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Item 1. Business

2023-03-09 compared with 2022-03-17 · 188 added, 257 removed, 753 unchanged (37% of the section changed)

We are a precision oncology medicine company pioneering the discovery and development of MasterKey therapies.

We target undrugged oncogenic driver mutations in patients with genetically defined cancers.

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

Our proprietary technology platform, which we refer to as our Mutation-Allostery-Pharmacology, or 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.

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.

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 clinical-stage product candidates, BDTX-1535 and BDTX-189, to potently and selectively inhibit families of oncogenic mutations which occur across a range of tumor types that affect the ErbB-1 epidermal growth factor receptor, or EGFR, and in the case of BDTX-189 also affect the tyrosine-protein kinase ErbB-2, or HER2.

We have designed these product candidates to bind to the active site of these mutant kinases and inhibit their function.

BDTX-1535 and BDTX-189 are also designed to spare normal, or wild type, EGFR (EGFR WT), which we believe will improve upon the toxicity profiles of current ErbB family inhibitors.

We are also leveraging our MAP drug discovery engine to identify other families of non-canonical mutations in validated oncogenes beyond the ErbB family, which has the potential to expand the reach of targeted therapies.

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.

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

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 families of undrugged driver mutations and their associated protein conformations.

We believe this 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:

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.

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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, 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 kinase inhibitors that target a range of driver mutations in cancer.

• 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.

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

A brain-penetrant inhibitor of EGFR oncogenic mutations, including canonical, intrinsic resistance, and acquired resistance mutations

Glioblastoma (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 percent of glioblastoma 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 glioblastoma 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 glioblastoma by earlier generation inhibitors, and iv) low levels of brain penetration.

We have shown in preclinical models that the mechanism of activation for these EGFR

oncogenic alterations involves the formation of a constitutive dimer that exhibits a conformation which leads to ligand-independent signaling and that is shared by a family of extracellular domain EGFR alterations expressed in glioblastoma.

In non-small cell lung cancer (NSCLC), EGFR inhibitors have demonstrated significant clinical benefit in patients with primary EGFR activating mutations and are the current first-line standard of care.

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.

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

BDTX-1535 is designed as a potent, selective, irreversible and brain-penetrant small molecule inhibitor that targets a family of EGFR oncogenic alterations including those expressed in glioblastoma 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 previously studied in glioblastoma.

Additionally, BDTX-1535 inhibits a spectrum of canonical, intrinsic resistance (Exon18, Exon 21, and others), and acquired resistance (C797S associated with resistance to third generation EGFR inhibitors) EGFR mutations found in patients with solid tumors such as NSCLC, including those with brain metastases.

The Investigational New Drug application, or IND, for BDTX-1535 was cleared by the U.S.

Food and Drug Administration (FDA) on January 6, 2022, and the Phase 1 clinical trial was initiated in the first quarter of 2022.

The Phase 1 dose-escalation portion will enroll patients harboring EGFR oncogenic alterations both in glioblastoma and NSCLC, with or without brain metastases.

An inhibitor of oncogenic mutations of EGFR and HER2

BDTX-189 is designed as an orally available, irreversible small molecule inhibitor that targets a spectrum of 48 non-canonical and canonical driver mutations of EGFR and HER2 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.

Currently, there are no drugs approved by the FDA that target all of these oncogenic mutations with a single therapy.

BDTX-189 is designed as a highly selective, potent inhibitor that targets this spectrum of oncogenic proteins defined by the non-canonical EGFR and HER2 driver mutations, while also sparing WT EGFR.

In preclinical models, BDTX-189 exhibited anti-tumor activity evidenced by potent tumor growth inhibition and tumor regression.

We initiated the MasterKey-01 trial in January of 2020.

Clinical data obtained from the MasterKey-01 study to date have demonstrated a favorable tolerability profile for BDTX-189 and early signs of clinical activity in patients whose tumors are driven by MasterKey mutation families, including two confirmed partial responses in heavily pretreated patients who remained on treatment for more than 10 months.

The dose-escalation portion of the trial has been completed with the recommended Phase 2 dose, or RP2D, established.

