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Item 1. Business

2022-03-17 compared with 2021-03-25 · 486 added, 430 removed, 524 unchanged (64% of the section changed)

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

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, platform, 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 a single small molecule therapy in a tumor-agnostic manner, termed a MasterKey therapy.

We have designed our lead product candidate, BDTX-189, to potently and selectively inhibit a spectrum of oncogenic proteins defined by mutations which occur outside the adenosine triphosphate, or ATP, site, and which we refer to as non-canonical mutations.

Non-canonical mutations occur across a range of tumor types that affect both the epidermal growth factor receptor, or EGFR, and the tyrosine-protein kinase ErbB-2, or HER2.

We have designed BDTX-189 to bind to the active site of these mutant kinases and inhibit their function.

BDTX-189 is also designed to spare normal, or wild type, EGFR, which we believe will improve upon the toxicity profiles of current ErbB kinase inhibitors.

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

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.

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.

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.

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

Our MAP platform is designed to reveal the oncogenic nature of families of undrugged driver mutations and their associated protein conformations.

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 platform is built on three central pillars:

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

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

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

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

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

This enables us to aggregate 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 allosteric mutations.

Utilizing our proprietary MAP platform, we are building a pipeline of orally available, potent and selective small molecule kinase inhibitors that target a range of driver mutations in cancer.

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.

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

An inhibitor of allosteric oncogenic mutations of ErbB

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 the ErbB kinases EGFR and HER2 while sparing wild type EGFR.

These mutations are prevalent in non-small cell lung cancer, or NSCLC, breast, gastric, colon, and endometrial cancers.

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.

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 ErbB driver mutations, while also sparing WT EGFR.

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 and are currently evaluating BDTX-189 in the Phase 1 dose-escalation portion of the trial.

This portion is designed to determine the recommended Phase 2 dose, characterize pharmacokinetics, or PK, and safety, and assess preliminary indications of anti-tumor activity for BDTX-189.

The Phase 2 portion will determine the anti-tumor activity of BDTX-189, as measured by the overall response rate, or ORR, and duration of response, or DOR, in patients with solid tumors that have an EGFR or HER2 exon 20 insertion mutation or allosteric HER2 mutation determined using NGS, or next-generation sequencing.

The results from the Phase 1/2 trial will help to inform our subsequent clinical development strategy, subject to discussions with the FDA, with a potential to pursue an accelerated approval of BDTX-189 for patients with mutations of the ErbB family across one or more solid tumor types as a tumor agnostic indication.

A brain-penetrant inhibitor of EGFR mutations, including allosteric and canonical EGFR mutations

BDTX-1535 is designed as a brain-penetrant small molecule inhibitor that targets a spectrum of EGFR mutations, including allosteric and canonical mutations.

EGFR mutations covered by BDTX-1535 include those that are frequently observed in glioblastoma, sometimes in groups.

Therefore, there is a critical need for a brain-penetrant inhibitor that potently and selectively targets the full array of mutations that contribute to the development of glioblastoma.

Additionally, BDTX-1535 is designed to inhibit a spectrum of allosteric, canonical and resistance (C797S, associated with resistance to osimertinib) EGFR mutations found in solid tumors, such as NSCLC, including those with brain metastases.

Glioblastoma is a difficult-to-treat, aggressive type of cancer that can occur in the brain or spinal cord.

Current therapy consists primarily of surgical resection of the tumor followed by radiation and chemotherapy and has only a 25 percent survival rate two years after diagnosis.

Almost 50 percent of glioblastoma tumors express one or more allosteric EGFR mutations 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 these allosteric EGFR mutations within individual patients, (ii) insufficient drug potency for allosteric EGFR mutations and (iii) low levels of brain penetration.

We have shown that the mechanism of activation for these allosteric EGFR mutations involves the formation of a constitutive dimer and a shared conformation by the spectrum of allosteric EGFR mutations expressed in glioblastoma.

BDTX-1535 potently and selectively inhibited this spectrum of allosteric mutants and achieved tumor-growth inhibition and regression in the in vivo animal models we have utilized.

Additionally, we have observed measurable brain exposure in animal models.

Investigational New Drug application, or IND,-enabling studies of BDTX-1535 are ongoing, and we anticipate submitting an IND for BDTX-1535 in the first half of 2022.

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.

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.

Early-stage programs

We are also progressing our early-stage research programs targeting groups of allosteric mutations in kinases relevant to cancer and/or rare genetic diseases that we have developed utilizing our MAP platform.

Our programs in B-Raf Proto-Oncogene, or BRAF, and fibroblast growth factor receptor, or FGFR, are advancing through lead optimization, and we anticipate filing an IND for each program in 2022.

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

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 mutations with individual small molecule therapies.

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.

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.

The critical components of our strategy include:

• Rapidly advance our lead product candidate, BDTX-189, through clinical development, as a tumor-agnostic, spectrum-selective small molecule therapy.

We believe BDTX-189 has the potential to treat multiple tumors and become the first agent approved to address allosteric ErbB mutations.

Enrollment and dosing are ongoing in the Phase 1 dose-escalation portion of our MasterKey-01 Phase 1/2 trial in solid tumors with genetically defined alterations, including allosteric mutations in EGFR and HER2.

• 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.

If successful in achieving clinically meaningful anti-tumor activity across a range of allosteric ErbB mutations and solid tumor types, we plan to meet with regulatory authorities to discuss expedited regulatory approval strategies.

• Rapidly advance BDTX-1535 through IND-enabling studies and into clinical development.

We believe that BDTX-1535 could offer an improved approach in glioblastoma by potently and selectively inhibiting the spectrum of allosteric mutant EGFR kinases expressed in glioblastoma tumors with a brain-penetrant compound.

We anticipate filing an IND in the first half of 2022.

• Select a development candidate from the lead molecules in each of our BRAF and FGFR programs and rapidly advance each into clinical development.

We believe that the lead molecules in our BRAF and FGFR programs could overcome the limitations of current therapies in each target area.

Our BRAF molecules are designed as potent MasterKey inhibitors of Class II/III (non-V600) mutations without inducing paradoxical activation.

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

We anticipate filing an IND for each program in 2022.

• Expand our pipeline of potent and selective small molecule inhibitors to fully exploit the potential of our proprietary MAP platform.

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.

• 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 platform 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 allosteric activating mutations.

• Continue to invest in our proprietary MAP platform to identify and characterize new mutation families.

We plan to continue to innovate our MAP platform 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 allosteric mutations and deep understanding of chemistry, as well as both internally and externally available computational technologies.

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

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

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.

• 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.

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.

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

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

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

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

Our history and team

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Epstein and Dr.

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

Elizabeth Buck in 2014 and, beginning in 2017, together with Versant Ventures started building the MAP drug discovery engine and chemistry 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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and founder of Archemix Corporation, where he led the advancement of multiple product candidates into the clinic across several therapeutic areas.

Thomas Leggett, our Chief Financial Officer, was previously Chief Financial Officer at Axcella Health, Inc.

Christopher D.

Roberts, our Chief Scientific Officer, was previously Entrepreneur in Residence at S.R.

One Limited, the corporate venture capital arm of GlaxoSmithKline plc.

Elizabeth Buck, Ph.D., our Executive Vice President of Discovery & Translational Sciences, previously led preclinical pharmacology and oncology translational research at OSI Pharmaceuticals, Inc.

Rachel Humphrey, M.D., our Chief Medical Officer, previously served as Chief Medical Officer at CytomX Therapeutics, Inc.

Humphrey supervised the development of the early and late-stage clinical development of Yervoy (ipilimumab) at Bristol Myers Squibb and Nexavar (sorafenib) at Bayer AG.

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

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

Karsten Witt, M.D., our Senior Vice President of Non-Clinical Development, previously led clinical development at Array Biopharma 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.

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

Background on and limitations of previous generations of targeted therapies

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

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

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

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

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Limitations of current targeted therapies

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

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

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

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

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

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

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

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

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

These include the ATP-site mutations, EGFR exon 19 deletions and L858R (left panel), as well as an additional spectrum of mutations occurring outside of the ATP site, including EGFR-Viii (middle panel) and EGFR exon 20 insertions (right panel).

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 recent study demonstrated that 75 percent of oncologists in the United States employ genetic sequencing.

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

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

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

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

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

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The Black Diamond Therapeutics approach

At Black Diamond Therapeutics, our goal is to bring precision oncology medicine to a greater number of patients.

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

Our drug development efforts leverage our novel findings that:

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

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

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

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

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

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

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

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

Our MAP platform

Our MAP platform is built on three central pillars:

Our MAP drug discovery engine

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

Mutation—Allostery—Pharmacology.

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

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

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

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

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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 allosteric 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 BDTX-189 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 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 (EGFR-Viii, EGFR-Vii, EGFR-Vvi, 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 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).

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

In the case of wild type EGFR, this is a transient dimer conformation.

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.

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

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

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

Wild type EGFR 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.

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

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.

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

Our team of experienced medicinal chemists seek 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.

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.

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 wild type EGFR.

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).

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).

Our product candidates and development programs

We are leveraging our MAP platform 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 spectrum-selective small molecule kinase inhibitors that target genetic drivers in several cancers.

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

An inhibitor of allosteric oncogenic drivers of ErbB

Allosteric ErbB mutations 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.

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.

