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Item 1. Business

2021-03-25 compared with 2020-03-24 · 307 added, 233 removed, 647 unchanged (45% of the section changed)

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

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

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

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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.

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

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.

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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 submitted our IND for BDTX-189 in November 2019, which was allowed by the U.S.

Food and Drug Administration, or FDA, on December 13, 2019.

We have since begun enrollment and dosing of patients in the Phase 1 portion of our MasterKey-01 trial to pursue a tumor-agnostic development strategy.

We continue to make progress on identifying a development candidate for treatment of GBM patients expressing allo-EGFR.

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.

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

Improved genetic sequencing of cancers has led to the discovery of additional genetic alterations responsible for cancer development and growth.

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

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

We believe our MAP platform will allow us to reveal the oncogenic nature of families of undrugged driver mutations and their associated protein conformations.

Our MAP platform 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:

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

Our MAP platform algorithm uses genetic and proteomic features to rank mutations for potential oncogenicity.

We use our algorithm as a machine learning tool to classify mutations as either pathogenic or benign and predict the probability, or MAP score, that a mutation is pathogenic.

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

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

• Target —Using these shared characteristics, we seek to develop single small molecule product candidates, each designed to inhibit only the intended mutation family.

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

• 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.

• 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.

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

An inhibitor of non-canonical and additional oncogenic mutations of ErbB

BDTX-189 is designed to be an orally available, irreversible small molecule inhibitor that targets a family of non-canonical and canonical driver mutations of the ErbB kinases EGFR and HER2.

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

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.

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

BDTX-189 is designed to be a highly selective, potent inhibitor that targets this family of oncogenic proteins defined by the non-canonical ErbB driver mutations, while also sparing wild type EGFR.

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.

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

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

We have since begun enrollment and dosing of patients in the Phase 1 portion of our MasterKey-01 trial.

We are currently evaluating escalating doses of BDTX-189 in the Phase 1 portion of the trial, which is designed to determine the recommended Phase 2 dose and to assess preliminary indications of anti-tumor activity.

The Phase 2 portion will determine the ORR and duration of response 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.

Depending on results from the Phase 1/2 trial, we may either expand the Phase 2 portion of the trial or initiate a second Phase 2 trial in order to pursue an accelerated approval of BDTX-189, subject to discussions with FDA, for patients with mutations of the ErbB family across one or more solid tumor types as a tumor agnostic indication.

Glioblastoma program:

Allosteric-EGFR mutation inhibitors

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.

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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 family of allosteric EGFR mutations expressed in glioblastoma.

Our lead molecules potently and selectively inhibited this family of allosteric mutants and achieved tumor-growth inhibition and regression in the in vivo animal models we have utilized.

Additionally, our lead molecules are designed to be brain penetrant and we have observed measurable brain exposure in animal models.

We are completing preclinical characterization of our glioblastoma candidate leads and plan to select a development candidate in 2020.

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.

Early-stage programs

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

These programs are currently progressing through lead optimization.

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.

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The critical components of our strategy include:

• Rapidly advance our lead drug 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 independent of tissue of origin and become the first agent approved to address allosteric ErbB mutations.

We have begun enrollment and dosing of patients in the Phase 1 portion of our MasterKey-01 Phase 1/2 trial in solid tumors with genetically defined allosteric mutations in EGFR and HER2.

We are conducting our clinical studies in a genetically-defined patient population and leverage learnings from recently approved tumor-agnostic drugs to inform the clinical and regulatory pathways for BDTX-189 in order to mitigate potential development risks.

• 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.

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 our glioblastoma program to identify a lead small molecule product candidate and progress it through clinical development.

We believe that the lead molecules in our glioblastoma program could overcome the limitations of current therapies by potently and selectively inhibiting the family of allosteric mutant EGFR kinases expressed in glioblastoma tumors with a brain penetrant compound.

We plan to select a development candidate in 2020.

• 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.

We believe that the general principles for mutation-driven conformational change that we have identified for the ErbB family can also apply to other oncogenic proteins.

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.

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

We plan to expand our MAP platform to enable new insights into canonical and non-canonical mutations and to accelerate our ability to identify other mutational drivers, including those involved in rare diseases, as well as oncology.

We will continue to enhance our proprietary computational algorithms by leveraging our extensive in-house expertise in allosteric mutations and deep understanding of chemistry.

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 enter into strategic partnerships to maximize the potential of our pipeline and our proprietary MAP platform.

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

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

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.

