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Item 1. Business

2024-03-12 compared with 2023-03-09 · 246 added, 311 removed, 630 unchanged (47% of the section changed)

We are a clinical-stage precision oncology medicine company focused on pioneering the discovery and development of novel MasterKey therapies.

We target families of oncogenic mutations in patients with genetically defined cancers.

We are a clinical-stage oncology company focused on the development of MasterKey therapies to treat patients with genetically defined tumors.

The foundation of our company is built upon a deep understanding of cancer genetics, onco-protein structure and function, and medicinal chemistry.

Our proprietary technology platform, which we refer to as our Mutation-Allostery-Pharmacology (MAP) drug discovery engine, is designed to allow us to analyze population-level genetic sequencing data to discover oncogenic mutations that promote cancer across tumor types.

Our goal is to identify families of mutations that can be inhibited with MasterKey therapies, thereby providing precision oncology to greater numbers of patients with genetically defined tumors.

We have designed our product candidates to be potent, brain penetrant and selective MasterKey inhibitors of oncogenic mutational families which occur across a range of tumor types.

Our lead product candidate, BDTX-1535, is designed to selectively and irreversibly inhibit a family of oncogenic mutations in the ErbB-1 epidermal growth factor receptor (EGFR) which are resistant to current generation tyrosine kinase inhibitors (TKIs), while sparing wild type EGFR (EGFR WT) activity.

We are currently evaluating BDTX-1535 in the dose escalation portion of a Phase 1 clinical trial in non-small cell lung cancer (NSCLC) patients with EGFR resistance mutations, with or without brain metastases, and glioblastoma multiforme (GBM).

Our second product candidate, BDTX-4933, is designed to be a brain penetrant and highly selective and potent inhibitor of oncogenic BRAF Class I, II, III and active RAF dimers promoted by upstream oncogenic alterations, such as RAS mutations, which has the potential to avoid paradoxical activation.

We expect to initiate a Phase 1 clinical trial for BDTX-4933 in select indications for patients harboring all-class BRAF or RAS mutations in the first half of 2023.

We are also leveraging our MAP drug discovery engine to identify other families of oncogenic mutations in validated oncogenes, which have the potential to expand the reach of MasterKey therapies.

In order to focus on progressing our pipeline through important upcoming milestones for BDTX-1535 and BDTX-4933, as well as on our discovery efforts, in April 2022, we announced the discontinuation of the development of BDTX-189, our EGFR/HER2 Exon 20 targeted therapy.

In December 2022, we announced the spinout of undisclosed early discovery stage antibody programs enabled by the MAP drug discovery engine into Launchpad Therapeutics, Inc.

(Launchpad), a new company formed to exploit the MAP drug discovery engine for the discovery, development and commercialization of large molecule therapeutics.

Approved targeted therapies, such as kinase inhibitors, have transformed the treatment of cancers and demonstrated a significant benefit to certain patients by treating active site mutations in a single tumor type.

Our MasterKey therapies are designed to address a broad spectrum of genetically defined tumors, overcome resistance, minimize wild-type mediated toxicities, and be brain-penetrant to treat central nervous system (CNS) disease.

Our compounds target families of oncogenic mutations in clinically validated pathways.

We are advancing two clinical-stage programs:

BDTX-1535, a brain-penetrant, fourth-generation epidermal growth factor receptor (EGFR) MasterKey inhibitor, targeting epidermal growth factor receptor mutant (EGFRm) non-small cell lung cancer (NSCLC) and glioblastoma (GBM), and BDTX-4933, a brain-penetrant, RAF MasterKey inhibitor targeting KRAS, NRAS and BRAF alterations in solid tumors.

The Black Diamond Therapeutics approach

Our goal is to bring targeted oncology therapies to patients with genetically defined cancers who have limited treatment options.

Our drug development efforts leverage our novel findings that:

• mutations throughout a gene can drive oncogenic activation and change the drug selectivity profile of their active sites;

• these oncogenic mutations can be grouped into families because they drive similar protein structural changes, and exhibit a shared selectivity profile;

• a family of oncogenic proteins can therefore be inhibited by a single molecule that targets the active site regardless of where it appears on the protein.

Our MasterKey therapies were discovered using our proprietary MAP drug discovery engine which is built on three central pillars:

identification of oncogenic mutations in protein kinases, confirmation of oncogenicity of mutations based upon cell and tumor models, and pharmacologic inhibition of the relevant mutations while sparing wild-type.

Approved targeted therapies, such as kinase inhibitors, have transformed the treatment of cancers and demonstrated a significant benefit in certain patients by treating active site mutations in a single tumor type.

Improved genetic sequencing of human cancers has led to the discovery of additional oncogenic genetic alterations.

These genetic alterations were previously unaddressed, unsuccessfully targeted or overlooked.

Our MAP drug discovery engine is designed to reveal the oncogenic nature of undrugged driver mutations and their associated protein conformations.

We discover MasterKey therapies to target families of oncogenic driver mutations by exploiting their shared activating conformation.

We believe our MasterKey approach offers a substantial opportunity to expand the number of patients who could benefit from precision oncology medicines.

Our proprietary MAP drug discovery engine is built on three central pillars and enables the discovery of MasterKey inhibitors:

• Mutations —Through comprehensive analysis of population-level genetic sequencing data, we identify oncogenic mutations among hundreds of unique alterations within a single gene.

We use our algorithm as a machine-learning tool to predict the oncogenicity of various uncharacterized mutations, thereby isolating oncogenic driver mutations from those mutations that are not believed to cause cancer, and which are referred to as silent and passenger mutations.

• Allostery —We confirm the oncogenicity of the identified mutations through cell and tumor models and reveal how these mutations drive conformational changes in proteins.

This enables us to group subsets of mutations into families based upon similar protein structures and shared selectivity profiles.

• Pharmacology —Using these shared characteristics, we seek to develop single small molecule product candidates, which we call MasterKey inhibitors, each designed to inhibit an entire family of oncogenic mutations.

Utilizing our proprietary MAP drug discovery engine, we are building a pipeline of orally available, potent and selective small molecule MasterKey inhibitors that target families of driver mutations in individual oncogenes for the treatment of cancer.

Our MasterKey therapies are designed to target families of oncogenic driver mutations by exploiting their shared activating conformation.

We believe our MasterKey approach offers a substantial opportunity to expand the number of patients who could benefit from targeted oncology medicines.

Black Diamond Therapeutics pipeline

We have a pipeline of orally available, potent and selective small molecule MasterKey inhibitors that target families of driver mutations in individual oncogenes for the treatment of cancer and genetic diseases.

Our pipeline includes two product candidates for which we are conducting clinical trials, and other development candidates for which we are evaluating potential strategic partnerships.

An overview of our pipeline of product candidates is shown in the table below.

a brain penetrant, mutant selective, irreversible EGFR MasterKey inhibitor

In NSCLC, EGFR inhibitors have demonstrated significant clinical benefit in patients with primary EGFR activating mutations and are the current first-line standard of care.

However, over time, almost all patients acquire resistance and relapse.

Furthermore, up to half of all NSCLC patients either have central nervous system (CNS) metastases at diagnosis or will develop them while on treatment, which contributes to increased resistance and a poor prognosis.

The majority of first- and second-generation EGFR inhibitors do not adequately penetrate the CNS.

While osimertinib displays some CNS penetration and delays the progression of CNS metastases, there are few options remaining to patients when resistance inevitably arises.

GBM is a difficult-to-treat, aggressive malignancy of the central nervous system.

Standard therapy at diagnosis consists of surgical resection followed by radiation and chemotherapy, but prognosis remains poor, with only approximately 25% of newly diagnosed patients surviving two years or longer after diagnosis.

Almost 50% of GBM tumors express one or more EGFR oncogenic alterations that affect the extracellular region of the receptor tyrosine kinase, consequently promoting oncogenic activation.

We believe that current targeted therapies have been unsuccessful in treating GBM due to (i) the concurrent expression of different EGFR oncogenic alterations within individual patients, (ii) insufficient drug potency across different EGFR oncogenic alterations, (iii) paradoxical activation of mutant EGFR commonly found in GBM by earlier generation inhibitors, and (iv) low levels of brain penetration.

In preclinical models, we have shown that the mechanism of activation for these EGFR oncogenic alterations involves the formation of a constitutive dimer that exhibits a conformation, leading to ligand-independent signaling shared by a family of extracellular domain EGFR alterations expressed in GBM.

BDTX-1535 is designed to be a potent, selective, irreversible, oral and brain penetrant small molecule inhibitor that targets families of EGFR oncogenic alterations.

In preclinical studies, we have observed BDTX-1535 to inhibit a family of classical driver (Ex19del, L858R), intrinsic resistance (Exon18, Exon 21, and others), and acquired resistance (C797S associated with resistance to third generation EGFR inhibitors) EGFR mutations expressed in NSCLC patients.

In other preclinical studies, BDTX-1535 has demonstrated inhibition of EGFR alterations commonly found in patients with GBM that promote a constitutive dimer without paradoxical activation.

As such, BDTX-1535 has the potential to fill a critical need for a brain penetrant inhibitor that addresses the limitations of other EGFR directed therapies.

The IND for BDTX-1535 was cleared by the U.S.

Food and Drug Administration (FDA) in the first quarter of 2022, and we also initiated a Phase 1 clinical trial in the first quarter of 2022.

BDTX-1535 is currently being evaluated in the dose escalation portion of a Phase 1 clinical trial in GBM patients and NSCLC patients with EGFR resistance mutations, with or without brain metastases.

We expect to provide an update on clinical data from the Phase 1 clinical trial in the second half of 2023.

a brain-penetrant, irreversible EGFR MasterKey inhibitor with broad mutation coverage

We believe that BDTX-1535 has the potential to treat patients with EGFRm NSCLC in both early-line and later-line settings based upon BDTX-1535’s ability to address approximately 50 oncogenic mutations with greater potency than other EGFR tyrosine kinase inhibitor’s (TKIs), as well as uniquely target the C797S resistance mutation which can be acquired after treatment with osimertinib.

Historically, EGFR inhibitors have demonstrated significant clinical benefit in patients with classical EGFR activating mutations and are the current first-line standard of care.

However, over time, almost all patients acquire resistance mutations and relapse.