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

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

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

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

EGFR oncogenic mutations are expressed throughout the target sequence.

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

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

The formatting of these constitutive dimers is essential for oncogenicity.

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

We believe that current targeted therapies have been unsuccessful in treating 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.

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.

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.

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.

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

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

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

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

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

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.

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

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

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

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

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

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

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.

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 of ErbB kinases in HER2 and EGFR.

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

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

We are currently enrolling patients in the Phase 1 dose-escalation portion of the trial, which is designed to determine the recommended Phase 2 dose, characterize the PK and safety, and assess preliminary indications of anti-tumor activity of BDTX-189.

The open-label Phase 2 portion is expected to determine the ORR and DOR in patients with solid tumors that have an allosteric HER2 mutation, or EGFR or HER2 exon 20 insertion mutation determined using NGS, or next-generation sequencing.

The figure below shows the selectivity pattern for BDTX-189 for non-canonical oncogenic mutations and additional oncogenic drivers of ErbB (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 allosteric ErbB mutant variants tested with an average selectivity versus wild type EGFR 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 wild-type activity, or HER2-positive.

We continue to evaluate BDTX-189’s activity in areas where we believe there may be additional opportunities.

As shown in the figure below, BDTX-189 inhibited the proliferation of both BaF3 transformants (engineered cell lines) and patient derived cell lines expressing the EGFR Exon 20 insertion mutants EGFR-NPH and EGFR-ASV.

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

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

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.

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

As illustrated in the figures below, BDTX-189 was observed to be well suited to engage and inactivate the allosteric ErbB 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 HER2-S310F, EGFR-Viii (both BaF3 and GBM6 patient derived glioblastoma tumors) or HER2-YVMA BaF3 allograft tumors resulted in potent and sustained suppression of target phosphorylation for at least 24 hours following dosing.

BDTX-189 inhibits the activity across a range of EGFR and HER2 mutants in vivo (50mpk QD acute oral dosing), including mutants with a range of in vitro IC50 values.

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.

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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.

Clinical development plan

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 is ongoing in the Phase 1 dose-escalation portion of our MasterKey-01 trial.

We intend to pursue a tumor agnostic development strategy.

We have designed the initial study to be a combined Phase 1/2 clinical trial which is intended to allow a seamless transition from the Phase 1 dose-escalation portion into a Phase 2 portion to expedite development of this product candidate.

The Phase 1 portion is designed to determine the recommended Phase 2 dose, characterize the PK and safety, and assess preliminary indications of anti-tumor activity of BDTX-189.

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

The Phase 1 trial is a two-step process where step one is a single-patient cohort, accelerated dose-escalation process until grade 2 drug-related adverse events are observed or until a predefined dose level is reached.

Step 2 is designed to provide the flexibility to enroll three or more patients in dose-escalating cohorts, which is intended to allow evaluation of drug tolerability as well as enrollment of patients with allosteric ErbB mutations or HER2 amplification at relevant exposures to evaluate early anti-tumor proof-of-concept.

The study is primarily evaluating once daily dosing, but will also assess more frequent dosing schedules, such as twice daily, if the drug pharmacology or patient tolerability suggest this could be a better approach.

In the Phase 1 portion, we plan to enroll up to 100 patients with advanced or metastatic solid tumors for whom no standard therapy is available or for whom standard therapy is considered unsuitable or intolerable, as determined by the investigator.

In the Phase 1 portion, we are enrolling and dosing patients with solid tumors that have alterations that may be associated with BDTX-189 anti-tumor activity based on preclinical data such as allosteric HER2 or HER3 mutation, EGFR/HER2 exon 20 insertion mutation, HER2 amplified/overexpressing tumor, EGFR exon 19 deletion or L858R mutation.

We are on track to complete the dose-escalation portion of the Phase 1 clinical trial in the first half of 2021.

We are working toward selection of the recommended Phase 2 dose for BDTX-189 and plan to initiate the safety expansion cohort in the second quarter 2021.

The open-label Phase 2 portion is expected to enroll up to 100 patients in multiple cohorts with solid tumors that have allosteric HER2 mutations, or EGFR or HER2 exon 20 insertion mutations determined using NGS, or next-generation sequencing.

The patient population will already have been treated with standard approved cancer therapies and have either relapsed or failed to respond to those therapies.

To be enrolled, patients must also be willing to provide tumor tissue for confirmatory mutation testing in order to facilitate our development of a companion diagnostic test.

We expect to enroll a population with a variety of different advanced or metastatic cancers including lung, breast, endometrial, and many other solid tumors.

The planned primary objective of the Phase 2 portion is to determine the anti-tumor activity of BDTX-189 in patients preselected with allosteric ErbB mutations and evaluate this in each of the cohorts.

The Phase 2 portion of the MasterKey-01 study is on track to begin in the second half of 2021.

If the combined efficacy data from the Phase 1 and 2 portions of the trial show adequate anti-tumor activity across the mutation spectrum and tumor types, we anticipate that we may either expand the Phase 2 portion or initiate a second Phase 2 trial in order to pursue an accelerated approval path, if available, with the FDA for a tumor agnostic indication.

This approach is similar to the precedent established by Keytruda in MSI-high/dMMR cancers and Vitrakvi or larotrectinib, or Rozlytrek or entrectinib, in NTRK fusions cancers.

A larger sample size may be needed for some mutations and/or tumor types to achieve this goal.

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 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 is potentially registrational and may support a new drug application, we may 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 is not based on any safety findings from the MasterKey-01 trial and has no impact on completion of our Phase 1 study (including the planned safety expansion cohort).

We have initiated the three-month GLP toxicology studies and do not anticipate any delays to our clinical trial timelines for BDTX-189.

We believe that ORR and DOR combined with a favorable safety profile may, subject to further discussions with FDA, support filing for accelerated approval provided we can obtain data from a sufficiently large sample size across the mutation spectrum and tumor types.

While an accelerated approval path cannot be guaranteed, if we obtain accelerated approval based on the outlined plan, the FDA will still require the conduct of a post-approval study to confirm clinical benefit.

Should the anti-tumor activity in certain subgroups be inadequate to support further development, we may not pursue the broader tumor agnostic population and instead limit enrollment to patients with tumor types and/or mutations that appear to derive the greatest clinical benefit.

We believe, subject to discussion with the FDA, that this may be achieved by either amending the Phase 2 portion of the planned study or opening a separate pivotal Phase 2 study to support accelerated approval.

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

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.

We plan on using one of the existing NGS tests which already include the allosteric ErbB mutations of interest to identify patients and to collaborate with one or more partners on development of a companion diagnostic test.

A brain-penetrant inhibitor of EGFR mutations, including allosteric EGFR mutations

According to the American Society of Clinical Oncology, there will be approximately 24,000 new cases of brain or spinal cord cancer in the United States in 2021.

Fifteen percent of patients with brain cancer have glioblastoma, a particularly aggressive form, and most of those patients die within 15 months of diagnosis.

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

These include large deletions of portions of the extracellular domain, including the mutants EGFR-Viii, EGFR-Vvi, and EGFR-Vii.

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

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

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

EGFR oncogenic mutations are expressed throughout the target sequence.

The figure below shows the frequency for EGFR oncogenic mutations expressed in glioblastoma (EGFR-Viii, EGFR-Vii, EGFR-Vvi, EGFR-G598 mutations, EGFR-A289V mutations) which was calculated as relative frequency within glioblastoma (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 tumor may co-express multiple different EGFR oncogenic mutations.

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

The formatting of these constitutive dimers is essential for oncogenicity.

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

We believe this is due to (i) inability to inhibit the entire group of allosteric glioblastoma mutations expressed in a given tumor, (ii) the inability to target the constitutive dimer conformation and (iii) poor brain penetration.

The figure below illustrates distinct allosteric EGFR oncogenic mutations (EGFR-Viii, EGFR-Vii, EGFR-Vi, EGFR-A289V) that similarly promote a constitutive dimer conformation, which is different from the transient dimer conformation for wild type EGFR.

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

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

We have applied our platform and our proprietary chemistry know-how to design and develop potent and selective inhibitors targeting a group of glioblastoma constitutive dimer EGFR mutations described above.

In November 2020, we announced the nomination of BDTX-1535 as a development candidate for the treatment of glioblastoma.

In cell-based assays, BDTX-1535 achieved potent MasterKey inhibition of all members of the family of oncogenic EGFR variants expressed in glioblastoma with selectivity versus wild type EGFR.

Anti-proliferative activity against BaF3 transformants expressing allosteric EGFR oncogenes versus EGFR WT expressing A431 cells

Additionally, in mouse models, BDTX-1535 demonstrated a pharmacokinetic profile that supports its ability to penetrate the blood-brain barrier.

BDTX-1535 achieved complete and sustained inhibition of the phosphorylated state of EGFR in mouse models bearing Ba/F3 allosteric EGFR mutants, as well as tumor growth inhibition in mouse models bearing intracranial PDX tumors expressing allosteric EGFR mutants.

Bioluminescence imaging in mice expressing intracranial GBM6 patient derived tumors.

Mice were treated orally with 50mg/kg of BDTX-1535

IND-enabling studies for BDTX-1535 are ongoing, and we anticipate filing an IND in the first half of 2022.

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

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.

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.

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

Classification of BRAF mutations.

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

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

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.

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.