Due to the rapid evolution of the treatment landscape in NSCLC harboring either EGFR or HER2 exon 20 insertion mutations, we announced in January 2022 that we would gate the initiation of the Phase 2 portion of the MasterKey-01 study and determine next steps in development based on further clinical data obtained from the safety expansion cohort at the recommended Phase 2 dose.

A brain-penetrant inhibitor of oncogenic BRAF Class I, II and III alterations

FDA-approved BRAF inhibitors against V600E (Class I) mutations are not active against non-canonical oncogenic BRAF mutations.

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 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.

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

In addition, the approved 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 central nervous system (CNS) tumors or with brain metastasis, but currently approved drugs have poor intrinsic brain penetration.

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.

Our development candidate, BDTX-4933, is designed to be a highly selective, potent and brain-penetrant small molecule inhibitor that targets a family of Class I, II, and III canonical and non-canonical BRAF alterations while avoiding paradoxical activation.

We initiated IND-enabling studies for BDTX-4933 in the first quarter of 2022.

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.

Early-stage programs

We are also progressing our early-stage research programs targeting groups of oncogenic mutations in kinases relevant to cancer and/or rare genetic diseases that we have developed utilizing our MAP drug discovery engine, including our program targeting fibroblast growth factor receptor, or FGFR.

We anticipate selection of a development candidate for our FGFR program in 2022.

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 tumor-agnostic product candidates aimed at delivering safe and effective medicines to patients.

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.

The critical components of our strategy include:

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

We believe that BDTX-1535 could offer an improved approach in glioblastoma 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.

The Phase 1 clinical trial for BDTX-1535 was initiated in the first quarter of 2022.

• Continue to study BDTX-189 in the Phase 1 safety expansion cohort to inform the next steps in clinical development as a selective MasterKey therapy.

We believe BDTX-189 has the potential to treat multiple tumors with one of the many validated oncogenic EGFR and HER2 mutations.

Enrollment and dosing are ongoing in the Phase 1 monotherapy safety expansion portion of our MasterKey-01 Phase 1/2 trial in patients with selected solid tumors with genetically defined alterations, including oncogenic mutations in EGFR and HER2.

Eligible patients are identified by standard, commercially available NGS panels.

BDTX-189 has demonstrated a favorable tolerability profile and early signs of clinical activity in patients whose tumors are driven by oncogenic EGFR and HER2 mutations.

We plan to evaluate further data from the safety expansion cohort to determine next steps in the development of BDTX-189.

• Rapidly advance BDTX-4933 into IND-enabling studies.

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

We anticipate initiating IND-enabling studies in 2022.

• Select a development candidate for our FGFR program for clinical development.

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

Our FGFR molecules are designed as potent and selective MasterKey inhibitors of FGFR2/3 mutations that spare FGFR1 and have activity against gatekeeper mutations.

We anticipate selection of a development candidate for our FGFR program in 2022.

• 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 for which 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 active site.

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 into canonical and non-canonical mutations and to accelerate our ability to identify other mutational drivers, both in oncology and non-oncology settings.

We will continue to enhance our proprietary computational algorithms by leveraging both our extensive in-house expertise in MasterKey mutation families and deep understanding of chemistry, as well as both internally and externally available computational technologies.

Through our strategic partnership with OpenEye Scientific we are integrating new molecular dynamic modeling tools to support our drug discovery efforts.

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.

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Epstein and Dr.

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

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.

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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 Interim Chief Financial Officer, previously served as Principal and was a member of the investment team at Versant Ventures.

Karsten Witt, M.D., our Interim Chief Medical Officer, previously led clinical development at Array Biopharma Inc.

and OSI Pharmaceuticals, Inc.

Witt has been involved in eight regulatory approvals, four of which are related to Tarceva (erlotinib), an approved kinase inhibitor for the treatment of certain lung and pancreatic cancers.

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.

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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 exon 20 insertions (right panel).

Emergence of genetic sequencing as standard of care in treating cancer

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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 percent of oncologists in the United States employ genetic sequencing.

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.

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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 BDTX-189 product candidate.

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.

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

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

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 glioblastoma (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).

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.

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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 BDTX-189, as evidenced below with potent inhibition of proliferation against cells transformed by the HER2-R103Q mutation.

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 drug sensitivity profile, or pharmacology, of the ATP site is altered.

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.

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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 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.

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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 dimer conformation.

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—develop mutation spectrum-selective drugs to our targets

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 seek 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.