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

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

Thomas Leggett, our Chief Financial Officer, was previously Senior Vice President of Finance and Chief Financial Officer at Axcella Health, Inc.

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.

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

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

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.

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.

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

Background on and limitations of previous generations of targeted therapies

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

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

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

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

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

Limitations of current targeted therapies

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

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.

While EGFR-targeted therapies, including erlotinib and osimertinib, have proven to be effective in patients with ATP-site mutations, limited response has been observed to these inhibitors 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.

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.

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Emergence of genetic sequencing as standard of care in treating cancer

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

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

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

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

• these oncogenic mutations can be grouped as 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.

• 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.

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

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:

Discover—Reveal—Target.

Discover—identify mutations and rank for potential oncogenicity

Mutation—Allostery—Pharmacology.

Mutation—identify mutations and rank for potential oncogenicity

Our discovery process begins by identifying oncogenic mutations.

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

This algorithm is designed to identify potential oncogenic mutations within the vast landscape of potentially insignificant mutations.

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

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

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We found newly characterized mutations to be sensitive to BDTX-189, as evidenced below with potent inhibition of proliferation against cells transformed by the HER2-R103Q mutation.

Reveal—understanding the mechanism for oncogenic activation

We evaluate the oncogenicity of these mutations occurring outside of the ATP site, which have not been targeted and use our preclinical models to reveal how mutations drive protein conformation change to promote oncogenicity.

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

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

The drug selectivity patterns of mutant EGFR and HER2 kinases provide evidence of unique conformational states driven by mutation.

Allostery—understanding the mechanism for oncogenic activation

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

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

We use this information to aggregate mutations 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.

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

Target—develop mutation spectrum-selective drugs to our targets

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.

Using a multidimensional medicinal chemistry lead identification and optimization strategy and leveraging 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.

We utilized the cell and tumor models developed under our “Reveal” pillar as biological screens which recapitulate the tumor biology for these mutations.

We used these models to identify our ErbB clinical candidate, BDTX-189.

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.

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

An inhibitor of non-canonical mutations and additional 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 eight percent.

An inhibitor of allosteric oncogenic drivers of ErbB

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 to be an orally available irreversible, small molecule inhibitor that targets undrugged oncogenic driver mutations of ErbB kinases in HER2 and EGFR.

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

We have since begun enrollment and dosing of patients in the Phase 1 portion of our MasterKey-01 trial.

As part of our IND-enabling studies for BDTX-189, we conducted good laboratory practice, or GLP, safety pharmacological and toxicological studies of BDTX-189 in laboratory animals.

We believe that the results of these studies suggest that BDTX-189 has an acceptable safety profile for the conduct of our planned Phase 1/2 trial.

The results of these studies have also informed our selection of a starting dose for testing in humans.

The open-label Phase 2 portion is expected to determine the objective response rate, or ORR, and duration of response 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.

Depending on results from the Phase 1/2 trial, we anticipate that, subject to discussions with FDA, we may either expand the Phase 2 portion of the trial or initiate a second Phase 2 trial in order to pursue an accelerated approval, if available, of BDTX-189 for patients with mutations of the ErbB family across one or more solid tumor types as a tumor agnostic indication.

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) as well as comparable data for erlotinib and osimertinib (each as determined by measuring 50 percent inhibition, or IC50, values).

The data in the figure below were generated through head-to-head comparisons of BDTX-189 to erlotinib and osimertinib.

We conducted the head-to-head comparisons by determining the in vitro anti-proliferative activity for each molecule against a panel of cell lines, which included BaF3 transformants for various EGFR and HER2 mutations, patient-derived cell lines expressing EGFR mutations and cells expressing either wild type EGFR or wild type HER2.

The head-to-head comparisons were conducted under the same experimental conditions for each molecule.

BDTX-189 potently inhibited the proliferation of BaF3 cells transformed by allosteric EGFR mutations and allosteric HER2 mutations when evaluated in vitro .

BDTX-189 additionally inhibited the proliferation of lung cancer patient-derived cells expressing EGFR exon 20 insertions (CUTO-14 and CUTO-17 cell lines), and human tumor cells expressed amplified wild type HER2 (BT-474 cells).

BDTX-189 further inhibited the proliferation of BaF3 cells transformed by EGFR ATP-site mutations, including the EGFR exon 19 deletion E745-750 and EGFR-L858R, and extracellular domain EGFR mutations, including EGFR-Viii, when evaluated in vitro .

In each case, BDTX-189 inhibits the targeted ErbB mutation more potently than wild type EGFR.