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

MasterKey property of BDTX-4933 inhibitor:

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

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.

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.

Early-stage programs

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

Of these 92 kinases, we applied our MAP scoring algorithm to six kinases, including all ErbB family members, other RTKs (FGFR2/3) and a non-receptor kinase (BRAF).

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

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

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

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

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

Additionally, both approved drugs and product candidates that are currently in clinical development lead to paradoxical activation of wild type-RAF and select non-canonical mutations, which can lead to secondary malignancies.

Our BRAF program leverages our MAP Platform to (i) define the full spectrum of oncogenic Class II and Class III mutations expressed by human cancers, which includes groups of novel oncogenic mutations that we have validated internally;

(ii) classify mutations according to unifying conformational changes;

and (iii) design small molecule inhibitors that are active against the full spectrum of BRAF oncogenic mutations.

Our BRAF program compounds are MasterKey therapies designed to target clusters of known and novel oncogenic BRAF Class II/Class III alterations, while avoiding paradoxical activation independent of context.

Tumor regression in mouse models has been observed.

We anticipate filing an IND for the BDTX BRAF program in 2022.

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

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

While these mutations have been targeted by two first generation pan-FGFR inhibitors (erdafitinib and pemigatinib), 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.

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 Platform to (i) define the full spectrum of FGFR2/3 oncogenic mutations, which are allosteric;

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 Platform drug discovery platform is differentiated by its capability to identify development candidates that are selective versus FGFR1.

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

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.

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 filing an IND for the BDTX FGFR program in 2022.

Our collaboration with Ridgeline Therapeutics

During our initial years of operation, we built and conducted our research and development activities via a collaborative model with Ridgeline Therapeutics GmbH, or Ridgeline, a wholly-owned subsidiary of Versant Ventures, our largest shareholder.

Ridgeline is a company incubator and discovery engine of Versant focused on providing drug discovery expertise.

By leveraging Ridgeline’s deep experience in the areas of discovery, drug design and medicinal chemistry together with our biology expertise, we were able to accelerate the discovery and development of spectrum selective and highly potent small molecule inhibitors targeting the oncogenic driver mutations in our lead programs.

We entered into a services agreement (the “Service Agreement”) with Ridgeline in March 2017, amended in November 2017, December 2018 and March 2020, or the Service Agreement.

In March 2020, we transitioned from our previous service model with Ridgeline to a more limited consulting arrangement.

We have continued to build our internal chemistry, manufacturing and controls, biology and preclinical development capabilities through key additional hires and have assumed all activities that were previously conducted by Ridgeline on our behalf.

All results, inventions, and products and any related intellectual property that arose from services provided by Ridgeline are owned by us.

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

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

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

For example, we expect BDTX-189 will compete against approved and in-development compounds in the following spaces:

• In the EGFR Exon 20 insertion NSCLC space:

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

mobocertinib (TAK-788), which is under development by Takeda Pharmaceutical Company Ltd;

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

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

• In the HER2 Exon 20 insertion NSCLC space:

trastuzumab deruxtecan (DS-8201), which is marketed by Daiichi Sankyo Company Ltd.

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

• In patients with EGFR acquired resistance:

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

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

BLU-701 and BLU-945, which are under development by BluePrint Medicines Corporation;

and BBT-176, which is being developed by Bridge Biotherapeutics, Inc.

• In patients with EGFR intrinsic resistance:

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

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

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

• In patients with EGFR alterations present in glioblastoma:

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

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

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

RO7428731, which is under development by Hoffman Roche;

TAS2940, which is under development by Taiho Oncology, Inc.;

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 Jiansu Hengrui Medicine Co Ltd.

• In the allo-HER2 space:

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.

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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), Blueprint Medicines Corporation, Deciphera Pharmaceuticals, Inc., Turning Point Therapeutics, Inc., Mirati Therapeutics, Inc., Relay Therapeutics, 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.

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In addition, a number of established research-based pharmaceutical and biotechnology companies may acquire products in late stages of development to augment their internal product lines, which may provide those companies with an even greater competitive advantage.

Manufacturing

We do not have any manufacturing facilities or personnel.

Manufacturing and Supply

We do not own or operate, and currently have no plans to establish, any manufacturing facilities.

We currently rely, and expect to continue to rely, on third parties for the manufacture of our product candidates undergoing preclinical testing, as well as for clinical testing and commercial manufacture if our product candidates receive marketing approval.

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

We expect to continue to develop product candidates that can be produced cost-effectively at contract manufacturing facilities.

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

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

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As with other biotechnology and pharmaceutical companies, our ability to maintain and solidify our proprietary and intellectual property position for our product candidates and technologies will depend on our success in obtaining effective patent claims and enforcing those claims if granted.

However, our pending provisional and PCT patent applications, and any patent applications that we may in the future file or license from third parties, may not result in the issuance of patents and any issued patents we may obtain do not guarantee us the right to practice our technology in relation to the commercialization of our products.

However, our pending patent applications, and any patent applications that we may in the future file or license from third parties, may not result in the issuance of patents and any issued patents we may obtain do not guarantee us the right to practice our technology in relation to the commercialization of our products.

We also cannot predict the breadth of claims that may be allowed or enforced in any patents we may own or in-license in the future.

Any issued patents that we may own or in-license in the future may be challenged, invalidated, circumvented or have the scope of their claims narrowed.

Any issued patents that we own, or may own or in-license in the future may be challenged, invalidated, circumvented or have the scope of their claims narrowed.

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

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The restoration period granted on a patent covering a product is typically one-half the time between the effective date of a clinical investigation involving human beings is begun and the submission date of an application, plus the time between the submission date of an application and the ultimate approval date.

The restoration period cannot be longer than five

years and the total patent term, including the restoration period, must not exceed 14 years following FDA approval.

The restoration period cannot be longer than five years and the total patent term, including the restoration period, must not exceed 14 years following FDA approval.

Only one patent applicable to an approved product is eligible for the extension, and only those claims covering the approved product, a method for using it, or a method for manufacturing it may be extended.

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In the future, if our product candidates receive approval by the FDA, we expect to apply for patent term extensions on any issued patents covering those products, depending upon the length of the clinical studies for each product and other factors.

There can be no assurance that our pending provisional or PCT 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.

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.

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 February 28, 2021, we own eleven U.S.

provisional patent applications, two pending U.S.

patent applications, and four Patent Cooperation Treaty, or PCT, patent applications.

We currently do not own or in-license any issued patents with respect to BDTX-189, our MAP platform or our Glioblastoma program, and our intellectual property portfolio is in its very early stages.

We do not currently own or in-license any issued patents or provisional or non-provisional patent applications covering our other product candidates or technology.

As of February 28, 2021, we own six U.S.

provisional patent applications, one pending U.S.

patent application, and three PCT patent applications that cover our tumor agnostic program.

The program includes six U.S.

As of March 1, 2022, we own 20 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.

or foreign patent issuing from these patent applications would be scheduled to expire in 2039 to 2042, 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.

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

patent application, and one PCT patent application that collectively cover the composition of matter for BDTX-189, polymorphs of BDTX-189, as well as methods of using and making BDTX-189.

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 February 28, 2021, we own one U.S.

patent application that covers our MAP platform and the use thereof in developing and applying therapeutics.

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.

MAP drug discovery engine

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

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

patent issued from this U.S.

patent application would be scheduled to expire in 2040, excluding any additional term for patent term adjustment or patent term extension.

As of February 28, 2021, we own two U.S.

provisional patent applications and one PCT patent application that cover our glioblastoma program, which are directed to the composition of matter for the drug candidates of the program, analogs thereof, as well as methods of using and making these compounds.

or foreign patent issued from these U.S.

pending applications would be scheduled to expire between 2040 and 2041, excluding any additional term for patent term adjustment or patent term extension.

As of February 28, 2021, we own one U.S.

provisional patent application that covers 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 this pending application would be scheduled to expire in 2042, excluding any additional term for patent term adjustment or patent term extension.

As of February 28, 2021, we own one U.S.

provisional 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, excluding any additional term for patent term adjustment or patent term extension.

Prosecution for these patent applications has not commenced and will not commence unless and until they are timely converted into U.S.

non-provisional or national stage applications.

Prosecution is a lengthy process, during which the scope of the claims initially submitted for examination by the USPTO are often significantly narrowed by the time they issue, if they issue at all.

or foreign patent issuing from these provisional or PCT patent applications (if timely converted to U.S.

non-provisional or foreign patent applications and such non-provisional or foreign applications are granted as issued patents), would be scheduled to expire in 2039 or 2040, 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.

Any of our pending PCT patent applications are not eligible to become issued patents until, among other things, we file national stage patent applications within 30 months in the countries in which we seek patent protection.

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

While we intend to timely file non-provisional and national stage patent applications relating to our provisional and PCT patent applications, we cannot predict whether any of our future patent applications for BDTX-189 or any of our other product candidates or technology will result in the issuance of patents that effectively protect BDTX-189 or our other product candidates or technology.

If we do not successfully obtain patent protection, or, even if we do obtain patent protection, if the scope of the patent protection we or our potential licensors obtain with respect to BDTX-189 or our other product candidates or technology is not sufficiently broad, we will be unable to prevent others from using our technology or from developing or commercializing technology and products similar or identical to ours or other competing products and technologies.

