Good morning, welcome. Thanks again for joining us at the Annual JPMorgan Healthcare Conference. I'm Eric Joseph, senior biotech analyst. Our first presenting company this morning is Black Diamond Therapeutics. It's my pleasure to welcome President and CEO, David Epstein, to tell us a little bit about the company. Before I hand it over to David, just a programming note. For folks who want to ask a question, feel free to do so by clicking the Ask a Question icon. I can ask on your behalf at the end of the presentation. With that, David, thanks again for sharing some of your time with us this morning. Take it away. Great. Thank you. Thank you, Eric, and thank you everybody for joining this morning. I want to take a moment to thank the employees and the investors in Black Diamond. It's been a great year, a challenging year for everybody, as I'm sure you all know, just want to acknowledge all of their great efforts. If you could turn for a moment to slide four in your deck, just a quick intro and just to level set and get everybody on the same page. As you appreciate, we're a precision medicine oncology company focusing on the development of tumor-agnostic therapies, and we do this through the following means. We take a look and examine population-level DNA sequencing information coming directly from patients. I'm focusing on bullet point two. We analyze that to identify rare and recurrent driver mutations. Once we've identified these mutations using our MAP platform, we seek to aggregate them into like families, and these are usually based on pharmacological similarities. We assume, and we have data to back this assumption, that these pharmacological similarities are based on similar conformational states of these mutant proteins. This allows us to do one important thing, and that's to develop spectrum selective master key inhibitors that target the entire family of mutant oncogenes, and that's unique. Again, population-level data that is essentially identified, rare and recurrent driver mutations are identified through a machine learning algorithm. We then test this in in vitro and in vivo models, and then develop spectrum selective inhibitors. Our lead candidate is BDTX-189. It's an oral irreversible small molecule inhibitor. Again, it's a master key compound inhibiting upwards of 48 allosteric lesions in both HER2 and EGFR. We're in the midst of a phase I, phase II clinical trial. We initiated the trial not even a year ago, and I'll give you an update on our status with that particular trial. Last year, we also gave guidance that we'd be bringing forward a compound that would target allosteric mutations in EGFR alone. These are tropic for GBM. We've developed BDTX-1535 as a development compound, nominated, and we've started IND-enabling studies for its use as a CNS penetrant molecule to treat glioblastoma. Now, I want to take you to slide five very quickly, and just to contrast what we're doing with what has been done before us. If you focus on the left, the classic approach is essentially a single set of mutations or a single mutation in a single tumor type. That's led to some fantastic improvements in patient outcome. We're really proud of those accomplishments. I and several founders of the company cut our teeth at OSI Pharmaceuticals, where we developed and worked on one of the early iterations of EGFR tyrosine kinase inhibitors in the form of erlotinib. Over the last 5- 10 years, there's been an expansion of genetic profiling, particularly of human tumors. We now know that there are upwards of a million patients' worth of data, either through subscription or in the public domain databases. Importantly, this is millions of unique mutations, not hundreds, and certainly not just focal to the active site. The critical observation is most of these patients and most of the mutations are essentially unannotated, and most of the patients derive essentially no actionable benefit. The idea of identifying rare and recurrent driver mutations, aggregating them into families, and then developing a precision medicine that can target that family, I think is hugely differentiating, and we've built the entire company and platform around this concept. I'd like to just quickly turn to slide six. This is an update on the pipeline. Obviously, BDTX-189, we'll give an update. We'll finish the phase I in the first half of this year, and we'll provide a clinical update at ASCO on the status of the phase I study. We've brought forth BDTX-1535 again for the treatment of allosteric mutations, focal to EGFR and tropic to glioblastoma, and we'll be in the clinic at the first half of 2022. The intention is to file the IND as quickly as we can. It's a complicated molecule, and we're going to need the full year to get it into development. Okay. I'd like people to turn to slide eight. We're going to spend four slides just describing the MAP platform, and then we'll get into the clinical program on BDTX-189. Again, we focus on population-level data, analyzing it to identify rare and recurrent mutations. The allostery portion allows us to discern whether these mutations are actually oncogenic driver mutations or silent mutations, because all of these mutations, not just most, all of these mutations are outside the canonical activating active site of just virtually every target we look at. They're allosteric in nature. They drive conformational change, and they change the