Okay. Great. We'll go ahead and get started here. So, thanks everybody for joining us here, second day of Piper Sandler's annual healthcare conference. I'm Joe Catanzaro, one of the biotech analysts here at Piper. It's my real pleasure to welcome Black Diamond Therapeutics for our next session here. Joining us is their CEO, Mark Velleca. Mark, thanks so much for joining us. Maybe before we kick into Q&A, I could give you a couple minutes to introduce Black Diamond, let everybody know what you've been up to and what we have to look forward to.
Sure. Thanks, Joe. It's a real pleasure to be here at the Piper conference this afternoon in New York, and welcome everyone who's joining on the webcast. Black Diamond is a clinical-stage precision oncology company, and we're focused on advancing a best- and potentially first-in-class fourth-generation EGFR inhibitor in non-small cell lung cancer, non-small cell lung cancer with additional opportunities in glioblastoma. So that program is in phase two, and we had some data earlier this fall, and it's advancing both in the recurrent setting and in the frontline setting, and we look forward to additional phase two data in 2025.
Great. That's perfect. Maybe it's a good first question. Should you mention sort of fourth-generation EGFR inhibitor? There have been a couple other programs that have been brought into the clinic. Stepping back a little bit, I guess when you were thinking about designing a fourth-generation EGFR inhibitor, what was the profile that you were looking to achieve, and how does it compare to maybe other recent attempts at fourth-gen inhibitors?
Yeah, there were three main design criteria in selecting 1535. The first was broad coverage against, you know, the most relevant oncogenic EGFR mutations, and we'll get into that in a moment. The second was long half-life and CNS penetrance to treat not just primary lung cancer but also CNS metastases and, again, potentially glioblastoma. The third was, you know, wide therapeutic window versus wild-type EGFR so that patients have favorable tolerability and safety. So you're really trying to thread that needle with potent activity on the mutant forms of EGFR, sparing wild-type, and having a once-daily oral pill to offer patients these benefits. So I think the competitor molecules over the past couple of years have focused on either only a handful of mutations or they have sacrificed activity versus wild-type, and therefore you don't get as good tolerability.
As you know, there are multiple options now for patients that are, other than small molecules where you, again, lose some of that tolerability.
Great. So you mentioned this sort of data back in September, the phase II data in the second line plus EGFR lung population after prior TKI. Maybe just sort of walk through what you see as sort of the major highlights in that initial data set.
Yeah. So again, first I'll focus on tolerability because it's so important if you're developing a drug that ultimately is going to be used in the frontline setting for years. We saw very favorable tolerability, only EGFR-mediated side effects that are managed very well with standard supportive care regimens. Only, no patients discontinued because of the known EGFR toxicities of rash, diarrhea, stomatitis, and paronychia. The second, obviously, you have to have good efficacy. And we saw that, though it's a preliminary data set across about 20 patients, robust response rates, again, across a range of mutations, and I know we're going to talk about mutations in a moment. And, again, encouraging, though early, durability.
So since you mentioned it, right, the different mutational backgrounds, how should we think about that in that second line plus population and whether moving forward or in the future we should consider sort of distinct populations among that basket?
Yeah. So, you know, there are many EGFR oncogenic EGFR mutations. The one that have been most studied and we've known about for the longest are the so-called classic mutations of exon 19 del, and L858R. With the advanced use of next-generation sequencing and liquid biopsies, we now realize there are over 50 oncogenic mutations in EGFR. And again, 1535 was designed to address all of them. And when we evaluated it in this recurrent setting, we looked at two distinct populations. One was the so-called non-classical mutations, so things other than exon 19 del , and L858R, most of which are insensitive to the leading EGFR TKI, osimertinib. And the other category is a known drug-resistance mutation for osimertinib called C797S. So those were the two cohorts we evaluated.
What we saw in the trial was essentially very similar response rates between these non-classical, mostly PACC mutations, which are the ones that are most insensitive to osimertinib and C797S.
I think you also cut the data in a way where you sort of consider the on-target resistance mutations and excluded a couple patients. Maybe you could talk through the biological rationale of why some of those solitary atypical mutations should not be considered on-target resistance.
Yeah. So again, most of these non-classical mutations are insensitive to osimertinib. However, there are a couple like 747, 861 that where osimertinib works, and these patients respond to osimertinib. And in fact, we in all these patients were post-osimertinib, so they had an opportunity to respond to osimertinib. But like any mutation where osimertinib works well, like the classicals, ultimately patients progress. In most of the cases, that progression is off-target. Maybe MET amplification comes up. In a subset, about 20%-25% of patients, they stay on-target, and they either accumulate or acquire additional EGFR mutations that are clearly resistant to osimertinib. And those, again, are two broad classes: PACC mutations and C797S.