While we intend to timely file non-provisional and national stage patent applications relating to our provisional and PCT patent applications, we cannot predict whether any of our future patent applications for BDTX-1535, BDTX-189 or any of our other product candidates or technology will result in the issuance of patents that effectively protect BDTX-1535, BDTX-189 or our other product candidates or technology.

If we do not successfully obtain patent protection, or, even if we do obtain patent protection, if the scope of the patent protection we or our potential licensors obtain with respect to BDTX-1535, BDTX-189 or our other product candidates or technology is not sufficiently broad, we will be unable to prevent others from using our technology or from developing or commercializing technology and products similar or identical to ours or other competing products and technologies.

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

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Although we take steps to protect our proprietary information, third parties may independently develop the same or similar proprietary information or may otherwise gain access to our proprietary information.

As a result, we may be unable to meaningfully protect our

trade secrets and proprietary information.

As a result, we may be unable to meaningfully protect our trade secrets and proprietary information.

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

Government regulation

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

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

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

The process of obtaining regulatory approvals of drugs and ensuring subsequent compliance with appropriate federal, state, local and foreign statutes and regulations requires the expenditure of substantial time and financial resources.

In the United States, where we are initially focusing our drug development, the FDA regulates drug products under the federal Food, Drug and Cosmetic Act, its implementing regulations and other laws.

In the United States, where we are initially focusing our drug development, the FDA regulates drug products under the U.S.

Federal Food, Drug and Cosmetic Act (FD&C Act), its implementing regulations and other laws.

Our product candidates are early-stage and none of our product candidates has been approved by the FDA for marketing in the United States.

If we fail to comply with applicable FDA or other requirements at any time with respect to product development, clinical testing, approval or any other legal requirements relating to product manufacture, processing, handling, storage, quality control, safety, marketing, advertising, promotion, packaging, labeling, export, import, distribution, or sale, we may become subject to administrative or judicial sanctions or other legal consequences.

These sanctions or consequences could include, among other things, the FDA’s refusal to approve pending applications, issuance of clinical holds for ongoing studies, suspension or revocation of approved applications, warning or untitled letters, product withdrawals or recalls, product seizures, relabeling or repackaging, total or partial suspensions of manufacturing or distribution, injunctions, fines, civil penalties or criminal prosecution.

Department of Justice or other governmental entities.

The process required by the FDA before our product candidates are approved as drugs for therapeutic indications and may be marketed in the United States generally involves the following:

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A new drug is eligible for Fast Track designation if it is intended to treat a serious or life-threatening disease or condition and demonstrates the potential to address unmet medical needs for such disease or condition.

designation provides increased opportunities for sponsor interactions with the FDA during preclinical and clinical development, in addition to the potential for rolling review once a marketing application is filed, meaning that the agency may review portions of the marketing application before the sponsor submits the complete application, as well as Priority Review, discussed below.

Fast Track designation provides increased opportunities for sponsor interactions with the FDA during preclinical and clinical development, in addition to the potential for rolling review once a marketing application is filed, meaning that the agency may review portions of the marketing application before the sponsor submits the complete application, as well as Priority Review, discussed below.

In addition, a new drug may be eligible for Breakthrough Therapy designation if it is intended to treat a serious or life-threatening disease or condition and preliminary clinical evidence indicates that the drug may demonstrate substantial improvement over existing therapies on one or more clinically significant endpoints, such as substantial treatment effects observed early in clinical development.

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The FDA and the sponsor must reach an agreement on the PSP.

A sponsor can submit amendments to an agreed-upon

initial PSP at any time if changes to the pediatric plan need to be considered based on data collected from preclinical studies, early phase clinical trials and/or other clinical development programs.

A sponsor can submit amendments to an agreed-upon initial PSP at any time if changes to the pediatric plan need to be considered based on data collected from preclinical studies, early phase clinical trials and/or other clinical development programs.

A drug can also obtain pediatric market exclusivity in the United States.

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In addition, drug manufacturers and their subcontractors involved in the manufacture and distribution of approved drugs are required to register their establishments with the FDA and certain state agencies and are subject to periodic unannounced inspections by the FDA and certain state agencies for compliance with ongoing regulatory requirements, including cGMP, which impose certain procedural and documentation requirements upon us and our contract manufacturers.

Manufacturers and other parties involved in the drug supply chain for prescription drug products must also comply with product tracking and tracing requirements and for notifying the FDA of counterfeit, diverted, stolen and intentionally adulterated products or products that are otherwise unfit for distribution in the United States.

Failure to comply with statutory and regulatory requirements can subject a manufacturer to possible legal or regulatory action, such as warning letters, suspension of manufacturing, product seizures, injunctions, civil penalties or criminal prosecution.

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On July 31, 2014, the FDA issued a final guidance document addressing the development and approval process for “In Vitro Companion Diagnostic Devices.” According to the guidance document, for novel therapeutic products that depend on the use of a diagnostic test and where the diagnostic device could be essential for the safe and effective use of the corresponding therapeutic product, the premarket application for the companion diagnostic device should be developed and approved or cleared contemporaneously with the therapeutic, although the FDA recognizes that there may be cases when contemporaneous development may not be possible.

However, in cases where a drug cannot be

used safely or effectively without the companion diagnostic, the FDA’s guidance indicates it will generally not approve the drug without the approval or clearance of the diagnostic device.

However, in cases where a drug cannot be used safely or effectively without the companion diagnostic, the FDA’s guidance indicates it will generally not approve the drug without the approval or clearance of the diagnostic device.

The FDA also issued a draft guidance in July 2016 setting forth the principles for co-development of an in vitro companion diagnostic device with a therapeutic product.

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Manufacturing, sales, promotion and other activities of product candidates following product approval, where applicable, or commercialization are also subject to regulation by numerous regulatory authorities in the United States in addition to the FDA, which may include the Centers for Medicare & Medicaid Services, or CMS, other divisions of the Department of Health and Human Services, or HHS, the Department of Justice, the Drug Enforcement Administration, the Consumer Product Safety Commission, the Federal Trade Commission, the Occupational Safety & Health Administration, the Environmental Protection Agency and state and local governments and governmental agencies.

Other healthcare laws

Other healthcare and privacy laws

Healthcare providers, physicians, and third-party payors will play a primary role in the recommendation and prescription of any products for which we obtain marketing approval.

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In the United States, these laws include, without limitation, state and federal anti-kickback, false claims, physician transparency, and patient data privacy and security laws and regulations, including but not limited to those described below.

• The federal Anti-Kickback Statute, which prohibits, among other things, persons and entities from knowingly and willfully soliciting, offering, paying, receiving or providing any remuneration (including any kickback, bride, or certain rebate), directly or indirectly, overtly or covertly, in cash or in kind, to induce or reward, or in return for, either the referral of an individual for, or the purchase, order or recommendation of, any good or service, for which payment may be made, in whole or in part, under a federal healthcare program such as Medicare and Medicaid;

a person or entity need not have actual knowledge of the federal Anti-Kickback Statute or specific intent to violate it in order to have committed a violation.

• The federal Anti-Kickback Statute, which prohibits, among other things, persons and entities from knowingly and willfully soliciting, offering, receiving or providing remuneration (including any kickback, bribe, or rebate), directly or indirectly in cash or in kind, to induce or reward either the referral of an individual for, or the purchase, lease, order, arrangement or recommendation of, any good, facility, item or service, for which payment may be made under federal and state healthcare programs such as Medicare and Medicaid.

A person or entity does not need to have actual knowledge of the federal Anti-Kickback Statute (AKS) or specific intent to violate it to have committed a violation.

Violations are subject to civil and criminal fines and penalties for each violation, plus up to three times the remuneration involved, imprisonment, and exclusion from government healthcare programs.

In addition, the government may assert that a claim that includes items or services resulting from a violation of the federal Anti-Kickback Statute constitutes a false or fraudulent claim for purposes of the civil False Claims Act.

• The federal civil and criminal false claims laws, including the civil False Claims Act, or FCA, which prohibit individuals or entities from, among other things, knowingly presenting, or causing to be presented, to the federal government, claims for payment or approval that are false, fictitious or fraudulent;

knowingly making, using, or causing to be made or used, a false statement or record material to a false or fraudulent claim or obligation to pay or transmit money or property to the federal government;

or knowingly concealing or knowingly and improperly avoiding or decreasing an obligation to pay money to the federal government.

In addition, the government may assert that a claim including items or services resulting from a violation of the AKS constitutes a false or fraudulent claim for purposes of the federal False Claims Act (FCA) or federal civil money penalties.

• The federal civil and criminal false claims laws, including the FCA, and civil monetary penalty laws which can be enforced through civil whistleblower or qui tam actions, which imposes civil and criminal penalties against individuals or entities for knowingly presenting or causing to be presented, to the federal government, claims for payment or approval from Medicare, Medicaid or other government payors that are false or fraudulent or making a false statement to avoid, decrease or conceal an obligation to pay to the federal government, with potential liability including mandatory treble damages and significant per-claim penalties.

Manufacturers can be held liable under the FCA even when they do not submit claims directly to government payors if they are deemed to “cause” the submission of false or fraudulent claims.

The FCA also permits a private individual acting as a “whistleblower” to bring actions on behalf of the federal government alleging

violations of the FCA and to share in any monetary recovery.

