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Item 1. Business

2025-03-06 compared with 2024-03-12 · 190 added, 229 removed, 647 unchanged (39% of the section changed)

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

We are a clinical-stage oncology company developing MasterKey therapies that target families of oncogenic mutations in patients with cancer.

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

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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.

Our lead clincal-stage program, BDTX-1535, a brain-penetrant, fourth-generation epidermal growth factor receptor (EGFR) MasterKey inhibitor, is currently being studied in a Phase 2 clinical trial in patients with epidermal growth factor receptor mutant (EGFRm) non-small cell lung cancer (NSCLC) and in an investigator-sponsored trial in patients with glioblastoma (GBM) with EGFR alterations.

We are actively evaluating partnership opportunities for a second clinical-stage program, 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 goal is to bring targeted oncology medicine to patients with genetically defined cancers who have limited treatment options.

Our drug development efforts leverage our novel findings that:

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• 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.

• 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.

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

identification of oncogenic mutations, 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.

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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.

Our pipeline includes two clinical-stage product candidates and one development-stage product candidate.

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

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.

We believe that BDTX-1535 has the potential to treat newly diagnosed patients with EGFRm NSCLC as well as those with recurrent disease, based upon BDTX-1535’s ability to address greater than 50 classical and non-classical oncogenic driver mutations with greater potency than other EGFR tyrosine kinase inhibitors (TKI’s), 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.

However, over time, almost all patients acquire resistance 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 resistance to treatment and a poor prognosis.

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

While the third-generation EGFR inhibitor osimertinib has been shown to exhibit some CNS penetration and delay the progression of CNS metastases, there are few options remaining to patients when resistance presents due to the acquired resistance mutation C797S or to “P-loop αC-helix compressing” mutations (PACC, a subset of non-classical mutations) that are insensitive to osimertinib.

BDTX-1535 has been observed to be highly brain-penetrant in preclinical tumor models and in the clinical setting.

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

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.

Food and Drug Administration (FDA) for the treatment of patients with EGFR mutant C797S-positive NSCLC whose disease has progressed on/after a third-generation EGFR TKI.

The increasing use of next-generation sequencing of newly diagnosed NSCLC tumors has revealed that 23-30% of EGFRm patients harbor one or more non-classical mutations.

Based upon real-world evidence gathered in collaboration with Guardant Health, these patients have significant unmet medical needs.

We presented real-world treatment outcomes for newly diagnosed NSCLC patients with non-classical EGFR mutations at the 2024 European Society for Medical Oncology (ESMO) Congress.

The analyses allowed association with real-world treatment practices and therapeutic outcomes.

The findings further demonstrated that current treatment practices for patients with non-classical mutations are heterogenous:

36% of patients received osimertinib or afatinib and 60% of patients received chemotherapy and/or immunotherapy.

Time to treatment discontinuation for patients with non-classical mutations was < 8 months, which is much shorter than the > 14 months observed for patients with a classical mutation who were receiving osimertinib.

Our preclinical data for BDTX-1535 showed greater potency against these non-classical mutations, including “P-loop αC-helix compressing” mutations (PACC), than currently available EGFR TKI’s that are used either off label or for a narrowly defined set of mutations in the first-line setting.

In the first quarter of 2024, we initiated a Phase 2 trial in newly-diagnosed patients with non-classical mutations.

Initial results from this trial in patients with newly-diagnosed EGFRm NSCLC are anticipated in the second quarter of 2025.

We have recently completed enrollment of BDTX-1535 in a Phase 2 clinical trial of 83 patients with EGFRm NSCLC in the second- and third-line settings.

In the third quarter of 2024, we announced initial data from this trial demonstrating encouraging clinical responses and durability of BDTX-1535 in patients with recurrent EGFRm NSCLC.

Based on pharmacokinetics, safety and tolerability data from the Phase 2 trial, the 200 mg daily dose of BDTX-1535 was selected for pivotal development, showing robust EGFRm target coverage and a favorable tolerability profile with no new safety signals observed.

The majority of adverse events were mild or moderate, and no new safety signals were observed.

The most common on-target treatment-related adverse events were rash (70%) and diarrhea (35%).

There were two cases of grade 3 rash, and no reported cases of grade 4 rash or grade 3/4 diarrhea.

Based on an August 2024 data cutoff, a preliminary overall response rate (ORR) of 42% was seen in 19 patients with known osimertinib resistance EGFR mutations (PACC “P-loop αC-helix compressing” and C797S mutations).

Acquisition of C797S was frequently observed in patients who progressed following treatment with osimertinib.

PACC mutations represent a structure-function group of non-classical oncogenic driver mutations which may accumulate or be acquired following treatment with osimertinib.

Encouraging durability was noted with a duration of response (DOR) of approximately eight months or more in the first three patients who achieved a partial response (PR), while 14 of the 19 patients remained on treatment.

We expect to present updated results from this trial in the second half of 2025.

In the second quarter of 2024, at the American Society of Clinical Oncology (ASCO) Annual Meeting, we presented preliminary results from the Phase 1 trial of BDTX-1535 in patients with relapsed/recurrent GBM, demonstrating encouraging duration of treatment and clinical activity, and a tolerability profile consistent with the initial safety data from the dose escalation portion of the Phase 1 trial.

