Hello, everyone, and thanks for continuing to join us on the Stifel Virtual Oncology Days. My name is Brad Canino. I'm very happy to be joined for the next fireside with the CEO of Black Diamond Therapeutics, Mark Velleca. Mark, thanks so much for joining us.
Thank you, Brad. Real pleasure to be with you today.
Kick off with an intro to Black Diamond and also discuss the recent Servier deal and how that positions the company to develop its lead asset now.
Sure. We're a clinical-stage oncology company developing oral therapies with best-in-class potential against validated targets. Our lead program, 1535, is being led by a very experienced team in both non-small cell lung cancer and glioblastoma. Importantly, we anticipate several clinical updates on both indications over the course of this year and next year. Our cash position actually affords us runway through all those milestones and into the fourth quarter of 2027. You mentioned the Servier deal, which was on our other clinical-stage compound, BDTX-4933, which is a RAS inhibitor that's in phase I. We announced that deal three weeks ago and are in the process of transitioning 4933 to Servier. That transition is going very well. We're confident in their ability to rapidly advance 4933 in multiple indications.
Importantly, we received $70 million upfront and are eligible to receive an additional $710 million in milestone payments plus royalties on sales. That capital has significantly extended our runway and affords us the opportunity to move 1535 into pivotal development next year.
Great. For 1535, where you're bringing in some non-classical EGFR mutant non-small cell lung cancer, can you talk about the current and investigational treatment landscape for these patients?
Yeah. Most patients with so-called non-classical EGFR mutations, or I'll abbreviate them as NCMs, still get chemotherapy. That's about 60% of patients still receiving chemotherapy. Another 15% to 20% get afatinib, and the remainder receive osimertinib. There really is no standard of care. Unfortunately, most patients typically discontinue those treatments in eight months or less. That's in stark contrast to newly diagnosed patients with classical mutations. Nearly all of those patients in the frontline setting get osimertinib, and they can stay on therapy for two, three years. Now, as far as the competition, there are some small molecules other than 1535 that are in development for patients with NCMs, but they're really repositioned drugs. One is furmonertinib from ArriVent. It's a third-generation TKI, much like osimertinib.
At higher doses, it does have some activity on a small subset of NCMs, particularly in the PAC class. ORIC-114 is another one. It's an exon 20 drug that also has some activity on NCMs, but neither molecule was really optimized to have this broad spectrum of activity on NCMs. We are the leading fourth-generation TKI with the broadest spectrum of activity, preclinically demonstrated in over 50 NCMs. I know we'll talk about our data in the recurrent setting. Clearly, these are actionable mutations in the clinic.
What do recent real-world data show about the frequency of these non-classical mutations as we think about addressable patient numbers across the globe?
Yeah, it's a real market. This is not a niche indication. It's actually a couple- to threefold larger than exon 20. I will point to a couple of data sets. One is our work with Guardant, looking at the Guardant Inform database in over 90,000 cases. These are data we presented at AACR last year. That tells us that 23% of EGFR mutant patients have a non-classical mutation. There was also a recent publication looking at the publicly available GENIE database, and that reports about 30% of patients with NCM. On average, about a quarter of the EGFR mutant landscape is non-classical.
Got it. You started to touch on this a little bit, but maybe to drill down more, how is 1535 designed to be a better option for these patients?
Structurally, it's different. It's a fourth-gen TKI, and it was really designed to potently inhibit the full spectrum of classical mutations. So maintaining potency on classical mutations is critical, and these non-classical mutations while maintaining selectivity over wild type so that it's well tolerated. It's also designed to be brain penetrant to treat CNS disease. That's critical. We believe that non-small cell lung cancer patients, because of these properties, broad spectrum activity, sparing wild type, brain penetrant, patients could benefit across all lines of treatment. Now, we're mostly focused on frontline at the moment, but this could be used in the adjuvant setting. As you know, we have data in the recurrent setting as well.