When an entity is determined to have violated the federal civil False Claims Act, the government may impose civil fines and penalties for each false claim, plus treble damages, and exclude the entity from participation in Medicare, Medicaid and other federal healthcare programs.

On November 20, 2020, the Office of Inspector General, or OIG, finalized further modifications to the federal Anti-Kickback Statute.

Under the final rules, OIG added safe harbor protections under the Anti-Kickback Statute for certain coordinated care and value-based arrangements among clinicians, providers, and others.

These rule (with exceptions) became effective January 19, 2021.

We continue to evaluate what effect, if any, these rules will have on our business.

• The federal civil monetary penalties laws, which impose civil fines for, among other things, the offering or transfer or remuneration to a Medicare or state healthcare program beneficiary if the person knows or should know it is likely to influence the beneficiary’s selection of a particular provider, practitioner, or supplier of services reimbursable by Medicare or a state health care program, unless an exception applies.

• The Health Insurance Portability and Accountability Act of 1996, or HIPAA, imposes criminal and civil liability for knowingly and willfully executing a scheme, or attempting to execute a scheme, to defraud any healthcare benefit program, including private payors, knowingly and willfully embezzling or stealing from a healthcare benefit program, willfully obstructing a criminal investigation of a healthcare offense, or falsifying, concealing or covering up a material fact or making any materially false statements in connection with the delivery of or payment for healthcare benefits, items or services.

Similar to the U.S.

federal Anti-Kickback Statute, a person or entity does not need to have actual knowledge of the healthcare fraud statute implemented under HIPAA or specific intent to violate it in order to have committed a violation.

• HIPAA, as amended by the Health Information Technology for Economic and Clinical Health Act of 2009, or HITECH, and their respective implementing regulations, imposes, among other things, specified requirements on covered entities and their business associates relating to the privacy and security of individually identifiable health information including mandatory contractual terms and required implementation of technical safeguards of such information.

HITECH also created new tiers of civil monetary penalties, amended HIPAA to make civil and criminal penalties directly applicable to business associates in some cases, and gave state attorneys general new authority to file civil actions for damages or injunctions in federal courts to enforce the federal HIPAA laws and seek attorneys’ fees and costs associated with pursuing federal civil actions.

• The Physician Payments Sunshine Act, enacted as part of the Patient Protection and Affordable Care Act, as amended by the Health Care and Education Reconciliation Act of 2010, or collectively, the ACA, imposed new annual reporting requirements for certain manufacturers of drugs, devices, biologics, and medical supplies for which payment is available under Medicare, Medicaid, or the Children’s Health Insurance Program, for certain payments and “transfers of value” provided to physicians (defined to include doctors, dentists, optometrists, podiatrists and chiropractors) and teaching hospitals, as well as ownership and investment interests held by physicians and their immediate family members.

Effective January 1, 2022, these reporting obligations will extend to include transfers of value made to certain non-physician providers such as physician assistants and nurse practitioners.

The FCA also permits a private individual acting as a “whistleblower” to bring actions on behalf of the federal government alleging violations of the FCA and to share in any monetary recovery.

• The federal Health Insurance Portability and Accountability Act of 1996 (HIPAA), which prohibits, among other things, knowingly and willfully executing or attempting to execute, a scheme or artifice to defraud any healthcare benefit program or obtain, by means of false or fraudulent pretenses, representations, or promises, any of the money or property owned by, or under the custody or control of, any healthcare benefit program, regardless of the payor (e.g., public or private), and knowingly and willfully falsifying, concealing or covering up by any trick or device a material fact or making any materially false, fictitious or fraudulent statements in connection with the delivery of or payment for, healthcare benefits, items or services relating to healthcare benefits, items or services relating to healthcare matters.

Similar to the AKS, a person or entity does not need to have actual knowledge of the statute or specific intent to violate it in order to have committed a violation.

• HIPAA, as further amended by the Health Information Technology for Economic and Clinical Health Act of 2009 (HITECH) and their respective implementing regulations, including the Final Omnibus Rule published in January 2013, which impose certain requirements, including mandatory contractual terms, on covered entities subject to the rule, such as health plans, healthcare clearinghouses and certain healthcare providers, as well as their respective business associates and their subcontractors that perform services for them that involve the creation, maintenance, receipt, use, or disclosure of, individually identifiable health information, relating to the privacy, security, and transmission of such individually identifiable health information relating to the privacy, security and transmission of individually identifiable health information.

HITECH also created new tiers of civil monetary penalties, amended HIPAA to make civil and criminal penalties directly applicable to business associates, and gave state attorneys general new authority to file civil actions for damages or injunctions in federal courts to enforce the federal HIPAA laws and seek attorneys’ fees and costs associated with pursuing federal civil actions.

In addition, there may be additional federal, state and non-U.S.

laws which govern the privacy and security of health and other personal information in certain circumstances, many of which differ from each other in significant ways and may not have the same effect, thus complicating compliance efforts.

Physician Payments Sunshine Act and its implementing regulations, which requires certain manufacturers of drugs, devices, biologics and medical supplies that are reimbursable under Medicare, Medicaid, or the Children’s Health Insurance Program, with specific exceptions, to report annually to CMS information related to certain payments and other transfers of value to physicians, nurse practitioners, certified nurse anesthetists, physician assistants, clinical nurse specialists, and certified nurse midwives as well as teaching hospitals.

Manufacturers are also required to disclose ownership and investment interests held by physicians and their immediate family members.

Effective January 1, 2022, these reporting obligations extend to include transfers of value made to certain non-physician providers (physician assistants, nurse practitioners clinical nurse specialists, certified registered nurse anesthetists and anesthesiologist assistants, and certified-nurse midwives).

In addition, many states also require reporting of payments or other transfers of value, many of which differ from each other in significant ways, are often not pre-empted, and may have a more prohibitive effect than the Sunshine Act, thus further complicating compliance efforts.

• Federal consumer protection and unfair competition laws, which broadly regulate marketplace activities and activities that potentially harm consumers.

• Analogous state and foreign fraud and abuse laws and regulations, such as state anti-kickback and false claims laws, which may be broader in scope and apply regardless of payor.

These laws are enforced by various state agencies and through private actions.

Some state laws require pharmaceutical companies implement compliance to comply with the pharmaceutical industry’s voluntary compliance guidelines and the relevant federal government compliance guidance, require drug manufacturers to report information related to payments and other transfers of value to physicians and other healthcare providers, and restrict marketing practices or require disclosure of marketing expenditures and pricing information.

State and foreign laws also govern the privacy and security of health information in some circumstances.

These data privacy and security

laws may differ from each other in significant ways and often are not pre-empted by HIPAA, which may complicate compliance efforts.

State and foreign laws also govern the privacy and security of health information in some circumstances.

These data privacy and security laws may differ from each other in significant ways and often are not pre-empted by HIPAA, which may complicate compliance efforts.

California recently enacted the California Consumer Privacy Act, or CCPA, which creates new individual privacy rights for California consumers (as defined in the law) and places increased privacy and security obligations on entities handling personal data of consumers or households.

The CCPA will require covered companies to provide certain disclosures to consumers about its data collection, use and sharing practices, and to provide affected California residents with ways to opt-out of certain sales or transfers of personal information.

The CCPA went into effect on January 1, 2020, and the California Attorney General commenced enforcement actions against violators beginning July 1, 2020.

While there is currently an exception for protected health information that is subject to HIPAA and clinical trial regulations, as currently written, the CCPA may impact our business activities.

The California Attorney General has proposed draft regulations, which have not been finalized to date, that may further impact our business activities if they are adopted.

The uncertainty surrounding the implementation of CCPA exemplifies the vulnerability of our business to the evolving regulatory environment related to personal data and protected health information.

The scope and enforcement of each of these laws is uncertain and subject to rapid change in the current environment of healthcare reform, especially in light of the lack of applicable precedent and regulations.

Federal and state enforcement bodies have recently increased their scrutiny of interactions between healthcare companies, including pharmaceutical manufacturers, and healthcare providers, which has led to a number of investigations, prosecutions, convictions and settlements in the healthcare industry.

It is possible that governmental authorities will conclude that our business practices do not comply with current or future statutes, regulations or case law involving applicable fraud and abuse or other healthcare laws and regulations.

If our operations are found to be in violation of any of these laws or any other related governmental regulations that may apply to us, we may be subject to significant civil, criminal and administrative penalties, damages, fines, imprisonment, disgorgement, exclusion from government funded healthcare programs, such as Medicare and Medicaid, reputational harm, additional oversight and reporting obligations if we become subject to a corporate integrity agreement or similar settlement to resolve allegations of non-compliance with these laws and the curtailment or restructuring of our operations.

If any of the physicians or other healthcare providers or entities with whom we expect to do business is found to be not in compliance with applicable laws, they may be subject to similar actions, penalties and sanctions.

Ensuring business arrangements comply with applicable healthcare laws, as well as responding to possible investigations by government authorities, can be time- and resource-consuming and can divert a company’s attention from its business.

• Federal government price reporting laws, which require us to calculate and report complex pricing metrics in an accurate and timely manner to government programs.

• Federal consumer protection and unfair competition laws, which broadly regulate marketplace activities and activities that potentially harm customers.