pharmacology, and that's shown on the far right, such that first-generation therapies just simply are not designed to target these mutations. They're significant commercially. They're important to patients, and there's really essentially a true unmet need. How does this work? Shown on slide nine is a depiction of the first step of identifying rare and recurrent mutations and annotating them with essentially a propensity for oncogenicity. On the far left, you see what is really the true picture of population level data for a single oncogene. Hundreds, if not thousands of point mutations spread throughout the entire oncogene. We use computational sciences both at the protein structure level as well as at the genomic level to rank order the oncogenic potential of each and every one of these mutations in each and every oncogene that we've studied. We provide a MAP score for every residue. High MAP score predicts a likely oncogenic mutation, low MAP score predicts silent or essentially inactive mutations. What we then do is we convert all of this information into empirical studies. This allows us to focus on the top mutations and then to annotate them in-house. We do that, on slide 10 is really a nice summary of the importance of looking at these mutations in the way that we do. You see four different forms of EGFR or HER2 in their dimeric state. In maroon are the regions where these oncogenic mutations lie. You'll note that they're in the extracellular ligand binding domain. You'll note that they're in the transmembrane region, the juxtamembrane regions, in cartoons two and three, as well as in the kinase domain itself, but not necessarily in the ATP site. This allows us to assess each and every one of these mutations in cell-based assays, convert them into in vivo models. What you see on the bottom is essentially the spectrum of mutations against which BDTX-189 was developed. As we've said in the past, this is upwards of 48 mutations. However, it's important to note as the data continues to accumulate, there are more and more mutations that are proximal to the anchor mutations that make up the core of this. We anticipate that those patients may also derive benefit with a molecule like BDTX-189. Slide 11 then is a summary of a MasterKey approach, where a single molecule has been developed that can target this family of activating mutations. We always get asked, how does this work? The very simple answer is we don't care about the activated state per se. The activated state is in the kinase domain where the business end of the molecule is. What we care about is whether these mutations are activating mutations and thus drive the kinase domain in an activated conformer that can be drugged by a novel molecule. That's what we do. Slide 12 then is a summary of all of the efforts over the last several years in essentially developing and perfecting the MAP platform. Obviously, we've got two lead programs targeting HER2 and EGFR that have derived themselves from this platform. We've assessed more than 300 oncogenes and tumor suppressors, focusing on the 92 kinases that are evident in all of these NGS platform panels. We focus down on the seven allosteric targets described here. We, this year, will update the community on our allosteric BRAF program, as well as our Allo-FGFR program. We're developing quite a bit of know-how in the ErbB space, and we're going to continue to iterate off of the learnings that we've obtained from both the GBM program as well as BDTX-189. As we move forward in 2021 and 2022, you'll hear more about the ErbB program in and of itself. Okay, let's focus now on BDTX-189. Just stopping voluntarily on slide 14. Again, it's a MasterKey inhibitor. It's a tyrosine kinase inhibitor. It is targeting the ATP active site. It's irreversible, so it targets the exact same cysteine residue that is present in many receptor tyrosine kinase. The exact same cysteine residue, 797 or 795, depending on your nomenclature, that are the targets of neratinib, TAGRISSO, and so on and so forth. I just want to reiterate on slide 15, the depth of value that is possible with BDTX-189. Today, the assessment that we've made is that this compound can treat upwards of 30,000 patients. Not just in lung cancer. We're often classed side by side with many of the other exon 20 inhibitors that are in development. We'll talk about that. The exon 20 space represents around 20%-30% of the inherent value in the BDTX-189 molecule. Breast cancer driven by allosteric mutations is quite significant. Solid tumors with specific mutations in HER2 S310 are of interest. It's the most prevalent mutation in HER2 and all solid tumors. We are the only company focusing on HER2 S310F. We have cohorts looking at all these mutations and other tumor types, hence the tumor agnostic strategy. We are opportunistic, and we are looking for other avenues for development of BDTX-189 given the selectivity profile. That's shown here on slide 16, where we've now presented this in several conferences. This is the spectrum of mutations that are in the target product profile for BDTX-189 shown on the far left, annotated and color-coded with respect to location on HER2 and EGFR cartoon on the lower left. The critical feature here is not only the broad-spectrum activity of this compound, but the fact that it spares wild-type in two gold standard wild-type EGFR cell-based assays. That spectrum of selectivity, at