Furthermore, up to half of all NSCLC patients either have CNS metastases at diagnosis or will develop them while on treatment, which contributes to increased risk of resistance to standard therapies and poor prognosis.

The majority of first and second-generation EGFR TKIs do not adequately penetrate the CNS and the third-generation EGFR inhibitor osimertinib has been shown to exhibit limited CNS penetration.

There are also few options remaining to patients when they become resistant to third generation EGFR TKIs.

Resistance can arise due to the acquired C797S resistance mutation and/or to a myriad of other oncogenic non-classical EGFR driver mutations.

There are presently no therapies approved for the treatment of patients with EGFRm NSCLC harboring the acquired resistance C797S mutation.

Based upon evolving real world evidence, we believe that non-classical mutations are also becoming increasingly present in patients newly diagnosed with NSCLC, as detected with next generation sequencing of tumors.

Afatanib is the only EGFR TKI approved for non-classical mutations and its label is limited to S768I, L861Q and G719X.

Our preclinical data for BDTX-1535 shows potent inhibition of a broad spectrum of non-classical EGFR mutations (approximately 50), including S768I, L861Q and G719X.

In our Phase 1 trial in patients with advanced/metastatic EGFRm NSCLC, BDTX-1535 was shown to be well tolerated and to achieve durable clinical responses in patients whose tumors expressed a range of mutation subtypes, including the acquired C797S resistance mutation and a range of non-classical mutations.

BDTX-1535 received Fast Track Designation from the U.S.

Food and Drug Administration (FDA) for the treatment of patients with metastatic EGFR C797S mutation-positive NSCLC, without T790M mutation, whose disease has progressed on/after a third-generation EGFR TKI.

We are currently evaluating BDTX-1535 in a Phase 2 clinical trial in patients with EGFRm NSCLC in the second and third-line settings with non-classical driver mutations and acquired C797S resistance mutation, and in the first-line setting in patients with non-classical EGFR mutations.

We expect to announce results from the second- and third-line cohorts in the third quarter of 2024 and results from the first-line cohort in 2025.

We are also assessing the potential development of BDTX-1535 for patients with EGFRm NSCLC following adjuvant treatment with osimertinib, where the broad mutation coverage of BDTX-1535 of C797S and non-classical mutations may be of benefit.

We released top-line recurrent GBM results from the BDTX-1535 Phase 1 dose escalation study in the fourth quarter of 2023, showing clinical activity in heavily pretreated patients with GBM.

BDTX-1535 was shown to be generally well tolerated and no new safety signals were observed.

In the fourth quarter of 2023, enrollment began in a “window of opportunity” Phase 0/1 trial of BDTX-1535 in patients with recurrent high-grade glioma.

The trial is sponsored by the Ivy Brain Tumor Center in Phoenix, Arizona and is enrolling patients prior to a planned surgical resection.

Patients achieving adequate drug levels in the gadolinium non-enhancing regions of the tumor will continue with treatment following surgery.

This study is primarily intended to assess drug levels of BDTX-1535 in brain tissue and to confirm EGFR mutation status, which may be altered with previous treatment such as radiation and chemotherapy.

We expect to present Phase 1 data and “window of opportunity” results in the second quarter of 2024, which will inform potential next steps in the development of BDTX-1535 in GBM.

a highly selective, brain-penetrant RAF MasterKey inhibitor

BRAF mutations are among the most common mutations found in tumors.

First-generation BRAF inhibitors have focused on V600E (Class I) mutations, but are not active against non-canonical oncogenic BRAF mutations.

First-generation BRAF inhibitors have focused on the canonical V600E (Class I) mutation but are not active against non-canonical oncogenic BRAF mutations.

Non-canonical oncogenic mutations, including BRAF-fusions, can drive RAS-independent (Class II) or RAS-dependent (Class III) RAF dimers.

In addition, current BRAF inhibitors can induce unwanted paradoxical activation that limits their breadth of activity and can result in cutaneous toxicity.

Furthermore, the expression of BRAF mutations commonly occurs in patients with CNS tumors or brain metastases, but currently approved BRAF inhibitors have poor intrinsic brain penetration.

As such, there remains a high unmet clinical need for a broad mutation spectrum and CNS penetrant BRAF inhibitor to treat patients expressing BRAF mutations with a precision medicine therapy.

BDTX-4933 is designed to be a potent and selective, reversible oral inhibitor that targets broad families of oncogenic Class II/III BRAF and Class I BRAF V600 mutations, along with constitutively active RAF dimers resulting from other upstream oncogenic MAPK pathway alterations, such as RAS alterations.

In preclinical models, we observed that BDTX-4933 achieved regression of tumors carrying BRAF Class I, II, and III mutations, NRAS alterations and demonstrated brain penetrant properties.

The IND for BDTX-4933 was cleared by the FDA in the first quarter of 2023.

We expect to initiate a Phase 1 clinical trial for BDTX-4933 in select indications for patients harboring all-class BRAF or RAS mutations in the first half of 2023.

Current BRAF inhibitors can induce unwanted paradoxical activation that limits their breadth of activity and can result in cutaneous toxicity.

First-generation BRAF inhibitors are also not active in the context of KRAS mutations, and there are currently no approved precision therapeutics to address tumors expressing non-G12C KRAS mutations.

Furthermore, the expression of BRAF and KRAS mutations commonly occurs in patients with CNS tumors or brain metastases, but currently approved BRAF inhibitors have poor intrinsic brain penetration.

As such, there remains a high unmet clinical need for a broad mutation spectrum and CNS-penetrant RAF inhibitor to treat patients expressing BRAF mutations and related RAS-dependent alterations.

BDTX-4933 is designed to be a potent and selective, reversible oral inhibitor that targets broad families of oncogenic BRAF, KRAS and NRAS alterations.

BDTX-4933 selectively targets constitutively active RAF dimers resulting from either BRAF mutations or other upstream oncogenic MAPK pathway alterations, such as KRAS and NRAS alterations.

In preclinical tumor models, we observed that BDTX-4933 demonstrated brain-penetrant activity and achieved regression of tumors carrying a broad spectrum of KRAS mutations, NRAS alterations, as well as BRAF Class I, II, and III mutations.

We initiated a Phase 1 clinical trial for BDTX-4933 in the second quarter of 2023 in patients with BRAF and select KRAS and NRAS mutation-positive cancers, with an emphasis on patients with non-G12C KRAS mutant NSCLC.

The trial is currently in dose escalation with data expected in the fourth quarter of 2024.

Early-stage programs

We are also advancing our early-stage programs targeting families of oncogenic mutations in validated oncogenes developed utilizing our MAP drug discovery engine and expect to progress our program targeting FGFR2/3, as well as another undisclosed program, toward development candidate nomination in 2023.

Our vision is to build a differentiated, global biopharmaceutical company by discovering, developing, and commercializing novel precision medicines for every patient with genetically defined tumors.

We are advancing the field of precision medicines through improved understanding of mutant protein conformations to (i) identify novel oncogenic driver mutations and (ii) target families of oncogenic mutations with individual MasterKey therapies.

We believe our strategy will enable us to become an industry leader in precision oncology medicine and advance a portfolio of MasterKey therapies aimed at delivering safe and effective medicines to patients.

We are seeking global partnership opportunities for our FGFR2/3 selective development candidate BDTX-4876, and for another development candidate against an undisclosed, validated oncogene.

Our vision is to build a differentiated, global biopharmaceutical company developing and commercializing novel medicines for patients with genetically defined tumors.

We are advancing compounds that have been discovered through improved understanding of mutant protein conformations to identify novel oncogenic driver mutations, and target families of oncogenic mutations with MasterKey therapies to address a greater number of patients.

Our strategy is to explore development of these compounds starting in later-line settings, and based on results, to expand development into early-line settings where patients with these mutations have few treatment options and well tolerated oral therapies have implicit advantages for patients as compared to intravenously administered chemotherapy, antibody, or conjugate-based therapies.

The critical components of our strategy include:

• Rapidly advance BDTX-1535 through early clinical development to address families of oncogenic alterations in patients with GBM and NSCLC.

We believe that BDTX-1535 could offer an improved approach in GBM and NSCLC by virtue of its ability to penetrate the blood brain barrier and potently, selectively and irreversibly inhibit a broad spectrum of EGFR alterations.

• Rapidly advance BDTX-4933 into early clinical development.

We believe that BDTX-4933 could offer an improved approach to addressing oncogenic BRAF Class I, II, III and RAS mutations expressed in patients with or without tumors in the central nervous system.

• Expand our pipeline of potent and selective MasterKey inhibitors to fully exploit the potential of our proprietary MAP drug discovery engine.

We believe that the general principles for mutation-driven conformational change that we have identified for our lead programs can be applied to other oncogenic proteins.

We also believe that our MAP drug discovery engine has identified undrugged driver mutations for cancer and we intend to design and develop highly selective and potent inhibitors to block the activity of these oncogenic proteins.

We are advancing several early-stage programs focused on targeting a range of driver mutations, including activating mutations outside of the active site.

We believe that the lead molecules in our FGFR program could overcome the limitations of current therapies.

Our FGFR molecules are designed to be potent and selective MasterKey inhibitors of FGFR2/3 mutations that spare FGFR1 and FGFR4, and to provide improved activity against gatekeeper mutations compared to currently approved pan-FGFR inhibitors.

We expect our FGFR program and one other undisclosed program in solid tumors to progress towards development candidate nomination in 2023.

• Continue to invest in our proprietary MAP drug discovery engine to identify and characterize new mutation families.

We plan to continue to innovate our MAP drug discovery engine to enable new insights and to accelerate our ability to identify mutational drivers.

We will continue to enhance our proprietary computational algorithms by leveraging both our extensive in-house expertise in MasterKey inhibitors that target mutation families and our deep understanding of chemistry and computational technologies.

By continuing to strengthen and expand our MAP drug discovery engine, we believe we can exploit the growing amount of genetic sequencing data to characterize mutations underlying human disease.

In December 2022, we announced the spinout of undisclosed early discovery stage antibody programs enabled by the MAP drug discovery engine into Launchpad, a new company formed to exploit the MAP drug discovery engine for the discovery, development and commercialization of large molecule therapeutics.

• Selectively evaluate strategic partnerships that may maximize the potential of our pipeline and our proprietary MAP drug discovery engine.