As shown in the figure below, BDTX-189 has been observed to inhibit the proliferation of BaF3 cells transformed by many oncogenic EGFR and HER2 mutants, with selectivity versus cells expressing the normal wild type EGFR (A431 and H292) (left chart).

Cellular potency, or anti-proliferative IC50, was determined by measuring the effect of various concentrations on the proliferation of cells over a 72-hour time period.

BDTX-189 also 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 (right chart).

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

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).

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

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

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 .

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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 has been observed to exhibit anti-tumor activity against allosteric HER2 mutant tumors, evidenced by both potent tumor growth inhibition and regression.

Daily dosing of BDTX-189 was well tolerated in athymic nude mice bearing HER2-S310F BaF3 allograft tumors up to 100mg/kg.

BDTX-189 demonstrated dose-dependent tumor growth inhibition (median tumor volume) at daily doses ranging from 15 mg/kg to 100 mg/kg.

BDTX-189 also demonstrated dose-dependent tumor regression at doses ranging from 30 mg/kg to 100 mg/kg.

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

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

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

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

BDTX-189 has also been observed to exhibit anti-tumor activity in athymic nude mice bearing patient derived xenografts, or PDX, expressing allosteric EGFR exon 20 insertion mutants.

BDTX-189, administered at a daily oral dose of 30mpk or 50mpk, demonstrated growth regression of CUTO-14 PDX tumors that express the EGFR mutation EGFR-ASV.

Clinical development plan

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

We have since begun enrollment and dosing of patients in the Phase 1 portion of our MasterKey-01 trial.

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.

We are currently evaluating multiple ascending oral doses of BDTX-189 in the Phase 1 portion of the trial, which is designed to assess the safety, tolerability and pharmacokinetic profile in order to determine the recommended Phase 2 dose.

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, which is intended to allow evaluation of drug tolerability as well as enrollment of patients with allosteric ErbB mutations at relevant exposures to evaluate early anti-tumor proof-of-concept.

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

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 have begun 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 targeting completion of the Phase 1 dose-escalation portion by the first half of 2021.

Preliminary efficacy data from Phase 1 patients with targeted allosteric mutations may further inform the optimal population for the Phase 2 portion of the trial.

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.

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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, colon, bladder, endometrial, and many other solid tumors.

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.

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

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

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.

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, we submitted a pre-IND meeting request to FDA and received written feedback from the FDA regarding our nonclinical plan and the proposed patient population, patient selection criteria and study endpoints for the planned Phase 1/2 trial for BDTX-189.

We believe that objective response rate, or ORR, and duration of response combined with a favorable safety profile may, subject to 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, FDA will still require the conduct of a post-approval study to confirm clinical benefit.

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 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.

We may also seek Fast Track or Breakthrough Therapy designation by the FDA.

We plan on using one of the existing FDA-approved companion diagnostic tests which already include the allosteric ErbB mutations of interest to identify patients or to collaborate with a partner on development of a new test.

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.

Glioblastoma program:

Allosteric-EGFR mutation inhibitors

According to the National Cancer Institute, there were an estimated 24,000 new cases of brain cancer in the United States in 2018.

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.

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.

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A given glioblastoma tumor may co-express multiple different EGFR oncogenic mutations.

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

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 allosteric-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 thus proved effective in treating patients that express these mutations.

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.

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

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

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.

We have identified several orally available, irreversible small molecule inhibitors, including BDTX-GBM-507 and BDTX-GBM-700, as development candidate lead molecules that have been observed to potently inhibit the group of extracellular domain allosteric mutants, as illustrated in the figure below, that form the constitutive dimer conformation.

Importantly, these development candidate leads have not been observed to potently inhibit the transient dimer conformation for the wild type EGFR.

Our glioblastoma development candidate leads are designed to achieve brain penetration in preclinical PK studies.

For example, a lead compound also demonstrated good brain penetration in mouse PK studies with a favorable total brain-to-plasma ratio.

BDTX-GBM-507 and BDTX-GBM-700 have been observed in vitro to inhibit the proliferation of BaF3 cells transformed by EGFR mutants expressed in glioblastoma tumors, with selectivity versus cells expressing the normal wild type EGFR (A431 cells).

Cellular IC50 values are shown.

We evaluated activity of our development candidate leads against glioblastoma EGFR mutants in vivo .

Acute oral dosing of lead molecule BDTX-GBM-507 in athymic nude mice bearing intracranial patient derived glioblastoma tumors (GBM6) showed effective suppression of ERK phosphorylation.