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-189, our ErbB 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-189 binds to the ATP-site to inhibit the constitutive dimer in a family of EGFR and HER2 mutations, while at the same time sparing inhibition of the normal EGFR WT.

We have validated the activity for BDTX-189 against the most commonly occurring mutations representing each of these types of mutations (HER2-S310F, HER2-R678Q, HER2-

L755S, HER2-V777L, HER2-V842I, the EGFR Exon 20 insertions EGFR-ASV/SVD/NPH/FQEA, the HER2 Exon 20 insertions HER2-YVMA/GSP, the EGFR Exon 19 deletion EGFR-746-750, and EGFR-L858R).

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 spectrum-selective small molecule kinase inhibitors that target genetic drivers in several cancers.

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 own worldwide commercial rights to all of our product candidates.

A brain-penetrant, irreversible inhibitor of EGFR alterations, including those present in glioblastoma and NSCLC

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

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

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

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

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.

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EGFR oncogenic mutations are expressed throughout the target sequence.

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

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 glioblastoma 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 glioblastoma that efficiently block the oncogenic activity across all of these various EGFR species.

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.

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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 glioblastoma 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 dimer conformation for EGFR WT.

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.

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

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

Current reversible EGFR inhibitors, including those proven clinically efficacious in NSCLC, have not demonstrated clinical activity in glioblastoma.

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 glioblastoma model expressing EGFRvIII, erlotinib results in paradoxical activation which increases tumor proliferation at certain dose levels.

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

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.

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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.

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

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

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 all members of the family of oncogenic EGFR variants expressed in glioblastoma and EGFR amplification with selectivity versus normally expressed EGFR WT as well as classical, intrinsic resistance and acquired resistance mutations expressed in NSCLC.

Anti-proliferative activity of BDTX-1535 against BaF3 transformants expressing an exemplary family of EGFR alterations associated with glioblastoma (A) and NSCLC (B) versus EGFR WT expressing H292 cells or EGFR amplified A431 cells.

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

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.

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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.

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

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 glioblastoma 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 glioblastoma as well as classical, intrinsic resistance, and acquired resistance mutations found in NSCLC patients.

Clinical development

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

Food and Drug Administration (FDA) on January 6, 2022, and the Phase 1 clinical trial was initiated in the first quarter of 2022.

The Phase 1 trial is an open-label, multicenter study designed to assess the safety, tolerability, pharmacokinetics and preliminary antitumor activity of BDTX-1535 in patients with glioblastoma and NSCLC harboring EGFR MasterKey alterations.

Our Phase 1 trial is an open-label, multicenter study designed to assess the safety, tolerability, pharmacokinetics and preliminary antitumor activity of BDTX-1535 in patients with either recurrent glioblastoma expressing EGFR alterations and patients with 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 18-21 or an acquired C797S mutation following 1st line therapy with a 3rd-generation EGFR inhibitor.

Once a provisional RP2D has been established, BDTX-1535 monotherapy will be explored in disease specific dose expansion cohorts to further evaluate safety, PK, and preliminary assessment of efficacy.

The disease specific dose expansion includes:

patients with recurrent glioblastoma 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) with and without brain metastases.

Our regulatory strategy includes pursuing a registration path for patients with recurrent glioblastoma in parallel with NSCLC patients with either intrinsic resistance mutations or acquired resistance mutations.

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

An inhibitor of oncogenic driver mutations of EGFR and HER2

Mutations in EGFR and HER2, both of the ErbB family, are found in one to two percent of a large variety of solid tumors but are overexpressed in tumors such as advanced NSCLC, invasive breast, bladder and endometrial cancer, where incidence ranges from two to seven percent.

Currently available EGFR and HER2 tyrosine kinase inhibitors or monoclonal antibodies have limited or no anti-tumor activity against these genetic alterations due to insufficient potency or lack of selectivity, which results in toxicity before adequate exposures can be achieved.

There remains a significant unmet medical need for new drugs that can extend targeted therapies to patients expressing non-canonical mutations outside of the ATP site.

BDTX-189 is designed as an orally available irreversible, small molecule inhibitor that targets undrugged oncogenic driver mutations in HER2 and EGFR.

These include extracellular domain mutations of HER2, as well as EGFR and HER2 kinase domain exon 20 insertions, and additional activating oncogenic driver mutations.

