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Item 1. Business

2021-02-25 compared with 2020-03-03 · 454 added, 617 removed, 833 unchanged (56% of the section changed)

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Our pipeline of over 30 development programs includes product candidates ranging from early discovery to late-stage development.

We have filed New Drug Applications, or NDAs, with the U.S.

Food and Drug Administration, or FDA, for two of our programs.

Several of our programs target indications that we believe present the potential for our product candidates, if approved, to target portions of market opportunities of at least $1.0 billion in annual sales.

We have initiated a rolling NDA submission for one of our product candidates, and have three product candidates in clinical trials that, if positive, we believe could support the filing of an application for marketing authorization.

We focus on genetic diseases because they exist at the intersection of high unmet patient need and tractable biology.

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We believe that this early-stage innovation represents one of the greatest practical sources for new drug creation.

We believe we have developed a sustainable and scalable product platform that supports the continued growth of our company and the advancement of our pipeline.

We believe we have developed a world-class drug engineering product platform that supports the continued growth of our company and the advancement of our pipeline.

Leveraging our product platform, we have a goal of adding two to three programs to our pipeline each year going forward.

Our platform is distinguished by several key elements:

World class discovery and development talent:

Our team has previously submitted over 30 INDs and 15 NDAs, in aggregate.

Our operations are overseen by a Management Committee that is comprised of renowned leaders in cancer and rare disease drug development.

Disciplined approach to target identification and prioritization:

We pair a systematic mapping of the genetic disease landscape with a proprietary set of over 10 criteria to narrow our focus on diseases with attractive attributes for drug development.

We look for diseases with high unmet need and well-characterized mechanisms that present opportunities to address the root cause of disease.

Opportunistic approach to drug candidate selection:

We seek the best science and drug mechanisms of action, wherever they can be found.

We accept programs that meet our standards at any stage of development, and we are agnostic to therapeutic area.

However, we only pursue programs with treatment modalities that we believe are biologically suited to address the target disease.

Focus at the level of each program:

We maintain a decentralized structure wherein each program is housed in its own subsidiary.

This allows us to build a team of experts and specialists tailored to the needs of each program, and who are economically incentivized at the program level.

We enable our subsidiary leaders to make certain operational decisions outside of a centralized management hierarchy, as we fundamentally believe that those operators who have the most intimate program knowledge are best positioned to make key operational decisions.

Operational efficiency:

We aim to rapidly and decisively advance our product candidates to objective critical decision points.

At each stage of research, discovery, or development, we direct resources toward the opportunities that we believe are the most promising, and we discontinue programs that do not meet performance thresholds.

We field a minimum viable team for each asset, with the goal of ensuring that each program has sufficient personnel to fit its purpose while reducing excess overhead costs.

We accomplish this by hiring the best talent, centralizing and sharing certain support functions across various programs, and leveraging external providers where appropriate.

This enables us to minimize traditionally fixed costs at the program level.

Portfolio breadth and diversification:

We have built a broad and diversified portfolio with over 20 programs that vary across stage of development, therapeutic category and modality.

We believe that our programs are biologically uncorrelated, covering different diseases, different targets, and different modalities, such that the results of one program will not impact the development of others.

Further, the breadth of our portfolio mitigates the impact of failure of any single program.

As a result, we can be objective about each of our programs and allocate capital efficiently, delivering staged funding across our portfolio based on each program’s scientific merits.

Optimized ownership for each program:

When we believe that we are best suited to continue a program’s development, we will continue to fund it internally.

If we believe a strategic partner is better suited to progress a program, we will consider externalizing development at economically attractive terms.

Our product platform supports the advancement of our current pipeline, which includes over 20 development programs that can be divided into four key categories:

Ten small molecule product candidates, in stages of development ranging from preclinical to rolling NDA submission.

Several of our product candidates in this category target some of the most prevalent Mendelian diseases, including ATTR and achondroplasia.

One of our programs in this category has received breakthrough therapy designation from the FDA.

