Welcome back to the 46th annual TD Cowen Healthcare Conference. Marc Frahm from the biotech team here at TD Cowen, and we're really happy to have with us for the next session here, Black Diamond Therapeutics and the CEO, Mark Velleca. The way this session's gonna work is Mark's gonna run through some slides, kind of general overview, level set people who may not be quite in the weeds on the story yet, and then I'll be back, and we'll do some Q&A with the remaining time. And people in the room are welcome to join if you have your own questions that we wanna get those answered for you as well. With that, I'll turn it over to Mark.
Great. Thanks, Marc, and the whole TD Cowen team for the opportunity to present the Black Diamond story today. This is to remind you that I will be making forward-looking statements. Black Diamond is a clinical stage oncology company developing precision small molecule therapies. We have a highly experienced team of drug developers and have rapidly moved our lead program, silevertinib, through phase 2 development in non-small cell lung cancer and are just about to initiate a phase 2 trial in glioblastoma, or GBM. We have a key catalyst upcoming next quarter when we expect to present PFS data for silevertinib in frontline non-small cell lung cancer patients. Our lean operating model gives us more than 2 years of runway and funds us through the phase 2 readout in the GBM trial. The target for silevertinib is the epidermal growth factor receptor, or EGFR.
It's been 20 years since the first so-called classical oncogenic mutations of EGFR were discovered, we've seen several generations of EGFR inhibitors approved over the past two decades for lung cancer patients with EGFR classical mutations. Currently, nearly all lung cancer patients with these classical mutations are treated with the third-generation drug Tagrisso, or osimertinib, they do very well. This is a large market, Tagrisso is expected to generate $8 billion in revenue this year. What's changed? Now, most patients undergo next-generation sequencing of their tumors, we have come to understand that there are more than 50 so-called non-classical EGFR mutations, for these patients, there are no good treatment options. This is why we are developing silevertinib. Silevertinib is the most advanced fourth-generation EGFR inhibitor in clinical development.
silevertinib is designed to potently inhibit the full spectrum of non-classical mutations and is highly brain penetrant, which is critical for treating lung cancer patients with CNS metastases and also patients with GBM. silevertinib has been tested in more than 200 patients and has demonstrated robust efficacy and good tolerability. Like Tagrisso, silevertinib is a once-daily oral pill. The market opportunity for silevertinib is quite large. About 1/4 of all EGFR mutant non-small cell lung cancer patients present with a non-classical mutation. We are currently focusing development in the frontline setting, shown here in the dotted box. We've also generated compelling data in the recurrent setting, here on the left, and could move into other frontline and/or adjuvant settings, shown here on the right. How are these patients currently treated?
Unfortunately, most frontline patients still receive chemotherapy, with the remainder either receiving afatinib or osimertinib. These treatments provide limited benefit, with progression-free survival of only six to 10 months, as shown in several recent studies depicted in the table in the center of this slide. silevertinib is being developed to address this significant unmet medical need. silevertinib has been shown to potently inhibit the full spectrum of non-classical mutations and is highly brain penetrant. Let's review some of the recent phase 2 data for silevertinib in patients with non-small cell lung cancer. In 2023, we initiated a phase 2 trial of silevertinib in non-small cell lung cancer, initially in the recurrent setting, cohorts 1 and 2. In 2024, we shared encouraging preliminary data from these cohorts and look forward to presenting final data at a medical meeting in the second quarter of this year.
In 2024, we began enrolling frontline patients into cohort 3. Today, I'd like to briefly highlight some of the key data in the frontline setting from our initial disclosure last December. We enrolled 43 patients that reflect the broad spectrum of non-classical mutations seen in a real-world setting. 35 distinct mutations were present in our patient population. Importantly, more than a third of the patients had untreated brain metastases, also reflecting the real-world setting. All patients were dosed at 200 milligrams once daily. In December of 2025, we presented promising response rate data, which I'll share next, and we look forward to presenting preliminary duration of response and progression-free survival data at a medical meeting in the second quarter of this year.