Given our potential to generate novel product candidates addressing a wide variety of cancers, we may consider and opportunistically enter into strategic partnerships around certain targets, product candidates and disease areas.

These collaborations could advance and accelerate our development programs to maximize their market potential and expand our MAP drug discovery engine capabilities.

• Generate Phase 2 clinical trial results for BDTX-1535 in 2L/3L EGFRm NSCLC to enable a potential pivotal trial.

We believe that BDTX-1535 is the most advanced fourth-generation EGFR TKI in development that uniquely targets the acquired C797S resistance mutation as well as non-classical mutations that can cause disease progression on a third-generation TKI.

• Advance BDTX-1535 rapidly through Phase 2 development in 1L non-classical EGFRm NSCLC to maximize the therapeutic potential of BDTX-1535.

We believe that the ability of BDTX-1535 to target approximately 50 oncogenic mutations that are not sufficiently addressed by existing therapies, as well as its oral administration and tolerability profile together with brain penetrance, offers significant potential to treat patients with non-classical mutations in the first-line setting.

• Outline a potential development path for BDTX-1535 in 1L newly diagnosed patients with EGFR altered GBM.

Based on Phase 1 data and results from the “window of opportunity” trial for BDTX-1535, we will determine potential next steps in the development of BDTX-1535 as a first-line treatment for newly diagnosed patients with EGFR altered GBM.

• Assess early dose escalation data from BDTX-4933 to evaluate future development potential.

We believe that BDTX-4933 could offer an improved approach to addressing oncogenic KRAS, NRAS and all classes of BRAF alterations expressed in patients with or without tumors in the central nervous system, and our initial focus is on non-G12C KRAS mutated NSCLC.

• Evaluate potential strategic partnerships that may maximize the potential of our pipeline.

We may consider and opportunistically enter into strategic partnerships around certain targets, product candidates and disease areas.

Our FGFR program and one other undisclosed program in solid tumors have reached development candidate stage, and we are evaluating out licensing opportunities for further development.

Our history and team

We were founded by Dr.

Epstein and Dr.

Elizabeth Buck in 2014 and, beginning in 2017, together with Versant Ventures, started building the MAP drug discovery engine.

We have assembled a team with significant expertise in drug discovery and development with particular strengths in the discovery of small molecule protein kinase inhibitors.

Epstein, Ph.D., our President and Chief Executive Officer, was previously Chief Scientific Officer at OSI Pharmaceuticals, Inc.

and founder of Archemix Corporation, where he led the advancement of multiple product candidates into the clinic across several therapeutic areas.

We were founded in 2014 and in 2017, together with Versant Ventures, we began building the MAP drug discovery engine to profile oncogenic mutations and create MasterKey Therapies.

We have assembled a team with significant expertise in drug development, with particular strength in small molecule protein kinase inhibitors and advancement of oncology drug candidates through clinical trials and regulatory approval.

Velleca, M.D., Ph.D., our Chairman, President and Chief Executive Officer was previously the Chief Executive Officer of G1 Therapeutics, Inc., where he led the advancement of multiple product candidates across several therapeutic areas, including leading its first therapy from investigational new drug (IND) application to FDA approval.

Elizabeth Buck, Ph.D., our Chief Scientific Officer, previously led preclinical pharmacology and oncology translational research at OSI Pharmaceuticals, Inc.

Sergey Yurasov, M.D., Ph.D., our Chief Medical Officer, previously served as Chief Medical Officer at Nuvation Bio.

Melanie Morrison, our Chief Development Officer, previously served as Senior Vice President, Program Management and Clinical Operations at Nuvation Bio.

Brent Hatzis-Schoch, our Chief Operating Officer and General Counsel, was previously General Counsel at Radius Health, Inc.

Fang Ni, Pharm.D., our Chief Business Officer and Chief Financial Officer, previously served as Principal and was a member of the investment team at Versant Ventures.

Sergey Yurasov, M.D., Ph.D., our Chief Medical Officer, previously served as Chief Medical Officer at Nuvation Bio.

Elizabeth Montgomery, our Chief People Officer, previously served as Chief People Officer at ClearView Healthcare Partners.

Background on and limitations of previous generations of targeted therapies

Background on targeted therapies

Cancer is a genetic disease that is caused by changes in DNA that control the way cells function, especially how they grow and divide, and has historically been diagnosed and treated based on a tumor’s organ site or tissue of origin.

Oncogene addiction, which is the dependency of tumors on genetic drivers for their growth and survival advantage, has enabled the pharmacological development of targeted therapies that exploit this dependency.

Recent advances in genetic sequencing and a better understanding of genetic alterations that drive cancers have facilitated more precise and histologically agnostic cancer drug development.

These targeted therapies have transformed the treatment of some cancers by providing substantial clinical benefit and have emerged as an important part of standard of care for cancer patients.

Worldwide sales of kinase inhibitors, one class of targeted therapies, exceeded $35 billion in 2019.

Furthermore, patients with tumors driven by oncogene addiction typically show rapid and measurable tumor shrinkage when exposed to drugs targeting the relevant alteration.

Such clinical responses can be dramatic enough in many cases to support expedited regulatory approval of these targeted therapies.

Yet, a recent analysis found that less than fifteen percent of patients with metastatic cancer have tumors with genetic profiles that could make them eligible for treatment with an approved precision oncology medicine.

Existing targeted therapies have been effective because they target genetically defined cancers driven by a single set of mutations.

Genetic sequencing of tumors reveals that many mutations remain uncharacterized, suggesting that there are additional mutations that can lead to oncogene addiction.

With its supplemental approval by the FDA in 2017, pembrolizumab, or Keytruda, was the first targeted oncology treatment approved for any solid tumor based on a molecular profile, regardless of the tumor’s site of origin.

In 2018, larotrectinib, or Vitrakvi, was approved by the FDA for neurotrophic tropomyosin receptor kinase, or NTRK, driven cancers, making it the first drug to be approved to treat a specific genetic alteration in a tissue agnostic fashion.

We believe that these advancements represent a fundamental change in the development of targeted therapies and will increasingly lead to cancer being characterized for treatment in a genetic, rather than in a tissue-specific manner.

Limitations of current targeted therapies

Current targeted therapies provide clinical benefit to patients expressing ATP-site mutations, but not to patients expressing other mutations.

Numerous other mutations beyond the active site mutations are known to the oncology clinical and research community, but those other mutations are often not currently targeted by approved inhibitors.

For example, while EGFR-targeted therapies, including erlotinib and osimertinib, have proven to be effective in patients with ATP-site mutations, limited response to these inhibitors has been observed when treating patients with cancers expressing other types of oncogenic EGFR driver mutations, including those expressed outside of the ATP site, such as EGFR exon 20 insertions, and extracellular domain mutations, such as EGFRvIII.

There remains a significant unmet medical need for new drugs that can extend precision medicines to patients expressing non-ATP site or non-canonical mutations.

The figure below depicts the oncogenic EGFR mutations, shown in magenta.

These include the ATP-site mutations, EGFR exon 19 deletions and L858R (left panel), as well as an additional spectrum of mutations occurring outside of the ATP site, including EGFRvIII (middle panel) and EGFR-L861X (right panel).

Emergence of genetic sequencing as standard of care in treating cancer

The cancer treatment landscape is rapidly evolving, and there is now widespread recognition that cancer is a disease of genetics, as much as it is a disease defined by histology or anatomical location.

This shift has been driven by the increased use of genetic sequencing coupled with the availability of approved targeted therapies.

The FDA has approved Foundation Medicine’s comprehensive genetic profiling test FoundationOne CDx and the Centers for Medicare & Medicaid Services announced coverage of next generation genetic sequencing tests, which we believe will further drive the use of genetic testing.

A 2019 study demonstrated that 75% of oncologists in the United States employ genetic sequencing.

As technological advancements in genetic sequencing improve and an increasing number of targeted therapies are developed, we believe that physicians will require molecular information about their patients’ cancers to determine the optimal course of treatment.

Not only have advances in genetic sequencing changed the standard of care for oncology patients, but they are also leading to transformations in the discovery and development of oncology drugs.

We believe that genetic sequencing enables the discovery of additional targets for drug development.

More than 400 cancer-associated genes are routinely sequenced, and analysis of this data has shown that mutations are not restricted to specific regions, but rather are spread more broadly throughout entire sequences of genes.

We believe that such mutations have not yet been systematically studied as potential drug targets or their oncogenic proteins targeted in drug discovery efforts, and that our ability to do so represents a significant opportunity to develop precision medicines in areas of major unmet medical need.

The Black Diamond Therapeutics approach

At Black Diamond Therapeutics, our goal is to bring precision oncology medicine to patients with genetically defined cancers who have limited treatment options.

Our drug development efforts leverage our novel findings that:

• mutations throughout a gene can drive oncogenic activation and change the drug selectivity profile of their active sites;

• these oncogenic mutations can be grouped into families because they drive similar protein structural changes, and exhibit a shared selectivity profile;

• a family of oncogenic proteins can therefore be inhibited by a single molecule that targets the active site regardless of where it appears on the receptor.

We believe we can address certain key limitations of current generation precision medicine therapies in oncology by applying our MAP drug discovery engine to identify and target novel classes of oncogenic mutations.

We believe this enables us to design and develop potential therapies for patients for whom there are currently no targeted treatment options.

Our MAP drug discovery engine

Our MAP drug discovery engine is built on three central pillars:

Mutation—Allostery—Pharmacology.

Mutation—identify mutations and rank for potential oncogenicity

Our discovery process begins by identifying oncogenic mutations.

We use population-level cancer genetic data obtained from all tumor types, to identify potential families of mutations that occur within individual oncogenes.

We have developed unique insights into the specific structural features of a protein that are associated with oncogenic mutations.

The algorithm underlying our MAP drug discovery engine scores each mutation for its potential oncogenicity, which we refer to as a MAP score.

We use our algorithm as a machine-learning tool to predict the oncogenicity of various uncharacterized mutations, isolating oncogenic driver mutations from the silent and passenger mutations.

We map these mutations onto the 3-dimensional structure of a protein to determine which of the many mutations expressed by human tumors occur at sites associated with oncogenicity.