On that, phase II development has been ongoing for some time now. You have had some changes in terms of development timelines and expected milestones and also priorities, I would say, over the past six months. Could you overview those?
Yeah, I think those are a reflection of changes in the competitive landscape. I think this is one of the things you have to do as you evaluate the competitive landscape and where you're going to have the most benefit to patients. I think we all recognize the contribution of infused agents, whether they're bispecifics like amivantamab or ADCs like Dato- DXd, but that's primarily to benefit patients with recurrent disease, right, where these are relatively cumbersome with high AE rates. What we've seen, at least in the launch of amivantamab, is these agents present real challenges to patients in the frontline setting. The success of osimertinib, again, tells us that patients prefer a well-tolerated oral treatment that offers them not just durable responses and survival, but quality of life.
What we aim for with 1535 is to deliver that kind of benefit for patients with non-classical mutations. Our focus, typically in oncology, is you start in oncology development, you start with later line patients and move upstream. We've now kind of really rapidly focused on frontline, those newly diagnosed patients looking for a better treatment option, because that's where we think 1535 can deliver the most value given the limited treatment options available. I know we'll talk about the data in the recurrent setting. Enrollment in the phase 2 cohorts in the recurrent setting is done, and we'll present the final data in the first half of next year. We reported the early data in September of last year. Pushing the data out for the frontline cohort is really just a reflection of wanting to see more mature data and more patients.
We have the runway now to do that. This was not an enrollment issue. It's cohort three enrollment's going well. We expect to have all 40 patients enrolled in that frontline cohort in the second half of this year. Now, we were initially projecting 20 patients of data in the first half of this year, but again, with the deal done, cash runway extended, and our desire to see some early PFS data, and really importantly, also to be able to couple this disclosure to an FDA meeting where we can talk about pathways to approval, we thought it was prudent to just say, let's have one disclosure, fourth quarter of the year, more patients, preliminary PFS, FDA feedback, all in one disclosure. Makes much more sense.
Now, you mentioned the recurrent data presented last year. It's a busy data set. I think as you're thinking about the focus on frontline, how would you describe the clinical profile in terms of what it shows about this drug's potential for frontline patients?
Yeah. First is, do you have your dose, and is it tolerable? I think the answer to that is yes. That's not just the phase two data from last year, but it's our phase one experience. It's very clear based on PK that 200 mg is well above the IC50s and indeed the IC90s for these non-classical mutations and still spares wild type. The AE profile looks much more osimertinib-like than it does afatinib-like, again, speaking to the selectivity. We don't see any off-target AEs, no QTc, no LFTs. There is a small percentage of patients that require a dose reduction, but that's simple. You go down to 150 or, if need be, to 100. Even at 100, as we saw in the phase one and in our randomized portion of the phase two, we saw responses. That's critical for frontline.
Tolerated, patients can stay on therapy to deliver durable responses. Second is that these mutations are actionable. Do you see responses across a broad spectrum of both PACC subset of non-classicals, C797S, classical, all three? The answer is yes. The third is brain responses. We have seen brain responses. I know we'll talk about GBM perhaps a little bit at the end, but we have very clear evidence now that this is a highly brain penetrant compound. All of those things we think bode well because the major means for progression on afatinib, which is not brain penetration, is CNS metastasis.
Yeah. Now, for this frontline phase two cohort that you're enrolling, how should investors think about the mutation types within the non-classical spectrum and frequency to expect of the enrolled cohort?
Yeah. We have really opened the funnel very wide. If you have a mutation other than exon 19 del or L858R, you are eligible, I should say, as long as it is not exon 20 or T790M. Those are exclusion mutations. You actually could have L858R plus a non-classical, right? It is not a subset. It is not just PAC mutations or a subset of PAC mutations. It is not just the three mutations in the afatinib label. It is all over the receptor, ectodomain, juxta-membrane domain, atypical exon 19 deletions, of which there are several. We are not over-indexing on any one mutation. It is a broad spectrum. That is really important because our goal is to have a broad label for all non-classical mutations. We want to generate a data set across all those categories of non-classical mutations.