This is the waterfall plot showing a confirmed objective response rate of 60% and a disease control rate of 93%. Along the bottom, you can see the different EGFR mutations that each patient had at diagnosis, with more than 1/3 of patients having multiple or compound mutations. I also want to highlight the robust CNS responses seen with silevertinib: 86%. Given how important CNS metastases are to disease progression, we believe that the high brain penetrance of silevertinib could drive prolonged PFS and OS for these patients. Indeed, early signs of durability, as shown on the swimmer plot, are encouraging, with 29 patients remaining on therapy, the longest for over 19 months. The AEs seen for silevertinib are typical for an EGFR TKI, with the only grade III AEs being EGFR-mediated, namely rash, diarrhea, stomatitis, and paronychia.
These AEs can be managed with standard supportive care and/or dose reductions without compromising efficacy. Importantly, less than 10% of these patients have discontinued silevertinib due to AEs. This slide shows all the responders seen across our phase 1 and phase 2 trials in both the recurrent and frontline setting. The green arrows point towards patients with confirmed responses at the 200-milligram starting dose, and the dark blue arrows point towards patients with confirmed responses at the 100-milligram starting dose. On the X-axis are the more than 50 non-classical mutations for which we have preclinical IC50 data, which is plotted as a blue dot. What is clear from this graph is that we see responses across the full spectrum of non-classical mutations.
To summarize, we believe that the frontline data presented so far are highly encouraging, and we are very much looking forward to presenting the preliminary PFS data at a medical meeting in the second quarter of this year. The potential strength of the phase two data will help us guide the pivotal development path. I'd like to finish by briefly covering our plans to also develop silevertinib in glioblastoma or GBM. As you are likely aware, the outlook for GBM patients remains bleak, with only about 5% of patients surviving out to five years. There are very limited treatment options, and the last drug approved and still in use today is temozolomide, which was back in 2005. There is no area of higher unmet need in oncology today than GBM.
We've known for some time that approximately 50% of patients with GBM present with an oncogenic alteration of EGFR, the most common being EGFR variant III, which is seen in approximately 30% of patients. silevertinib was designed to inhibit all the oncogenic alterations seen in GBM patients, including EGFR amplification and EGFR variant III. Why have previous attempts to drug EGFR and GBM failed? We believe that it's primarily due to two factors: the inability to potently inhibit the full spectrum of EGFR alterations seen in GBM and lack of brain penetrance. silevertinib is the first EGFR TKI that addresses these limitations. We've treated over 60 GBM patients with recurrent disease with silevertinib and have seen encouraging tolerability, preliminary evidence of clinical activity, and most importantly, brain penetrance.
The phase one, or so-called window of opportunity trial, clearly demonstrated that silevertinib can achieve pharmacologically relevant exposures in tumor tissue from non-contrast-enhancing regions of the brain. This has never been documented before with an EGFR TKI. Given all the data generated to date and the tremendous unmet need, we are excited to initiate a randomized phase two trial of silevertinib in newly diagnosed GBM patients next quarter. The design of that trial is shown on this slide. In the frontline setting, patients typically undergo surgery followed by a brief course of chemoradiation. It's at this point that we will randomize patients to either re-receive standard of care maintenance therapy of TMZ or TMZ plus silevertinib. The dose of silevertinib will have been determined by a brief safety run-in portion of the trial that will begin next quarter.
Once randomized, we will follow patients until progression, and PFS analyses will be performed by an independent data monitoring committee or IDMC. We expect to have preliminary PFS data from this trial in the first half of 2028. I'd like to finish with a brief overview of our entire pipeline. Today, I covered silevertinib, but we also have two other assets, BDTX-4933, a clinical-stage Ras/Raf inhibitor partnered with Servier, and a preclinical FGFR inhibitor, BDTX-4876. Milestone payments from the Servier deal and potential partnering revenue from 4876 are not factored into our cash runway. With that, I'd like to thank you for your attention and look forward to the Q&A from Marc Frahm and any others. Thank you.