For HER2 and EGFR, we observed that oncogenic mutations are distributed nearly uniformly throughout the sequence of these two genes, revealing many mutations occurring outside of the ATP site, which have not been targeted by drugs.

For example, applying our algorithm to all currently known mutations in HER2 alone reveals a subset of mutations with high MAP scores, which we believe is a predictor of oncogenicity.

For the ErbB family, we observed 3,868 unique mis-sense mutations (935 mutations in EGFR, 670 mutations in HER2, 794 mutations in HER3 and 1,469 mutations in HER4).

These mutations are distributed throughout the target sequence.

As illustrated in the figure below, we observed 670 unique mutations expressed in HER2, detected within a combined human tumor data set of approximately 70,000 cases (GENIE 5.0 and TCGA data sets).

Through this analysis, we re-identified or confirmed the known HER2 oncogenic mutations, which are the mutations that we targeted with our earlier generation product candidate.

We also identified an additional subset of mutations with high MAP scores, and we are currently validating these putative oncogenic mutations experimentally.

Our goal is to expand our targeted mutation family to potentially include this additional group of non-canonical mutations.

Our genetic sequencing analysis has identified a family of 48 non-canonical mutations in both the extracellular and kinase domains of EGFR and HER2.

The figure below is a compilation of the non-canonical EGFR and HER2 oncogenic mutations that we are targeting in both of our ErbB programs.

Each dot represents a unique non-canonical EGFR and HER2 oncogenic mutation found in individual tumors, while the height of each dot represents the frequency at which such mutation was found.

The sites of two mutations defined as canonical mutations are indicated.

The frequency for EGFR oncogenic mutations expressed in GBM was calculated as relative frequency within GBM.

The frequency for all other EGFR and HER2 mutations was calculated relative to all solid tumors (approximately 70,000 tumors within project GENIE 5.0 / TCGA dataset).

Specifically, the figure shows the prevalence of various types of alterations of EGFR expressed in GBM (EGFRvIII, EGFRvII, EGFRvVI, three mutations affecting EGFR-A289 and two mutations affecting EGFR-G598) and various types of EGFR and HER2 alterations expressed across solid tumors (two mutations affecting HER2-S310, HER2-R678Q, six unique mutations affecting HER2-L755, four unique mutations affecting HER2-V777, HER2-V842I, 46 unique mutations that are deletions within exon 19, and 28 unique mutations that are insertions within exon 20 and EGFR-L858R).

We selected 43 additional HER2 mutations to experimentally test for oncogenicity using the BaF3 transformation assay.

Thirty-three of the 43 mutations tested had high MAP scores and were therefore predicted to have oncogenic behavior, while ten of the 43 mutations had low MAP scores and were therefore not predicted to be oncogenic.

In this screen, we also tested HER2 WT and three HER2 mutations that we had already observed to have oncogenic behavior.

HER2 WT was unable to transform BaF3 cells to IL-3 independent proliferation, while all three validated HER2 oncogenic mutations (HER2-V842I, L755S and S310F) successfully transformed cells, as evidenced by greater than three-fold proliferation over a seven-day period.

Of the 33 mutations with high MAP scores that were predicted to be oncogenic, 15 were transformative.

In contrast, among the group of mutations with low MAP scores that were not predicted to have oncogenic behavior, only two transformed BaF3 cells to proliferate greater than three-fold over seven days.

We found newly characterized mutations to be sensitive to an earlier clinical candidate, as evidenced below with potent inhibition of proliferation against cells transformed by the HER2-R103Q mutation.

Allostery—understanding the mechanism for oncogenic activation

We evaluate the oncogenicity of these mutations occurring outside of the ATP site and use our preclinical models to reveal how they drive protein conformation change to promote oncogenicity.

We then use these models to determine whether the drug sensitivity profile, or pharmacology, of the ATP site is altered.

We use this information to group into oncogene families that share a similar ATP site pharmacology.

In the ErbB space, the drug selectivity patterns of mutant EGFR and HER2 kinases provide evidence of unique conformational states driven by mutation.

As illustrated in the figure below, dimerization is required for receptor activation, an important step in oncogenic signaling.

In EGFR WT, the binding of a ligand to the extracellular domain promotes an active dimer conformation.

In the case of EGFR WT, this is a transient ligand-induced dimer conformation.

We have discovered that a family of EGFR and HER2 mutations activate these kinases and promote oncogenicity by stabilizing the kinase in a unique constitutive dimer conformation.

Importantly, the constitutive dimer conformation results in a change in selectivity for drugs which bind to the ATP site, potentially reducing the effectiveness of currently approved targeted therapies, such as erlotinib.

The protein conformation for the active form of mutant ErbB receptors is unique from the conformation of EGFR WT.

EGFR WT is inactive in its monomeric form and activated upon the binding of an EGF ligand (shown in dark purple) to the extracellular domain, forming an active transient ligand-induced dimer conformation.

Oncogenic ErbB mutations (highlighted in magenta in this example) can promote a constitutive dimer conformation which has high activity and is oncogenic.

Pharmacology—developing mutation spectrum-selective (MasterKey Inhibitors) drugs to our targets

We apply molecular dynamics to simulate the conformational state for any given mutation, and in this manner deliver design ready conformations for drug discovery.

Our team of experienced medicinal and computational chemists seeks to leverage these conformations to design and identify small molecules that bind to the active site and inhibit the target only when it is in the unique conformation promoted by the non-canonical oncogenic mutations we identified.

Combining a multidimensional medicinal chemistry lead identification and optimization strategy with our proprietary know-how in drug design, we aim to identify small molecules with bespoke selectivity against the entire desired spectrum of mutations as a family, while at the same time sparing inhibition of the wild type form of the protein or other unwanted targets.

For the development of BDTX-1535, our product candidate that is currently in clinical development, we utilized these cell and tumor models as biological screens that recapitulate the tumor biology for these mutations.

BDTX-1535 binds to the ATP-site to inhibit the constitutive dimer in a family of EGFR mutations, while at the same time sparing inhibition of the normal EGFR WT.

In preclinical models, we have validated the activity for BDTX-1535 against the most commonly occurring of these types of mutations (EGFR vIII, EGFR amplification, EGFR Exon 19 deletion EGFR-746-750, EGFR-L858R, EGFR-C797S, EGFR-L861R and EGFR-G719X).

Our product candidates and development programs

We are leveraging our MAP drug discovery engine to develop a drug pipeline of orally available, potent and selective small molecule MasterKey therapies that target genetic drivers in several cancers.

We have a pipeline of orally available, potent and selective small molecule MasterKey therapies that target genetic drivers in several cancers.

We own worldwide commercial rights to all of our product candidates.

a brain penetrant, mutant selective, irreversible EGFR MasterKey inhibitor targeting EGFR mutations expressed in GBM and EGFR driver and resistance mutations in NSCLC

a brain-penetrant, mutant selective, irreversible EGFR MasterKey inhibitor targeting EGFR classical, non-classical, and acquired resistance mutations in NSCLC and EGFR alterations expressed in GBM

Background and limitations of current EGFR inhibitors

EGFR is a potent oncogene commonly altered in many cancers, including GBM and NSCLC.

EGFR alterations and EGFR mutations in GBM occur primarily in the extracellular domain, while NSCLC mutations more commonly impact the kinase domain.

Almost 50 percent of GBM tumors express one or more EGFR alterations that affect the extracellular region of the receptor kinase and promote oncogenic activation.

These include large deletions in the extracellular domain, including the mutants EGFRvIII, EGFRvVI, and EGFRvII.

These also include any one of a number of short variants, single amino acid substitutions affecting the extracellular domain, the most common of which are substitutions at position A289.

These mutants are constitutively active, exhibit sustained signaling that is resistant to downregulation, and are both transforming and tumorigenic.

Their expression has been associated with poor long-term overall survival.

EGFR oncogenic mutations are expressed throughout the target sequence.

The figure below shows the most frequent EGFR oncogenic mutations expressed in GBM (EGFRvIII, EGFRvII, EGFRvVI, EGFR-G598 mutations, EGFR-A289 mutations), which was calculated as relative frequency within GBM (Brennan et al Cell 2013).

Each dot represents a unique oncogenic mutation found in individual tumors and the height of each dot represents the frequency with which it was found.

A given GBM patient may co-express multiple different EGFR oncogenic mutations.

Therefore, we believe a critical challenge to overcome in drug discovery and clinical development of targeted therapies is to develop precision medicines for GBM that efficiently block the oncogenic activity across all of these various EGFR species.

We have shown that the mechanism of activation for these EGFR mutants requires formation of a covalent dimer, which is always active, also known as a constitutive dimer.

The formatting of these constitutive dimers is essential for oncogenicity.

No current generation EGFR-directed therapy has proved effective in treating patients that express these mutations.

We believe that current targeted therapies have been unsuccessful in treating GBM due to (i) the concurrent expression of these EGFR oncogenic alterations within individual patients, (ii) insufficient drug potency for EGFR oncogenic alterations, (iii) reversible binding mode leading to paradoxical activation and iv) low levels of brain penetration.

The figure below illustrates distinct EGFR oncogenic mutations (EGFRvIII, EGFRvII, EGFRvI, EGFR-A289V) that share the ability to promote constitutively active, ligand independent dimer conformation, which is different from the transient ligand-induced dimer conformation for EGFR WT.

For mutants, the region surrounding each mutation site is highlighted in magenta.

For EGFR WT, bound EGF ligand is shown in dark purple.

Currently approved reversible EGFR inhibitors, those proven clinically efficacious in NSCLC, have not demonstrated clinical activity in GBM.

We believe this is, in part, due to reversible inhibitors, such as erlotinib, causing paradoxical activation of EGFR alterations.

As shown in the figure below, erlotinib demonstrates antiproliferative activity in models harboring an exon 19 deletion mutation common in NSCLC.

However, in a GBM model expressing EGFRvIII, erlotinib results in paradoxical activation which increases tumor proliferation at sub-saturating dose levels.

We believe the irreversible binding profile of BDTX-1535 offers an opportunity to avoid paradoxical activation and potently inhibit the locked dimers formed by EGFR alterations commonly seen in GBM.

Reversible EGFR Inhibitors Show Potentially Detrimental Pharmacology in EGFR Driven GBM

In NSCLC, EGFR inhibitors have demonstrated significant clinical benefit in patients with primary EGFR activating mutations and are the current first-line standard of care.