least at the in vitro level, is anywhere from seven to several hundredfold, as you can see here. The thought process in the company was to spare wild-type, develop a spectrum-specific agent, but not to do so at the expense of off-target selectivity. You can see that we've achieved that with the kinome screen shown on the far right. Really what this molecule does is targets the ErbB family that's in the center, so that's EGFR, HER2 through three and four. Off-target activity for BLK as well as RIPK2, not targets that are expected to give rise to adverse toxicities. In effect, we'll talk about what we know about the toxicity of BDTX-189 subsequently. It's important to point out that while many of these mutations are exon 20 focused, again, it's not the majority of mutations. For those in the community that want to understand BDTX-189 relative to our nearest competitor compounds, be it the Cullinan compound mobocertinib, we believe that based on our data in head-to-head comparison, side by side in our cell-based assays, that we have what is probably best in class in terms of selectivity versus wild type. Hopefully, that selectivity translates into better tolerability, and the ability to dose escalate above the range of IC50 values that you saw in the previous slide. It is important to point out that a critical aspect of BDTX-189 is its ability to act as a hit-and-run tyrosine kinase inhibitor. This is really the first demonstration of a hit-and-run compound targeting solid tumors. There's obviously a history of this in the liquid tumor field. For now, let's just focus on BDTX-189. Lower left-hand panel shows rapid target engagement in a cell-based assay driven by the S310F mutation, and that inactivation is sustained out to 24 hours. It doesn't matter whether this inactivation occurs in the monomer or dimer form. Both are essentially equally inactivated within minutes. This translates into a rapid inactivation in an in vivo PK/PD model. As many of you know, we've been doing this as essentially a way of correlating the activity with the PK, in a number of models, and we won't go through that today. In red shows rapid inactivation after an oral dose that's sustained out to 24 hours. That uptick at 24 hours in red, we think relates to receptor recycling, certainly not due to resistance. This is a single-dose experiment in mice. Importantly, you see rapid absorption of the compound in black dashed lines, which is accompanied by rapid elimination, half-life in the timeframe of one to three hours, and at 24 hours, essentially fully eliminated, whereas the pharmacodynamic effects are sustained out beyond the period of time that the compound is present. This translates into dose-dependent tumor growth inhibition on slide 19, as well as tumor regression. You can see how we're range-bound in the ED50 values. We've used this to calculate and determine our human estimated clinical doses. All of this information will be laid out at the upcoming AACR meeting, how we've used PD/PK modeling, physiological-based PK modeling, and these datasets to drive the conclusion that we have the potential to target each and every one of the mutations that were identified in the previous slides. I'll just point out, what we're looking at here are two different mutations. HER2 S310F in an allograft model showing an ED50 of 30 mg/kg, and the EGFR exon 20 mutation, otherwise known as the ASV mutation, where the ED50 is 10 mg/kg. There appears to be really no correlation between IC50 value and the ED50 value. You can extract that data from the slides that we've provided you. All in all, this has led to a fairly benign tox profile. No ocular skin changes associated with wild-type EGFR was seen in our non-clinical studies. The only histopath finding that was target organ-directed is in the GI tract. It was focal, as many of you know, and is reversible. Essentially, this is a compound with no QTc liabilities, and so we anticipate no cardiovascular risk or low cardiovascular risk for this compound in the clinic. Slide 21, I think is the bread and butter. Obviously, many of you are very interested in this particular slide. We've completed, as given guidance, dose escalation, both in the QD and the BID cohorts. We've identified a maximum tolerated dose in both of these regimens. We're now examining food effect. I will save patient numbers for the question- and- answer period. We are on track for identifying a recommended phase II dose. We'll confirm that in the first quarter of this year, and then begin our safety expansion studies in quarter two of this year as well. Well en route to initiating what we believe will be registrationally focused phase II programs targeting this family of mutations. Just to reiterate, I know this question will come up again. Cohort 1 as designed, as shown on this slide, is focusing on non-small cell lung cancer in the exon 20 groups, both EGFR and HER2. That will likely be divided into two separate cohorts. Cohort 3 then, the breast cancer cohort will be focusing on allosteric mutations that are tropic for breast cancer. Cohort 3, as described here, is essentially the pure tumor-agnostic cohort looking at S310F or S310 mutations present in all tumor types. Everything else is then bundled into the last cohort, tumor types and mutations that are not being studied in cohorts one through three. Last few moments, just want to focus on BDTX-1535, again, our