All right. Thanks, Mark. We can get settled over here. Over the past year, or so when you had the data that you walked through with your, with silevertinib, there, you know, there have been a handful of other kind of presentation of data in kind of PAC or non-classical lung cancer settings. Just how do you kind of compare and contrast the efficacy you've been able to show so far with some of those other programs? Furmonertinib's probably the most prominent, but there are some other early stage programs that have also been showing small subsets of patients.
Yeah. I think, I think the one we get asked most about is Furmonertinib, the third-generation EGFR inhibitor from ArriVent, 'cause that molecule is, it is just entering pivotal development. They dosed their first patient end of last year. There's really three distinct differences in our data set from there. Some of them have to do with the trial, some of them with actually with the data. First, just talk a little bit about fermo. It's a third-gen molecule. It's dosed three times its approved dose in classical mutations, and it picks up activity in both Exon 20 and a subset of PACC mutations. What are the three differences? One is actually just the trial. Their trial, 22 patients, ours 43. Theirs run mostly in China, ours run almost all in the U.S. Second is mutational coverage.
I mentioned this in the talk. We enrolled patients that had 35 distinct non-classical mutations. Theirs, most of the patients had one of two PACC mutations, so a very small subset of the non-classical space. The most striking difference because, look, the response rates were similar, statistically no different, but the CNS response rates were different. Their CNS response rate 47%, ours 86%. That's key again because of the importance of CNS disease in these patients.
Just on that importance to CNS disease, you know, certainly that's a theme in lung cancer broadly, but how well is that described within these types of mutations?
It's actually more prevalent. More than a third of patients, just like our real world population in phase 2, present with these CNS metastases. They're untreated. At least a third, likely more, go on to progress through the CNS. There's actually published data for both osimertinib and afatinib, which gets given to these non-classical patients. It's quite interesting and unfortunate for those patients. Patients who have non-classical mutations treated with those drugs progress through the CNS at a much higher rate as patients treated with the same drugs who have classical mutations. It's a different disease. It's a really important sanctuary site for patients with these non-classical mutations, the only way you can treat them is with a highly CNS penetrant drug like silevertinib.
Okay. Also in that December data update, right, there was a higher rate of dose reductions in that dedicated cohort than I think you'd seen in prior trials. Do you have any sense of kind of what happened, what drove that? Then, you know, how do you think, one, regulators, but then also ultimately clinicians, you know, will deal with that?
There-- no doubt you saw the data and you've seen prior disclosures, higher rate of AEs in the frontline setting than in the recurrent setting. It's actually not so surprising. There's, again, published data, both rechallenged studies in patients who got a TKI, came off and then got a TKI in a later line setting. The AE seen in the recurrent setting are less than seen in the frontline setting. In other words, frontline patients are more sensitive to these EGFR mediated AEs, especially rash and diarrhea. We saw higher rates than what we'd reported before in the recurrent setting. We did see a high percentage of patients requiring dose reductions. However, only 9% of patients discontinued due to an AE. These are AEs that docs know how to manage. Standard supportive care regimens, no prophylaxis.
For rash it's creams or doxycycline. For diarrhea, it's loperamide. The dose reductions, very importantly, do not compromise efficacy. Docs are used to, "Yeah, I'll go down to 150." We've not seen any patients lose response by going to 150. In fact, we saw many patients gain their first response after they had been dose reduced.
I guess that raises the potential question of is the dosing kind of paradigm right now starting a little higher and having some of these patients come down to 150 the best approach or-?
I say $150 and go up. Yeah.
... or is it dose escalate if you need?
It, it's a, it's an interesting question. We've, we've had a dose optimization meeting with the FDA in the recurrent setting, we showed them the 100 versus 200 data. They had no objections to moving forward with 200, which is why 200 was the dose for frontline. Yeah, fair to say we're gonna have a lot of data to take to them in the end of phase 2 meeting. We'll have exposure response data. We'll have PopPK. We'll have median dose intensity in this trial. There are two ways. You could go in at 150, and some patients at 200 do a brief safety run and pick a dose. You could proceed as we are with 200 dose down, go to 150, go up to 200.