In NSCLC, EGFR inhibitors have demonstrated significant clinical benefit in patients with classical EGFR activating mutations (Exon19del, L858R) and are the current first-line standard of care.

However, over time, almost all patients acquire resistance and relapse.

For the third generation EGFR inhibitor osimertinib, acquired resistance can be associated with the acquisition of the EGFR-C797S mutation against which osimertinib is inactive.

Additionally, a subset of NSCLC patients at primary diagnosis harbor intrinsic resistance EGFR mutations including complex mutations that are poorly addressed with current therapies.

Furthermore, up to half of all NSCLC patients either have central nervous system (CNS) metastases at diagnosis or will develop them while on treatment.

For the third-generation EGFR inhibitor osimertinib, acquired resistance can be associated with the acquisition of a non-classical mutation (e.g., L747P, L718Q) or acquired C797S resistance mutation, against which osimertinib is inactive.

Additionally, a substantial fraction of NSCLC patients at primary diagnosis harbor non-classical EGFR mutations, including complex mutations that are poorly addressed with current therapies.

Furthermore, up to half of all NSCLC patients either have CNS metastases at diagnosis or will develop them while on treatment.

The majority of first- and second-generation EGFR inhibitors do not adequately penetrate the CNS, and while third-generation, brain-penetrant EGFR inhibitors such as osimertinib may delay the progression of CNS metastases, there are few options remaining to patients when resistance inevitably arises.

Thus, treatment for patients who have progressed on current EGFR targeted agents with acquired mutations that drive resistance, including for patients with brain metastases, remains an area of high unmet medical need in NSCLC.

Thus, treatment for patients who carry non-classical mutations at diagnosis or patients who have progressed on current EGFR targeted agents with acquired resistance mutations, including for patients with brain metastases, remains an area of high unmet medical need in NSCLC.

Our solution:

In November 2020, we announced the nomination of BDTX-1535 as a development candidate for the treatment of GBM and NSCLC with or without brain metastases.

BDTX-1535 is a potent, selective, irreversible, oral and brain penetrant small molecule inhibitor designed to address the critical unmet need in GBM and NSCLC driven by EGFR alterations.

The pharmacological activity of BDTX-1535 was optimized to inhibit a wide spectrum of EGFR mutations that drive acquired and intrinsic resistance mechanisms, as well as targeting the CNS tumor settings through its potential for high brain exposure.

In cell-based assays, BDTX-1535 achieved potent MasterKey inhibition of a family of oncogenic EGFR variants expressed in GBM and EGFR amplification with selectivity versus normally expressed EGFR WT.

This includes classical, intrinsic resistance and acquired resistance mutations expressed in NSCLC.

BDTX-1535 is not a potent inhibitor of Exon20 insertion driver mutations or the T790M resistance mutation.

BDTX-1535 demonstrates potent inhibition of driver mutations, C797S resistance mutation, and EGFR Amp preclinically compared to Osimertinib

MasterKey profile of BDTX-1535 demonstrates potent inhibition of oncogenic GBM mutational family preclinically compared to Osimertinib

Additionally, BDTX-1535 achieved complete and sustained inhibition (>24 hours) of the phosphorylated state of EGFR in a mouse model expressing the common glioblastoma mutation, EGFRvIII, consistent with its irreversible binding mechanism demonstrated in vitro to EGFR WT.

Furthermore, BDTX-1535 demonstrated tumor growth inhibition in a mouse model bearing intracranial GBM6 PDX expressing EGFRvIII and EGFR amplification, supporting its ability to penetrate the blood-brain barrier.

BDTX-1535 also achieved sustained inhibition (>24 hours) of the phosphorylated state of EGFR in cells harboring the NSCLC acquired resistance mutation, C797S, as well as tumor growth inhibition in a mouse model bearing PDX tumors expressing C797S.

This indicated that BDTX-1535 retains its ability to irreversibly bind to the serine 797 mutant residue that can be acquired after treatment with third generation EGFR tyrosine kinase inhibitors used in the first line setting.

Oral, single dose of BDTX-1535 resulted in sustained inhibition of EGFR autophosphorylation in subcutaneous monoclonal Ba/F3 tumors expressing EGFRvIII.

Oral, once daily administration of BDTX-1535 showed increased survival in mice bearing intracranial PDX tumors expressing EGFRvIII and amplified EGFR.

Mean tumor volume in mice expressing subcutaneous Ba/F3 allograft expressing Exon19del + C797S.

Mice were treated orally with 40mg/kg of BDTX-1535 and 25mg/kg of osimertinib.

Inhibition of the phosphorylated state of EGFR in cells harboring the NSCLC Exon19 deletion and the acquired resistance mutation, C797S, after washout.

Furthermore, in mouse models, BDTX-1535 achieved tumor growth inhibition and regression in multiple subcutaneous mouse models bearing PDX and allograft tumors representing a spectrum of EGFR alterations.

These models were selected to cover the EGFR alterations commonly found in patients with GBM as well as classical, intrinsic resistance, and acquired resistance mutations found in NSCLC patients.

% Regression in subcutaneous mouse models bearing PDX and allograft tumors expressing EGFR alterations commonly found in patients with GBM as well as classical, intrinsic resistance, and acquired resistance mutations found in NSCLC patients.

BDTX-1535 is a potent, selective, irreversible, oral and brain-penetrant small molecule inhibitor designed to address the critical unmet need in NSCLC and GBM driven by EGFR alterations.

The pharmacological activity of BDTX-1535 was optimized to inhibit a wide spectrum of EGFR mutations that drive resistance, and to target CNS tumors through its potential for high brain exposure.

EGFR is a potent oncogene commonly altered in many cancers, including NSCLC and GBM.

EGFR mutations in NSCLC commonly impact the kinase domain, while in GBM they occur primarily in the extracellular domain.

In cell-based assays, BDTX-1535 achieved potent inhibition of families of oncogenic EGFR mutations and selectivity versus normally expressed EGFR WT as compared to osimertinib.

This includes classical, non-classical, acquired C797S resistance mutation, and complex mutations expressed in NSCLC.

BDTX-1535 is not a potent inhibitor of Exon20 insertions or the T790M resistance mutation.

In cell-based assays, BDTX-1535 achieved potent MasterKey inhibition of a family of oncogenic EGFR variants expressed in GBM and EGFR amplification with high selectivity versus normally expressed EGFR WT.

Clinical development

The IND for BDTX-1535 was cleared by the FDA in the first quarter of 2022, and the first-in-human clinical trial (BDTX1535-101) was also initiated in the first quarter of 2022.

The Phase 1 dose escalation part of this trial is actively enrolling patients harboring EGFR oncogenic alterations both in GBM and NSCLC, with or without brain metastases.

BDTX1535-101 is an open-label, multicenter Phase 1 trial consisting of a dose escalation portion and disease specific dose expansion cohorts.

It is designed to assess the safety, tolerability, pharmacokinetics and preliminary antitumor activity of BDTX-1535 in patients with either recurrent GBM expressing EGFR alterations or advanced/metastatic NSCLC harboring sensitizing EGFR mutations, with or without brain metastases, who have progressed on an approved EGFR inhibitor.

Eligible NSCLC patients must have either an intrinsic resistance EGFR mutation in exon 18 or 21 or an acquired C797S mutation following prior therapy with a 3rd-generation EGFR inhibitor.

As opposed to a traditional “3+3” design, the dose escalation part is based on a Bayesian adaptive design which allows a various number of patients to be enrolled at each dose level to assess safety, tolerability and pharmacokinetics of BDTX-1535 in order to establish a maximum tolerated dose (MTD).

Once an MTD has been established, BDTX-1535 monotherapy will be explored in disease specific dose expansion cohorts to further evaluate safety, PK, and preliminary efficacy in order to establish a recommended phase 2 dose (RP2D).

The trial allows evaluation of two dose levels in a disease specific expansion cohort in order to further optimize the RP2D dose selection for an indication.

The disease specific dose expansion cohorts include:

patients with recurrent GBM with EGFR alterations, patients with locally advanced/metastatic NSCLC with an acquired resistance EGFR mutation (e.g., C797S) with and without brain metastases, and patients with locally advanced/metastatic NSCLC with oncogenic EGFR intrinsic resistance mutations (e.g., G719X), in each case with and without brain metastases.

The trial also includes a cohort of newly diagnosed glioblastoma patients to explore safety, tolerability, pharmacokinetics, and preliminary antitumor activity of BDTX-1535 in combination with temozolomide.

Our regulatory strategy includes pursuing a registration path for patients with recurrent GBM in parallel with NSCLC patients with either intrinsic resistance mutations or acquired resistance mutations who have progressed or are resistant to a third generation EGFR tyrosine kinase inhibitor (TKI).

We expect to provide an update on the clinical data obtained from the BDTX1535-101 Phase 1 clinical trial in the second half of 2023.

a highly selective, brain penetrant RAF MasterKey inhibitor targeting oncogenic BRAF Class I, II, III and activated RAF dimers in the setting of RAS mutations

The IND application for BDTX-1535 was cleared by the FDA in the first quarter of 2022, and the first-in-human clinical trial (BDTX1535-101) was also initiated in the first quarter of 2022.

The Phase 1 dose escalation part of this trial enrolled patients harboring EGFR oncogenic alterations both in NSCLC and GBM.

BDTX1535-101 is an open-label, multicenter Phase 1/2 trial consisting of a Phase 1 dose escalation portion (completed) and a multi-cohort Phase 2 dose expansion portion (enrolling).

The Phase 1 portion was designed to assess the safety, tolerability, pharmacokinetics and preliminary antitumor activity of BDTX-1535 in patients with either advanced/metastatic NSCLC harboring sensitizing EGFR mutations, with or without brain metastases, who have progressed on an approved EGFR inhibitor, or recurrent GBM expressing EGFR alterations.

Eligible NSCLC patients had either a non-classical EGFR mutation in exon 18 or 21 or an acquired C797S mutation following prior therapy with a third-generation EGFR inhibitor.

The dose escalation part was based on a Bayesian adaptive design which allowed a various number of patients to be enrolled at each dose level to assess safety, tolerability and pharmacokinetics of BDTX-1535 to establish a maximum tolerated dose (MTD).

