Good afternoon, everyone. My name is Poorna Kannan, and I'm an Associate at Needham. Thank you all for joining us this afternoon for Needham's 24th Annual Healthcare Conference. I'm really excited to be here joined with me today with Dr. Mark Velleca, CEO of Black Diamond Therapeutics, and Erica Jones, VP Finance of Black Diamond Therapeutics. Dr. Mark will be providing us a corporate presentation, and following that, we open the floor up to any questions that you may have. Just as a reminder, anyone who has any questions can just send it through the dashboard. Dr. Velleca, if you're ready, please take it away. Thank you.
Thank you, Poorna, for hosting us. It's a real pleasure to share the Black Diamond story with all of you here today. This slide's to remind you that I will be making forward-looking statements. Let's start with an overview of BDTX. Black Diamond is a clinical stage oncology company developing oral therapies with best-in-class potential against validated targets. We have an experienced team advancing our lead program, BDTX-1535, in both non-small cell lung cancer and glioblastoma. Importantly, we anticipate several clinical updates on both indications over the course of 2025 and 2026, and our cash position affords us runway through those milestones and into the Q4 of 2027. Jumping right into our pipeline. First, BDTX-1535, our potential best-in-class fourth-generation EGFR inhibitor. Last year, we presented robust phase II data in patients with recurrent non-small cell lung cancer, and I will review those data today.
Initial phase II results in newly diagnosed patients with non-small cell lung cancer are expected in the Q4 of this year. We are also exploring 1535's potential to benefit patients with GBM. Our collaborators at the Ivy Brain Tumor Center will be presenting data at AACR later this month from a trial in patients with recurrent GBM. Based on encouraging results in that study, the Ivy Center has just initiated another trial in newly diagnosed patients with GBM. Turning to our second compound, BDTX-4933, a RAF/RAS inhibitor that is in phase I. Last month, we announced a major partnership with Servier and are in the process of transitioning that program to our partner. The transition is going very well, and we are confident in Servier's 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. This capital has significantly extended our runway and affords us the opportunity to move 1535 into pivotal development next year. We also have an earlier stage program targeting FGFR and are seeking potential partners. Here's a look at the 1535 profile that we believe has first and best-in-class potential as a fourth-generation EGFR inhibitor. 1535 selectively targets all three categories of EGFR mutations: classical mutations, non-classical mutations, or NCMs, and the C797S resistance mutation. We believe that the profile of BDTX-1535 against the full spectrum of classical, non-classical, and C797S mutations gives us the opportunity to benefit non-small cell lung cancer patients with a well-tolerated brain-penetrant oral therapy across all lines of treatment, from the adjuvant setting to frontline and to patients with recurrent disease.
Before reviewing our clinical data, it's important to understand the EGFR mutation landscape in non-small cell lung cancer, which has evolved significantly over the last 20 years. It's also critical to remember the success of oral tyrosine kinase inhibitors as well-tolerated, highly effective treatments for patients with EGFR-mutant non-small cell lung cancer. The leading drug in this class, osimertinib or Tagrisso, generated over $6.5 billion in revenue for AstraZeneca last year. How did we get here? We began with an understanding that the classical EGFR oncogenic mutations, exon 19 del and L858R, could be effectively targeted with first and second-generation TKIs, and patients experienced robust, durable responses. The third-generation TKI, osimertinib, was originally approved in 2015 to address the T790M resistance mutation. As osimertinib became standard of care for frontline treatment, we now see very little T790M. Instead, the C797S resistance mutation has become more prevalent.
Most importantly, with the expansion of liquid biopsies and next-generation sequencing, we now know that non-small cell lung cancer can be driven not just by the two classical EGFR mutations, but by more than 100 non-classical mutations, or NCMs. Because current TKIs such as osimertinib do not adequately address these NCMs, there is a clear need for a fourth-generation TKI that covers a broader spectrum of EGFR mutations. BDTX-1535 is the most advanced fourth-generation TKI in development and has the potential to become a leading treatment for patients across all lines of therapy. What do we mean by non-classical mutations? These are mutations shown in blue here on the left that are found throughout the receptor, not just in the kinase domain, but also in the ectodomain and the juxta-membrane domain. Again, these non-classical mutations are bona fide oncogenic drivers, just like exon 19 del and L858R.
