinib, and most of the sites in the US, will be osomertenib. Some use afatinib, but it'll be a global trial. So certainly in Canada, Mexico, Brazil, Eastern Europe, Singapore, Taiwan, big parts of China, afatinab is widely used. Some pockets in Western Europe, up again more Osimertinib. So a global trial, I think a good mix of Afatinib and Osimartinib and the agency did suggest, again, we use both of those because if you think about global usage, there is both Afatinab and Osomertinab. And as far as dose of the control arm TKIs, does it have to be by labeled dose? Yes, labeled dose. Okay. So another, I think big thing investors were looking for in this disclosure that you guys had was dose for the phase three. There had been some concern that maybe 150 milligrams the FDA would make you run a lead-in trial for, but it seems like you guys came to pretty good terms on this. Very good terms. I'll speak about the discussion and kind of also the data set that we had walking into that meeting. So So the AEs that we had at 200 milligrams and the amount of dose reductions were a bit high. And you'd want to see in a frontline patient population a lower rate of initial AEs. Now what's clear is that these AEs were all EGFR mediated, right? Nothing new. It's rash, diarrhea mostly. With dose reductions, they come down immediately. You give standard supportive care that patients on osomertinib and afatinib get. So nothing alarming about the AEs, but the rate of dose reductions was relatively high. So we went to the agency and showed them 200 patients' worth of exposure response data from our phase one, where we went all the way from 50 to 300, to dose optimization that we did in the recurrent setting, showed them that we had CNS response data at 100 milligrams, showed them that the median dose intensity from this 43-patient trial was 126 milligrams. So when we suggested 150 as the dose for the pivotal, they said, makes sense. We accept your justification, but we do need to see some data starting at 150. So we've actually been enrolling at 150 since August, and we will bring them sufficient number. They didn't say, has to be this number with this much follow-up. Just bring us sufficient data, safety data, to show that you're dropping that dose reduction. And we're very confident we'll be able to do that without impairing the timeline for phase three initiation, which is expected in the second quarter. So now do you guys plan on, to the investment community, disclosing that? I think what we'll do is when we announce FPI, we'll say here's an updated safety cut and then at a medical meeting in the second half of the year show all of the data. But again, what the FDA wants us to do is check the box, you've shown us some safety data at 150, it's better than at 200 as documented by the rate of dose reductions, which happens in the first six weeks, so not a lot of follow-up, and then disclose the data at a medical meeting. And to be clear, there's no specific requirements the FDA want? They're not going to be looking at efficacy? No. going to be looking for a reduction in any specific ease? Sufficient amount of safety data primarily focused on rate of dose reductions. And then how quickly do you think you can get that to the FDA and then move into the initiation of the phase three trial? Both in the second quarter. Okay got it. So also today you guys disclosed that this phase three will also have a single arm a cohort for patients without brain metastases and you believe that you can almost follow the precedence of biostimertinib and you know rely on NCCN compendia to support utilization there in the real world. Can you speak a little bit more to the strategy and you have thoughts the FDA gave as far as feedback there? Yeah so you know we didn't specifically speak about the potential for approval in single arm because they know that they want to see randomized especially for PFS. But what we did say is, look, we want to have a one-trial approach. And again, the umbrella is if you have a non-classical, well, if you don't have a classical mutation or exon 20 insertion, you're in the trial. We know that at least 40%, maybe more, are going to have brain mets. They're going in the randomized portion. If you don t, you come onto this single-arm cohort. It's 80 patients. Our PFS in the 24 patients of phase 2 data that we have in that patient population is currently at 23.5 months not a single one of those patients in 16 months has developed a brain metastasis that's unheard of so we did talk to the agency about that and again it's not a label discussion now could it be when you have the data maybe but at a minimum we believe it will allow for NCCN inclusion and for a doc who is looking at a drug that can control CNS disease as well as this drug, we think it's going to be very straightforward for them to make the choice to prescribe tilivertinib in all of their non-classical patients if they have reimbursement based on NCCN. So the data that you showed working out PFS earlier today by brain mets versus non-brain mets almost makes all the cross-trial PFS comparisons that we've been doing over the last couple of years. A little silly, to be honest, now that I think about it. How do you kind of think about that moving forward as you think about positioning of your drug and how important maybe it is to consider that baseline characteristic when doing these cross-trail comparisons? Well, I think it's so interesting, right? Because EGFR mutant non-small cell lung cancer, it's a different disease. It has this propensity to go to the brain. And we have really good drugs like Tigriso. But again, this recent publication, it's very clear that there's still significant unmet medical need. And it's all due to CNS progression. And the way that patients are