We released top-line NSCLC results from the Phase 1 dose escalation trial in June 2023, and in October 2023 presented updated clinical data at the European Organization for Research and Treatment of Cancer-National Cancer Institute-American Association for Cancer Research (EORTC-NCI-AACR) Symposium on Molecular Targets and Cancer Therapeutics.

Data disclosed at the conference were from 27 patients with advanced/metastatic NSCLC who received once daily doses ranging from 25mg to 400mg.

Durable clinical responses were observed at a starting dose of 100mg once daily or above in patients with NSCLC who had multiple lines of prior therapy.

Five of the 13 patients with either a non-classical driver, the acquired C797S resistance mutation or complex mutations who had measurable disease at study start and underwent post-baseline tumor assessment, had a confirmed partial response (PR) by RECIST 1.1.

Evidence of reduction in brain metastases was observed, including a patient who had received greater than three prior lines of therapy.

Results presented showed that three responders continue on therapy for greater than six months (two confirmed PRs, one unconfirmed PR) and that one patient with confirmed PR continued on therapy for six months.

Two additional patients with stable disease were shown to continue on therapy for greater than 12 months.

Eradication of targeted variant alleles and significant circulating tumor DNA reductions were also observed for all NSCLC EGFR mutation subtypes in patients treated with BDTX-1535 across dose levels.

Osi = Osimertinib;

Afa = Afatinib;

Gefi = Gefitinib;

Daco = Dacomitinib;

Erlo = Erlotinib;

CPI = Checkpoint inhibitor, C = Chemotherapy;

# - mutations were absent on confirmatory test;

* uPR=unconfirmed partial response-patient had a PR on a post-baseline scan, but a radiologist was unable to confirm a response on a subsequent scan;

this patient remains on study treatment without evidence of PD.

**%SoD was updated to -50% from prior data release;

24July2023 BDTX-1535-101 clinical data extract;

Data from Poster at EORTC/AACR/NCI International Conference on Molecular Targets and Cancer Therapeutics October 2023

a) Dose was increased incrementally to 100 mg QD;

b) Dose was increased incrementally to 200 mg QD;

c) Received more than two prior lines of therapy;

d) Dose was reduced to 300 mg QD;

e) patient had a PR on a post-baseline scan, but a radiologist was unable to confirm a response on a subsequent scan;

this patient remains on study treatment without PD;

f) Patient had >20% increase in target lesions at cycle 11, however, continues the study treatment;

Data from Poster at EORTC/AACR/NCI International Conference on Molecular Targets and Cancer Therapeutics October 2023

Adverse event results included both the NSCLC and GBM cohorts.

A favorable emerging tolerability profile was demonstrated, and no unexpected safety signals were identified, with the majority of adverse events at doses of 100mg and 200mg once daily being mild or moderate.

No dose limiting toxicities were observed at 200mg once daily or below.

Treatment emergent adverse events (TEAEs) occurring in ≥6% patients;

All patients in 300 mg cohort received rash prophylaxis;

Rash group terms:

rash, rash maculo-papular, dermatitis acneiform;

*PPE = Palmar-plantar erythrodysaesthesia syndrome;

Data from Poster at EORTC/AACR/NCI International Conference on Molecular Targets and Cancer Therapeutics October 2023

The Phase 1 portion of the trial is now completed.

In September 2023 we dosed the first patients in the Phase 2 trial to assess overall response rate (ORR) by RECIST 1.1 and durability of response (DOR) in patients with EGFRm NSCLC in two cohorts:

one cohort with the EGFR acquired C797S resistance mutation after progression on a third-generation EGFR TKI, and the other cohort in non-classical driver mutations after progression on an EGFR TKI.

Enrollment continues in the two cohorts at both 100mg and 200mg doses, and we expect to disclose initial results from these two cohorts of the Phase 2 trial in the third quarter of 2024.

Following feedback received from the FDA in late 2023, in the first quarter of 2024, we initiated a Phase 2 cohort in first-line NSCLC patients harboring non-classical EGFR mutations.

Each of the three cohorts of the Phase 2 trial is anticipated to enroll up to 40 patients.

BDTX-1535 received Fast Track Designation from the FDA for the treatment of patients with metastatic EGFR C797S mutation-positive NSCLC, without T790M mutation, whose disease has progressed on/after treatment with a third-generation EGFR TKI.

We intend to meet with FDA as results become available from the Phase 2 expansion cohorts in patients with NSCLC to discuss a potential registrational path for BDTX-1535 in EGFRm NSCLC.

GBM is a difficult-to-treat, aggressive malignancy of the central nervous system.

Standard therapy at diagnosis consists of surgical resection followed by radiation and chemotherapy.

Prognosis remains poor, with only approximately 25% of newly diagnosed patients surviving two years or longer after diagnosis.

At the time of diagnosis, approximately 52% of GBM tumors express one or more EGFR oncogenic alterations that affect the extracellular region of the receptor tyrosine kinase, consequently promoting oncogenic activation.

In preclinical models, we have shown that the mechanism of activation for these EGFR oncogenic alterations involves the formation of a constitutive dimer that exhibits a conformation leading to ligand-independent signaling shared by a family of extracellular domain EGFR alterations expressed in GBM.

We believe that current EGFR targeted therapies have been unsuccessful in treating GBM due to (i) the concurrent expression of different EGFR oncogenic alterations within individual patients, (ii) insufficient drug potency across different EGFR oncogenic alterations, (iii) paradoxical activation of EGFRm commonly found in GBM caused by earlier-generation inhibitors, and (iv) low levels of brain penetration.

BDTX-1535 was designed to overcome these challenges and address the significant unmet need for new treatments for patients with GBM.

In December 2023, we announced dose escalation results in 22 patients with GBM that were treated at doses ≥100mg once daily demonstrating clinical activity in heavily pre-treated patients including 1 confirmed partial response and 8 patients with stable disease among 19 patients with measurable disease by RANO criteria.

Of 22 patients evaluable for efficacy, 3 patients were shown to be on therapy longer than 10 months, 1 patient longer than 6 months, and 5 patients longer than 4 months.

Importantly, historical progression free survival (PFS) in this population is expected to last approximate 2-4 months.

BDTX-1535 was shown to be generally well tolerated, with no new safety signals observed.

It is notable that patients’ EGFR status was not able to be confirmed prior to dosing in this trial, which is an important consideration for future development.

An investigator sponsored “window of opportunity” Phase 0/1 trial of BDTX-1535 is ongoing in patients with recurrent high-grade glioma who are undergoing surgical intracranial tumor resection.

This trial will provide data on BDTX-1535 drug levels in the brain, and also confirm the EGFR mutation status of patients’ tumors.

GBM are highly pleiomorphic tumors known to evolve with therapeutic treatments such as radiation and chemotherapy, thereby potentially changing EGFR mutation status over time.

We expect to present clinical data from the dose escalation study and the “window of opportunity” study at a medical meeting in the second quarter of 2024.

These results will inform potential further development in newly diagnosed GBM patients harboring EGFR alterations.

We believe that a randomized trial in newly diagnosed GBM patients with confirmed EGFR alteration status may be the most appropriate strategy for evaluating the potential benefit of BDTX-1535 for this indication.

a highly selective, brain-penetrant RAF MasterKey inhibitor targeting oncogenic mutations in KRAS, NRAS, and BRAF Class I, II, III

Background and limitations of RAF inhibitors

BRAF mutations are among the most common mutation found in tumors.

BRAF mutations are among the most common mutations found in tumors.

Oncogenic alterations affecting BRAF include the V600E mutation (Class I) active site mutation together with families of non-canonical BRAF mutations (Class II and Class III) that are active as dimers.

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Approved BRAF inhibitors can lead to unwanted paradoxical activation, which may lead to poor efficacy and secondary malignancies.

Classification of BRAF mutations.

Class I, V600, signals as a monomer in an RAS-independent manner and constitutively activates the mitogen activated protein kinase (MAPK) signaling pathway.

Class II and III BRAF mutations signal as dimers in an RAS-independent, and -dependent, respectively, and currently there are no approved therapies for these BRAF dimer mutations.

First generation BRAF V600E-selective inhibitors are inactive against BRAF dimers, Class II and Class III.

Our solution:

BDTX-4933 is designed as a brain penetrant, small molecule MasterKey reversible oral inhibitor of oncogenic BRAF Class I, II and III active RAF dimers promoted by upstream oncogenic alterations expressed by human cancers, while avoiding paradoxical activation.

We believe that BDTX-4933 could offer an improved approach for treating melanoma, NSCLC and other solid tumors expressing Class I mutations with brain metastases as well as cancers expressing Class I, II and III alterations, including CNS diseases such as gliomas.

BDTX-4933 is designed as a brain-penetrant, oral small molecule MasterKey inhibitor of oncogenic KRAS, NRAS and BRAF Class I, II and III mutations, while avoiding paradoxical activation.

We believe that BDTX-4933 could offer an improved approach for treating solid tumors expressing activating MAPK pathway alterations, including those with brain metastases.

In cell-based assays, BDTX-4933 demonstrated potent inhibition of a wide spectrum of BRAF alterations including fusions and exhibited dose-dependent inhibition of cell proliferation.

In preclinical BRAF-driven tumor models expressing Class I, II and III mutations, daily dosing of BDTX-4933 demonstrated dose-dependent tumor growth inhibition, tumor regression and survival advantage consistent with potent on-target and on-pathway inhibition.

In preclinical tumor models expressing KRAS, NRAS, and BRAF Class I, II and III mutations, daily dosing of BDTX-4933 demonstrated dose-dependent tumor growth inhibition, tumor regression and survival advantage consistent with potent on-target and on-pathway inhibition.

BDTX-4933 also demonstrated robust brain penetration properties and activity in intracranial mouse tumor models expressing the Class I V600E mutation.

MasterKey property of BDTX-4933 inhibitor:

BDTX-4933 inhibitor demonstrates robust anti-tumor activity and regression across preclinical tumor models representing all 3 classes of BRAF mutations.

Survival rate of tumor bearing mice.

BDTX-4933 inhibitor treated animals show significant extended survival compared to vehicle.