brain-penetrant tyrosine kinase inhibitor that was developed against a family of mutations that are evident in GBM. I'd like to turn your attention to slide 24, just to remind you that the location of these mutations is focal to the extracellular ligand binding domain. There are no mutations in the kinase domain to speak of in EGFR. All these mutations result in a constitutively active, covalently dimerized form of EGFR. We've now published that in various poster presentations, a manuscript now submitted and under review describing all of this information. It is important to point out that the work that was done in the previous years with tyrosine kinase inhibitors did not appreciate the fact that there were additional mutations that occurred in the same patient population, even in the same patients carrying these mutations in the extracellular ligand binding domain. It is critical that a molecule not only cross the blood-brain barrier, but that it's able to inactivate each and every one of these mutations, because any one patient can carry one or more of these in an individual tumor. That data is shown in essentially a Venn diagram on the far right of slide 24. Very quickly, slide 25 just summarizes, we think, the differentiating properties of 1535. Again, pan-selectivity against the allosteric EGFR variants expressed in GBM, as shown in the middle panel for 1535. A slightly sparing wild-type activity and certainly a completely differentiated profile in comparison to osimertinib. This has resulted in, on slide 26, essentially substantial brain penetrance as well as activity in an orthotopic brain patient-derived xenograft model, and that data is shown on slide 26. We'll have a lot more to say about the GBM program as we move forward through our IND-enabling studies. I just want to take this time to thank the team, to thank you for your patience and your interest in the company, and most importantly, to thank the clinicians and the patients who participated in our phase I, phase II program. With that, Eric, I'll turn it over to you for questions. Great. Thanks for that presentation and overview, David. I guess, yes, let's go to the highly anticipated or sought-after question, really is just a little more granularity on the patient numbers of treatment cohorts, and really the mutational backgrounds that we might see comprising the phase I data looking to ASCO later in the first half. Yeah. I think it's gone, I think, well, as you've heard. We have now treated up to, or in the range of 40 - 50 patients in the phase I program. Given the fact, and you've heard us make this statement in the past, but it's just absolutely true, given the fact that the heterogeneity of the target product profile, upwards of 48, and in fact, we're including patients who could receive benefits. Those are HER2-amplified patients that are carrying activating mutations, so-called canonical mutations, that didn't respond to prior treatment with an EGFR or HER2-directed agent. Those patients are also included in the trial. It's important to point out that many of these patients are also carrying CNS lesions into the study. The patient demographics are pretty complicated. It is, at this point in time, I think, impossible to draw a specific conclusion about the activity of the drug in a given tumor type or with a given mutation. That said, we think we're on track with essentially the initial deadline for ASCO submission, to submit with 40 patients worth of data. That will include the identification of MTD in both of these dosing regimens. At the time of ASCO, we'll outline our food effect studies, we'll summarize our efforts in identifying the recommended phase II dose, and we'll certainly summarize our conversations with the FDA with respect to how we're going to plan and organize these four or five phase II programs that are diagrammed as part B on the clinical development slide. I think we're just going to have to hold our breath a little bit longer as we work through the data. Obviously, I think you should expect to see data that will allow you and the rest of the community to do a head-to-head comparison in the safety and tolerability of BDTX-189, in comparison to those competitors that we all know, particularly in the exon 20 space. There will be sufficient data to compare the thesis that this means of identifying essentially a wild-type sparing molecule that is dosed with a short half-life will in fact spare these EGFR-mediated off-target toxicities of the skin and the eye, and whether or not the gut toxicities that we see in the preclinical data actually are what are the dose-limiting toxicities in the clinical studies. I think you'll have sufficient data to draw that conclusion. Certainly, we will put forth as much data with respect to biological activity of BDTX-189 in this diverse patient population. I just want to remind you and everyone else, the intention of this study is safety, tolerability, and dosing. We think we have achieved the initial objective of being able to answer that in a very clear-cut and concise manner for you and the community. I will say that I want to make sure that everyone understands that the initial thesis that drove the company through its IPO was this hit-and-run strategy, and the ability to use these kinds of molecules to infer a human clinical dose. We will have the data that will allow that direct comparison. It is important to understand