Currently, there are no FDA approved drugs that target all of these mutations with a single small molecule therapy.

We are currently enrolling patients in the Phase 1 monotherapy safety expansion portion of the trial at the RP2D in patients with selected tumor types with EGFR or HER2 mutations, including exon 20 insertions.

The figure below shows the selectivity pattern for BDTX-189 for non-canonical oncogenic mutations and additional oncogenic drivers of EGFR and HER2 (with wild type for reference), each as determined by measuring 50 percent inhibition, or IC50, values.

In cell-based assays, BDTX-189 achieved potent inhibition of each of the 48 oncogenic ErbB mutant variants tested with an average selectivity versus EGFR WT of greater than 50-fold, including the family of EGFR and HER2 exon 20 insertion mutations.

BDTX-189 has demonstrated in vitro activity against the canonical activating EGFR mutations (exon 19 deletion and L858R mutation), as well as potent HER2 WT activity, or HER2-positive.

A favorable therapeutic window over EGFR WT was a key design objective in the ErbB program.

BDTX-189 achieved high selectivity for cells expressing the targeted oncogenic EGFR and HER2 mutants and the compound spares cells expressing EGFR WT (A431 and H292).

We believe BDTX-189 has an excellent kinome selectivity profile, as determined using the DiscoverX KINOMEscan methodology testing 468 kinases.

BDTX-189 exhibited binding affinity for the isolated kinase domains of EGFR and HER2 of less than 1nM.

All but eight kinases outside of the ErbB family showed no or very poor binding when BDTX-189 was tested at a single concentration of 100nM, with selectivity estimated to be greater than 125-fold for EGFR selectivity and greater than 30-fold for HER2 selectivity.

The selectivity for ErbB kinases versus a small subset of kinases (BLK, BTK, LCK, LOK and MEK5) was determined to be greater than 10-fold.

The only kinase that was bound with less than 10-fold selectivity is RIPK2, and this activity is not expected to be dose limiting.

In preclinical animal models, BDTX-189 was observed to have high potency and fast irreversible inactivation of the desired mutations.

BDTX-189 displayed a favorable pharmacokinetic profile with fast absorption, good exposure and subsequent swift elimination, together with rapid irreversible target inhibition.

BDTX-189 was observed to be well suited to engage and inactivate the EGFR and HER2 mutants in vivo.

In acute dose pharmacokinetic/pharmacodynamic, or PK/PD, studies, oral administration of BDTX-189 to athymic nude mice bearing a range of EGFR and HER2 mutations resulted in potent and sustained suppression of target phosphorylation for at least 24 hours following dosing.

As shown in the figures below, BDTX-189 demonstrated dose-dependent tumor inhibition and regression in both engineered HER2 S310F tumor models and EGFR Exon 20 insertion patient-derived xenograft, or PDX, models.

(a) Daily dosing of BDTX-189 was evaluated in athymic nude mice bearing HER2 S310F Ba/F3 allograft tumors up to 100 mg/kg daily dose;

(b) Daily dosing of BDTX-189 at an oral dose of 1 to 50 mg/kg was evaluated in athymic nude mice bearing CUTO-14 PDX tumors that express the EGFR mutation EGFR ASV.

We used a PK/PD analysis of the HER2-S310F BaF3 allograft tumor inhibition studies to assess the PK/PD driver for efficacy using different doses and dose regimens to project expected human exposures to be associated with anti-tumor activity.

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.

Clinical development

We submitted our IND for BDTX-189 in November 2019, which was allowed by the FDA on December 13, 2019.

Enrollment and dosing of patients in the Phase 1 dose-escalation portion of our MasterKey-01 trial has been completed with the recommended Phase 2 dose, or RP2D, established to be 800 mg once daily with a meal (non-fasting) which also was endorsed by the FDA.

The Phase 1 safety expansion cohort is currently enrolling at the RP2D to further evaluate the safety, PK and preliminary efficacy in patients with selected tumor types and genomic alterations to inform the future development of the program.

Our Phase 1 portion was designed to allow for greater flexibility and precision to determine the appropriate dose and schedule for further clinical evaluation.