These non-classical mutations cause the EGFR to adopt a unique oncogenic conformation that can be potently inhibited by 1535. Collaborating with Guardant and in a presentation at AACR last year, we demonstrated that non-classical mutations comprise approximately 23% of EGFR-mutant non-small cell lung cancer. This is a patient population that is significantly larger than patients with exon 20 mutations. Our results are in general agreement with a recently published paper mining the public GENIE database that demonstrated non-classical mutations in 30% of patients. Next, let's consider how these patients with NCMs are currently treated. At a presentation at ESMO last year, we reported real-world evidence, shown here on the left, that approximately 60% of these NCM patients receive chemotherapy, with the remainder receiving either osimertinib or afatinib. Unfortunately, as shown on the right, all of these patients discontinue treatment in eight months or less.
This underscores the significant unmet medical need for new treatment options for patients with non-classical mutations. Importantly, our real-world evidence is consistent with recently published PFS data, as shown on the right of this slide. Patients with non-classical mutations, whether treated with osimertinib or afatinib, have significantly shorter progression-free survival than patients with classical mutations. This significant unmet medical need is recognized by the FDA. Our goal is to advance 1535 as the first drug to be approved to treat frontline patients with the full spectrum of these non-classical oncogenic driver mutations, shown on the left. Let's turn now to the data, both preclinical and clinical. This slide shows that 1535 can potently inhibit the full spectrum of non-classical mutations. Working with John Heymach's lab at MD Anderson Cancer Center, we profiled 1535 in cellular assays across more than 50 NCMs, shown in blue.
These non-classical mutations are categorized by where they reside in the receptor, for example, PAC, ectodomain, et cetera. We also evaluated 1535 on the classical mutations, exon 19 del and L858R, shown here on the left in black, as well as the C797S mutation, shown in orange on the right. These are cellular IC50s, and you can see that 1535 has low nanomolar to subnanomolar potency across more than 90% of these cell lines. Also on this slide, we've plotted the exposures achieved in our phase I clinical trial, and you can see coverage of the full spectrum of mutations at the 200 milligram dose being taken forward through late-stage development. Importantly, at these doses, we maintain a wide therapeutic window versus wild-type EGFR, shown on the far left, which explains the overall favorable safety and tolerability profile of 1535.
How does the potency of 1535 on non-classical mutations stack up against osimertinib? Those data are shown on this slide. While osimertinib does inhibit the L861Q mutation, it has weak activity on nearly all of the other NCMs. Moreover, when you consider the NCMs that are frequently co-expressed with the classical mutation L858R, osimertinib has weak activity versus the potent inhibition seen by 1535. This is important because it has been known for several years that patients with L858R mutations do less well on osimertinib versus exon 19 del patients, and this may be due to L858R patients more commonly co-expressing NCMs than exon 19 del patients. Indeed, our real-world data demonstrate exactly this. As shown on the left, we found striking differences between exon 19 del, which rarely co-expresses non-classical mutations, compared to L858R, which more commonly co-expresses non-classical mutations.
The Kaplan-Meier plot on the right shows significantly shorter time on treatment for L858R patients versus exon 19 del and a mere five months' time on treatment for L858R patients that co-express NCMs. We believe that the co-expression of non-classical mutations with L858R could be a major driver for this discrepancy because osimertinib has limited potency on non-classical mutations. Here we show the current treatment landscape for patients with EGFR-mutant non-small cell lung cancer, and we split the patient population between those with classical mutations on the left and those with non-classical mutations on the right. While this very large market is currently dominated by osimertinib, there are at least two opportunities for 1535 to demonstrate its first and best-in-class profile and capture significant market share.
Our phase I proof of concept data and initial phase II data released last fall clearly demonstrate the potential of 1535 in the recurrent setting, that is, in patients who have progressed after osimertinib. Our focus now is on demonstrating the benefit of 1535 to patients in the frontline setting. This is where we think 1535 can deliver the most value given the limited treatment options currently available. We are on track to deliver phase II data for this frontline patient population in the Q4 of this year and also expect to provide a regulatory update on our plans for pivotal development. Let's turn now to a quick review of the phase I data. The trial enrolled 54 patients with recurrent disease, half with non-small cell lung cancer and half with GBM.