Our collaborators at the Ivy Brain Tumor Center also presented initial intratumoral pharmacokinetic data from a “window of opportunity” study in patients with recurrent high-grade glioma (HGG) with EGFR alterations and/or fusions at initial diagnosis.

This study, also known as a Phase 0/1 “Trigger” trial, is sponsored by the Ivy Brain Tumor Center in Phoenix, Arizona.

Initial results from this investigator-sponsored trial demonstrated that BDTX-1535 exceeded the pre-specified threshold for drug concentration in the brain tumor tissue and was generally well tolerated.

In the fourth quarter of 2024, at the European Association of Neuro-Oncology (EANO) Annual Meeting and the Society of Neuro-Oncology (SNO) Annual Meeting, the Ivy Brain Tumor Center presented additional promising data from the trial which demonstrated that BDTX-1535 penetrates rarely accessible regions of glioblastoma and suppresses EGFR signaling in patient tumors.

The study, sponsored by the Ivy Brain Tumor Center, is expected to expand into a “Phase 0/2” trial in newly diagnosed glioblastoma patients with EGFR alterations in the first quarter of 2025.

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 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.

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.

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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.

In the fourth quarter of 2024, we announced we are deprioritizing BDTX-4933 and actively seeking partnerships for this asset, as we focus our resources on our lead program, BDTX-1535.

Early-stage programs

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.

We are exploring partnership opportunities for our FGFR2/3 selective development candidate BDTX-4876.

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.

We are advancing compounds that have been discovered through improved understanding of mutant protein conformations to (i) identify novel oncogenic driver mutations and (ii) 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:

• 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.

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

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, offers significant potential to treat patients with EGFRm NSCLC.

Based on initial clinical data from newly diagnosed patients anticipated in the second quarter of 2025, we plan to seek regulatory feedback on a potential registrational path for BDTX-1535 in first-line EGFRm NSCLC patients with non-classical mutations in the second half of 2025.

We also expect to complete the evaluation of BDTX-1535 in patients with recurrent EGFRm NSCLC and explore potential combination opportunities to maximize the therapeutic potential of BDTX-1535 in the recurrent setting.

• Generate clinical data for BDTX-1535 in first-line patients with EGFR altered GBM to support a potential pivotal study.

Based on results from the Phase 0/2 “window of opportunity” trial for BDTX-1535 in newly diagnosed patients with GBM with EGFR alterations anticipated to start in the first quarter of 2025, we anticipate planning for a potential pivotal trial of BDTX-1535 as a first-line treatment in that setting.

• Evaluate potential strategic partnerships to maximize the value of our pipeline and to provide non-dilutive funding for the further development of BDTX-1535.

We are actively evaluating potential partnership opportunities for BDTX-4933, our Phase 1 clinical program targeting KRAS, NRAS and BRAF alterations.

We are also exploring potential partnership opportunities and strategic alternatives for our FGFR program, BDTX-4876.

Our history and team

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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.

Mark 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 its first therapy from investigational new drug (IND) filing to FDA approval.

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

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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.

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

and Erika Jones, our Senior Vice President of Finance and Principal Financial and Accounting Officer, previously served as the Director of Finance at Axcella Health Inc.

Our product candidates and development programs

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

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

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

Background and limitations of current EGFR inhibitors

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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 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.

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 resistance mutation C797S, against which osimertinib is inactive.

Additionally, a subset 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.

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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.

This includes classical, non-classical, acquired resistance, 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.

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.

Clinical development

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.

The Phase 1 dose escalation part of this trial enrolled patients harboring EGFR oncogenic alterations both in NSCLC and GBM and was completed in 2023.

Clinical data from the dose escalation portion of the trial demonstrated promising clinical activity and a favorable tolerability profile for BDTX-1535 in the recurrent setting.

In the third quarter of 2023, we began the BDTX-1535 Phase 2 NSCLC clinical trial to assess ORR by RECIST 1.1 and DOR in patients with NSCLC in two initial cohorts:

one cohort with the EGFR acquired resistance C797S mutation after progression on a third-generation EGFR TKI, and the other cohort in non-classical driver mutations (NCMs) after progression on an EGFR TKI, in each case with and without brain metastases.

In September 2024, we announced initial data from the Phase 2 trial demonstrating encouraging clinical responses and durability of BDTX-1535 in the second- and third-line settings.

The majority of adverse events were mild or moderate, and no new safety signals were observed.

The most common on-target treatment-related adverse events were rash (70%) and diarrhea (35%).

There were two cases of grade 3 rash, and no reported cases of grade 4 rash or grade 3/4 diarrhea.

Based on an August 2024 data cutoff, a preliminary ORR of 42% was seen in 19 patients with known osimertinib resistance EGFR mutations (PACC “P-loop αC-helix compressing” and C797S mutations).

Acquisition of C797S was frequently observed in patients who progressed following treatment with osimertinib.

PACC mutations represent a structure-function group of non-classical oncogenic driver mutations which may accumulate or be acquired following treatment with osimertinib.

Encouraging durability was noted with a DOR of approximately eight months or more in the first three patients who achieved a PR, while 14 of the 19 patients remained on treatment as of the cut-off date.