The Phase 1 trial was a two-step process where step one was a single-patient cohort, accelerated dose-escalation process until grade 2 drug-related adverse events were observed or until the 400 mg once daily dose level was opened for enrollment.

Step 2 was designed to provide the flexibility to enroll three or more patients in dose-escalating cohorts.

The study initially evaluated once daily dosing in fasted state, but also evaluated a twice daily dosing schedule.

In the Phase 1 dose-escalation portion, 59 patients were enrolled in the once daily dose schedule with advanced or metastatic solid tumors for whom no standard therapy was available or for whom standard therapy was considered unsuitable or intolerable, as determined by the investigator.

The patients were heavily pretreated with multiple different solid tumors expressing multiple EGFR or HER2 genomic alterations.

This includes 31 patients treated at 800 mg, with 18 patients administered BDTX-189 under fasting conditions and 13 patients administered BDTX-189 once daily with a meal which was determined to be the RP2D and schedule.

The dose of 800 mg once daily either fasting or non-fasting was well tolerated with no dose-limiting toxicities reported and a low rate of typical EGFR wild type skin disorders.

The pharmacokinetics of BDTX-189 showed dose-dependent increases in exposures up to and including 800 mg.

There was also evidence of early signs of clinical antitumor activity including two confirmed partial responses in patients who remained on treatment for more than 10 months.

We are currently enrolling the safety expansion cohort at the RP2D to inform the future development of the program.

Our regulatory strategy includes periodic dialogue with the FDA regarding the study design, patient population, study endpoint and companion diagnostic strategy for the BDTX-189 development program.

For example, in March 2021, we met with the FDA to discuss the registrational potential and design of the then planned Phase 2 portion of the trial.

At the meeting with the FDA, the FDA notified us that, because the Phase 2 portion of the trial would be potentially registrational and support a new drug application, we could only enroll up to 50 patients in Phase 2 before results of routine three-month good laboratory practice, or GLP, toxicology studies have been submitted and accepted by the FDA.

This partial clinical hold on Phase 2 enrollment was not based on any safety findings from the MasterKey-01 trial and has no impact on completion of our Phase 1 study (including the currently enrolling safety expansion cohort).

We have completed the three-month GLP toxicology studies and submitted the reports to the FDA who accepted the findings and lifted the partial clinical hold in January 2022.

In July 2020, the FDA granted Fast Track designation to BDTX-189 for the treatment of adult patients with solid tumors harboring an oncogenic HER2 mutation or an EGFR or HER2 Exon 20 insertion mutation who have progressed following prior treatment and who have no satisfactory treatment options.

We may also seek Breakthrough Therapy designation by the FDA.

A brain-penetrant, small molecule inhibitor of BRAF class I, II and III alterations

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

Background and limitations of RAF inhibitors

BRAF mutations are among the most common mutation 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.

While the V600E Class I mutation has been successfully targeted in melanoma, there are currently no approved therapies that target the full spectrum of Class II and Class III mutations that are expressed in melanoma and a range of other solid tumors.

While the V600E Class I mutation has been successfully targeted in melanoma and other solid tumors, there are currently no approved therapies that target the full spectrum of Class II and Class III mutations that are expressed in melanoma and a range of other solid tumors.

Additionally, expression of all classes of BRAF mutations commonly occurs in patients with CNS tumors or with brain metastasis, which currently remain unaddressed by approved drugs due to their poor brain penetration.

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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.

FDA approved BRAF V600E- selective inhibitors are inactive against BRAF dimers, Class II and Class III.

Our BRAF development candidate, BDTX-4933, is designed as a brain-penetrant, small molecule MasterKey inhibitor of oncogenic BRAF Class I, II and III alterations expressed by human cancers, while avoiding paradoxical activation.

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.

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, consistent with potent on-target and on-pathway inhibition.

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.

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

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

BDTX-4933 inhibitor exhibits CNS exposure and anti-tumor activity in intracranial BRAF mutant mouse model.

(Left) Representative images of bioluminescence (BLI) of BRAF V600E cancer cells labeled with luciferase reporter in animals.

The BLI from the tumor is increased in vehicle treated animals after 15 days of dosing.

Meanwhile, BDTX-4933 inhibitor treated animals show very low or no BLI.

(Right) Survival rate of tumor bearing mice.

Survival rate of tumor bearing mice.