What we learned in the trial is that those patients who had the osimertinib-sensitive non-classical mutations and didn't show the appearance of known resistance mutations, they weren't going to respond to any EGFR inhibitor. Those were the three that we cut from the denominator.
I know you guys have been very clear that 200 mg is a very obvious move forward dose given the safety and the efficacy you're seeing there. The trial did include a dose optimization, and you did dose some patients at 100 mg, though we didn't see data there. I know I've gotten some questions on that. Maybe just talk through the decision to just sort of clearly focus on the patients at 200 mg and kind of put the 100 mg sort of behind you in the past.
Yeah. Well, I will say, you know, you will see the full data set in 2025. You know, we're going to have 80 patients' worth of data, 20 at 100 and 60 at 200 very soon. Going to have finish that enrollment. So you will see the full data set, including the 100 mg. But maybe we can talk a little bit about Project Optimus and the reason why we did this. From the phase 1 dose escalation, it was clear that 300 was the MTD, 200 based on PK looked like the right dose. But because of Project Optimus, you have to, according to the agency's guidelines, evaluate the next lower dose. And the best way to do that, and we actually had agreement with the agency on the best way to do that, was through randomization. So we randomized 20 patients at 100, 20 patients at 200.
Very early on, we saw and we shared these data with the agency in the fall: clear benefit of 200 versus 100. Tolerability was very good at 200, but you do sacrifice a bit of efficacy because the PK, the coverage of the targets, isn't as good at 100. So the overall risk-benefit profile clearly favors 200. Every patient since that randomization has been dosed at 200. All of the frontline patients from day one have been dosed at 200. And the dose reduction that's required in less than one in five patients, it's not required frequently, is to 150. So 100 we just don't think is a dose to focus on because we're not using it. Again, we'll share it when we present the full data set at the medical meeting.
I think the other question within the data set back in September is looking at the Swimmer's plot and seeing some patients who are still on therapy but had documented progression. I know, you know, investors sort of focus on that and calculating PFS and all of that, but I look at it more so from maybe what it means in terms of patient interest in an oral well-tolerated drug in this setting. Wondering if you had any sort of anecdotal or even sort of high-level views of what you're hearing from physicians or specific within those patients.
No, it's a great point because ultimately patients stay on therapies where they feel better. And the chief complaint per patient with lung cancer is that they, you know, have a persistent cough and they struggle to breathe. They have dyspnea on exertion. They really are challenged because they have lung cancer. And a drug like 1535 clearly reducing their tumor burden, they breathe easier, they feel better. Now, radiographically, you could have the appearance of a new target lesion or a new non-target lesion or, you know, growth of 20% in a target lesion that radiographically per RECIST you have progressed.
However, the bulk of the patient's disease is still well controlled, and to your point, the side effect profile is well tolerated, so they're perfectly happy to continue to take a once-daily oral pill, feel better, their overall disease control rate is good, so they stay on therapy, and that's why we had, you know, 14 of 19 patients, even though many of those patients had radiographically progressed, stay on therapy.
Yeah. So you provided, I think, a little bit of a snippet of what we can expect in 2025. I guess specific to the 1Q25 update that you've guided towards from within this cohort.
Yeah.
Maybe just talk through what we should expect and what some of the key questions that we might get answers to, within that data set.
Yeah. I think that the biggest criticism of the September data set, even though again, we stand by the drug clearly showing good activity and good tolerability, is that it was premature, right? We had three patients who had responded, but they didn't yet have an opportunity to have that first scan showing a response confirmed in the second scan. And the overall time that, you know, the mean follow-up time was 4.7 months. So we really couldn't show, to your point about the swimmer plots, a good durability where you could calculate a PFS. So, you know, we understand that. We have an opportunity in 2025 to get this right.
I can tell you both in the first line data set, which is also coming in 2025, and an update on the recurrent setting. We'll make sure we have a mature data set. If that means we need to push it slightly, we will. We'll reassess that early next year.
but maybe still under the assumption of a 1Q25 update, you mentioned sort of 20 plus 60 gets us to 80.
Yeah.
Should that be our anticipation in 1Q or, you know, will it be somewhere in between what we saw in September and what the ultimate sort of full enrollment?