Genetic Dermatology:

Four small molecule and protein replacement product candidates, in stages of development ranging from preclinical to Phase 3.

One of our programs in this category has received breakthrough therapy designation from the FDA.

Targeted Oncology:

Four targeted oncology programs, in stages of development ranging from preclinical to Phase 3, that address key oncogenic pathways including FGFR, KRAS and SHP2.

These programs have potentially broad applicability across a number of solid tumor types with high unmet patient need.

Gene therapy:

Three programs focused on Mendelian diseases that are particularly suited to gene therapy, all of which are in preclinical development.

Our gene therapy programs are led by executives who have substantial domain expertise and are recognized leaders in this field, and we are actively building our gene therapy capabilities.

Of our development programs, we believe the following, which we refer to as our key value drivers, have the greatest potential to drive significant value for our company due to a combination of factors, including their stage of development, potential availability of expedited development pathways, degree of unmet medical need and potential market size in the applicable target indication:

BBP-265 (also known as AG10, under development at our subsidiary, Eidos Therapeutics, Inc.), a small molecule stabilizer of TTR that is in an ongoing Phase 3 clinical trial for the treatment of ATTR-CM.

Infigratinib (also known as BBP-831), a small molecule selective FGFR1-3 inhibitor being developed for the treatment of FGFR-driven cancers and achondroplasia, for which we intend to submit an NDA in 2020 for the treatment of CCA as a second-line or later therapy.

BBP-631, an AAV5 gene transfer product candidate in preclinical development for the treatment of CAH, driven by 21OHD.

BBP-454, a preclinical development program for small molecule inhibitors of KRAS for the treatment of pan-mutant KRAS-driven cancers, which act via two novel binding pockets.

The following table summarizes our significant development programs, their estimated patient populations, their therapeutic modalities and their development status:

KEY VALUE DRIVERS

BBP-265/AG10 (Eidos):

Our drug engineering platform is characterized by four stages:

Discover, Create, Test and Deliver.

We identify novel genetic disease targets and focus only on well-described diseases that can be targeted at their source.

Our target identification engine is driven by three core areas of strength.

We pair a systematic mapping of the 7,000 known genetic diseases with leading computational genomics and statistical genetics capabilities and partner with top academic institutions.

We currently have over 15 academic partnerships.

Our target identification process is overseen by an investment committee that is comprised of renowned leaders in cancer and rare disease drug development with proven track records.

We select the optimal therapeutic modality to target each disease at its source.

We have industry-leading capabilities across four modalities:

medicinal chemistry, therapeutic proteins, gene therapy and antisense oligonucleotides.

We choose the treatment modality that we believe is best biologically suited to address the root cause of the disease.

Our research leaders have a productive history of developing novel therapeutics.

Together with the investment committee, the team has previously submitted over 100 Investigational New Drug applications, or INDs, and 20 NDAs, in aggregate.

We have built a leading, global clinical development footprint.

We have over 18 ongoing clinical trials across five different therapeutic areas, at over 400 trial sites in 26 countries.

Across these trials, we have built a central information repository and operational toolkit for best practices for enrollment, protocol quality, site activation, contract research organization, or CRO, quality and regional performance.

Our development is led by expert, dedicated teams in each therapeutic area who have the expertise to pursue unique and creative clinical and regulatory strategy.

We are building capabilities to deliver our potential products to patients across the globe.

We intend to build global commercial infrastructure to leverage our drug and disease expertise, including diagnostic partnerships, disease awareness strategies and country-specific early access programs.

We have already pursued commercial partners in strategic geographies for select programs.

We believe we have developed a world class drug engineering platform that is sustainable and scalable, and already producing results.

The discovery platform has yielded over 30 programs in the pipeline.

We have filed over 10 INDs since 2015 and are testing our product candidates in over 18 clinical trials across the globe.

Our pipeline includes over 30 development programs.