We do not think this is gonna impede the initiation of a pivotal trial in this setting.
Okay. You know, as you mentioned the kind of encouraging durability data, but obviously early in that, in that cut 'cause that was really a response rate cut. As that does mature this year and you get to duration of response, PFS, what does good data look like in your?
Yeah
in your view?
Well, in our view, first you really need to wait till you have median follow-up time of 12 months. That happens to land right around ASCO. When we say medical meeting in the second quarter, that's when we think we can cut the data and get a really good look at PFS. I mentioned in the talk current treatments for these patients, PFS anywhere from 6 to 10 months. A PFS of 15 months, that's a really clinically meaningful benefit for these patients. That's always been our benchmark, 15 months, and, you know, we look forward to presenting the data in the second quarter.
Okay. Maybe can you talk through kind of the strategic rationale? You talked about lung cancer needing a partner to move forward. Maybe how do you come to that conclusion? Why is that the best path forward? Is that something you can do now, or do you kinda need to know some of the early answers from GBM to figure out how to manage the different indications?
Yeah. Well, I'll just say at the outset, we have been having some partnering dialogue starting late last summer. Most of the interest is in the frontline population because, again, a lot of white space, there are no approved drugs. Some of those are also interested in GBM. I think historically, indication splits have not worked well in oncology deals. I think we obviously wanna preserve shareholder value in any kind of deal that we do. You know, this drug could be quite important, not just in lung cancer, but also in GBM, so the deal structure would have to reflect that. The reason we've talked openly about the potential of a partner in lung is it's lung cancer and it's EGFR where, you know, the prevalence of EGFR in Asia is much higher.
Having either a regional player in Asia helping or having a global partner, as long as the economics, again, preserve shareholder value, that's another way to solve for the capital needs required to run the pivotal study.
Okay. Maybe on GBM, just I mean, can you walk through the trial design? Is that now a fully finalized trial design, or are there still some, you know, odds and ends that need to be finalized?
All buttoned up.
Okay.
I'll just say we submitted the protocol to the agency. We got a few comments. We responded to the comments. They said we're good to go. We have central IRB approval. You can look at the details of the trial on ClinicalTrials.gov. We expect to start next quarter with the initial safety run-in. There is a lot of investigator enthusiasm for this trial because they don't have anything for these patients, and they know the drug. They like the design. It fits in kind of the standard treatment practice. From an execution perspective, yeah, we can do this trial.
You mentioned this, there's the safety run-in portion.
Yeah.
I think what you talked about reporting data, you know, a minute ago, that's after the safety run-in once you get to.
Yeah
the main meat of it.
Yeah.
When do you think you can finish the safety run-in and kind of focus the trial on the real go-forward dose?
Yeah. The safety run-in's pretty simple. 150 milligrams plus TMZ. You wait 30 days. If it looks good, you go 200 milligrams plus TMZ. You wait 30 days, three patients each. If you get a DLT at 200, 150 is your dose. If you don't get a DLT at 200 is your dose, and you move forward. Takes, you know, only a few months to clear. We expect to be done with that safety run-in by the end of Q3 and starting the randomized portion. You'd hear about FPI in the safety run-in, and you'll hear about FPI in the randomized sometime in the fourth quarter.
Okay. Is that a purely internal decision, or do you go to the FDA with those data?
Pretty much an internal decision because we've already told them that's what we're gonna do.
Yeah.
They understand the definitions of DLTs, so it doesn't require us to go to the agency.
Okay. For the trial, just, you know, how should we think about once you get into beyond the safety run-in? I mean, you talked about having data in maybe 2028, right? Like, what gives you know... How do you kinda come to that expectation on enrollment timelines? 'Cause, you know, as you pointed out in your comments, like, there's not a lot of history here in GBM. How do you kinda get comfortable with what a likely enrollment rate is gonna be?