Data from September 23, 2024 disclosure;

*Retrospective liquid and tissue biopsy NGS testing;

Pt 2118 withdrew consent prior to first scan (see patient in swimmer plot);

O-osimertinib;

C- carboplatin, Cis – cisplatin, Pem- pemetrexed;

Pac- paclitaxel;

B- bevacizumab;

HER3-Dxd- patritumab deruxtecan;

Data from September 23, 2024 disclosure;

N=19 in swimmer plot, including Pt 2118 who withdrew consent (WC) prior to first scan *Patient discontinued (pneumonitis)

We have recently completed enrollment of BDTX-1535 in 83 patients with recurrent EGFRm NSCLC, and expect to present updated results in the second half of 2025.

We are also exploring potential combination opportunities for BDTX-1535 in the recurrent setting.

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

The cohort can enroll up to 40 patients at a 200 mg dose.

Initial results from the first-line cohort are anticipated in the second quarter of 2025.

We intend to meet with FDA as results become available from the Phase 2 first-line cohort in patients with NSCLC to discuss a potential registrational path.

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

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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.

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.

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.

In the fourth quarter of 2023, we announced dose escalation results in 22 patients with GBM 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.

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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.

In the second quarter of 2024, at the ASCO Annual Meeting, we presented preliminary data from the Phase 1 trial of BDTX-1535 in patients with relapsed/recurrent GBM, demonstrating encouraging duration of treatment and clinical activity, and a tolerability profile consistent with the initial safety data from the dose escalation portion of the Phase 1 trial presented in 2023.

Also, in the second quarter of 2024, initial results were presented at the ASCO Annual Meeting from an investigator (Ivy Brain Tumor Center) sponsored “window of opportunity” trial of BDTX-1535 in patients with recurrent high-grade glioma with EGFR alterations and/or fusions at initial diagnosis and who underwent surgical intracranial tumor resection.

The data presented demonstrated that BDTX-1535 exceeded the pre-specified threshold for drug concentration in the brain tumor tissue and was generally well tolerated with expected EGFR-mediated side effects.

Additional promising results from this trial were presented by the investigator at the EANO and SNO meetings in the fourth quarter of 2024.

The data demonstrated that BDTX-1535 penetrates rarely accessible regions of glioblastoma and suppresses EGFR signaling in patient tumors.

In the first quarter of 2025, the program is expected to expand into a Phase 0/2 “window of opportunity” trial in newly diagnosed glioblastoma patients with EGFR aberrations.

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

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

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.

In the fourth quarter of 2023, we presented mechanism of action data for BDTX-4933 at the European Organization for Research and Treatment of Cancer-National Cancer Institute-American Association for Cancer Research (EORTC-NCI-AACR) Symposium on Molecular Targeted 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.

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Clinical development

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

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.

The IND for BDTX-4933 was cleared by the FDA in the first quarter of 2023 and, in the second quarter of 2023, we initiated a Phase 1 clinical trial for BDTX-4933 to evaluate the safety, tolerability, pharmacokinetics and preliminary anti-tumor activity of BDTX-4933 in RAF/RAS-mutant solid tumors.

In the fourth quarter of 2024, we announced that we are deprioritizing BDTX-4933 and would seek partnerships to focus resources on our lead program, BDTX-1535.

Early-stage programs

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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

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.

We are currently exploring 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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As a result, our competitors may discover, develop, license or commercialize products before or more successfully than we do.

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, including for example:

We face competition with respect to our current product candidate and will face competition with respect to our 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, including:

• 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 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.;

combination of amivantamab, or Rybrevant, and lazertinib, or Lazcluze, which is marketed by Janssen Biotech, Inc.;

patritumab deruxtecan, which is under development by Merck and Daiichi Sankyo Co.;

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

ivonescimab, which is under development by Summit Therapeutics and Akeso;

TAS3351, which is under development by Taiho Oncology;

BBT-207, which is under development 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.

afatinib, or Gilotrif, which is marketed by Boehringer Ingelheim and approved as first-line treatment of NSCLC patients with S768I, L861Q, and/or G719X mutations;

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

Furmonertinb, which is under development by Arrivent Biopharma and Shanghai Allist Pharmaceuticals;

and ORIC-114, which is under development by ORIC Pharmaceuticals.

• In patients with EGFR alterations present in GBM:

ERAS-801, which is under development by Erasca, Inc.;

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

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.;

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;

Deciphera Pharmaceuticals, Inc.

(acquired by Ono Pharmaceutical Co., Ltd.);

Verastem, Inc.;

Relay Therapeutics, Inc.;

and Quanta Therapeutics.

Taiho Oncology, Inc.;

and Incyte Corp.

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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The chemistry appears amenable to scale up and does not currently require unusual equipment in the manufacturing process.

We expect to continue to develop product candidates that can be produced cost-effectively at third-party contract manufacturing organizations, or CMOs.

We expect to continue to develop product candidates that can be produced cost-effectively at third-party contract manufacturing organizations (CMOs).

We generally expect to rely on one or more potential partners for the manufacture of companion diagnostics for our products, which are assays or tests to identify an appropriate patient population.

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For example, we cannot be certain of the priority of inventions covered by pending third-party patent applications.

If third parties prepare and file patent applications in the United States that also claim technology or therapeutics to which we have rights, we may have to participate in interference proceedings in the USPTO to determine priority of invention, which could result in substantial costs to us, even if the eventual outcome is favorable to us, which is highly unpredictable.

Patent and Trademark Office (USPTO) to determine priority of invention, which could result in substantial costs to us, even if the eventual outcome is favorable to us, which is highly unpredictable.