The following table summarizes our development programs, their estimated patient populations, their therapeutic modalities and their development status:

Of our development programs, we believe the following, to which we refer as our core value drivers, have the greatest potential to drive significant near-term value for our company due to a combination of factors, including their stage of development, potential availability of expedited development pathways, degree of unmet medical need and potential market size in the applicable target indication:

Acoramidis (also known as AG10 and BBP-265), a small molecule stabilizer of transthyretin, or TTR, that is in an ongoing Phase 3 clinical trial for the treatment of TTR amyloidosis-cardiomyopathy, or ATTR-CM.

Low-dose infigratinib (also known as BBP-831), a small molecule selective FGFR1-3 inhibitor that is an ongoing Phase 2 clinical trial for the treatment of achondroplasia in pediatric patients.

BBP-631, an AAV5 gene transfer product candidate for the treatment of congenital adrenal hyperplasia, or CAH, driven by 21-hydroxylase deficiency, or 21OHD, for which we anticipate initiating a first-in-human Phase 1/2 trial in the second half of 2021, with initial data anticipated in late 2021 or early 2022.

Encaleret, a small molecule antagonist of the calcium sensing receptor, or CaSR, that is in an ongoing Phase 2 proof-of-concept clinical trial for Autosomal Dominant Hypocalcemia Type 1, or ADH1.

CORE VALUE DRIVERS

Acoramidis (Eidos):

TTR Amyloidosis

We are developing BBP-265, also known as AG10, an oral small molecule TTR, stabilizer, for the treatment of TTR amyloidosis, or ATTR, including both cardiomyopathy and polyneuropathy manifestations, or ATTR-CM and ATTR-PN, respectively.

A Phase 3 clinical trial in ATTR-CM, known as the ATTRibute study, is currently ongoing, and we anticipate initiating a Phase 3 clinical trial in ATTR-PN in the first-half of 2020.

We anticipate reporting of 12-month 6MWD data from the Phase 3 ATTRibute study in patients in ATTR-CM in 2021.

We are developing acoramidis, also known as AG10 and BBP-265, an oral small molecule TTR, stabilizer, for the treatment of TTR amyloidosis, or ATTR.

A Phase 3 clinical trial in patients with ATTR-CM, known as the ATTRibute-CM study, is currently ongoing.

We anticipate reporting top-line 12-month 6-minute walking distance, or 6MWD, data from the ATTRibute-CM study in late 2021 or early 2022.

Disease Overview

ATTR is a disease caused by destabilization of TTR tetramers resulting in amyloid deposition.

ATTR is a disease caused by destabilization of TTR tetramers resulting in progressive amyloid deposition.

TTR is a protein that occurs naturally in the form of a tetramer, which is a molecular structure consisting of four identical subunits, or monomers, and performs multiple physiologic roles, including the transport of essential hormones and vitamins.

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wild-type ATTR cardiomyopathy, or ATTRwt-CM, which results from an age-related process;

mutant ATTR cardiomyopathy, or ATTRm-CM;

and ATTR polyneuropathy, or ATTR-PN, which is only associated with TTR mutants.

variant ATTR cardiomyopathy, or ATTRv-CM;

and ATTR polyneuropathy, or ATTR-PN, which is only associated with TTR variants.

All three forms of the disease are progressive and fatal.

ATTRwt-CM and ATTRm-CM patients generally present with symptoms later in life (older than 50) and have median life expectancies of three to five years from diagnosis.

ATTRwt-CM and ATTRv-CM patients generally present with symptoms later in life (older than 50) and have median life expectancies of three to five years from diagnosis if untreated.

ATTR-PN presents either in a patient’s early 30s or later (older than 50), and results in a median life expectancy of five to ten years from diagnosis.

Progression of all forms of the disease causes significant disability, impacts productivity and quality of life, and creates a significant economic burden due to the costs associated with patient need for supportive care.

As the disease progresses, ATTRwt-CM and ATTRm-CM patients may require frequent hospitalizations and repeated interventions.