BDTX-GBM-507, administered orally at 50mpk to athymic nude mice bearing intracranial GBM6 patient derived xenografts expressing EGFR-Viii, was observed to result in inhibition of ERK signaling in tumor.

We are completing preclinical characterization our glioblastoma candidate leads and plan to nominate a development candidate in 2020.

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.

Early-stage programs

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

We believe these general principles also apply to targets associated with diseases outside of oncology.

We are currently evaluating additional groups of targets, including allosteric FGFR3 mutations and allosteric BRAF mutations, among others, for drug discovery.

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

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).

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 together with a range of other solid tumors.

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.

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.

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;

(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.

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

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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.

Alexander Mayweg, one of our founders and a member of our board of directors, is a managing director of Ridgeline and a partner of Versant, and Fang Ni, our former interim Chief Business Officer, is a principal of Versant.

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

BDTX-189, our lead product candidate for which we submitted an IND in November 2019, which was allowed by the FDA on December 13, 2019, and have since begun enrollment and dosing of patients in the Phase 1 portion of our MasterKey-01 trial, as well as the lead compounds for our glioblastoma program have been developed under this collaboration with Ridgeline.

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

In 2019, in consideration for the services provided under the agreement, we paid Ridgeline $950,000 a month, which was reconciled on a quarterly basis with actual expenses incurred by Ridgeline on our behalf and a corresponding reconciling payment was made by us to (or received by us from) Ridgeline each quarter.

Certain executives and employees of Ridgeline have also received equity grants from the Company.

No milestone or royalty payments are owed to Ridgeline.

During 2019 we continued to build our internal chemistry, manufacturing and controls, biology and preclinical development capabilities through key additional hires to assume activities conducted by Ridgeline on our behalf and are transitioning from our current service model to a more limited consulting arrangement with Ridgeline in 2020.

For more information, see Item 9B of this Annual Report.

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.

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 that BDTX-189 will compete against approved drugs, including neratinib, which is marketed by Puma Biotechnology, Inc., under the trade name Nerlynx, osimertinib, which is marketed by AstraZeneca plc under the trade name Tagrisso, and trastuzumab deruxtecan (DS-8201), which is marketed by Daiichi Sankyo Company Ltd.

and AstraZeneca plc under the trade name Enhertu.

In the allosteric HER2 patient population we expect competition from drugs in late-stage clinical development, including ZW25 and ZW49, which are under development by Zymeworks Inc.

and Beigene Co., Ltd.

We also expect BDTX-189 will compete in the exon 20 insertion patient population against other drugs under development, including poziotinib, which is under development by Spectrum Pharmaceuticals, Inc., tarloxotinib, which is under development by Rain Therapeutics Inc., TAK-788, which is under development by Takeda Pharmaceutical Company Ltd, and JNJ-61186372, which is under development by Janssen Research & Development, LLC.

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.

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:

neratinib, which is marketed by Puma Biotechnology, Inc.

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

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

(recently acquired by Eli Lilly and Company), Blueprint Medicines Corporation, Deciphera Pharmaceuticals, Inc., Turning Point Therapeutics, Inc., and Mirati Therapeutics, Inc.

(acquired by Eli Lilly and Company), Blueprint Medicines Corporation, Deciphera Pharmaceuticals, Inc., Turning Point Therapeutics, Inc., Mirati Therapeutics, Inc., Relay Therapeutics, Inc.

and Kinnate Biopharma, Inc.

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

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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.

All of our drug candidates are small molecules and are manufactured in synthetic processes from available starting materials.

All of our product candidates are small molecules and are manufactured via synthetic processes from available starting materials.

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 generally expect to rely on third parties for the manufacture of companion diagnostics for our products, which are assays or tests to identify an appropriate patient population.

Depending on the technology solutions we choose, we may rely on multiple third parties to manufacture and sell a single test.

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.

Commercialization

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We believe that such an organization will be able to address the community of oncologists who are the key specialists in treating the patient populations for which our product candidates are being developed.

Outside the United States, we expect to enter into distribution and other marketing arrangements with third parties for any of our product candidates that obtain marketing approval.

Outside the United States, we may enter into distribution and other marketing arrangements with third parties for any of our product candidates that obtain marketing approval.

We also plan to build a marketing and sales management organization to create and implement marketing strategies for any products that we market through our own sales organization and to oversee and support our sales force.

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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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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.

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

As of February 29, 2020, we own five U.S.

provisional patent applications and two Patent Cooperation Treaty, or PCT, patent applications.

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 29, 2020, we own one U.S.