In addition, because of the extensive time required for clinical development and regulatory review of a product candidate we may develop, it is possible that, before any of our product candidates can be commercialized, any related patent may expire or remain in force for only a short period following commercialization, thereby limiting the protection such patent would afford the respective product and any competitive advantage such patent may provide.

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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, 2024, we own 14 U.S.

provisional patent applications, seven pending U.S.

As of February 28, 2025, we own ten U.S.

provisional patent applications, six U.S.

patent applications, and one issued U.S.

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

We also own seven Patent Cooperation Treaty (PCT) patent applications, 71 foreign patent applications, and two issued foreign patent.

or foreign patent issuing from these patent applications would be scheduled to expire in 2039 to 2045, 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.

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, 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.

Below is an overview of patent applications covering BDTX-1535, BDTX-4933, BDTX-4876, and our MAP drug discovery engine.

As of February 28, 2025, we own seven U.S.

provisional patent applications, three U.S.

patent applications, five PCT patent applications, 45 foreign patent applications, and two issued foreign patents 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 2045, 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.

As of February 23, 2024, we own one pending U.S.

patent application, one 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, and 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 28, 2025, we own six U.S.

provisional patent applications, one U.S.

patent application, one PCT patent application, and 16 foreign patent applications that cover our BRAF program, including the composition of matter for BDTX-4933, polymorphs of BDTX-4933, formulations of 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 2045, assuming that conversions are timely made based upon U.S.

As of February 28, 2025, we own one U.S.

patent application, one PCT patent application, and ten foreign patent applications that cover our FGFR program, including the composition of matter for BDTX-4876, polymorphs of BDTX-4876, as well as methods of using and making BDTX-4876.

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

MAP drug discovery engine

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If we do not timely file non-provisional patent applications, we may lose our priority date with respect to our provisional patent applications and any patent protection on the inventions disclosed in our provisional patent applications.

While we intend to timely file non-provisional and national stage patent applications relating to our provisional and PCT patent applications, we cannot predict whether any of our future patent applications for BDTX-1535, BDTX-4933 or any of our other product candidates or technology will result in the issuance of patents that effectively protect BDTX-1535, BDTX-4933 or our other product candidates or technology.

If we do not successfully obtain patent protection, or, even if we do obtain patent protection, if the scope of the patent protection we or our potential licensors obtain with respect to BDTX-1535, BDTX-4933 or our other product candidates or technology is not sufficiently broad, we will be unable to prevent others from using our technology or from developing or commercializing technology and products similar or identical to ours or other competing products and technologies.

While we intend to timely file non-provisional and national stage patent applications relating to our provisional and PCT patent applications, we cannot predict whether any of our future patent applications for BDTX-1535, BDTX-4933, BDTX-4876, or any of our other product candidates or technology will result in the issuance of patents that effectively protect BDTX-1535, BDTX-4933, BDTX-4876, or our other product candidates or technology.

If we do not successfully obtain patent protection, or, even if we do obtain patent protection, if the scope of the patent protection we or our potential licensors obtain with respect to BDTX-1535, BDTX-4933, BDTX-4876, or our other product candidates or technology is not sufficiently broad, we will be unable to prevent others from using our technology or from developing or commercializing technology and products similar or identical to ours or other competing products and technologies.

For more information regarding the risks related to our intellectual property, please see “Risk Factors—Risks Related to our Intellectual Property.”

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Government regulation

The FDA and other regulatory authorities at federal, state and local levels, as well as in foreign countries, including the European Union, extensively regulate, among other things, the research, development, testing, manufacture, quality control, import, export, safety, effectiveness, labeling, packaging, storage, distribution, record keeping, approval, advertising, promotion, marketing, post-approval monitoring and post-approval reporting of drugs.

The FDA and other regulatory authorities at federal, state and local levels, as well as in foreign countries, including the European Union (EU), extensively regulate, among other things, the research, development, testing, manufacture, quality control, import, export, safety, effectiveness, labeling, packaging, storage, distribution, record keeping, approval, advertising, promotion, marketing, post-approval monitoring and post-approval reporting of drugs.

We, along with our vendors, contract research organizations and contract manufacturers, will be required to navigate the various preclinical, clinical, manufacturing and commercial approval requirements of the governing regulatory agencies of the countries in which we wish to conduct studies or seek approval of our product candidates.

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• submission to the FDA of an IND application, which must become effective before clinical trials may begin;

• approval by an Institutional Review Board, or IRB, or independent ethics committee at each clinical trial site before each trial may be initiated;

• performance of adequate and well-controlled clinical trials in accordance with applicable IND regulations, good clinical practice, or GCP, requirements and other clinical trial-related regulations to establish the safety and efficacy of the investigational product for each proposed indication;

• submission to the FDA of a New Drug Application, or NDA;

• approval by an Institutional Review Board (IRB) or independent ethics committee at each clinical trial site before each trial may be initiated;

• performance of adequate and well-controlled clinical trials in accordance with applicable IND regulations, good clinical practice (GCP) requirements and other clinical trial-related regulations to establish the safety and efficacy of the investigational product for each proposed indication;

• submission to the FDA of a New Drug Application (NDA);

• a determination by the FDA within 60 days of its receipt of an NDA, to accept the filing for review;

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Under the FD&C Act, the FDA incentivizes the development of drugs that meet the definition of a “rare pediatric disease,” defined to mean a serious or life-threatening disease in which the serious of life-threatening manifestations primarily affect individuals aged from birth to 18 years and the disease affects fewer than 200,000 individuals in the United States or affects more than 200,000 in the United States and for which there is no reasonable expectation that the cost of developing and making in the United States a drug for such disease or condition will be received from sales in the United States of such drug.