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

We anticipate initiating IND-enabling studies for the BDTX-4933 program in 2022.

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.

Early-stage programs

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

We believe these general principles also apply to targets associated with diseases outside of oncology, and we are currently evaluating additional groups of targets for drug discovery.

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.

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While these mutations have been targeted by three first generation pan-FGFR inhibitors (erdafitinib, pemigatinib and infigratinib), clinical success has been hindered by dose limiting toxicities related to on-target inhibition of FGFR1, which causes hyperphosphatemia and the need for significant dose interruptions and dose reductions, and even discontinuation.

Furthermore, current FGFR inhibitors are limited by acquired resistance due to mutation of gatekeeper positions in FGFR2/3, which are residues that modulate access to the ATP-binding site.

These limitations limit the efficacy of current generation FGFR targeted therapies.

Our FGFR program leverages our MAP drug discovery engine to (i) define the full spectrum of FGFR2/3 oncogenic mutations;

(ii) classify mutations according to unifying conformational changes;

and (iii) design small molecule inhibitors that are active against the full spectrum of oncogenic FGFR2/3 mutations, exhibit improved resistance profile versus the clinically relevant gatekeeper mutations and achieve selectivity versus FGFR1.

We believe that our MAP drug discovery engine drug discovery platform is differentiated by its capability to identify development candidates that are selective versus FGFR1.

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 selection of a development candidate for the BDTX FGFR program in 2022.

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

Undisclosed program

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

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

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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 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:

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

• In patients with EGFR alterations present in glioblastoma:

• In patients with EGFR alterations present in GBM:

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

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

There are currently compounds approved and in development which target the EGFR/HER2 pathway and against which we expect BDTX-189 to compete:

• In the EGFR exon 20 insertion NSCLC patient population:

amivantamab, which is under development by Janssen Research & Development, LLC and has been granted accelerated approval by the FDA;

mobocertinib (TAK-788), which is under development by Takeda Pharmaceutical Company Ltd and has been granted accelerated approval by the FDA;

CLN-081, which is under development by Cullinan Oncology, Inc.

and has been granted Breakthrough Therapy Designation by the FDA;

DZD9008, which is under development by Dizal Pharmaceutical Co., Ltd.

and has been granted Breakthrough Therapy Designation by the FDA;

ORIC-114 (formerly VRN-07), which is under development by ORIC Pharmaceuticals, Inc.;

and BLU-451, which is under development by BluePrint Medicines Corporation.

• In the HER2 exon 20 insertion NSCLC patient population:

trastuzumab deruxtecan, which is marketed by Daiichi Sankyo Company, Ltd.

and AstraZeneca plc under the trade name Enhertu and is currently approved for HER2+ breast and gastric cancers;

poziotinib, which is under development by Spectrum Pharmaceuticals, Inc.;

and pyrotinib, which is under development by Jiangsu Hengrui Pharmaceuticals Company Ltd.

• In the allo-HER2 patient population:

neratinib, which is marketed by Puma Biotechnology, Inc.

under the trade name Nerlynx and is currently approved for HER2+ breast cancer.

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

• 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, Theseus Pharmaceuticals, Inc., Voronoi Inc., Deciphera Pharmaceuticals, Inc., Turning Point Therapeutics, Inc., Mirati Therapeutics, Inc., Relay Therapeutics, Inc.

and Kinnate Biopharma Inc.

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

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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There can be no assurance that our pending patent applications will issue or that we will benefit from any patent term extension or favorable adjustments to the terms of any patents we may own or in-license in the future.

In addition, the actual protection afforded by a patent varies on a product-by-product basis, from country-to-country, and depends upon many factors, including the type of patent, the scope of its coverage, the availability of regulatory-related extensions, the availability of legal remedies in a particular

country and the validity and enforceability of the patent.

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

As of March 1, 2022, we own 20 U.S.

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

provisional patent applications, four pending U.S.

patent applications, and one issued U.S.

We also own eight Patent Cooperation Treaty, or PCT, patent applications and 27 foreign patent applications.

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

or foreign patent issuing from these patent applications would be scheduled to expire in 2039 to 2043, 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 March 1, 2022, we own six U.S.

provisional patent applications, one U.S.

patent application, and one PCT patent application, and 10 foreign patent applications that cover our glioblastoma program, including the composition of matter for BDTX-1535, polymorphs of BDTX-1535, as well as methods of using and making BDTX-1535.