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

or foreign patent issued from this PCT patent application would be scheduled to expire in 2039, 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 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.

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.

or foreign patent issued from these pending applications would be scheduled to expire between 2039 and 2041, 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.

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

We are continuing to assess whether we will convert this U.S.

provisional patent application into a non-provisional patent application and ultimately seek patent protection for our MAP platform, or instead maintain the intellectual property described in this provisional patent application as a trade secret.

or foreign patent issued from this U.S.

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

Glioblastoma program

patent application that covers our MAP platform 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 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.

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.

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

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.

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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.

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.

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.”

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Each protocol, and any subsequent amendments to the protocol, must be submitted to the FDA as part of the IND.

Furthermore, each

clinical trial must be reviewed and approved by an IRB for each institution at which the clinical trial will be conducted to ensure that the risks to individuals participating in the clinical trials are minimized and are reasonable related to the anticipated benefits.

Furthermore, each clinical trial must be reviewed and approved by an IRB for each institution at which the clinical trial will be conducted to ensure that the risks to individuals participating in the clinical trials are minimized and are reasonable related to the anticipated benefits.

The IRB also approves the informed consent form that must be provided to each clinical trial subject or his or her legal representative, and must monitor the clinical trial until completed.

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Orphan product exclusivity could block the approval of one of our products for seven years if a competitor obtains approval for the same therapeutic agent for the same indication before we do, unless we are able to demonstrate that our product is clinically superior.

If an orphan designated product receives marketing approval for an

indication broader than what is designated, it may not be entitled to orphan exclusivity.

If an orphan designated product receives marketing approval for an indication broader than what is designated, it may not be entitled to orphan exclusivity.

Further, orphan drug exclusive marketing rights in the United States may be lost if the FDA later determines that the request for designation was materially defective or the manufacturer of the approved product is unable to assure sufficient quantities of the product to meet the needs of patients with the rare disease or condition.

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

Congress has extended the PRV program until September 30, 2020, with the potential for PRVs to be granted until 2022.

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

Expedited development and review programs for drugs

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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.

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.

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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post-approval requirements for drugs

requirements, which include restrictions on promoting products for unapproved uses or patient populations (known as “off-label use”) and limitations on industry-sponsored scientific and educational activities.

Drugs manufactured or distributed pursuant to FDA approvals are subject to pervasive and continuing regulation by the FDA, including, among other things, requirements relating to recordkeeping, periodic reporting, product sampling and distribution, reporting of adverse experiences with the product, complying with promotion and advertising requirements, which include restrictions on promoting products for unapproved uses or patient populations (known as “off-label use”) and limitations on industry-sponsored scientific and educational activities.

Although physicians may prescribe legally available products for off-label uses, manufacturers may not market or promote such uses.

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Companion diagnostics are regulated as medical devices by the FDA.

In the United States, the FD&C Act and its implementing regulations, and other federal and state statutes and regulations govern, among other things, medical device design and development, preclinical and clinical testing, premarket clearance or approval, registration and listing, manufacturing, labeling,

storage, advertising and promotion, sales and distribution, export and import, and post-market surveillance.

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

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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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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.

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.

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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.

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.

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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 will commence 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 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.

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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 and healthcare providers, which has led to a number of investigations, prosecutions, convictions and settlements in the healthcare industry.

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.

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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.

Current and future healthcare reform legislation

In the United States and some foreign jurisdictions, there have been, and likely will continue to be, a number of legislative and regulatory changes and proposed changes regarding the healthcare system directed at broadening the availability of healthcare, improving the quality of healthcare, and containing or lowering the cost of healthcare.

For example, in March 2010, the United States Congress enacted the Affordable Care Act, which, among other things, includes changes to the coverage and payment for products under government health care programs.

The Affordable Care Act includes provisions of importance to our potential product candidates that:

For example, in March 2010, the United States Congress enacted the ACA, which, among other things, includes changes to the coverage and payment for products under government health care programs.

The ACA includes provisions of importance to our potential product candidates that:

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

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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 Affordable Care Act, or 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, and the Trump Administration has 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.

Additionally, 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.

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.

Other legislative changes have been proposed and adopted in the United States since the Affordable Care Act was enacted.

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.

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

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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 2020 contains further drug price control measures that could be enacted during the 2020 legislative session, or in other future legislation, including, for example, measures to permit Medicare Part D plans to negotiate the price of certain drugs under Medicare Part B, to allow some states to negotiate drug prices under Medicaid, and to eliminate cost sharing for generic drugs for low-income patients.