Again, I think it benefits everybody to see a more fulsome data set that's as mature as possible. And given, you know, the restructuring that we did in the, you know, just a couple months ago, we had the runway to do it.
Yeah. The other thing you've guided towards, in 1Q25 with regards to this setting, so second line plus is a regulatory update. So what are some of the key questions you're asking the FDA as you engage with them on potential paths forward?
Yeah. So, we've had, you know, a productive dialogue with the agency. As you know, we have Fast Track designation for the C797S mutation population. You know, one of the dialogues we're having with the agency is continuing to educate them about what we mean by non-classical mutations. And I know when we talk about label, we'll get to that again. So that's a key point of conversation. The second is, you know, unmet need. And we already have, again, admission from the agency that newly diagnosed patients with non-classical mutations represent a significant unmet medical need, which is important when you think about potential accelerated approval paths. The third piece and the thing that we're going to be focused on in 2025 is pathways to approval.
Now, that includes both recurrent setting where we already have data, but we, again, as a small biotech company, need to be mindful of where we're going to deploy our resources. So we'd also like to potentially share some first-line data with them as well and have, you know, a conversation that includes both opportunities.
I guess as we think about that, is there a situation where you have to pick one opportunity or the other, or will there be potentially opportunity to maybe continue to pursue both?
Potentially. I mean, it's, we'll see about capital requirements, potential partnerships. Clearly, the biggest opportunity to benefit patients and the biggest market opportunity is frontline.
Yeah.
I know we'll talk about competition. We don't see any competitive threat in frontline, non-classical, and we'll talk about furmonertinib. In the recurrent setting, you know, there's amivantamab plus chemo, which was just approved in September that's starting to get some market share. There's the HER3 ADC that will likely get approved next year. There's Dato-DX, which I think we're going to see data from in three days, in this EGFR mutant subset that reportedly is approvable, efficacy data. So we're mindful of that, and we you know continue to push forward in frontline.
Maybe on this latter point of sort of competitive landscape, current offerings for patients post-osimertinib.
Yeah.
With classical mutations, what do you think 1535 needs to show, to be competitive with sort of in the mindset of it being an oral targeted therapy versus, you know, an IV chemo-based kind of regimen?
Chemo at best delivers 30%, so you need to be north of that. I think when you consider some of these other regimens like amivantamab plus chemo, you probably need to be closer to 40% with six months DOR.
Yeah. The other question I wanted to ask as we think about potential opportunities, and we'll get to first line, maybe rounding out the second line plus population is, as you've screened patients who have progressed on prior TKI osimertinib, what's your current view around the prevalence of patients who, in fact, have on-target by your definition resistance, acquired resistance mutations?
about 20% to 25% of patients will stay on-target.
Do you think, again, as we think about regulatory paths, whether that on-target, I mean, you mentioned like speaking with the FDA and helping them sort of understand non-classical, whether that definition gets further refined or you're pretty comfortable with how you're sort of currently defining patients?
I think, yeah, they are familiar with the PACC classification. We know that, because there have been prior publications on that, and we're, you know, continuing to educate them. This is more for frontline on what we mean by things that are not PACC but non-classical.
Yeah. So maybe that's a good segue to the frontline non-classical cohort that you have also guided towards 1Q25 data. Maybe there too, speak to the kind of data set we can expect to see. And I know you've spoken to previously how kind of finding these patients and tracking them down and getting them onto trials takes a little bit different calculus than cohorts one and two. So maybe help us sort of understand that a little bit.
Yeah. So first, the quantum of data that we'd like to have, at least 20 patients, right? I think you really need at least 20 patients to start calculating ORR. And you'd like to have, especially in the first line setting, even more follow-up time, right? Because the DOR duration of response in frontline should be at least 12 months. You know, we just started enrolling this trial this spring. So again, at least 20 patients all with the potential to have confirmed responses, and good time of follow-up. Now, the second part of your question was finding these patients and enrolling.
Yeah.
Yeah. The enrollment dynamic in recurrent setting, pretty straightforward. You're in large medical centers. Docs know about patients that progress on TKIs. They've heard about 1535 because, you know, they're in these big academic centers. In the community is where most of these patients first present. And the doc gets the sequencing report either from the lung biopsy or from the liquid biopsy. And if they don't recognize it as exon 19 del or L858R, the two classical mutations, they don't know what to do. So they and we have now real-world data on this. Most of them are still getting chemotherapy. So there's an educational component here.