We presented mechanism of action data for BDTX-4933 in October 2023 at the EORTC-NCI-AACR Symposium on Molecular Targets and Cancer Therapeutics demonstrating that BDTX-4933 forms a “RAS/RAF clamp” by blocking activating RAS mutations upstream and locking it in an inactivated form.

We believe this is a differentiated mechanism of action within the RAF and RAS landscape.

Zhang, W., Cell Res.

Yuan, J., J Hematol Oncol 13, 113 (2020);

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Clinical development

The IND for BDTX-4933 was cleared by the FDA in the first quarter of 2023.

We expect to initiate a Phase 1 clinical trial for BDTX-4933 in select indications for patients harboring all-class BRAF or RAS mutations in the first half of 2023.

an inhibitor of oncogenic mutations of EGFR and HER2

BDTX-189 was designed as an orally available small molecule MasterKey inhibitor to target a family of non-canonical and canonical driver mutations of EGFR and HER2, including Exon20 insertion, while sparing EGFR WT while also being a potent inhibitor of HER2 wild type (HER2 WT).

These mutations are present in solid tumors including NSCLC, breast, gastric, colon, and endometrial cancers.

To focus on progressing our pipeline through important upcoming milestones for BDTX-1535 and BDTX-4933 as well as our discovery efforts, in April 2022, we announced the discontinuation of the development of BDTX-189.

In the second quarter of 2023, we initiated a Phase 1 clinical trial for BDTX-4933.

The Phase 1 trial is currently enrolling patients in the dose escalation portion of the trial, with a focus on patients with non-G12C KRAS mutated NSCLC.

The objective of the dose escalation portion of the trial is to evaluate the safety, tolerability, pharmacokinetics and preliminary anti-tumor activity of BDTX-4933.

Based on these results, we will determine potential next steps in the development of this product candidate.

Early-stage programs

We are applying our MAP drug discovery engine to the analysis of the mutation landscape of more than 300 genes, including 92 kinases within Foundation Medicine’s FoundationOne CDx test panel.

We are advancing several early programs focused on targeting a range of driver mutations, including activating mutations.

As part of our ongoing efforts to leverage our know-how regarding mutations in the ErbB family, we continue to investigate novel potent and selective compounds directed against this family of targets.

Oncogenic mutations affecting FGFR2 and FGFR3 (including short variant point mutations and fusions) are expressed across a range of cancers such as bladder and cholangiocarcinoma.

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These limitations curtail the efficacy of current-generation FGFR targeted therapies.

BDTX FGFR program compounds are MasterKey inhibitors of oncogenic FGFR2/3 mutations with selectivity versus FGFR1 and activity against gatekeeper mutations.

Tumor regression in mouse models has been observed.

We anticipate progressing towards selection of a development candidate for the BDTX FGFR program in 2023.

BDTX-4876 is a MasterKey inhibitor of oncogenic FGFR2/3 mutations with selectivity versus FGFR1/4.

In preclinical tumor models, dose dependent tumor regression was demonstrated, and bone growth was also observed in a preclinical model supporting the potential development of BDTX-4876 in musculoskeletal dysplasia.

We nominated BDTX-4876 as a development candidate in 2023 and are currently exploring potential partnerships for further development of this program.

Undisclosed program

We expect one other undisclosed program in solid tumors to progress to development candidate nomination in 2023.

In 2023 we also nominated a development candidate for a program with an undisclosed target in solid tumors, and are evaluating potential partnerships for further development of this program.

Our industry is intensely competitive and subject to rapid and significant technological change.

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We face competition with respect to our current product candidates and will face competition with respect to future product candidates, from segments of the pharmaceutical, biotechnology and other related markets that pursue targeted therapies for patients with genetically defined cancers.

There are currently compounds approved and in development which target the EGFR pathway and against which we expect BDTX-1535 to compete:

There are currently compounds approved and in development which target the EGFR pathway and against which we expect BDTX-1535 to compete, including for example:

• In patients with EGFR acquired resistance:

combination of amivantamab, or Rybrevant®, and lazertinib, the former of which is marketed by and the latter of which is being developed by Janssen Biotech, Inc.;

patritumab deruxtecan, which is being developed by Daiichi Sankyo Co.;

BLU-525 and BLU-945, which are under development by BluePrint Medicines Corporation;

and BBT-176, which is being developed by Bridge Biotherapeutics, Inc., and THE-349 under development by Theseus Pharmaceuticals, Inc.

• In patients with EGFR intrinsic resistance:

afatinib, or GILOTRIF, which is marketed by Boehringer Ingelheim and approved as first-line treatment of NSCLC patients with exon 18 mutations;

osimertinib, or TAGRISSO, which is marketed by AstraZeneca plc and is being prescribed off-label for NSCLC patients with exon 18 mutations;

and neratinib, which is marketed by Puma Biotechnology, Inc.

patritumab deruxtecan, which is being developed by Merck & Co., Inc., and Daiichi Sankyo Co.;

datopotamab deruxtecan, which is developed by AstraZeneca plc and Daiichi Sankyo Co.;

BBT-207, which is being developed by Bridge Biotherapeutics, Inc.;

and JIN-A02, which is under development by J Ints Bio.

• In patients with EGFR non-classical mutations:

afatinib, or Gilotrif® (Boehringer Ingelheim International GmbH) and approved as first-line treatment of NSCLC patients with S768I, L861Q, and/or G719X mutations;

osimertinib, or Tagrisso® (AstraZeneca plc) which may be prescribed off-label for NSCLC patients with exon 18 mutations;

and furmonertinib, which is under development by Arrivent Biopharma and Shanghai Allist Pharmaceuticals.

• In patients with EGFR alterations present in GBM:

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WSD-0922-FU, which is under development by Wayshine Biopharm International Ltd.;

CM93, which is under development by Crimson Biopharm Inc.;

RO7428731, which is under development by Hoffman Roche;

TAS-2940, which is under development by Taiho Oncology, Inc.;

and epitinib, which is under development by Hutchison MediPharma Ltd.

There are currently compounds in development which target the RAS-RAF pathway and against which we expect BDTX-4933 to compete:

and TAS-2940, which is under development by Taiho Oncology, Inc.

There are currently compounds in development by several companies targeting the RAS-RAF pathway and against which we expect BDTX-4933 to compete, including for example:

• In patients with BRAF Class II/III mutations and other RAS mutations:

Day One Biopharmaceuticals, Inc., Kinnate Biopharma Inc., Jazz Pharmaceuticals plc, F.

Hoffmann-La Roche AG, Erasca, Inc., Mirati Therapeutics, Inc., Boehringer Ingelheim Pharmaceuticals, Inc., Verastem, Inc., Revolution Medicines, Inc., Fore Biotherapeutics Inc., Nested Therapeutics Inc., and C4 Therapeutics, Inc.

In addition, there are other small molecule and precision oncology-focused companies with whom we may eventually compete, including Loxo Oncology, Inc.

(acquired by Eli Lilly and Company), SpringWorks Therapeutics, Inc., Centessa Pharmaceuticals plc, Voronoi Inc., Deciphera Pharmaceuticals, Inc., and Relay Therapeutics, Inc.

Day One Biopharmaceuticals, Inc.;

Jazz Pharmaceuticals plc;

Erasca, Inc.;

Mirati Therapeutics, Inc.;

Jiangsu Hengrui;

Revolution Medicines, Inc.;

Fore Biotherapeutics Inc.;

Incyte Corporation, and Astellas Pharmaceuticals.

In addition, there are other small molecule and precision oncology-focused companies with whom we may eventually compete, including Lilly Loxo Oncology;

Voronoi Inc.;

Deciphera Pharmaceuticals;

Verastem, Inc.;

Relay Therapeutics, Inc;

and Quanta Therapeutics.

Our competitors may obtain regulatory approval of their products more rapidly than we may or may obtain patent protection or other intellectual property rights that limit our ability to develop or commercialize our product candidates.

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Patent term may be inadequate to protect our competitive position on our products for an adequate amount of time.

As of February 23, 2023, we own seven U.S.

provisional patent applications, four pending U.S.

As of February 23, 2024, we own 14 U.S.

provisional patent applications, seven pending U.S.

patent applications, and one issued U.S.

We also own ten Patent Cooperation Treaty, or PCT, patent applications and 28 foreign patent applications.

We also own six Patent Cooperation Treaty, or PCT, patent applications and 45 foreign patent applications.

or foreign patent issuing from these patent applications would be scheduled to expire in 2039 to 2044, excluding any additional term for patent term adjustment or patent term extension, and assuming that conversions are timely made based upon U.S.

provisional patent applications, that national phase entries are timely made based upon the pending PCT applications, and the payment of all applicable maintenance or annuity fees.

As of February 23, 2023, we own one U.S.

patent application, and two PCT patent application, and 15 foreign patent applications that cover our non-small cell lung cancer and glioblastoma program, including the composition of matter for BDTX-1535, polymorphs of BDTX-1535, as well as methods of using and making BDTX-1535.

Below is an overview of patent applications covering BDTX-1535, BDTX-4933, our FGFR program and our MAP drug discovery engine.

As of February 23, 2024, we own eight U.S.

patent applications, and one PCT patent application, and 29 foreign patent applications that cover our non-small cell lung cancer and glioblastoma program, including the composition of matter for BDTX-1535, metabolites of BDTX-1535, formulation of BDTX-1535, polymorphs of BDTX-1535, as well as methods of using and making BDTX-1535.

or foreign patent issued from these pending applications would be scheduled to expire between 2040 and 2044, assuming that national phase entries are timely made based upon the pending PCT applications, excluding any additional term for patent term adjustment or patent term extension.

As of February 23, 2023, we own three U.S.

provisional patent applications, one PCT patent application, and one foreign patent application that cover our BRAF program, including the composition of matter for BDTX-4933 as well as methods of using and making BDTX-4933.

As of February 23, 2024, we own two U.S.

provisional patent applications, two PCT patent applications, and seven foreign patent applications that cover our BRAF program, including the composition of matter for BDTX-4933 as well as methods of using and making BDTX-4933.

or foreign patent issued from these pending applications would be scheduled to expire between 2042 and 2043, assuming that conversions are timely made based upon U.S.