Additionally, the Trump administration 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, has already started the process of soliciting feedback on some of these measures and, at the same time, is immediately implementing others under its existing authority.

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.

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

For example, in December 2019, the FDA issued a notice of proposed rulemaking that, if finalized, would allow for the importation of certain prescription drugs from Canada.

FDA also issued a Draft 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.

The regulatory and market implications of the notice of proposed rulemaking and Draft Guidance are unknown at this time, but legislation, regulations or policies allowing the reimportation of drugs, if enacted and implemented, could decrease the price we receive for our products and adversely affect our future revenues and prospects for profitability.

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.

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.

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

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

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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.

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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From time to time and in the future, our operations may involve the use of hazardous and flammable materials, including chemicals and biological materials, and may also produce hazardous waste products.

Even if we contract with third

parties for the disposal of these materials and waste products, we cannot completely eliminate the risk of contamination or injury resulting from these materials.

Even if we contract with third parties for the disposal of these materials and waste products, we cannot completely eliminate the risk of contamination or injury resulting from these materials.

In the event of contamination or injury resulting from the use or disposal of our hazardous materials, we could be held liable for any resulting damages, and any liability could exceed our resources.

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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 27 EU Member States plus Iceland, Liechtenstein and Norway), medicinal products must be authorized for marketing by using either the centralized authorization procedure or national authorization procedures.

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.

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.

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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 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 during a period of eight years from the date on which the reference product was first authorized in the EU.

The market exclusivity period prevents a successful generic or biosimilar applicant from commercializing its product in the EU until ten years have elapsed from the initial authorization of the reference product in the EU.

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 if (1) it is intended for the diagnosis, prevention or treatment of a life-threatening or chronically debilitating 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) the product, without the benefits derived from orphan status, would not generate sufficient return in the EU to justify investment;

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 will be of significant benefit to those affected by the condition.

In the EEA 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.

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 EU for pediatric studies.

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

Additionally, marketing authorization may be granted to a similar product for the same indication at any time if (i) the second applicant can establish that its product, although similar, is safer, more effective or otherwise clinically superior;

(ii) the applicant consents to a second orphan medicinal product application;

or (iii) the applicant cannot supply enough orphan medicinal product.

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.

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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.

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.

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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.

residents in the EU.

This expansion would incorporate any clinical trial activities in EU members states.

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

A transition period began on February 1, 2020, during which European Union pharmaceutical law remains applicable to the United Kingdom.

This transition period is due to end on December 31, 2020.

Since the regulatory framework for pharmaceutical products in the United Kingdom covering quality, safety and efficacy of pharmaceutical products, clinical trials, marketing authorization, commercial sales and distribution of pharmaceutical products is derived from European Union directives and regulations, Brexit could materially impact the future regulatory regime which applies to products and the approval of product candidates in the United Kingdom.

It remains to be seen how, if at all, Brexit will impact regulatory requirements for product candidates and products in the United Kingdom.

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).

Human Capital Resources

In order to achieve the goals and expectations of our Company, it is crucial that we continue to attract and retain top talent.

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.

Fifteen of our employees have Ph.D.

31 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.

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We consider our relationship with our employees to be good.

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

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

Accordingly, we are committed to their health, safety and wellness.

We provide our employees and their families with access to a variety of innovative, flexible and convenient health and wellness programs, including benefits that provide protection and security so they can have peace of mind concerning events that may require time away from work or that impact their financial well-being;

that support their physical and mental health by providing tools and resources to help them improve or maintain their health status and encourage engagement in healthy behaviors;

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.

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

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

In addition to salaries, these programs include potential annual discretionary bonuses, stock awards, a 401(k) Plan, healthcare and insurance benefits, health savings and flexible spending accounts, paid time off, family leave, and flexible work schedules, among others.

In addition to our broad-based equity award programs, we have used targeted equity-based grants with vesting conditions to facilitate retention of personnel.

We lease a facility containing approximately 25,578 square feet of office space for our principal office, which is located at One Main Street, Cambridge, MA 02142.

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 our lease for this location expires on December 31, 2020.

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.

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 February 11, 2021.

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 1M1, for the purposes of conducting laboratory research, business planning and related activities.

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.

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On January 2, 2018, we changed our name to Black Diamond Therapeutics, Inc.

Our principal executive offices are located at 139 Main Street, Cambridge, MA 02142, and our telephone number is 617-252-0848.

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

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

7 unchanged sentences

(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.

Financial Information and Segments

11 unchanged sentences

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