We actually have to get out into the community, tell docs that there may be a better option for their patients than chemotherapy because we, again, we have real-world data showing that it performs poorly in the frontline non-classical setting, and we're getting there. Definitely enrollment is ramping up. You know, they also start to see data from our investigator meetings, so it has been a slower ramp for sure than recurrent, but it's certainly picking up.
Maybe on some of the real-world analysis that you've done, maybe a two-part or one, maybe you could speak to the prevalence of these atypical mutations and what we're learning and maybe where that prevalence rate is tracking towards. And then within your expected data set, the diversity of non-classical mutations that you might expect to see there.
Yeah. There, there are over 50 of them, maybe upwards of 100, some more common than others. They're all over the receptor. Most of them are in the kinase domain, but there are others, you know, extracellular domain, juxtamembrane domain. The largest subgroup are the PACC mutations. As a class, all non-classicals represent probably about 25% of all EGFR mutant non-small cell lung cancer. So about a quarter, you know, of the, of the osimertinib market.
And then in terms of the diversity within maybe this initial cohort?
Oh, that we'll see. Our funnel is wide open. So I know, you know, we'll if we think about the furmonertinib data set, there's essentially two mutations, both of them PAC mutations. We are allowing PAC, non-PAC, extracellular domain, juxtamembrane domain, atypical exon 19 deletions, which, there's a lot of those, many of them with poor performance to osimertinib. So you'll see a wide array of mutations in the data set.
Since you mentioned furmonertinib, we saw that data set at World Lung back in September. What read-through does that data set with that molecule provide, and maybe the potential actionability of these atypical mutations?
Yeah. They, you know, they saw a response rate of 62%. That's what you should see. That's what afatinib has told us over the years, anywhere from the kind of 50s to up to 70, depending on the mutation. So that was good to see. Again, it was only, only really on two mutations. I think tolerability, we like our tolerability profile. We don't have LFT elevations. We don't have QTc, and our rates of diarrhea are actually lower than osimertinib.
Another question I often get is sort of looking back at the September data set and maybe looking at the patients with non-classical mutations, the read-through that setting and that in those patients provide to what the drug could potentially do in a treatment naive patient. I'm wondering if you have any views on that, whether there's any prior experience with other EGFR TKIs as they move sort of later line, earlier line, what the delta you might see there.
I mean, it's typically 10, 20, could be 30 points. I think what we know is these patients have been on osimertinib a long time. They have the opportunity to accumulate all kinds of mutations, some of them on-target, but even with accumulation of on-target, they've got other stuff going on. So that's a really tough-to-treat patient population. Someone who's treatment-naive, whose lung cancer arose from an EGFR oncogenic mutation, should respond at a much higher rate.
So, I want to talk a little bit about the potential regulatory path in a frontline non-classical population. And I've heard sort of mixed views. I've talked to physicians who believe like there is a significant unmet need here, and with a good enough efficacy profile, the FDA should be amenable to potentially single-arm accelerated path. And then maybe there are others who say, you know, it's frontline, you probably got to run a randomized trial. Any feedback you've gleaned, I guess, in your investigator interactions?
Yeah. I'd agree with both of those bookends, if you will. What the agency has told us already is that there's a significant unmet need for this patient population. So that language, which we have, tells us that there is an accelerated approval option. Now, whether that comes from a single-arm study or, you know, a randomized study where you have an interim read on ORR, we'll see. There is, in addition to Project Optimus, there's another guide, another requirement, you know, Project FrontRunner, which pretty clearly states you need to run a randomized study at some point. So I think it depends on the strength of the data. You know, you have eye-popping ORRs with good durability. You definitely have that opportunity.
The other question on the regulatory front is, you know, we've spoken how many atypical mutations there are, PACC, non-PACC, juxtamembrane, and others, you know, how you go about running a study in a way where you could capture the breadth of those mutational profiles and put that into a single label.
Yeah. So, again, here the agency has helpful guidance for development of agents for rare mutations. And there's precedents, like exon 14 skipping drugs, the RET drugs, where trials were run where the label ultimately read out on a group of mutations for which there weren't patients even enrolled in the study. What the agency wants you to do is take that diversity of mutations and group them into structure-function groups that make sense. We are doing that with others like the PACC group, this classical-like group, and these juxtamembrane and extracellular membrane groups. So we think if we can get patients from each of those three classes, we can get a broad label.
Perfect. Well, with that, we're perfectly right on time. So thanks, Mark. Thanks for your thoughts. Obviously looking really forward to the data in 2025. So thanks everybody for tuning in and take care and enjoy the rest of your day.
Great. Thanks, Joe.