managed now is they have to get radiation, which has significant sequelae. So if docs have an option that can spare patient radiation and live longer, because again, the data from that paper, half those patients had radiation, they still only had a five-month progression-free survival. Can we actually dive into that a little bit more? I think you're kind of thinking about expectations for performance of osimertinib in your control arm without radiation there. What should we expect? Well, again, 5.1 is based on 44 patients of data from phone catering following these patients, half of whom had radiation. The PFS was five months. So now in our trial, they're not going to have had radiation, so I think it's hard to assume that it's going to go up. So again, I think we're more than adequately powered for PFS. And in the 43 patients, or in your data set, had patients, what percent of patients, or I guess how many patients had not had prior radiation? None of them had prior radiations, none of them, and we were at 12.2. So, again, I think it's more than adequately powered. I think when you double PFS in a patient population, that's clinically meaningful to patients. Because osomertinib in classical mutations is kind of the gold standard for EGFR, Can you remind us how in the FLORA trial osmertinib did in patients with brain mats versus patients without brain mats? Yeah. So in patients without, so for us in patients with non-classical mutations, no brain mats, we're at 23.5 months. In the FLORAS study, now again, in the Flora study, they allowed radiation, right? In classical mutations without brain, it was 19 months. So we're at 23 and a half, they were at 19. So as far as changing of the paradigm and not needing radiation to get this big type of PFS, how do you think about new enrollment in your trial in the context of will docs want to give radiation just because that's what they know works best with osmertinib? Yeah, well we've gotten that question a lot from investors like well is this gonna complicate Trial enrollment, like aren't the docs going to want to reflexively do radiation? And so this is where you really understand the specifics. If a patient has a symptomatic brain lesion where you can go in and irradiate, let's say they're having a seizure, they can irradiat that lesion, and they are almost certainly going to have other lesions. They can still go on the trial because you can count those other lesiones as target lesions and the radiated lesion because you got to do what's right for the patient right yeah and you you're never going to jeopardize the patient's well-being you're going to treat it if it's symptomatic they can still be eligible and that's the other interesting thing reading them the this this recent publication when these patients present it's typically with more than one lesion and that one lesION that's symptomatic can be irradiated and they're still on the trial so you can have both. Yeah. And that 23 plus month PFS that you guys showed, were you guys, in the patients without baseline brain mets, were your guys actively surveillancing for brain mets? Yeah, I'm glad you asked that too. You can't detect things if you're not looking for them. We look every six weeks. So every six week patients are getting surveillance MRI. And so at 23 and a half months, a single patient has we've seen or at 16 months median follow-up told that 23.5 months PFS not a single patient have we seen brain mets and that's with every six weeks surveillance not always done in every other trial and again competitor trials not always and maybe getting a little ahead of things because I know you know OS isn't you just need to show non-inferiority on OS in the phase three correct actually no detriment no non-interiority is big statistical hurdle. No detriment. Okay, even easier. But in the phase two trial, you did see meaningful amounts of, you know, trepion progression. Yeah. Is this by protocol going to be allowed in the Phase 3 trial? And, you Know, is this something that you think would be reflected in the real world? I think it, I don't know the specific answer to the protocol since Sergey's not sitting next to me, so I don' t want to answer it wrong. We do think it has real-world impact. Again, because if patients are experiencing clinical benefit, they should continue to take this drug. If they've had a radiographic progression in the thorax that's not symptomatic, and their brain disease is under control, I think most of those patients will decide to stay on the drug, and that will have meaningful OS implications. Why did the FDA agree to no detriment that seems very unlike unlike the FDA especially in lung cancer because they know we have a great drug with great CNS activity we need to we need to adhere to their guidelines CNS ORR is in the guidelines for a brain active drug PFS is clearly in the guy for lung cancer showings statistically improvements significant improvement in PFS will give us full approval okay can Can you speak to the data disclosures that you guys will have coming for this phase three trial? Yeah, so for the phase three, we'll have the cohort four data that we mentioned next year. There are two, the open label cohort we spoke about, interestingly, the agency said, you know, you have this brain active drug, leptomeningeal disease patients, these are patients really with the worst prognosis, you should run a small cohort there because there's a high end that needs to run a smaller cohort. For those who are less familiar with this indication, can you? So leptomeningeal disease is these are, so your CNS, your brain's spinal cord is covered in meninges, and when patients have what's called leptomeningeal disease, they're small studded mutations throughout. It's almost like the brain is encased in a mutation