Additionally, we are subject to state and foreign equivalents of each of the healthcare laws and regulations described above, among others, some of which may be broader in scope and may apply regardless of the payor.

states have adopted laws similar to the AKS and FCA, and may apply to our business practices, including, but not limited to, research, distribution, sales or marketing arrangements and claims involving healthcare items or services reimbursed by non-governmental payors, including private insurers.

In addition, some states have passed laws that require pharmaceutical companies to comply with the April 2003 Office of Inspector General Compliance Program Guidance for Pharmaceutical Manufacturers and/or the Pharmaceutical Research and Manufacturers of America’s Code on Interactions with Healthcare Professionals.

Several states also impose other marketing restrictions or require pharmaceutical companies to make marketing or price disclosures to the state and require the registration of pharmaceutical sales representatives.

State and foreign laws, including for example the EU General Data Protection Regulation (GDPR), which became effective May 2018 also govern the privacy and security of health information in some circumstances, many of which differ from each other in significant ways and often are not preempted by HIPAA, thus complicating compliance efforts.

There are ambiguities as to what is required to comply with these state requirements and if we fail to comply with an applicable state law requirement we could be subject to penalties.

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

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

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

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

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

Moreover, agreements with physicians often must be the subject of prior notification and approval by the physician’s employer, his or her competent professional organization and/or the regulatory authorities of the individual EU Member States.

These requirements are provided in the national laws, industry codes or professional codes of conduct applicable in the EU Member States.

Failure to comply with these requirements could result in reputational risk, public reprimands, administrative penalties, fines or imprisonment.

The scope and enforcement of these laws is uncertain and subject to rapid change in the current environment of healthcare reform, especially in light of the lack of applicable precedent and regulations.

Federal and state enforcement has led to a number of investigations, prosecutions, convictions and settlements in the healthcare industry.

Ensuring that our internal operations and future business arrangements with third parties comply with applicable healthcare laws and regulations will involve substantial costs.

It is possible that governmental authorities will conclude that our business practices do not comply with current or future statutes, regulations, agency guidance or case law involving applicable fraud and abuse or other healthcare laws and regulations.

If our operations are found to be in violation of any of the laws described above or any other governmental laws and regulations that may apply to us, we may be subject to significant penalties, including administrative, civil and criminal penalties, damages, fines, disgorgement, the exclusion from participation in federal and state healthcare programs, reputational harm, and the curtailment or restructuring of our operations, as well as additional reporting obligations and oversight if we become subject to a corporate integrity agreement or other agreement to resolve allegations of non-compliance with these laws.

Further, defending against any such actions can be costly and time-consuming, and may require significant financial and personnel resources.

Therefore, even if we are successful in defending against any such actions that may be brought against us, our business may be impaired.

If any of the physicians or other providers or entities with whom we expect to do business are found to not be in compliance with applicable laws, they may be subject to criminal, civil or administrative sanctions, including exclusions from government funded healthcare programs and individual imprisonment.

If any of the above occur, our ability to operate our business and our results of operations could be adversely affected.

Insurance Coverage and Reimbursement

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

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

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

Current and future healthcare reform legislation

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

Since its enactment, there have been numerous judicial, administrative, executive, and legislative challenges to certain aspects of the ACA, and we expect there will be additional challenges and amendments to the ACA in the future.

For example, various portions of the ACA are currently undergoing legal and constitutional challenges in the Fifth Circuit Court, and the United States Supreme Court.

Additionally, the Trump Administration issued various Executive Orders which eliminated cost sharing subsidies and various provisions that would impose a fiscal burden on states or a cost, fee, tax, penalty or regulatory burden on individuals, healthcare providers, health insurers, or manufacturers of pharmaceuticals or medical devices, and Congress has introduced several pieces of legislation aimed at significantly revising or repealing the ACA.

It is unclear whether the ACA will be overturned, repealed, replaced, or further amended, especially under the Biden administration.

We cannot predict what affect further changes to the ACA would have on our business.

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

On June 17, 2021, the U.S.

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

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

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

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

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

• 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, 2021 due to the COVID-19 pandemic.

Proposed legislation, if passed, would extend this suspension until the end of the 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.

Moreover, payment methodologies may be subject to changes in healthcare legislation and regulatory initiatives.

For example, CMS may develop new payment and delivery models, such as bundled payment models.

In addition, recently there has been heightened governmental scrutiny over the manner in which manufacturers set prices for their commercial products, which has resulted in several Congressional inquiries and proposed and enacted state and federal legislation designed to, among other things, bring more transparency to product pricing, review the relationship between pricing and manufacturer patient programs, and reform government program reimbursement methodologies for pharmaceutical products.

For example, at the federal level, the Trump administration’s budget for fiscal year 2021 included a $135 billion allowance to support legislative proposals seeking to reduce drug prices, increase competition, lower out-of-pocket drug costs for patients, and increase patient access to lower-cost generic and biosimilar drugs.

On March 10, 2020, the Trump administration sent “principles” for drug pricing to Congress, calling for legislation that would, among other things, cap Medicare Part D beneficiary out-of-pocket pharmacy expenses, provide an option to cap Medicare Part D beneficiary monthly out-of-pocket expenses, and place limits on pharmaceutical price increases.

Additionally, the Trump administration also previously released a “Blueprint” to lower drug prices and reduce out of pocket costs of drugs that contains additional proposals to increase drug manufacturer competition, increase the negotiating power of certain federal healthcare programs, incentivize manufacturers to lower the list price of their products, and reduce the out of pocket costs of drug products paid by consumers.

HHS solicited feedback on some of these measures and has implemented others under its existing authority.

For example, in May 2019, CMS issued a final rule to allow Medicare Advantage Plans the option of using step therapy, a type of prior authorization, for Part B drugs beginning January 1, 2020.

This final rule codified CMS’s policy change that was effective January 1, 2019.

It is unclear whether the Biden administration will challenge, reverse, revoke or otherwise modify these executive and administrative actions after January 20, 2021.

Congress and the Trump administration each indicated that it will continue to seek new legislative and/or administrative measures to control drug costs.

The FDA published a final rule, effective November 30, 2020, that allows for the importation of certain prescription drugs from Canada.

Under the final rule, states and Indian Tribes, and in certain future circumstances pharmacists and wholesalers, may submit importation program proposals to the FDA for review and authorization.

Separately, the FDA also issued a final guidance document outlining a potential pathway for manufacturers to obtain an additional National Drug Code, or NDC, for an FDA-approved drug that was originally intended to be marketed in a foreign country and that was authorized for sale in that foreign country.

Individual states in the United States have also increasingly passed legislation and implemented regulations designed to control pharmaceutical product pricing, including price or patient reimbursement constraints, discounts, restrictions on certain

product access and marketing cost disclosure and transparency measures, and, in some cases, designed to encourage importation from other countries and bulk purchasing.

• On April 13, 2017, CMS published a final rule that gives states greater flexibility in setting benchmarks for insurers in the individual and small group marketplaces, which may have the effect of relaxing the essential health benefits required under the ACA for plans sold through such marketplaces.

• On May 30, 2018, the Right to Try Act, was signed into law.

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Under certain circumstances, eligible patients can seek treatment without enrolling in clinical trials and without obtaining FDA permission under the FDA expanded access program.

There is no obligation for a drug manufacturer to make its drug products available to eligible patients as a result of the Right to Try Act, but the manufacturer must develop an internal policy and respond to patient requests according to that policy.

There is no obligation for a pharmaceutical manufacturer to make its drug products available to eligible patients as a result of the Right to Try Act.

• 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.

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.

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

Specifically, there has been heightened governmental scrutiny over the manner in which manufacturers set prices for their marketed products, which has resulted in several U.S.

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

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

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

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

and directs the FDA to work

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

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

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

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

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

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.

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.

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

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

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The conduct of such a clinical trial could be expensive and result in delays in commercialization.

In the European Union, or EU, pricing and reimbursement schemes vary widely from country to country.

Some of our manufacturers are located outside of the United States.

There is currently significant uncertainty about the future relationship between the U.S.

and various other countries, including China, with respect to trade policies, treaties, government regulations and tariffs.

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

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

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

and uncertainty regarding how the U.S.

or foreign governments will act with respect to tariffs, international trade agreements and policies, further governmental action related to tariffs, additional taxes, regulatory changes or other retaliatory trade measures in the future could occur with a corresponding detrimental impact on our business and financial condition.

In the EU, pricing and reimbursement schemes vary widely from country to country.

Some countries provide that products may be marketed only after a reimbursement price has been agreed.

Some countries may require the completion of additional studies that compare the cost-effectiveness of a particular product candidate to currently available therapies or so-called health technology assessments, in order to obtain reimbursement or pricing approval.

For example, the European Union provides options for its member states to restrict the range of products for which their national health insurance systems provide reimbursement and to control the prices of medicinal products for human use.

European Union member states may approve a specific price for a product or it may instead adopt a system of direct or indirect controls on the profitability of the company placing the product on the market.

For example, the EU provides options for its Member States to restrict the range of products for which their national health insurance systems provide reimbursement and to control the prices of medicinal products for human use.

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

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

Recently, many countries in the European Union 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 European Union.

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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Political, economic and regulatory developments may further complicate pricing negotiations, and pricing negotiations may continue after reimbursement has been obtained.

Reference pricing used by various European Union member states, and parallel trade, i.e., arbitrage between low-priced and high-priced member states, can further reduce prices.