that to do that, I think those who are deeply steeped in the assessment of this company and the compound prior to the IPO will appreciate the modeling that was done on this type of compound to get to a estimated human clinical dose. Again, we'll have all of that data available at AACR, so that by the time we get to ASCO, a direct assessment of whether we could predict what we were going to get and did we get it, both in terms of safety, tolerability, and exposure. Of course, any attendant biological activity we'll report on as well. We're pretty happy with where we've gotten to. Did all this through the COVID crisis, as many of you did. Again, I just really want to thank the teams for doing this under what really is an incredible year. I'm happy to answer any more questions on that. Yeah. When it comes to biological activity, right, it might be tough to get sort of a clear signal just given the heterogeneity of the population. Is there an opportunity to assess pharmacodynamic activity in a tumor? Yeah that would require biopsies, but that might be challenging in this patient population. Biopsies were optional. Okay. We do have a few samples. I think it's a little early right now. We're trying to assess whether we'll have that data. It'll be looking at downstream ERK signaling, as we've done in our preclinical assessment. Certainly the goal in this year is to have that information. I think the team is working to get that. We'll see how far we get. I just want to come back because the other question that I know you're going to ask is, will there be enough depth in the dataset to provide an ORR? Absolutely not. I just want to really make sure that we level set. Biological activity assessment is going to be inherent in what we present. Given the fact that we've essentially said that we've tested this compound in 40 - 50 patients in this phase I portion, the majority of those patients, more than half, essentially, had to have received sub-efficacious exposures. The other half may have received efficacious exposures. That's the analysis that we're now doing. That's the analysis that we'll provide at ASCO. Even with that, the range of people, of mutations that have come in on this study is just too great to provide a meaningful ORR today. We will, of course, take a look at the patients that continue to come in before the final data cutoff, and we'll provide an update as to how we're doing. As it stands now, I think we should just focus on the PK/PD, the activity data attendant with that in ancillary groups of patients. We'll move forward from there with the recommended phase II dose and the expansion cohorts moving forward into the phase II. I think this could relate to either the phase I or the expansion phase II cohorts. I guess, what are the eligibility criteria with respect to either first or second-generation EGFR inhibitors or other exon 20 inhibitors? If they had an exon 20 mutation or a HER2 amplification, or a canonical mutation in EGFR, they were eligible as long as they didn't respond to that therapy. Okay. If they couldn't tolerate the therapy, or if they just progressed on that therapy and never responded, then they can come onto the trial. That, I think, is the reason why we were able to get so rapidly through the dose expansion, dose escalation cohorts within a year. We really haven't even been into the study for a full year. That said, we're going to tighten up those criteria now going into the safety expansion studies. I think there's discussion on the team about whether we will eliminate patients or prevent patients from entering the study who have CNS lesions. We wanted to answer that question. I think at this point in time, I think it's safe to say that BDTX-189 is not blood-brain barrier penetrant. It wasn't designed to do so. It's a Type II inhibitor. That leads to the question of are we developing agents that can cross the blood-brain barrier and target some or all of these lesions? Yeah. Absolutely, the answer is yes. That's not part of this study. I think what we want to do is focus BDTX-189 on the patients that can, in fact, respond under recommended phase II dose conditions and get an answer as to whether we have path forward in all of these cohorts. The intent is to study that extensively through this year and to have more robust activity information for you and the community by the end of 2021 and into 2022. Okay. Yeah. I guess, many incremental preclinical work that you've done since the IPO with respect to the, I guess, durability of effect in some of the more rare allosteric mutation subsets, let's call it those Cohort 4 subsets, do you have an incremental sense? Yeah of the ability to more durably get tumor regressions or tumor growth inhibition in those mutation backgrounds? Yeah, I think from a preclinical assessment, we actually are starting those studies now. I think there's a lot of benefit to focus on what we're learning from the Summit study and the continued publication from Puma and others around the use of neratinib in this setting. That says to us that these mutations lead to clinically active oncogene-driven tumors, and that they can be targeted. Really the focus here is to essentially provide an agent that can be dosed over a long period, and tolerated over a long period, so that we can actually assess tolerability and durability in a clinical setting. You can see the impact of that when you look at