As the disease progresses, ATTRwt-CM and ATTRv-CM patients may require frequent hospitalizations and repeated interventions.

ATTR-PN patients experience gradual loss of the ability to walk without assistance, and autonomic nervous system function affecting digestion and blood pressure.

The worldwide estimated prevalence of ATTRwt-CM, ATTRm-CM, and ATTR-PN is approximately 400,000, 40,000, and 10,000, respectively.

The worldwide estimated prevalence of ATTRwt-CM, ATTRv-CM, and ATTR-PN is approximately 400,000, 40,000, and 10,000, respectively.

However, we believe that the cardiomyopathic forms of the disease are significantly underdiagnosed.

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Our Product Concept

BBP-265 is a clinical-stage orally-administered, small molecule TTR stabilizer being developed to treat ATTR at its source by reducing the level of amyloid formation through TTR stabilization.

Acoramidis is a clinical-stage, orally administered, small molecule TTR stabilizer being developed to treat ATTR at its source by reducing the level of amyloid formation through TTR stabilization.

This has been shown in preclinical studies and clinical trials to prevent the dissociation of tetrameric TTR into monomers, and in preclinical studies, to reduce the rate of amyloid fibril formation.

In addition, BBP-265 has been shown to lead to increased circulating levels of tetrameric TTR.

BBP-265 has been designed to bind TTR in a way that causes TTR’s conformational structure to mimic that of the well-characterized T119M variant, a naturally occurring rescue mutation which super stabilizes the TTR tetramer.

T119M has been observed to prevent the dissociation of TTR tetramers into monomers;

In addition, acoramidis has been shown to lead to increased circulating levels of tetrameric TTR.

Acoramidis has been designed to bind TTR in a way that causes TTR’s conformational structure to mimic that of the well-characterized T119M variant, a naturally occurring rescue mutation that super stabilizes the TTR tetramer.

The T119M variant has been observed to prevent the dissociation of

TTR tetramers into monomers;

T119M tetramers dissociate 40-fold more slowly than wild-type tetramers in biochemical assays.

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As a result, we believe that serum TTR is a predictive biomarker for disease prognosis and that there may be a relationship between more effective TTR stabilization, serum TTR levels and improved clinical outcomes.

Based on head-to-head preclinical data, we believe that BBP-265 has the potential to stabilize TTR to a greater extent than other TTR stabilizers.

Human genetics suggest TTR stability is associated with disease severity

The above chart shows the correlation between TTR stability, as assessed using recombinant protein in vitro, and disease severity in ATTR patients.

Patients with TTR variants that result in highly destabilized TTR are nearly 100% likely to develop the disease, like those with the L55P gene variant.

Patients who have super-stabilized TTR, as in the case of individuals with the T119M gene variant, are protected against ATTR and cerebrovascular diseases.

We believe that TTR is an important plasma protein as evidenced by the fact that it is highly evolutionarily conserved, existing in high concentrations in all vertebrates.

We believe that therapies that increase serum TTR are likely to result in better clinical outcomes than therapies that decrease TTR serum levels, assuming similar levels of monomer reduction.

This hypothesis is further supported by two prospective studies of 68,602 participants in Denmark over an average 32 years of clinical follow-up, which showed that individuals who inherited the T119M mutation in the absence of a TTR pathogenic gene had higher circulating TTR concentrations, had a lower range of cerebrovascular events, especially fatal or debilitating stroke, and had a five-to-ten year increase in life expectancy relative to the general population.

Additionally, data from a retrospective study at Boston University, suggests a correlation between serum TTR changes and mortality in ATTRwt-CM patients.

Based on head-to-head preclinical data, we believe that acoramidis has the potential to stabilize TTR to a greater extent than other TTR stabilizers.

Clinical Data

In April 2018, we initiated our Phase 2 randomized, placebo-controlled, dose-ranging clinical trial of BBP-265 in 49 patients with symptomatic ATTR-CM, of which 14 had ATTRm-CM.