Reference pricing used by various EU Member States, and parallel trade, i.e., arbitrage between low-priced and high-priced member states, can further reduce prices.

There can be no assurance that any country that has price controls or reimbursement limitations for pharmaceutical products will allow favorable reimbursement and pricing arrangements for any products, if approved in those countries.

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The failure to comply with any of these laws or regulatory requirements subjects firms to possible legal or regulatory action.

Depending on the circumstances, failure to meet applicable regulatory requirements can result in criminal prosecution, fines or other penalties, injunctions, exclusion from federal healthcare programs, requests for recall, seizure of products, total or partial suspension of production, denial or withdrawal of product approvals, relabeling or

repackaging, or refusal to allow a firm to enter into supply contracts, including government contracts.

Any claim or action against us for violation of these laws, even if we successfully defend against it, could cause us to incur significant legal expenses and divert our management’s attention from the operation of our business.

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To market any product outside of the United States, we would need to comply with numerous and varying regulatory requirements of other countries regarding safety and efficacy and governing, among other things, clinical trials, marketing authorization or identification of an alternate regulatory pathway, manufacturing, commercial sales and distribution of our products.

For instance, in the United Kingdom and the European Economic Area, or the EEA (comprised of the 28 EU Member States plus Iceland, Liechtenstein and Norway), medicinal products, including advanced therapy medicinal products, or ATMPs, are subject to extensive pre- and post-market regulation by regulatory authorities at both the EEA and national levels.

ATMPs comprise gene therapy products, somatic cell therapy products and tissue engineered products.

Gene therapy products deliver genes into the body that lead to a therapeutic, prophylactic or diagnostic effect.

Libmeldy is authorized as a gene therapy product in the EEA, and we anticipate that our gene therapy development products would also be regulated as ATMPs in the EEA.

• Centralized procedure —If pursuing marketing authorization of a product candidate for a therapeutic indication under the centralized procedure, following the opining of the European Medicines Agency’s, or EMA, Committee for Medicinal Products for Human Use, or CHMP, the European Commission issues a single marketing authorization valid across the EEA.

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

For medicines that do not fall within these categories, an applicant has the option of

submitting an application for a centralized marketing authorization to the EMA, as long as the medicine concerned contains a new active substance not yet authorized in the EEA, is a significant therapeutic, scientific or technical innovation, or if its authorization would be in the interest of public health in the EEA.

Under the centralized procedure the maximum timeframe for the evaluation of an MAA by the EMA is 210 days, excluding clock stops, when additional written or oral information is to be provided by the applicant in response to questions asked by the CHMP.

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

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

For medicines that do not fall within these categories, an applicant has the option of submitting an application for a centralized marketing authorization to the EMA, as long as the medicine concerned contains a new active substance not yet authorized in the EU, is a significant therapeutic, scientific or technical innovation, or if its authorization would be in the interest of public health in the EU.

Under the centralized procedure the maximum timeframe for the evaluation of a marketing authorization application, or MAA, by the EMA is 210 days, excluding clock stops, when additional written or oral information is to be provided by the applicant in response to questions asked by the CHMP.

Clock stops may extend the timeframe of evaluation of an MAA considerably beyond 210 days.

Where the CHMP gives a positive opinion, it provides the opinion together with supporting documentation to the European Commission, who makes the final decision to grant a marketing authorization, which is issued within 67 days of receipt of the EMA’s recommendation.

Accelerated assessment might be granted by the CHMP in exceptional cases, when a medicinal product is expected to be of a major public health interest, particularly from the point of view of therapeutic innovation.

The timeframe for the evaluation of an MAA under the accelerated assessment procedure is 150 days, excluding clock stops.

If the CHMP accepts such request, the time limit of 210 days will be reduced to 150 days, excluding clock stops, but it is possible that the CHMP may revert to the standard time limit for the centralized procedure if it determines that the application is no longer appropriate to conduct an accelerated assessment.

• National authorization procedures —There are also two other possible routes to authorize products for therapeutic indications in several countries, which are available for products that fall outside the scope of the centralized procedure:

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Following this, additional marketing authorizations can be sought from other EU countries in a procedure whereby the countries concerned recognize the validity of the original, national marketing authorization.

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

The data exclusivity period , if granted, prevents generic or biosimilar applicants from relying on the preclinical and clinical trial data contained in the dossier of the reference product when applying for a generic or biosimilar marketing authorization for a period of eight years from the date on which the reference product was first authorized in the EEA.

During the additional two-year period of market exclusivity, a generic or biosimilar marketing authorization can be submitted, and the innovator’s data may be referenced, but no generic or biosimilar product can be marketed until the expiration of the market exclusivity period.

The ten-year market exclusivity period can be extended to a maximum of eleven years if, during the first eight years of those ten years, the marketing authorization holder obtains an authorization for one or more new therapeutic indications which, during the scientific evaluation prior to their authorization, are held to bring a significant clinical benefit in comparison with existing therapies.

Even if an innovative medicinal product gains the prescribed period of data exclusivity, another company may market another version of the product if such company obtained marketing authorization based on a MAA with a complete independent data package of pharmaceutical tests, preclinical tests and clinical trials.

The criteria for designating an “orphan medicinal product” in the EEA are similar in principle to those in the United States.

In the EEA a medicinal product may be designated as orphan medicinal product if it meets the following criteria:

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

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

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

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

A separate application will, however, still be required.

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

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

The data exclusivity period, if granted, prevents generic or biosimilar applicants from relying on the preclinical and clinical trial data contained in the dossier of the reference product when applying for a generic or biosimilar marketing authorization in the EU for a period of eight years from the date on which the reference product was first authorized in the EU.

During the additional two-year period of market exclusivity, a generic or biosimilar marketing authorization can be submitted, and the innovator’s data may be referenced, but no generic or biosimilar product can be marketed in the EU until the expiration of the market exclusivity period.

There is no guarantee that a product will be considered by the EMA to be an innovative medicinal product, and products may not qualify for data exclusivity.

Even if a product is considered to be an innovative medicinal product so that the innovator gains the prescribed period of data exclusivity, another company could nevertheless also market another version of the product if such company obtained a marketing authorization based on an MAA with a complete, independent data package of pharmaceutical tests, preclinical tests and clinical trials.

The criteria for designating an “orphan medicinal product” in the EU are similar in principle to those in the United States.

In the EU a medicinal product may be designated as orphan medicinal product if it meets the following criteria:

(1) it is intended for the diagnosis, prevention or treatment of a life-threatening or chronically debilitating condition;

(2) either (a) the prevalence of such condition must not be affecting more than five in 10,000 persons in the EEA when the application is made, or (b) without the benefits derived from orphan status, it must be unlikely that the marketing of the medicine would generate sufficient return in the EEA to justify the investment needed for its development;

and (3) there exists no satisfactory method of diagnosis, prevention or treatment of such condition authorized for marketing in the EEA, or if such a method exists, the product will be of significant benefit to those affected by the condition.

(2) either (a) such condition affects no more than five in 10,000 persons in the EU when the application is made, or (b) without the benefits derived from orphan status, it is unlikely that the marketing of the medicine would generate sufficient return in the EU to justify the necessary investment in its development;

and (3) there exists no satisfactory method of diagnosis, prevention or treatment of such condition authorized for marketing in the EU, or if such a method exists, the product would be of significant benefit to those affected by that condition.

Orphan medicinal products are eligible for financial incentives such as reduction of fees or fee waivers and are, upon grant of a marketing authorization, entitled to ten years of market exclusivity for the approved therapeutic indication.

During this ten-year orphan market exclusivity period, no marketing authorization application shall be accepted, and no marketing authorization shall be granted for a similar medicinal product for the same indication.

An orphan product can also obtain an additional two years of market exclusivity in the EEA for pediatric studies.

During this ten-year orphan market exclusivity period, no MAA shall be accepted, and no marketing authorization shall be granted for a similar medicinal product.

A “similar medicinal product” is defined as a medicinal product containing a similar active substance or substances as contained in an authorized orphan medicinal product, and which is intended for the same therapeutic indication.

An orphan product can also obtain an additional two years of market exclusivity in the EU for pediatric studies.

The ten-year market exclusivity may be reduced to six years if, at the end of the fifth year, it is established that the product no longer meets the criteria for orphan designation, for example, if the product is sufficiently profitable not to justify maintenance of market exclusivity.

Otherwise, orphan medicine marketing

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

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

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

From January 1, 2021, a separate process for orphan drug designation will apply in Great Britain.

There will be no pre-marketing authorization orphan designation (as there is in the EEA) and the application for orphan designation will be reviewed by the MHRA at the time of the marketing authorization application.

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

there must be no satisfactory method of diagnosis, prevention or treatment of the condition concerned in Great Britain).

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

The Clinical Trials Directive 2001/20/EC, the Directive 2005/28/EC on GCP and the related national implementing provisions of the individual EU Member States govern the system for the approval of clinical trials in the European Union.

Under this system, an applicant must obtain prior approval from the competent national authority of the EU Member States in which the clinical trial is to be conducted.

Furthermore, the applicant may only start a clinical trial at a specific study site after the competent ethics committee has issued a favorable opinion.

The clinical trial application must be accompanied by, among other documents, an investigational medicinal product dossier (the Common Technical Document) with supporting information prescribed by Directive 2001/20/EC, Directive 2005/28/EC, where relevant the implementing national provisions of the individual EU Member States and further detailed in applicable guidance documents.