sheet, and it's a miserable prognosis. It's two, three, at best four or five months PFS, no good treatments. So could this drug give benefit to those patients? And the FDA brought it up to you? They brought it to us. They said, you know, you should really consider doing this. And we're like, okay, so we're going to enroll. So that trial will read out preliminary, and the open-label non-CNS will read up 28, and the CNS-ORR in 29. We also have a GBM trial, and we have six minutes left. We can talk about GBM if you want. Yeah, just last question on CNSORR. For the accelerated approval endpoint, the catalyst you're getting to in in 2029, can you speak to what percent of the, would all patients have to be enrolled, would there have to a certain amount of durability? All patients would be enrolled, but we expect that at that time a final patient enrollment will have the data we need to go to the agency. Okay, so glioblastoma. Yeah. So, you know, this is a drug that has best-in-class brain activity. We've known for 20 years that half of patients with glioblastoma have an EGFR alteration. They're different than the EGF-R alterations you see in non-cell cell lung cancer. And there's also EGR amplification, which is very different. And it's seen in colorectal cancer and head and neck cancer. Again, silivertinib was designed at the get-go to potently target those EGfr alterations in glioblastoma, and is the only EGFR TKI to potently inhibit EGF amplification. So we did a phase one study in gliobastoma, recurrent glioblastoma. Very tough to treat. We saw a response. We saw some prolonged stabilization of disease, decent tolerability. So we started this phase two trial. We had this window of opportunity data, knowing that the drug gets into the brain really well. we've gone through the safety run-in, not surprisingly, the dose is 150. We're combining it with the standard of care, temozolomide, the last drug to be approved for glioblastoma 21 years ago. So it's silivertinib plus temozomide versus temozonamide alone. It's a randomized phase two trial governed by an IDMC, an independent data monitoring committee. So the company is now blinded. Now that IDMC is tasked with looking at an interim PFS endpoint. If that PFS endpoint is positive, they'll say that endpoint's positive, and we will then convert the trial to a phase three with OS as the endpoint. We'll have that interim PFC data in the first half of 2028. Got it. So that's a call option, if you will, on the investment. We all know how tough GBM is to treat. Every reason an EGFR inhibitor has failed, silibertinib addresses. Brain penetrance, potency on the mutations, paradoxical activation. We are not a paradoxical activator. Can you speak to TAM of the opportunity you're going after? Yeah, it's almost 50,000 patients globally with an EGR mutation in GBM. So it's, you know, and the unmet need, there's no higher in oncology yeah there's no higher and oncology and as far as you know cash runaway you know what's baked in so what's big then is certainly the the GBM trial getting the the lung trial started but we will need additional capital to get through you know those those approval endpoints and you know my job is to bring that capital to to so that we get this drug to patients and I I'm confident that we can whether that's through dilutive or non dilutive sources There's also you know a meaningful ex-us market here our partnerships, you know, potentially In the mix to talk about, you ex ex US rights and You know you for the phase 3 and lung cancer, you noted that this was a global trial Are you guys already initiating activities outside of the US and Canadian sites you're involved in? We are. Certain things you have to do in Japan, for example, to stand up a trial, well underway. We were busy at ESMO talking to international investigators from Singapore, Taiwan, China, Western and Eastern Europe, South America. And then as far as manufacturing, drug supply, is everything ready to go? Not an issue. Registration batches made, stability done, we've done our radio labeled study in Healthy Volunteers. So all of the kind of ADME work that you, I mean this is truly a phase three, big pharma phase three ready program. Yeah. Have you guys received more engagement maybe from strategic sense? I think just like investors, people want to know whether the FDA is with you or against you. So we're really pleased the FDA isn't with us. Very much so. Seems like it. So on the 150-milligram dose, considering this isn't something that you originally investigated in the Phase II trial, was this like a new pill that you had to formulate? No, no. Great question. So the pill strengths are 175. 275. So the 200 milligram dose was 100, two pills. That step down was 275s. So now we start with 275, we can go to 150, or sorry, to 100, single 100. And then we can even go to 75. And we had patients go all the way down to 75 from 200. But again, we haven't lost any efficacy. None. You guys even saw some deepening of responses. Deepening of response is after dose reduction. Those dose reductions happen in the first four to six weeks. And can you, what dose are you guys using in the glioblastoma trial? 150. Yeah, so that was the safety run-in. So a nice concordance there between what's going to be, so two 75 milligram tablets. Great. We're just about out of time. We have another minute if there's anything else that you want to say that has gone unsaid, but we covered a lot. Not at all. Thank you, Laura. It was really great to be here on an important day for Black Diamond. And more importantly, I think an important day for patients with non-small cell lung cancer with brain metastasis. Absolutely. And we appreciate you guys being here. I know it's a very busy day for you guys. Thank you. Of course. All right.