The sponsor of a product candidate for a rare pediatric disease may be eligible for a voucher that can be used to obtain a priority review for a subsequent human drug application after the date of approval of the rare pediatric disease drug product, referred to as a priority review voucher, or PRV.

A sponsor may request rare pediatric disease designation from the FDA prior to the submission of its NDA.

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If a PRV is received, it may be sold or transferred an unlimited number of times.

Congress has extended the PRV program through September 30, 2024, with potential for PRVs to be granted through September 30, 2026.

The FDA’s rare pediatric disease priority voucher program began to sunset on December 20, 2024, on failure to pass a continuing resolution package that included its reauthorization.

Under the amended statutory sunset provisions, after December 20, 2024, the FDA may award a priority review voucher for an approved rare pediatric disease product application only if the sponsor has rare pediatric disease designation for the drug and if that designation was granted by December 20, 2024.

After September 30, 2026, the FDA may not award any rare pediatric disease priority review vouchers.

Congress may vote to reauthorize this program, but its future remains unknown at this time.

Expedited development and review programs for drugs

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Pediatric information and pediatric exclusivity

Under the Pediatric Research Equity Act, or PREA, certain NDAs and certain supplements to an NDA must contain data to assess the safety and efficacy of the drug for the claimed indications in all relevant pediatric subpopulations and to support dosing and administration for each pediatric subpopulation for which the product is safe and effective.

Under the Pediatric Research Equity Act (PREA), certain NDAs and certain supplements to an NDA must contain data to assess the safety and efficacy of the drug for the claimed indications in all relevant pediatric subpopulations and to support dosing and administration for each pediatric subpopulation for which the product is safe and effective.

The FDA may grant deferrals for submission of pediatric data or full or partial waivers.

The Food and Drug Administration Safety and Innovation Act, or FDASIA, amended the FD&C Act to require that a sponsor who is planning to submit a marketing application for a drug that includes a new active ingredient, new indication, new dosage form, new dosing regimen or new route of administration submit an initial Pediatric Study Plan, or PSP, within 60 days of an end-of-Phase 2 meeting or, if there is no such meeting, as early as practicable before the initiation of the Phase 3 or Phase 2/3 study.

The Food and Drug Administration Safety and Innovation Act (FDASIA) amended the FD&C Act to require that a sponsor who is planning to submit a marketing application for a drug that includes a new active ingredient, new indication, new dosage form, new dosing regimen or new route of administration submit an initial Pediatric Study Plan (PSP) within 60 days of an end-of-Phase 2 meeting or, if there is no such meeting, as early as practicable before the initiation of the Phase 3 or Phase 2/3 study.

The initial PSP must include an outline of the pediatric study or studies that the sponsor plans to conduct, including study objectives and design, age groups, relevant endpoints and statistical approach, or a justification for not including such detailed information, and any request for a deferral of pediatric assessments or a full or partial waiver of the requirement to provide data from pediatric studies along with supporting information.

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Finally, there are state and foreign laws governing the privacy and security of health information, many of which differ from each other in significant ways and often are not preempted by HIPAA, thus complicating compliance efforts.

The provision of benefits or advantages to physicians to induce or encourage the prescription, recommendation, endorsement, purchase, supply, order or use of medicinal products is prohibited in the EU.

The provision of benefits or advantages to physicians is also governed by the national anti-bribery laws of EU Member States, such as the UK Bribery Act 2010.

Violation of these laws could result in substantial fines and imprisonment.

Payments made to physicians in certain EU Member States must be publicly disclosed.

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Even if favorable coverage and reimbursement status is attained for one or more products for which a company or its collaborators receive regulatory approval, less favorable coverage policies and reimbursement rates may be implemented in the future.

Further, due to the ongoing COVID-19 pandemic, millions of individuals have lost or will be losing employer-based insurance coverage, which may adversely affect our ability to commercialize our products.

Current and future healthcare reform legislation

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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;

• On March 11, 2021, President Biden signed the American Rescue Plan Act of 2021 into law.

In addition to provider payment cuts under Medicare, the American Rescue Plan Act of 2021 also eliminated the statutory Medicaid drug rebate cap, previously set at 100% of a drug’s average manufacturer price, for single source and innovator multiple source drugs, beginning January 1, 2024.

These laws and regulations may result in additional reductions in Medicare and other healthcare funding available for healthcare providers and may otherwise affect the prices we may obtain for any of our product candidates for which we may obtain regulatory approval or the frequency with which any such product candidate is prescribed or used.

• In August 2022, the Inflation Reduction Act of 2022 (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 which began in 2025;

impose new manufacturer financial liability on certain drugs under Medicare Part D;

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Congressional inquiries and proposed and enacted federal and state legislation designed to, among other things, bring more transparency to drug pricing, reduce the cost of prescription drugs under Medicare, and review the relationship between pricing and manufacturer patient programs.