Eligible patients were randomized in a 1:1:1 ratio to placebo or 400 mg or 800 mg of BBP-265 twice daily.

The primary objective of the trial was to evaluate the safety and tolerability of BBP-265 administered to adult subjects with symptomatic ATTR-CM.

The secondary objectives were to characterize the pharmacokinetics, or PK, of BBP-265 in symptomatic ATTR-CM subjects and to describe the pharmacodynamics, or PD, properties of BBP-265, as well as the PK-PD relationship of BBP-265.

In April 2018, we initiated our Phase 2 randomized, placebo-controlled, dose-ranging clinical trial of acoramidis in 49 patients with symptomatic ATTR-CM, of which 14 had ATTRv-CM.

Eligible patients were randomized in a 1:1:1 ratio to placebo or 400 mg or 800 mg of acoramidis twice daily.

The primary objective of the trial was to evaluate the safety and tolerability of acoramidis administered to adult subjects with symptomatic ATTR-CM.

The secondary objectives were to characterize the pharmacokinetics, or PK, of acoramidis in symptomatic ATTR-CM subjects and to describe the pharmacodynamics, or PD, properties of acoramidis, as well as the PK-PD relationship of acoramidis.

The PD assessments of TTR stabilization were measured by fluorescent probe exclusion, Western blot and serum prealbumin (TTR).

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Enrolled symptomatic ATTR-CM subjects ranged in age from 60 to 86 years of age, with a mean age of 74.1, and 92% of subjects were male.

In this trial, we enrolled subjects exclusively with advanced disease, with 29% of subjects presenting with New York Heart Association (NYHA) Class III heart failure symptoms and a high baseline NT-proBNP with a mean of 3,368 pg/mL.

In this trial, we enrolled subjects exclusively with advanced disease, with 29% of subjects presenting with New York Heart Association , or NYHA , Class III heart failure symptoms and a high baseline NT-proBNP with a mean of 3,368 pg/mL.

Additionally, on average, subjects had relatively low TTR at baseline with a mean of 22.0 mg/dL.

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The subject disposition and baseline characteristics are shown below.

BBP-265 400 mg

BBP-265 800 mg

Acoramidis 400 mg

Acoramidis 800 mg

Characteristic

Age, mean (range)

ATTRm-CM, n (%)

ATTRv-CM, n (%)

NYHA Class III, n (%)

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TTR normal range = 20 – 40 mg/dL

Overall, BBP-265 was well-tolerated in symptomatic ATTR-CM subjects with no lab safety signals of potential clinical concern attributed to study drug.

In this trial, 88% of subjects administered placebo experienced AEs and 63% and 69% of subjects administered 400 mg and 800 mg BBP-265 experienced AEs, respectively.

Overall, acoramidis was well-tolerated in symptomatic ATTR-CM subjects with no lab safety signals of potential clinical concern attributed to study drug.

In this trial, 88% of subjects administered placebo experienced adverse events, or AEs, and 63% and 69% of subjects administered 400 mg and 800 mg acoramidis experienced AEs, respectively.

In both the placebo and active treatment groups, most of the AEs were mild to moderate in severity.

The most commonly observed AEs, occurring in four or more subjects across the treatment and placebo groups, were atrial fibrillation, constipation, diarrhea and muscle spasms.

Three subjects reported SAEs during this study.

Three subjects reported serious adverse events, or SAEs, during this study.

One placebo-treated subject experienced two SAEs, of atrial fibrillation and congestive heart failure and another placebo-treated subject experienced cellulitis in their lower extremity.

One BBP-265 treated subject experienced an SAE of shortness of breath on study, which was considered unlikely to be related to study drug.

One acoramidis treated subject experienced an SAE of shortness of breath on study, which was considered unlikely to be related to study drug.

As shown in the chart below, subjects in the placebo group experienced a mean 7% reduction in the circulating tetrameric TTR concentrations compared to baseline.