The enrollment rate, again, there isn't anything for these patients. Many of these same investigators have tried other EGFR attempts. They love this drug because it hits all the alterations. If you take EGFR variant III, how many times have we tried to treat EGFR variant III? Most of the time, you're just going after EGFR variant III. 90% of patients with EGFR variant III have some other EGFR alteration, like amplification. Just going after EGFR variant III isn't gonna cut it. They've worked on something that's a paradoxical activator or doesn't get into the brain. We check all those boxes. It's GBM. Doesn't mean it's gonna work, but it doesn't have any of the liability. The investigator is very enthusiastic. We're confident we can enroll this in 18 months, gets us to data in early 2028.
Okay. What is... You mentioned the disclosure strategy kind of around the safety run-in.
Yeah.
What's the disclosure strategy as you kind of work towards that 2028 data? Do you intend to give periodic updates?
No
on enrollment criteria?
IDMC.
Okay.
It's an independent data monitoring committee, the company pretty much.
Yeah
... to the data.
Like, I mean, but also on, like, enrollment progress.
Oh, yeah. Enrollment progress, for sure.
Like, would you, like, if.
Well, yeah. If we're falling behind or if we're crushing it and enrolling in 12 to 15 months, we'd certainly let people know when LPI is happening. You know, the data will get announced once we have that, you know, interim analysis look at PFS. You know, the bar, unfortunately, you know, in this setting, PFS is four or five months. If you had a three-month benefit, I mean, you look at the Optune, you look at TMZ, they only in the same setting, the only two drugs approved, one a device, one a drug, it's really a two, three, four-month benefit.
Okay. Have you thought much about kind of what the criteria are around those interim analyses? One, I guess event threshold-?
Yeah
Also, you know, usually the DSMB has some sort of guidance as to kind of how to approach it and when.
Yeah
... to think about stopping.
Yep
... and-
We have all of the, early stoppage rules, event rate, number of events seen, hazard ratio calculations. We believe that this is a well-powered trial to pick up the kind of differences that I just showed with 150 patients.
Okay. anything... You know, EGFR, these are certainly two settings for EGFR. EGFR can be overexpressed and mutated in a lot of other places. Any plans to go-
In other tumor types?
Okay.
It's a interesting question. We've talked about it 'cause we have this really interesting activity on amplified EGFR, which is where the antibodies typically work outside of lung cancer. No immediate plans.
Okay.
Maybe with a potential partner.
Okay. Yeah, go ahead.
Feel free not to answer my question, but I'm trying to figure out, and this is what I've been wrestling with lately, you're going after one of the three holy grails of cancer in glio, as well as non-small cell lung cancer, where there's competition, but a much bigger patient population. Data's coming up soon, and I'm weighing that against the fact that if I did my math right, your stock has, like, a negative or $0 enterprise value. What do you think, and this is if you're comfortable, that Wall Street is missing? To me it seems contradictory that the stock should be as cheap as it is given the opportunities that you're looking at in the data you've presented.
Yeah. Sometimes the market gets it wrong. That's all I can say. I'm not commenting specifically to our stock, but sometimes the market gets it wrong. Sometimes they get it right.
Maybe also for the webcast, the question in the audience, in case it wasn't picked up, was, you know, where's the disconnect between, you know, the data and kind of what the investor reaction has been or the Wall Street share price? Maybe to say it a different way. You know, in your conversations with other analysts, with investors, what's the... Is it something about the side effect profile, the efficacy data? Just where's the pushback where you're like, "This is where we're really excited, and we don't feel the same excitement from the other side?
I think part of it is it's not a fully baked data set yet. They wanna see the PFS data. Part of it's a competitive landscape. Part of it is, you know, precision small molecule oncology. Again, been doing this a long time. Pendulums swing. You just need to live to see the pendulum swing your way.
Okay. Any others? All right, I think we'll cut it off there. Thanks a lot, Mark, for joining.
Yeah. Thank you, Marc.
The team from Black Diamond.
Yep.