What efficacy outcomes will be the focus of the phase II frontline cohort?
It's a mix of response rate and PFS. In talking to investigators about where the current treatments are not working for patients with non-classical mutations, and I mentioned this at the outset, it's really poor PFS anywhere from six to nine months, depending on whether it's chemo or afatinib or osimertinib. We think a PFS of 12 months or greater would be a clear win. You have to have a good response rate, 50% or greater. You also have to consider, and this factors into the PFS equation, is disease control rate. Prolonged stable disease is also important in this patient population. If they're having clinical benefit, maybe they don't have a resist response, but they have clinical benefit and are not progressing, that's important because ultimately, approval is going to be based on some survival signal. This is frontline therapy.
Project Front Runner tells us that you need survival benefit for frontline therapy, whether that's PFS or OS.
Yeah. With PFS being a focus, what was the timeline of enrollment for this cohort? When did it start, and when do you expect to have it completed? The question is really how much maturity will be expected for these durability estimates when you give the data in the fourth quarter of this year?
Yeah. As you know, we were initially guiding to 20 patients' worth of data in this quarter, second quarter. That tells you that we've got 20 patients enrolled, obviously. In the fourth quarter, there'll be some good maturity on those 20 patients. Again, I said at the outset, we'll have all 40 enrolled by the time of the data disclosure. Now, those patients that we're currently enrolling, obviously less mature on the PFS side, we do not expect to be at median PFS for the patients that will be reporting. We're only going to report patients who have had the opportunity for two scans post-treatment. What we will be able to look at is PFS rates at six months and nine months.
Given the numbers I just gave you, we think that's something that's meaningful and will be enough, again, to inform our conversation with the FDA.
You gave your benchmarks what you think is good in terms of outcomes for ORR and PFS. On safety, would you expect the safety profile to be similar to the recurrent phase two data set you showed last September?
It should be, but there are some important differences to consider. One is that patients who are treatment naive are more likely to experience the typical AEs seen with an EGFR TKI, most notably rash. That is because patients in the recurrent setting may have developed some tolerance to their prior treatment. The good thing here is we know how to treat these. We have good supportive care measures. We just use those. For those few patients that require a dose reduction, we can quickly do that. Yeah, it might be slightly higher, but it is well managed. We can support patients through it and, if need be, have a dose reduction.
For those dose reductions for the on-target toxicity, where is the dose going from and to? What's the confidence that the level of dose reduced to will maintain the required broad pathway inhibition spectrum?
Yeah. All patients in this cohort three, the frontline cohort, are being enrolled at 200 mg once daily. Again, for the few patients that may require a dose reduction, they go to 150. If another reduction is required, and it could be, we have a 100 mg dose available. What's the confidence that we'll see responses in those rare patients that might require two dose reductions? We've seen responses both in the phase I and the phase 2 at a 100 mg starting dose. We know based on our PK data that at 100 mg, you cover most of these mutations. We know at 200 mg, you cover all of them. I think our confidence is quite high that we have the right dose.
When you present these data to investors, how will that be aligned with an FDA meeting and registrational plan?
Yeah, this was part of our calculus on pushing the disclosure out, right? Rather than have, here's the data and stay tuned for next steps, we now have the opportunity to say, here's the data and here are the next steps that have been informed by an FDA meeting. Our plan is to bring all data to date. That's all data. It includes the recurrent, the 83 patients in the recurrent setting, all of the frontline patients enrolled to date to the FDA in the fourth quarter and discuss our registrational plans for potential frontline approval. We will disclose the outcome of that meeting along with the data in one fourth quarter disclosure.
Can you talk about what key questions about the registrational plan you're going to seek to get answers for when you go to meet with the FDA and get feedback?