As a reminder, the non-small cell lung cancer results were presented at the 2023 EORTC meeting, and the GBM data were presented at the 2024 ASCO meeting. We tested once-daily doses ranging from 25-400 milligrams. The MTD was 300 milligrams, and we saw anti-tumor activity at doses of 100 milligrams and higher, including durable radiographic responses and clearance of ctDNA. 1535 also demonstrated a generally well-tolerated profile with very few grade three or grade three or greater adverse events. Based on these encouraging results, we moved 1535 into a phase II trial across three cohorts. The design of that trial is summarized on this slide. Cohorts one and two include patients in the second or third line setting post-osimertinib, whose tumors have either a non-classical mutation or a C797S mutation.
Initial data from cohorts one and two were reported last September, and I will briefly review those data next. We are also enrolling frontline patients with non-classical mutations into cohort three and look forward to reporting initial data from that cohort in the Q4 of this year. The adverse event profile for 1535 is shown on this slide. At the go-forward daily dose of 200 milligrams, AEs are mostly grade one, two, and are typical for an EGFR inhibitor: rash, diarrhea, stomatitis, and paronychia. Importantly, no off-target toxicities were observed. The overall AE profile and small percentage of patients requiring a dose reduction are similar to what is seen with osimertinib and speaks to 1535's wide therapeutic window versus wild-type EGFR. A well-tolerated profile is critical to allow patients to remain on therapy and have the opportunity for prolonged clinical benefit.
The swimmer plot shown on this slide shows both the durability of responses and the time on treatment. You can see that as of the cutoff date, several patients remain on 1535 for greater than six months, which is the typical time to progression for chemotherapy. It is not just patients who remain in response that stay on therapy. Patients also have prolonged stable disease, and there are several patients who continue to derive clinical benefit from 1535 despite having had a radiographic progression. This speaks to the well-tolerated profile of 1535. Here's the waterfall plot for the efficacy of evaluable patients. There was a striking heterogeneous mix of mutation types that can be seen in the table below.
We saw an approximately 40% preliminary response rate in patients who had either the PAC subset of non-classical mutations in cohort one or the C797S mutation for patients in cohort two. This slide summarizes an important learning from our phase II trial and is consistent with other recent publications evaluating patients who have progressed on osimertinib. First, and not shown on this slide, most patients who progress on osimertinib do not stay on pathway. That is, they progress because they have another mutation beyond the EGFR, for example, in the MET oncogene. For those patients that do stay on pathway, they acquire or accumulate other EGFR mutations that are insensitive to osimertinib. These are the PAC subset of non-classical mutations and the C797S mutation. The broad clinical activity seen for 1535 across multiple EGFR mutations is summarized on this slide. Patients with just C797S and classical mutations respond.
Patients with C797S mutations and non-classical mutations respond, and patients with the PAC subset of non-classical mutations respond, and patients with all three types of mutations respond. Importantly, we know that there are a couple of non-classical mutations, such as L861Q, for which osimertinib does provide some benefit. L861Q patients who progress on osimertinib without evidence of an EGFR resistance mutation would not be expected to respond to 1535. However, we fully expect treatment-naive L861Q patients to respond to 1535 in the frontline setting. We are enrolling the full spectrum of non-classical mutations, not just PAC, into the frontline cohort of our phase II trial. Let us summarize the phase II data in recurrent non-small cell lung cancer and its implications going forward.
We believe that 1535's well-tolerated profile, broad spectrum of activity across multiple EGFR mutations, and clear evidence of brain penetrance, which we will cover next, bode well for robust activity in the frontline setting. We expect to report data from frontline patients in cohort three, along with FDA feedback on our path to potential approval in the Q4 of this year. We look forward to reporting the final data from cohorts one and two next year. Regarding the competitive landscape, we recognize the contribution of infused agents such as bispecific antibodies and ADCs to the treatment of patients with recurrent non-small cell lung cancer. However, these agents present special challenges to patients in the frontline setting. The success of osimertinib tells us that patients with classical mutations prefer a well-tolerated oral treatment that offers them both durable responses and quality of life.