In April 2014, the new Clinical Trials Regulation, (EU) No 536/2014 (Clinical Trials Regulation) was adopted.

It is expected that the new Clinical Trials Regulation (EU) No 536/2014 will apply following confirmation of full functionality of the Clinical Trials Information System (CTIS), the centralized European Union portal and database for clinical trials foreseen by the regulation, through an independent audit.

The regulation becomes applicable six months after the European Commission publishes notice of this confirmation.

The Clinical Trials Regulation will be directly applicable in all the EU Member States, repealing the current Clinical Trials Directive 2001/20/EC.

Conduct of all clinical trials performed in the European Union will continue to be bound by currently applicable provisions until the new Clinical Trials Regulation becomes applicable.

The extent to which ongoing clinical trials will be governed by the Clinical Trials Regulation will depend on when the Clinical Trials Regulation becomes applicable and on the duration of the individual clinical trial.

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

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

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

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

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.

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

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

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

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

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

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

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

The method of assessing conformity varies depending on the class of the product, but normally involves a third-party assessment by a “Notified Body”.

This third-party assessment may consist of an audit of the manufacturer’s quality system and specific testing of the manufacturer’s product.

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

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

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

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

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

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

The main characteristics of the regulation include:

a streamlined application procedure via a single-entry point, the “EU portal”;

a streamlined application procedure via a single-entry point, the Clinical Trials Information Systems, or “CTIS”;

a single set of documents to be prepared and submitted for the application as well as simplified reporting procedures for clinical trial sponsors;

and a harmonized procedure for the assessment of applications for clinical trials, which is divided in two parts.

Part I is assessed by the competent authorities of all EU Member States in which an application for authorization of a clinical trial has been submitted (Member States concerned).

Part I is assessed by coordinated assessment of the competent authorities of all EU Member States in which an application for authorization of a clinical trial has been submitted (Member States concerned), of the review of a Reference Member State.

Part II is assessed separately by each Member State concerned.

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

It is expected that the new Clinical Trials Regulation will come into effect following confirmation of full functionality of the Clinical Trials Information System, the centralized European Union portal and database for clinical trials foreseen by the new Clinical Trials regulation, through an independent audit, which is currently expected to occur in December 2021.

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

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

residents in the EU.

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

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

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

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

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

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 European Union to the United States or other regions that have not been deemed to offer “adequate” privacy protections.

Failure to comply with the requirements of the GDPR and the related national data protection laws of the European Union Member States, which may deviate slightly from the GDPR, may result in fines of up to 4% of global revenues, or €20,000,000, whichever is greater.

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.

Failure to comply with the requirements of the GDPR and the related national data protection laws of the EEA Member States, which may deviate slightly from the GDPR, may result in fines of up to 4% of global revenues, or €20 million, whichever is greater.

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

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

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

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

Non-compliance with the UK GDPR may result in monetary penalties of up to £17.5 million or 4% of worldwide revenue, whichever is higher.

Although the UK is regarded as a third country under the EU’s GDPR, the European Commission has now issued a decision recognizing the UK as providing adequate protection under the EU GDPR and, therefore, transfers of personal data originating in the EU to the UK remain unrestricted.

Like the EU GDPR, the UK GDPR restricts personal data transfers outside the UK to countries not regarded by the UK as providing adequate protection.

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

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

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

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

Enforcement uncertainty and the costs associated with ensuring GDPR compliance are onerous and may adversely affect our business, financial condition, results of operations and prospects.

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Brexit and the Regulatory Framework in the United Kingdom

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

Thereafter, in March 2017, the country formally notified the European Union of its intention to withdraw pursuant to Article 50 of the Lisbon Treaty.

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

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

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

The United Kingdom and European Union have signed a European Union-United Kingdom Trade and Cooperation Agreement, which became provisionally applicable on January 1, 2021 and will become formally applicable once ratified by both the United Kingdom and the European Union.

This agreement provides details on how some aspects of the United Kingdom and European Union’s relationship regarding medicinal products will operate, particularly in relation to Good Manufacturing Practice, however there are still many uncertainties.

Many of the regulations that now apply in the United Kingdom following the transition period (including financial laws and regulations, tax, intellectual property rights, data protection laws, supply chain logistics, environmental, health and safety laws and regulations, medicine approval and regulations, immigration laws and employment laws), will likely be amended in future as the United Kingdom determines its new approach, which may result in significant divergence from European Union regulations.

This lack of clarity on future United Kingdom laws and regulations and their interaction with the European Union laws and regulations increases our regulatory burden of operating in and doing business with both the United Kingdom and the European Union.

The long-term effects of Brexit will depend in part on how the European Union-United Kingdom Trade and Cooperation Agreement, and any future agreements signed by the United Kingdom and the European Union, take effect in practice.

Such a withdrawal from the European Union is unprecedented, and it is unclear how the restrictions on the United Kingdom’s access to the European single market for goods, capital, services and labor within the European Union and the wider commercial, legal and regulatory environment, could impact our current and future operations and clinical activities in the United Kingdom.

We may also face new regulatory costs and challenges that could have an adverse effect on our operations as a result of Brexit.

The European Union, the United Kingdom will lose the benefits of global trade agreements negotiated by the European Union on behalf of its members, which may result in increased trade barriers that could make our doing business in the European Union or European Economic Area more difficult.

We expect that, now the transition period has expired, Brexit could lead to legal uncertainty and potentially divergent national laws and regulations as the

United Kingdom determines which European Union laws to replicate or replace, including those related to the regulation of medicinal products.

Any of these effects of Brexit, and others we cannot anticipate, could negatively impact our business and results of operations in the United Kingdom.

Any of these effects of Brexit, among others, could materially adversely affect the business, business opportunities, and financial condition of our Company.

The uncertainty concerning the United Kingdom’s legal, political and economic relationship with the European Union following Brexit may also be a source of instability in the international markets, create significant currency fluctuations, and/or otherwise adversely affect trading agreements or similar cross-border co-operation arrangements (whether economic, tax, fiscal, legal, regulatory or otherwise).

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

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

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

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

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

Human Capital Resources

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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 February 28, 2021, we had 73 full-time employees.

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

29 of our employees have Ph.D.

The following table shows the number of full-time employees as of February 28, 2021 engaged in either research and development or administrative functions, broken out by location.

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

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We consider our relationship with our employees to be good.

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

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

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.

In 2021, approximately 63% 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.

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 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.

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.

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

We also lease a facility containing approximately 2,357 square feet of office space, which is located at 139 Main Street, Cambridge, MA 02142.

The lease expires on April 30, 2022, subject to an option to extend the lease for three additional years.

We also lease approximately 1,500 square feet of laboratory space and 500 square feet of office space at 25 Health Sciences Drive, Stony Brook, NY 11790 and we are in the process of renegotiating our lease for this location.

In December 2020 we entered into an agreement to lease approximately 18,120 square feet of office and laboratory space at 430 East 29th Street, New York, New York 10016.

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

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

In addition, we also have a license to use the private and shared laboratory and office facilities at 180 Varick Street, New York, NY 10014.

The license expires on December 31, 2021, however, the Company may terminate the lease with 30-days’ notice.

For our Canadian subsidiary, we have a non-exclusive license to occupy a portion of a building located at 661 University Avenue, Toronto, Ontario M5G 0B7, for the purposes of conducting laboratory research, business planning and related activities.

The license expires on April 1, 2022.

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

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

Our website address is https://www.blackdiamondtherapeutics.com.

The information contained in or accessible from our website is not incorporated into this Annual Report, and you should not consider it part of this Annual Report.

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

On February 3, 2020, we completed our initial public offering, or IPO, pursuant to which we issued and sold, 12,174,263 shares of our common stock, including the exercise in full by the underwriters of their option to purchase up to 1,587,947 additional shares of common stock, at a public offering price of $19.00 per share.

The gross proceeds from the IPO were $231.3 million and the net proceeds were $212.1 million, after deducting underwriting discounts and commissions and other estimated offering expenses.

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

We will remain an emerging growth company until the earlier of:

(i) the last day of the fiscal year (a) following the fifth anniversary of the completion of the IPO, (b) in which we have total annual gross revenue of at least $1.07 billion, or (c) in which we are deemed to be a large accelerated filer, which means the market value of our common stock that is held by non-affiliates exceeds $700.0 million as of the prior June 30th, and (ii) the date on which we have issued more than $1.0 billion in non-convertible debt during the prior three-year period.

As of June 30, 2020, the market value of our stock held by non-affiliates was greater than $700 million.

As of January 1, 2021, we ceased to be a smaller reporting company.

(i) the last day of the fiscal year (a) following the fifth anniversary of the completion of the initial public offering (“IPO”), (b) in which we have total annual gross revenue of at least $1.07 billion, or (c) in which we are deemed to be a large accelerated filer, which means the market value of our common stock that is held by non-affiliates exceeds $700.0 million as of the prior June 30th, and (ii) the date on which we have issued more than $1.0 billion in non-convertible debt during the prior three-year period.

Financial Information and Segments

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Available Information

Our Internet address is www.

blackdiamondtherapeutics.com.

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

Our Internet address is www.blackdiamondtherapeutics.com.

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

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

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.

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

What changed 10-K

Item 1. Business