Yeah. It's the usual. The design, randomize, the endpoints, and label whenever you're heading into the agency to talk about an approval pathway. First, the design. Our expectation is a randomized trial. Again, tells us that. It's really, what's the comparator arm? Is it chemo? Most patients get chemo. Is it physician's choice? Could be. Or is there potentially an opportunity for a synthetic control arm or potentially a control that's bolstered by a synthetic control arm? We're definitely looking at that. Endpoints, again, we think PFS will definitely be there and potentially final OS data as well with a known response rate that you'd have to hit. On label, we've already started to have this discussion. Our goal is to have a broad label for all NCMs. Fortunately, there is FDA guidance on drugs for rare mutations.
That speaks to grouping mutations by structure function categories. We've already done that with the NCMs, PAC, classical-like, juxta-membrane or ectodomain. We expect to have patients enrolled from all three of those categories.
On the synthetic control arm potential that you mentioned, would that be based on real-world data, or would it be prospective chart reviews of patients that you do concurrently with the trial in an active arm?
Looking at both of those possibilities.
Is there enough real-world data out there at this point?
There is, surprisingly, as our ESMO presentation last year told us, there is. All these patients are getting next-gen sequencing.
Yeah. Yeah. That was going to be another one of my questions. How easily are these patients found in the community setting and found not just that they have an EGFR mutation, but that it's a known mutation that is not quite as well addressed by osimertinib as your classical mutations are?
Yeah. They are definitely known because every physician gets this report of it, whether it's exon 19 [audio distortion] or something else they don't know what to do with. There is an education component to let them know that there is another option. It's 1535, and that speaks to the work we've done on enrollment, which has picked up nicely. I think it's always an education process when docs have a category of patients where there's not an established standard of care.
Yeah. Yeah. Now, what would you say investors should keep in mind as they compare your future frontline data and development strategy to the recently presented data of ArriVent's frrmo, that you mentioned?
Yeah. The furmo data was on two PACC mutations, two out of a category of close to 100. It was at a dose much higher than what's approved with concomitant increases in AEs. There were non-off-target effects. I think these are all things that could have an impact on durability and time on treatment. I know we're going to get ArriVent is guiding towards an update later this quarter. Maybe ask me that question again after their update.
Keep that in mind. As we think about the market opportunity, from your internal estimates, what do you think that is, especially for a drug that can address broadly these 100 different non-classical EGFR mutant patients?
It's a big market. I mean, non-classical mutations, as we talked about at the outset, it's approximately a quarter of all EGFR mutant non-small cell lung cancers. Bigger than exon 20. You look at osimertinib, which is the clear drug of choice for newly diagnosed patients with classical mutations. It did $6.6 billion last year. It's on its way to $8 billion. This is a $2 billion plus peak annual projection type of market.
Maybe I'll squeeze in the question on business development for this particular asset, particularly if you're going to think about running a randomized study as well, a more robust study. How are you thinking about commercializing this drug and what Black Diamond wants to do and what it might look to do to partner?
Yeah. Look, lung cancer is a big competitive space. I think when you're looking to launch globally, you're going to want to do that with a partner, ultimately. I think as far as running the trial, we're very well equipped to do that here in the U.S. I think there might be some advantages to having a regional partner, especially given the increased prevalence of EGFR mutations in Asia.
Just to close out, what additional work is being done in GBM? How should investors think about this as an opportunity for potential value creation?
Yeah, it's a really interesting call option, if you will. I mean, we all know how tough GBM is, but we also know that 1535 could address the shortcomings of all other attempts to drug the EGFR. We have now definitive proof of brain penetrance in patients with glioblastoma. That cannot be disputed. That Ivy Brain Tumor Center that ran that study feels confident to now run a frontline, a newly diagnosed study, which has a treatment phase. We all know, unfortunately, the very short survival time for patients with GBM. We can get a read there in a capital-efficient way in the next year or two.
Yeah. Excellent. Mark, it's always a pleasure to speak with you and the ongoings at Black Diamond. Thank you so much for joining our virtual event.
Thank you, Brad. Appreciate the time. Have a great day.