At the federal level, President Biden signed an Executive Order on July 9, 2021 affirming the administration’s policy to (i) support legislative reforms that would lower the prices of prescription drug and biologics, including by allowing Medicare to negotiate drug prices, by imposing inflation caps, and, by supporting the development and market entry of lower-cost generic drugs and biosimilars;

and (ii) support the enactment of a public health insurance option.

Among other things, the Executive Order also directs HHS to provide a report on actions to combat excessive pricing of prescription drugs, enhance the domestic drug supply chain, reduce the price that the Federal government pays for drugs, and address price gouging in the industry;

and directs the FDA to work with states and Indian Tribes that propose to develop section 804 Importation Programs in accordance with the Medicare Prescription Drug, Improvement, and Modernization Act of 2003, and the FDA’s implementing regulations.

FDA released such implementing regulations on September 24, 2020, which went into effect on November 30, 2020, providing guidance for states to build and submit importation plans for drugs from Canada.

On September 25, 2020, CMS stated drugs imported by states under this rule will not be eligible for federal rebates under Section 1927 of the Social Security Act and manufacturers would not report these drugs for “best price” or Average Manufacturer Price purposes.

Since these drugs are not considered covered outpatient drugs, CMS further stated it will not publish a National Average Drug Acquisition Cost for these drugs.

If implemented, importation of drugs from Canada may materially and adversely affect the price we receive for any of our product candidates.

At a federal level, President Trump reversed some of President Biden’s executive orders including rescinding Executive Order 14087 entitled “Lowering Prescription Drug Costs for Americans.” President Trump may issue new executive orders designed to impact drug pricing.

A number of these and other proposed measures may require authorization through additional legislation to become effective.

Congress and the Trump administration have indicated that they will continue to seek new legislative measures to control drug costs.

On November 30, 2020, HHS published a regulation removing safe harbor protection for price reductions from pharmaceutical manufacturers to plan sponsors under Part D, either directly or through pharmacy benefit managers, unless the price reduction is required by law.

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The IRA further extended the delay in implementing this rule under 2032.

Although a number of these and other proposed measures may require authorization through additional legislation to become effective, and the Biden administration may reverse or otherwise change these measures, both the Biden administration and Congress have indicated that they will continue to seek new legislative measures to control drug costs.

Outside the United States, ensuring coverage and adequate payment for a product also involves challenges.

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Increased tariffs could potentially disrupt our existing supply chains and impose additional costs on our business.

Additionally, it is possible further tariffs may be imposed that could affect imports of active pharmaceutical ingredients, or APIs, used in our product candidates, or our business may be adversely impacted by retaliatory trade measures taken by China or other countries, including restricted access to such raw materials used in our product candidates.

Additionally, it is possible further tariffs may be imposed that could affect imports of active pharmaceutical ingredients (APIs) used in our product candidates, or our business may be adversely impacted by retaliatory trade measures taken by China or other countries, including restricted access to such raw materials used in our product candidates.

Given the unpredictable regulatory environment in China and the U.S.

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EU Member States may approve a specific price for a product or it may instead adopt a system of direct or indirect controls on the profitability of the company placing the product on the market.

Other Member States allow companies to fix their own prices for products, but monitor and control prescription volumes and issue guidance to physicians to limit prescriptions.

Other EU Member States allow companies to fix their own prices for products, but monitor and control prescription volumes and issue guidance to physicians to limit prescriptions.

Recently, many countries in the EU have increased the amount of discounts required on pharmaceuticals and these efforts could continue as countries attempt to manage healthcare expenditures, especially in light of the severe fiscal and debt crises experienced by many countries in the EU.

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For instance, in the EU, medicinal products are subject to extensive pre- and post-market regulation by regulatory authorities at both the EU and national levels.

• Centralized procedure —If pursuing marketing authorization of a product candidate for a therapeutic indication under the centralized procedure, following the opining of the European Medicines Agency’s, or EMA, Committee for Medicinal Products for Human Use, or CHMP, the European Commission issues a single marketing authorization valid across the EU, and in the additional Member States of the European Economic Area (Iceland, Liechtenstein and Norway).

• Centralized procedure —If pursuing marketing authorization of a product candidate for a therapeutic indication under the centralized procedure, following the opinion of the European Medicines Agency’s, (EMA), Committee for Medicinal Products for Human Use (CHMP), the European Commission issues a single marketing authorization valid across the EU, and in the additional countries of the European Economic Area (Iceland, Liechtenstein and Norway).

The centralized procedure is compulsory for human medicines derived from biotechnology processes or advanced therapy medicinal products (such as gene therapy, somatic cell therapy and tissue engineered products), products that contain a new active substance indicated for the treatment of certain diseases, such as HIV, AIDS, cancer, neurodegenerative disorders, diabetes, autoimmune diseases and other immune dysfunctions, viral diseases, and designated orphan medicines.

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Under the above described procedures, before granting the marketing authorization, the EMA or the competent authorities of the Member States of the EU make an assessment of the risk-benefit balance of the product on the basis of scientific criteria concerning its quality, safety and efficacy.

Now that the United Kingdom (which comprises Great Britain and Northern Ireland) has left the European Union, Great Britain will no longer be covered by centralized marketing authorizations (under the Northern Ireland Protocol, centralized marketing authorizations will continue to be recognized in Northern Ireland).

All medicinal products with a current centralized marketing authorization were automatically converted to Great Britain marketing authorizations on January 1, 2021.