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patent application, one U.S.

patent and 12 foreign patent applications that cover our tumor agnostic program, including the composition of matter for BDTX-189, polymorphs of BDTX-189, as well as methods of using and making BDTX-189.

or foreign patent issued from these pending applications would be scheduled to expire in 2039, excluding any additional term for patent term adjustment or patent term extension, assuming national phase entries are timely made based upon the pending PCT application and payment of all applicable maintenance or annuity fees.

As of February 23, 2023, we own one PCT patent application that covers our FGFR program, which is directed to the composition of matter for the compounds of the program, analogs thereof, as well as methods of using and making these compounds.

or foreign patent issued from this pending application would be scheduled to expire in 2042, assuming that conversions are timely made based upon U.S.

provisional patent application, and nine foreign patent applications that covers our FGFR program, which is directed to the composition of matter for the compounds of the program, analogs thereof, polymorphs of these compounds, as well as methods of using and making these compounds.

or foreign patent issued from this pending application would be scheduled to expire between 2042 and 2044, assuming that conversions are timely made based upon U.S.

provisional patent applications, that national phase entries are timely made based upon the pending PCT applications, excluding any additional term for patent term adjustment or patent term extension.

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Pediatric exclusivity, if granted, adds six months to existing exclusivity periods and patent terms.

This six-month exclusivity, which runs from the end of other exclusivity protection or patent term, may be granted based on the voluntary completion of a pediatric study in accordance with an FDA-issued “Written Request” for such a study, provided that at the time pediatric exclusivity is granted there is not less than nine months of term remaining.

post-approval requirements for drugs

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Unless an exemption or FDA exercise of enforcement discretion applies, diagnostic tests generally require marketing clearance or approval from the FDA prior to commercialization.

The two primary types of FDA marketing authorization applicable to a medical device are clearance of a premarket notification, or 510(k), application, and approval of a premarket approval, or PMA, application.

The primary types of FDA marketing authorization applicable to a medical device are clearance of a premarket notification, or 510(k), submission, approval of a premarket approval, or PMA, application, or grant of a de novo request for classification.

To obtain 510(k) clearance for a medical device, or for certain modifications to devices that have received 510(k) clearance, a manufacturer must submit a premarket notification demonstrating that the proposed device is substantially equivalent to a previously cleared 510(k) device or to a preamendment device that was in commercial distribution before May 28, 1976, or a predicate device, for which the FDA has not yet called for the submission of a PMA.

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The draft guidance describes principles to guide the development and contemporaneous marketing authorization for the therapeutic product and its corresponding in vitro companion diagnostic.

To date, the FDA has required premarket approval for nearly all companion diagnostics for cancer therapies.

In January 2024, FDA announced its intention to initiate the reclassification process for most in vitro diagnostics, including companion diagnostics.

Further, FDA indicated that in addition to the reclassification process, FDA will continue taking a risk-based approach in the initial classification of individual in vitro diagnostics to determine whether a new test may be classified into class II through the de novo classification process.

In so doing, FDA indicated that it may regulate most future companion diagnostics as class II devices.

Once cleared or approved, the companion diagnostic device must adhere to post-marketing requirements including the requirements of the FDA’s quality system regulation, adverse event reporting, recalls and corrections along with product marketing requirements and limitations.

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• created an annual, nondeductible fee on any entity that manufactures or imports specified branded prescription drugs and biologic products, apportioned among these entities according to their market share in certain government healthcare programs;

• expanded eligibility criteria for Medicaid programs by, among other things, allowing states to offer Medicaid coverage to certain individuals with income at or below 133% of the federal poverty level, thereby potentially increasing a manufacturer’s Medicaid rebate liability;

• expanded eligibility criteria for Medicaid programs, thereby potentially increasing a manufacturer’s Medicaid rebate liability;

• expanded manufacturers’ rebate liability under the Medicaid Drug Rebate Program by increasing the minimum rebate for both branded and generic drugs and revising the definition of “average manufacturer price,” or AMP, for calculating and reporting Medicaid drug rebates on outpatient prescription drug prices;

• addressed a new methodology by which rebates owed by manufacturers under the Medicaid Drug Rebate Program are calculated for drugs that are inhaled, infused, instilled, implanted or injected;

• expanded the types of entities eligible for the 340B drug discount program;

• established the Medicare Part D coverage gap discount program by requiring manufacturers to provide point-of-sale-discounts off the negotiated price of applicable brand drugs to eligible beneficiaries during their coverage gap period as a condition for the manufacturers’ outpatient drugs to be covered under Medicare Part D;

• created a new Patient-Centered Outcomes Research Institute to oversee, identify priorities in, and conduct comparative clinical effectiveness research, along with funding for such research.

Since its enactment, there have been judicial, Congressional and executive challenges to certain aspects of the ACA.

On June 17, 2021, the U.S.

Supreme Court dismissed the most recent judicial challenge to the ACA brought by several states without specifically ruling on the constitutionality of the ACA.

Prior to the Supreme Court’s decision, President Biden issued an executive order to initiate a special enrollment period from February 15, 2021 through August 15, 2021 for purposes of obtaining health insurance coverage through the ACA marketplace.

The executive order also instructed certain governmental agencies to review and reconsider their existing policies and rules that limit access to healthcare, including among others, reexamining Medicaid demonstration projects and waiver programs that include work requirements, and policies that create unnecessary barriers to obtaining access to health insurance coverage through Medicaid or the ACA.

It is unclear how other healthcare reform measures of the Biden administration or other efforts, if any, to challenge, repeal or replace the ACA will impact our business.

• created a Patient-Centered Outcomes Research Institute to oversee, identify priorities in, and conduct comparative clinical effectiveness research, along with funding for such research.

Other legislative changes have been proposed and adopted in the United States since the ACA was enacted:

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It is impossible to determine whether similar taxes could be instated in the future.

• On March 11, 2021, President Biden signed the American Rescue Plan Act of 2021 into law, which eliminates the statutory Medicaid drug rebate cap, currently set at 100% of a drug’s average manufacturer price, for single source and innovator multiple source drugs, beginning January 1, 2024.

Due to the Statutory Pay-As-You-Go Act of 2010, estimated budget deficit increases resulting from the American Rescue Plan Act of 2021, and subsequent legislation, Medicare payments to providers will be further reduced starting in 2025 absent further legislation.

• In August 2022, the Inflation Reduction Act of 2022, or IRA, was signed into law and includes several provisions that may impact our business to varying degrees, including provisions that reduce the out-of-pocket cap for Medicare Part D beneficiaries to $2,000 starting in 2025;

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The aforementioned EU rules are generally applicable in the European Economic Area, or EEA, which consists of the EU Member States, plus Norway, Liechtenstein and Iceland.

The collection and use of personal health data in the EEA, previously governed by the provisions of the Data Protection Directive, is now governed by the General Data Protection Regulation, or the GDPR, which became effective on May 25, 2018.

While the Data Protection Directive did not apply to organizations based outside the EEA, the GDPR has expanded its reach to include any business, regardless of its location, that provides goods or services to residents in the EU.

The collection and use of personal data in the EEA is governed by the General Data Protection Regulation, or the GDPR, which became effective on May 25, 2018.

The GDPR has extraterritorial application and applies to organizations based outside the EEA that provide goods or services to residents in the EU.

This expansion would incorporate any clinical trial activities in EU Members States.

The GDPR imposes strict requirements on controllers and processors of personal data, including special protections for “sensitive information” which includes health and genetic information of data subjects residing in the EEA.

GDPR grants individuals the opportunity to object to the processing of their personal information, allows them to request deletion of personal information in certain circumstances, and provides the individual with an express right to seek legal remedies in the event the individual believes his or her rights have been violated.

GDPR grants individuals a number of data protection rights which they can exercise in relation to their personal information.

Further, the GDPR enables individuals to claim damages for violations and introduces the right for non-profit organizations to bring claims on behalf of data subjects.

Further, the GDPR imposes strict rules on the transfer of personal data out of the EEA to the United States or other regions that have not been deemed to offer “adequate” privacy protections.

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The UK government has confirmed that personal data transfers from the UK to the EEA remain free flowing.

There is significant uncertainty related to the manner in which data protection authorities will seek to enforce compliance with GDPR.

There is uncertainty related to the manner in which data protection authorities will seek to enforce compliance with GDPR.

For example, it is not clear if the authorities will conduct random audits of companies doing business in the EEA, or if the authorities will wait for complaints to be filed by individuals who claim their rights have been violated.

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13 of our employees have Ph.D.

degrees, three have Pharm.D.

degrees, and two have M.D.

degrees, four have Pharm.D.

degrees, and three have M.D.

The following table shows the number of full-time employees as of February 15, 2024 engaged in either research and development or administrative functions.

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We consider our relationship with our employees to be good.

Black Diamond is committed to a culture of diversity, equity and inclusion.

This commitment is reflected in our corporate goals and underpins our social, cultural and philanthropic initiatives.

Black Diamond has adopted policies and initiatives that foster an inclusive work environment and diverse workforce.

Our commitment to inclusivity is reflected in our corporate goals and underpins our social, cultural and philanthropic initiatives.

We work collaboratively with external organizations to attract, retain and develop diverse talent by ensuring we have a culture of inclusivity for all.

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The lease expires on August 31, 2028, subject to an option to extend the lease for five additional years.

In December 2022 we entered into a sublease for one floor, approximately 14,439 square feet, of our Cambridge, MA office space, which also terminates on August 31, 2028.

We also lease approximately 18,120 square feet of office and laboratory space at 430 East 29th Street, New York, New York 10016.

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Our principal executive offices are located at One Main Street, Cambridge, MA 02142, and our telephone number is 617-252-0848.

We have two subsidiaries, Black Diamond Therapeutics (Canada) Inc., which was incorporated in 2018, and Black Diamond Therapeutics Security Corporation, which was incorporated in 2019.

As of December 31, 2023 we have one subsidiary, Black Diamond Therapeutics Security Corporation, which was incorporated in 2019.

Our second subsidiary, Black Diamond Therapeutics (Canada) Inc., which was incorporated in 2018, was dissolved in October 2023.

We are an “emerging growth company” as defined in the Jumpstart Our Business Startups Act of 2012.

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Compared sentence by sentence after normalising whitespace, quotation marks, case and digits, so re-formatting and restated figures do not read as changed language. Wording changes appear as one removal and one addition. The current filing and the prior one are authoritative.

What changed 10-K

Item 1. Business