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.

or foreign patent issued from these pending applications would be scheduled to expire between 2040 and 2042, 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.

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.

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 March 1, 2022, we own three U.S.

provisional patent applications, one pending U.S.

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

patent application, one U.S.

patent, and three PCT patent applications, and 14 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 between 2039 and 2042, excluding any additional term for patent term adjustment or patent term extension, and assuming national phase entries are timely made based upon the pending PCT application and payment of all applicable maintenance or annuity fees.

As of March 1, 2022, we own two U.S.

provisional patent applications and one PCT patent application that cover our BRAF 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 these pending applications would be scheduled to expire in 2042, assuming that conversions are timely made based upon U.S.

As of March 1, 2022, we own two U.S.

provisional patent applications and one PCT patent application that cover 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 these pending application would be scheduled to expire in 2042, assuming that conversions are timely made based upon 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.

MAP drug discovery engine

As of March 1, 2022, we own one U.S.

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

patent application that covers our MAP drug discovery engine and the use thereof in developing and applying therapeutics.

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These clinical trials are intended to establish the overall risk/benefit ratio of the investigational product and to provide an adequate basis for product approval and physician labeling.

In August 2018, the FDA released a draft guidance entitled “Expansion Cohorts:

In March 2022, the FDA released a final guidance entitled “Expansion Cohorts:

Use in First-In-Human Clinical Trials to Expedite Development of Oncology Drugs and Biologics,” which outlines how drug developers can utilize an adaptive trial design commonly referred to as a seamless trial design in early stages of oncology drug development (i.e., the first-in-human clinical trial) to compress the traditional three phases of trials into one continuous trial called an expansion cohort trial.

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Accelerated approval is usually contingent on a sponsor’s agreement to conduct additional post-approval studies to verify and describe the product’s clinical benefit.

The FDA may withdraw approval of a drug or indication approved under accelerated approval if, for example, the confirmatory trial fails to verify the predicted clinical benefit of the product.

In addition, unless otherwise informed by the FDA, the FDA currently requires, as a condition for accelerated approval, that all advertising and promotional materials that are intended for dissemination or publication within 120 days following marketing approval be submitted to the agency for review during the pre-approval review period, and that after 120 days following marketing approval, all advertising and promotional materials must be submitted at least 30 days prior to the intended time of initial dissemination or publication.

Under the Food and Drug Omnibus Reform Act of 2022 (FDORA), the FDA may require, as appropriate, that such trials be underway prior to approval or within a specific time period after the date of approval for a product granted accelerated approval.

Under FDORA, the FDA has increased authority for expedited procedures to withdraw approval of a drug or indication approved under accelerated approval if, for example, the confirmatory trial fails to verify the predicted clinical benefit of the product.

In addition, for products being considered for accelerated approval, the FDA generally requires, unless otherwise informed by the FDA, that all advertising and promotional materials that are intended for dissemination or publication within 120 days following marketing approval be submitted to the agency for review during the pre-approval review period.

Additionally, after 120 days following marketing approval, all advertising and promotional materials must be submitted at least 30 days prior to the intended time of initial dissemination or publication.

Even if a product qualifies for one or more of these programs, the FDA may later decide that the product no longer meets the conditions for qualification or the time period for FDA review or approval may not be shortened.

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• In August 2011, the Budget Control Act of 2011, among other things, included aggregate reductions of Medicare payments to providers of 2% per fiscal year, which went into effect in April 2013 and, due to subsequent legislative amendments to the statute, will remain in effect through 2030, unless additional Congressional action is taken.

Pursuant to the Coronavirus Aid, Relief, and Economic Security Act, also known as the CARES Act, as well as subsequent legislation, these reductions have been suspended from May 1, 2020 through March 31, 2022 due to the ongoing COVID-19 pandemic.

Following the temporary suspension, a 1% payment reduction will occur beginning April 1, 2022 through June 30, 2022, and the 2% payment reduction will resume on July 1, 2022.

• In January 2013, the American Taxpayer Relief Act of 2012 was signed into law, which, among other things, further reduced Medicare payments to several providers, including hospitals, imaging centers and cancer treatment centers, and increased the statute of limitations period for the government to recover overpayments to providers from three to five years.