For a period of two years from January 1, 2021, the Medicines and Healthcare products Regulatory Agency, or MHRA, the UK medicines regulator, may rely on a decision taken by the European Commission on the approval of a new marketing authorization in the centralized procedure, in order to more quickly grant a new Great Britain marketing authorization.

A separate application will, however, still be required.

The MHRA also has the power to have regard to marketing authorizations approved in EU Member States through decentralized or mutual recognition procedures with a view to more quickly granting a marketing authorization in the United Kingdom or Great Britain.

In the EU, new products for therapeutic indications that are authorized for marketing (i.e., reference products) qualify for eight years of data exclusivity and an additional two years of market exclusivity upon marketing authorization.

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Otherwise, orphan medicine marketing exclusivity may be revoked only in very select cases, such as if (i) it is established that a similar medicinal product is safer, more effective or otherwise clinically superior to the authorized product;

(ii) the marketing authorization holder of the authorized orphan product consents to a second orphan medicinal product application;

(ii) the marketing authorization holder of the authorized orphan product consents to a second product application;

or (iii) the marketing authorization holder of the authorized orphan product cannot supply enough orphan medicinal product.

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Orphan designation does not convey any advantage in, or shorten the duration of, the regulatory review and approval process.

Since January 1, 2021, a separate process for orphan designation has applied in Great Britain.

There is now no pre-marketing authorization orphan designation (as there is in the EU) in Great Britain and the application for orphan designation will be reviewed by the MHRA at the time of an MAA for a UK or Great Britain marketing authorization.

The criteria for orphan designation are the same as in the EU, save that they apply to Great Britain only (e.g.

there must be no satisfactory method of diagnosis, prevention or treatment of the condition concerned in Great Britain, as opposed to the EU, and the prevalence of the relevant condition must not be more than 5 in 10,000 in Great Britain).

In May 2017, the EU adopted the Regulation (EU) 2017/746 on in vitro diagnostic medical devices, or IVDR, which will become applicable on 26 May 2022 and will repeal Directive 98/79/EC on in vitro diagnostic medical devices.

In May 2017, the EU adopted the Regulation (EU) 2017/746 on in vitro diagnostic medical devices, or IVDR, which became applicable on 26 May 2022 and repealed Directive 98/79/EC on in vitro diagnostic medical devices.

Devices that comply with the requirements of the IVDR will be entitled to bear the CE conformity marking, indicating that the device conforms to the general safety and performance requirements of the IVDR, and, accordingly, can be commercially distributed throughout the EU (in-vitro diagnostic medical devices cannot be marketed in the EU without a CE Mark).

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Similar to the United States, the various phases of non-clinical and clinical research in the EU are subject to significant regulatory controls.

In April 2014, the new Clinical Trials Regulation, (EU) No 536/2014 (Clinical Trials Regulation) was adopted, which replaced the Clinical Trials Directive 2011/20/EC on January 31, 2022.

In April 2014, new Clinical Trials Regulation, (EU) No 536/2014 (Clinical Trials Regulation) was adopted, which replaced the Clinical Trials Directive 2001/20/EC on January 31, 2022.

The Clinical Trials Regulation is directly applicable in all the EU Member States, meaning no national implementing legislation is required.

The transitory provisions of the new Regulation offer sponsors the possibility to choose between the requirements of the previous Directive and the new Regulation if the request for authorization of a clinical trial is submitted in the year after the new Regulation became applicable.

If a clinical trial continues for more than three years from the day on which the Clinical Trials Regulation became applicable the Clinical Trials Regulation will at that time begin to apply to the clinical trial.

The new Clinical Trials Regulation aims to simplify and streamline the approval of clinical trials in the EU.

The Clinical Trials Regulation aims to simplify and streamline the approval of clinical trials in the EU.

The main characteristics of the regulation include:

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However, overall related timelines will be defined by the Clinical Trials Regulation.

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 data in the EEA is governed by the General Data Protection Regulation, or the GDPR, which became effective on May 25, 2018.

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

The collection and use of personal data in the EEA is governed by the General Data Protection Regulation (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.

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As a result of the implementation of the GDPR, we may be required to put in place additional mechanisms ensuring compliance with the new data protection rules.

In addition, further to the UK’s exit from the EU on January 31, 2020, the GDPR ceased to apply in the UK at the end of the transition period on December 31, 2020.

However, as of January 1, 2021, the UK’s European Union (Withdrawal) Act 2018 incorporated the GDPR (as it existed on December 31, 2020 but subject to certain UK specific amendments) into UK law, referred to as the UK GDPR.

In addition, further to the United Kingdom (UK)’s exit from the EU on January 31, 2020, the GDPR ceased to apply in the UK at the end of the transition period on December 31, 2020.

However, as of January 1, 2021, the UK’s EU (Withdrawal) Act 2018 incorporated the GDPR (as it existed on December 31, 2020 but subject to certain UK specific amendments) into UK law, referred to as the UK GDPR.

The UK GDPR and the UK Data Protection Act 2018 set out the UK’s data protection regime, which is independent from but aligned to the EU’s data protection regime.

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Brexit and the Regulatory Framework in the United Kingdom

On June 23, 2016, the electorate in the United Kingdom voted in favor of leaving the European Union (commonly referred to as “Brexit”).

The United Kingdom formally left the European Union on January 31, 2020.