TAK-788, with a seven-month durability, 43% response rate in a population that doesn't really respond well to any therapy. I think that sets a benchmark. Obviously, more to think about with all these other mutations, but that's sort of how we're thinking about it. I guess if we're thinking about the timelines related to the phase II expansion cohorts. there is some precedent that by the exon 20 lung cancer studies. How should we be thinking about the pace of enrollment in, say, the breast cancer cohort or the S310F, based on sort of the frequency with which those mutations populate? This is the group of patients, just focusing on breast cancer alone in sort of Cohort 2 as described here. These are non-HER2 amplified patients, so these would be considered essentially HER2 negative in an IHC format, and therefore would have been sequenced. This is a significant group of patients. If you go back to essentially our summary slide on the patient numbers, this is a large group of patients. It's upwards of 8,500 patients per year. In percentages they're low, but given the fact that there are almost 300,000 women with breast cancer in the United States alone annually, one can then determine the prevalence. We're seeing these patients on the study. These patients are being sequenced. We don't have hard numbers for the percentage of breast cancer patients that should've been sequenced are being sequenced, but there's enough that we've been able to fill the cohorts as we've gone through the dose expansion studies, dose escalation studies, with virtually examples of all of these clusters of mutations. At this point in time, we don't have enough data to say one way or another, but I think we should expect significant uptick in the enrollment as we proceed into the phase II. And- We'll certainly give an update on the number of sites that we're going to open all of that, I would say, as we proceed through the spring. Certainly, the BDTX-1535 compound is sort of the next priority moving into the GBM space, but I am curious about ongoings kind of further in sort of more of the discovery programs, looking at allosteric BRAF mutations, FGFR, PI3 kinase. Maybe you can just sort of tease us a little bit more as to where things stand on those programs, how far we might be from developing candidates being nominated there. Thanks for the question. Obviously, we've made, I think, a huge push to get out from the umbrella of being a single asset company. Happy to report that we have viable chemical matter for both the BRAF and the FGFR programs. We have just submitted abstracts to present a summary of the data without declaring the compound at the TAT meeting in March, so I would look to that. We will update the GBM program at AACR. Our Allo-FGFR, Allo-BRAF programs are on track for development compound nomination this year. Initiation of the IND enabling studies and filing the INDs for those two programs next year. Really happy with the progress. I will reiterate that we believe we have the first example of an FGFR program that is truly sparing of wild-type FGFR1. As I think the field knows, FGFR1 is the EGFR wild-type equivalent of the dose-limiting toxicity target. So we have compounds that actually can spare wild-type FGFR1 and target allosteric mutations and fusion proteins in FGFR2 and 3. Also, we've demonstrated that we can do that and pick up some of the gatekeeper mutations that have been identified in FGFR. These compounds are biologically active in preclinical models, pharmacodynamically active. We have essentially shown it's the same phenomenon. Mutations outside the canonical active site have a profound effect on pharmacology. When you focus this way, I believe, and I think the team is now convinced, that when you focus mutation first, you can design and discover molecules that spare unintended off-target activities like FGFR1. As you know, the field is littered with statements about FGFR1 selectivity, and that selectivity is essentially met with dose reduction and cessation of therapy. I think clinically, I don't think those are statements in fact, and so we'll come forward with our molecule, and we'll see whether we're able to succeed in the clinic with that kind of profile. The BRAF space, we understand the Class 2, Class 3 arguments, and we think that they're valid. We are developing molecules that inhibit the BRAF dimers. It's important to point out that this concept of allosteric mutations that have originally been classed as Class 2 and Class 3 is absolutely the same thing. It's just that the platform that we've built allows us to assess all mutations in the physical cluster that would contribute to either a Class 2 or a Class 3 annotation. The sense that you get from the MAP platform, it's just a more holistic way of looking at all mutations that are present in the patient population, assessing them, aggregating them, and then building the programs first around that. This idea of screening against wild type and then retrofitting to mutant, it's just not something we're interested in doing because it doesn't lead to differentiated molecules. I think you'll see this year that this platform is truly enabling and truly differentiating. Great. Thanks so much again for your time, David. We really appreciate it. Thank you for the time. Thanks, everybody, for tuning in. Yep. Yep. All right. Stay healthy. Have a good morning. You, too. You too. Take care. Bye-bye.