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• On May 23, 2019, CMS published a final rule to allow Medicare Advantage Plans the option of using step therapy for Part B drugs beginning January 1, 2020.

• On December 20, 2019, former President Trump signed into law the Further Consolidated Appropriations Act (H.R.

• On December 20, 2019, the Further Consolidated Appropriations Act was signed into law (H.R.

1865), which repealed the Cadillac tax, the health insurance provider tax, and the medical device excise tax.

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

• 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;

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

allow the U.S.

government to negotiate Medicare Part B and Part D price caps for certain high-cost drugs and biologics without generic or biosimilar competition, including small molecule drugs;

and require companies to pay rebates to Medicare for certain drug prices that increase faster than inflation, also including small molecule drugs.

Additionally, there has been increasing legislative and enforcement interest in the United States with respect to drug pricing practices.

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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.

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.

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

Further, on November 20, 2020 CMS issued an Interim Final Rule implementing the Most Favored Nation, or MFN, Model under which Medicare Part B reimbursement rates would have been be calculated for certain drugs and biologicals based on the lowest price drug manufacturers receive in Organization for Economic Cooperation and Development countries with a similar gross domestic product per capita.

However, on December 29, 2021 CMS rescinded the Most Favored Nations rule.

Additionally, 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.

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.

The rule also creates a new safe harbor for price reductions reflected at the point-of-sale, as well as a safe harbor for certain fixed fee arrangements between pharmacy benefit managers and manufacturers.

Pursuant to court order, the removal and addition of the aforementioned safe harbors were delayed and recent legislation imposed a moratorium on implementation of the rule until January 1, 2026.

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.

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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.

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.

The downward pressure on healthcare costs in general, particularly prescription products, has become intense.

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

or (iii) the marketing

authorization holder of the authorized orphan product cannot supply enough orphan medicinal product.

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

Orphan designation must be requested before submitting an application for marketing approval.

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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.

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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To facilitate talent attraction and retention, we strive to make Black Diamond a safe and rewarding workplace, with opportunities for our employees to grow and develop in their careers, supported by strong compensation, benefits and health and wellness programs, and by programs that build connections between our employees.

As of March 1, 2022, we had 88 full-time employees.

As of February 15, 2023, we had 65 full-time employees.

17 of our employees have Ph.D.

The following table shows the number of full-time employees as of March 1, 2022 engaged in either research and development or administrative functions, broken out by location.

Function US Canada

degrees, three have Pharm.D.

degrees, and two have M.D.

The following table shows the number of full-time employees as of February 15, 2023 engaged in either research and development or administrative functions.

All of our employees are located in the United States.

Function Employees

Research and development 43

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

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

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

In 2022, approximately 67% of our new hires came from underrepresented categories, including women and racial or ethnic minorities.

As of March 1, 2022, approximately 52% of the Company's workforce, and 47% of our employees in managerial roles, identified as female.

As of March 1, 2022, approximately 25% of our workforce, and 21% of our employees in managerial roles, identified as racially or ethnically diverse.

As of February 15, 2023, approximately 58% of the Company's workforce, and 49% of our employees in managerial roles, identified as female.

As of February 15, 2023, approximately 29% of our workforce, and 23% of our employees in managerial roles, identified as racially or ethnically diverse.

The success of our business is fundamentally connected to the well-being of our employees.

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and that offer choice where possible so they can customize their benefits to meet their needs and the needs of their families.

In response to the ongoing COVID-19 pandemic, we implemented significant changes that we determined were in the best interest of our employees, as well as the communities in which we operate, and which comply with government regulations.

This includes having most of our non-laboratory employees work from home, while implementing additional safety measures for employees continuing critical on-site work.

We provide robust compensation and benefits programs to help meet the needs of our employees.

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We have included our website address in this Annual Report solely as an inactive textual reference.

Our filings with the SEC may be accessed through the SEC’s Interactive Data Electronic Applications system at http://www.sec.gov.

Our filings with the SEC may be accessed through the SEC’s website at www.sec.gov.

All statements made in any of our securities filings, including all forward-looking statements or information, are made as of the date of the document in which the statement is included, and we do not assume or undertake any obligation to update any of those statements or documents unless we are required to do so by law.

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