That is what we aim to achieve with 1535 for patients with non-classical mutations. As shown on this slide, the total addressable market for patients with these non-classical mutations is quite large. We estimate it to be one quarter of the osimertinib market, and 1535 usage in the adjuvant and frontline setting could provide patient benefit for many months to years. Next, let's spend a few minutes discussing a second indication, which we are advancing with 1535, glioblastoma or GBM. In GBM, oncogenic alterations of EGFR are present in approximately 50% of cases, and these mutations are complex and heterogeneous. Given the potency of 1535 against these mutations, we have an opportunity to benefit patients with GBM who have few alternatives beyond chemo and radiation. We know why prior attempts to treat GBM with EGFR inhibitors have failed, and we believe that the profile of 1535 addresses these shortcomings.
1535 potently inhibits all the relevant oncogenic drivers. Its covalent binding prevents paradoxical activation, and it spares wild-type EGFR so patients can tolerate therapy. Finally, it is brain penetrant. Regarding status and next steps in GBM, we presented encouraging phase I data in heavily pretreated patients at last year's ASCO meeting. Our collaborators at the Ivy Brain Tumor Center have been conducting a phase zero one trial in recurrent GBM patients to confirm 1535 brain exposure, and more specifically to assess if sufficient concentrations of 1535 are achieved in brain tumor tissue for potential therapeutic benefit. Those data were presented last year and, as we will review in a moment, clearly demonstrate the brain penetrance of 1535. Initial overall survival data from the phase zero one trial will be presented at AACR later this month.
With these promising data sets in hand, the Ivy Brain Tumor Center just began a phase zero one trial in newly diagnosed GBM patients. As with non-small cell lung cancer, we believe that 1535 has the potential to deliver the biggest impact in the frontline setting. Let's quickly review the pharmacokinetic and pharmacodynamic data from the phase zero one trial in patients with recurrent GBM. On the left of this slide is a plot showing the concentration of 1535 from individual patients. As you can see, nearly all patients showed levels of 1535 that exceed the IC50 threshold by fivefold. Importantly, drug levels were measured from non-contrast enhancing regions of brain tumor tissue, clearly demonstrating 1535's brain penetrant properties. Moreover, as shown on the right, five days of 1535 dosing appear to drive a pharmacodynamic effect with a marked reduction in phospho-EGFR versus archival samples.
Updated results from this trial will be presented later this month at AACR, along with preliminary overall survival data. Our collaborators at the Ivy Brain Tumor Center are now advancing 1535 into a phase zero one study in newly diagnosed patients. This trial will be able to assess the pharmacodynamic effects of 1535 from paired pre- and post-treatment biopsies. Importantly, this trial will also have a treatment phase. Patients will initially receive 1535 combined with standard of care radiation therapy before being moved into a more prolonged treatment phase with 1535 monotherapy. Summing up here with our upcoming milestones, we have a steady flow of clinical catalysts for 1535 over the next 12 months. For GBM, there will be a presentation at AACR later this month reporting initial overall survival data for the phase zero one trial in patients with recurrent disease.
In the first half of next year, we expect initial phase zero one data from the trial in newly diagnosed GBM patients. For non-small cell lung cancer, in the Q4 of this year, we expect to report initial phase II data for 1535 in the frontline setting, along with information on path to approval based on FDA feedback. We will report the final phase II results of 1535 in recurrent non-small cell lung cancer in the first half of next year. Importantly, we have sufficient cash on hand to advance 1535 into pivotal development next year and an anticipated runway well into the Q4 of 2027. With that, I'd like to thank you for your attention and would be happy to take any questions.
Thank you so much, Doctor, for this wonderful presentation. We have a few questions here, so I'll just get started.
I guess something that's imminent now, you're going to be going to the FDA to get the approval pathway. Do you anticipate any changes to that approval pathway given the recent changes to the FDA?