There was an initial transitional period, during which European Union’s rules continued to apply in the United Kingdom, which ended on December 31, 2020.

The United Kingdom and European Union have signed a European Union-United Kingdom Trade and Cooperation Agreement, or the TCA, which was provisionally applicable since January 1, 2021 and has been formally applicable since May 1, 2021.

The TCA includes specific provisions concerning pharmaceuticals, which include the mutual recognition of GMP, inspections of manufacturing facilities for medicinal products and GMP documents issued, but does not foresee wholesale mutual recognition of UK and EU pharmaceutical regulations.

At present, Great Britain has implemented EU legislation on the marketing, promotion and sale of medicinal products through the Human Medicines Regulations 2012 (as amended) (under the Northern Ireland Protocol, the EU regulatory framework will continue to apply in Northern Ireland).

The regulatory regime in Great Britain therefore largely aligns with current EU regulations, however it is possible that these regimes will diverge in the future now that Great Britain’s regulatory system is independent from the EU and the TCA does not provide for mutual recognition of UK and EU pharmaceutical legislation.

The UK formally left the EU on January 31, 2020.

As a result of the Northern Ireland protocol, following Brexit, the EMA remained responsible for approving novel medicines for supply in Northern Ireland under the EU centralized procedure, and a separate authorization was required to supply the same medicine in Great Britain (England, Wales and Scotland).

On February 27, 2023, the UK government and the EC announced a political agreement in principle to replace the Northern Ireland Protocol with a new set of arrangements, known as the “Windsor Framework”.

The Windsor Framework was approved by the EU-UK Joint Committee on March 24, 2023, and the medicines aspects of the Windsor Framework have applied since January 1, 2025.

This new framework fundamentally changes the previous system under the Northern Ireland Protocol, including with respect to the regulation of medicinal products in the UK.

In particular, the MHRA is now responsible for approving all medicinal products destined for the UK market (i.e., Great Britain and Northern Ireland), and the EMA no longer has any role in approving medicinal products destined for Northern Ireland under the EU centralized procedure.

A single UK-wide MA will be granted by the MHRA for all novel medicinal products to be sold in the UK, enabling products to be sold in a single pack and under a single authorization throughout the UK.

In addition, the new arrangements require all medicines placed on the UK market to be labelled “UK only”, indicating they are not for sale in the EU.

On January 1, 2024, the MHRA put in place a new international recognition framework which means that the MHRA may have regard to decisions on the approval of MA’s made by the EMA and certain other regulators when determining an application for a new UK MA.

There is now no pre-MA orphan designation in the UK.

Instead, the MHRA reviews applications for orphan designation in parallel to the corresponding MAA.

The criteria are essentially the same, but have been tailored for the UK market, i.e., the prevalence of the condition in the UK (rather than the EU) must not be more than five in 10,000.

Should an orphan designation be granted, the period of market exclusivity will be set from the date of first approval of the product in the UK.

Human Capital Resources

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As of February 28, 2025, we had 24 full-time employees.

13 of our employees have Ph.D.

degrees, four have Pharm.D.

Three of our employees have Ph.D.

degrees, three have Pharm.D.

degrees, and three have M.D.

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We consider our relationship with our employees to be good.

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.

In 2023, approximately 69% of our new hires came from underrepresented categories, including women and racial or ethnic minorities.

As of February 28, 2025, approximately 58% of the Company's workforce, and 57% of our employees in managerial roles, identified as female.

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The lease expires on June 30, 2032, subject to an option to extend the lease for five additional years.

In June 2024, we entered into a sublease for our office and laboratory space in New York, NY.

The sublease terminates on June 30, 2026, with the option to extend to June 30, 2027.

We believe that our current facilities are adequate for our current needs and that suitable additional or substitute space at commercially reasonable terms will be available as needed to accommodate any future expansion of our operations.

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(i) the last day of the fiscal year (a) following the fifth anniversary of the completion of the initial public offering (IPO), (b) in which we have total annual gross revenue of at least $1.235 billion, or (c) in which we are deemed to be a large accelerated filer, which means the market value of our common stock that is held by non-affiliates exceeds $700.0 million as of the prior June 30th, and (ii) the date on which we have issued more than $1.0 billion in non-convertible debt during the prior three-year period.

Effective as of December 31, 2025, the fifth anniversary of the closing of our IPO, we will no longer qualify as an “emerging growth company.”

Financial Information and Segments

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Our Internet address is www.blackdiamondtherapeutics.com.

Our Annual Reports on Form 10-K, Quarterly Reports on Form 10-Q, Current Reports on Form 8-K, including exhibits, proxy and information statements and amendments to those reports filed or furnished pursuant to Sections 13(a), 14, and 15(d) of the Securities Exchange Act of 1934, as amended, or the Exchange Act, are available through the “Investors & News” portion of our website free of charge as soon as reasonably practicable after we electronically file such material with, or furnish it to, the SEC.

Our Annual Reports on Form 10-K, Quarterly Reports on Form 10-Q, Current Reports on Form 8-K, including exhibits, proxy and information statements and amendments to those reports filed or furnished pursuant to Sections 13(a), 14, and 15(d) of the Exchange Act are available through the “Investors & News” portion of our website free of charge as soon as reasonably practicable after we electronically file such material with, or furnish it to, the SEC.

Information on our website is not part of this Annual Report or any of our other securities filings unless specifically incorporated herein by reference.

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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