Not that we've seen so far. You know, Dr. Pastor is still heading the oncology division. We've heard, you know, the review staff are intact. We're in contact with our program manager. So, you know, as of today, we anticipate being able to have that meeting towards the end of this year. Great. That sounds good. Another question we have here is that EGFR is a pretty competitive space.
Which therapies do you see as direct competition in non-classical mutation? And are there any specific mutation types that you see BDTX-1535 being like a clear winner?
Yeah. First, it's important to remember that 1535 was designed as a fourth-generation inhibitor to inhibit these non-classical mutations as well as the classical mutations. The competitor compound that's at a similar stage of development from osimertinib, which I think we'll see some additional data on later this quarter, is a third-generation inhibitor. It's very similar to osimertinib. At higher doses than what it's approved for in China for patients with classical mutations, you do see some activity on exon 20 and on a subset of PAC mutations, but it does not have the broad spectrum of activity of 1535. The same could be said for the ORX compound, which was also developed primarily for exon 20. You know, remember 1535, classical mutations, non-classical mutations, C797S. We don't have activity on exon 20. There's competition in that space. That's not where we're going.
Okay.
That makes a lot of sense. As for the data that's expected in Q4, the phase II data, what is the clinical benchmark in these patients? And will this cohort include patients who also have CNS metastasis?
Yeah. So the included criteria, we allow patients with CNS metastases. We know this drug's brain penetrant. We've actually seen CNS responses in phase I and in phase II. So those patients are being enrolled. That's in the recurrent setting and obviously could be enrolled in the frontline setting as well. And the benchmark that we see is approximately 50% response rate and a PFS benefit of 12 months or greater.
Okay. That's really helpful. And could you provide an overview of the market opportunity that you see with an EGFR non-small cell lung cancer, GBM, and like a breakdown within the different mutations?
I know you provided the patient overview, but just market options would be helpful as well.
Yeah. There are a multitude of alterations and amplifications that interestingly are different than in non-small cell lung cancer. Many GBM patients you see, the predominant variant is called variant three. You also see just amplification of the EGFR receptor, and then you see multiple other alterations. It is a non-overlapping set of mutations, but 1535 potently inhibits all of them. We expect to be able to treat all GBM patients who have one of these EGFR alterations. It is about half of newly diagnosed patients have one of these oncogenic EGFR alterations. That is about 7,000 patients a year.
I guess in terms of next steps, once you have presented the phase I data in the recurrent patients, like what are the next steps in GBM?
It's really being run through our collaborator at the Ivy Brain Tumor Center. That's an IST. It's a very similar trial to what was done in the recurrent setting. It's a so-called trigger trial or window of opportunities trial, except it's newly diagnosed patients. Patients come in, they have a needle biopsy, they're tested whether they have EGFR or not. They get five days of our drug. They have their resection, their actual surgical resection of their tumor. We could actually see whether the drug, we know it's getting into the tissue, is it having a pharmacodynamic effect now in a paired biopsy? The patient can continue to receive 1535 first in combination with standard of care radiotherapy, radiation therapy, and then as monotherapy. There will be a survival component.
As we're all aware, unfortunately, you know, the survival for patients with GBM is quite short. This is a trial that we think can give us a meaningful readout on a potential survival benefit for 1535 in newly diagnosed GBM patients. Okay. That's helpful to know. In terms of the, if you're preparing for phase III, post the final results for phase II, what kind of trial setting could we anticipate trial design? What do you think would be the competitor arm in that study? Yeah. We have several options on the whiteboard. Ultimately, the data from this phase II trial and our conversation with the agency will, you know, shape the final design. Certainly, a randomized trial versus chemotherapy, which is, you know, the most commonly used treatment for frontline NCM patients, is one.
You know, we are looking at the potential for a synthetic control arm as well because, you know, there are so many of these mutations and we have, in our collaboration with Guardant, a lot of data on how these patients are faring with what is out there as far as chemo, afatinib, and osimertinib.
Okay. Okay. That is really helpful to know. These were all the questions that we had on our end. Thank you for providing all the color and the presentation. With that, we are at time. I just want to thank everyone for joining us today. I want to thank Dr. Velleca and Erica Jones for being with us here today. Hope you all have a good rest of the day. Thank you.
Thank you all again.