Conversely, subjects administered either 400 mg or 800 mg BBP-265 showed a dose-dependent statistically significant mean increase in circulating TTR of 36% and 50%, respectively, compared to baseline.

Compared to placebo, both the 400 mg and 800 mg BBP-265 arms demonstrated statistically significant increases in mean circulating TTR (p<0.0001 for both arms).

p-value is a statistical calculation that relates to the probability that the difference between groups happened by chance, with a p-value of less than 0.05 (i.e., less than 5% probability that the difference happened by chance) generally being used as the threshold to indicate statistical significance.

There was a greater observed treatment effect in subjects with mutant ATTR-CM as compared to subjects with wild-type ATTR-CM, which we believe can be explained, in part, by the lower absolute serum TTR of mutant ATTR-CM subjects at baseline.

The following chart shows that treatment with BBP-265 restored serum TTR concentrations to within the normal range in all subjects at Day 28.

Ex vivo stabilization assays demonstrated near-complete TTR stabilization by BBP-265, with greater than 90% average tetramer stabilization across subjects treated with 400 mg and 800 mg BBP-265 as shown in the chart below.

The stabilization response was consistent across mutant and wild-type TTR carriers and replicates previously reported clinical and preclinical TTR stabilization data.

Conversely, subjects administered either 400 mg or 800 mg acoramidis showed a dose-dependent statistically significant mean increase in circulating TTR of 36% and 50%, respectively, compared to baseline.

Compared to placebo, both the 400 mg and 800 mg acoramidis arms demonstrated statistically significant increases in mean circulating TTR (p<0.0001 for both arms).

p-value is a statistical calculation that relates to the probability that the difference between groups happened by chance, with a p-value of less than 0.05 ( i.e.

, less than 5% probability that the difference happened by chance) generally being used as the threshold to indicate statistical significance.

There was a greater observed treatment effect in subjects with variant ATTR-CM as compared to subjects with wild-type ATTR-CM, which we believe can be explained, in part, by the lower absolute serum TTR of variant ATTR-CM subjects at baseline.

The following chart shows that treatment with acoramidis restored serum TTR concentrations to within the normal range in all subjects at Day 28.

Ex vivo stabilization assays demonstrated near-complete TTR stabilization by acoramidis , with greater than 90% average tetramer stabilization across subjects treated with 400 mg and 800 mg acoramidis , as shown in the chart below.

The stabilization response was consistent across variant and wild-type TTR carriers and replicates previously reported clinical and preclinical TTR stabilization data.

Interim analysis of the ongoing Phase 2 open-label extension, or OLE, study was completed on August 31, 2019 in conjunction with annual regulatory reporting and review, at which time 41 participants remained in the study.

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Three (6.4%) additional patients enrolled in the study had discontinued treatment, including one participant who underwent cardiac transplantation for their disease.

Adverse events reported in the OLE study were generally consistent with the underlying ATTR-CM disease state and no safety signals of potential clinical concern were associated with the administration of AG10 in the study.

Forty-six (97.9%) patients experienced a treatment-emergent adverse event reported during the study, with falls, congestive cardiac failure, dyspnea, and acute kidney injury the most commonly reported adverse events.

Nineteen (40.4%) participants experienced a treatment-emergent serious adverse event reported during the study, with congestive cardiac failure (10.6%) and acute kidney injury (8.5%) the most commonly reported serious adverse events.

AEs reported in the OLE study were generally consistent with the underlying ATTR-CM disease state and no safety signals of potential clinical concern were associated with the administration of acoramidis in the study.

Forty-six (97.9%) patients experienced a treatment-emergent AE reported during the study, with falls, congestive cardiac failure, dyspnea and acute kidney injury the most commonly reported AEs.

Nineteen (40.4%) participants experienced a treatment-emergent SAE reported during the study, with congestive cardiac failure (10.6%) and acute kidney injury (8.5%) the most commonly reported SAEs.

The rate of all-cause mortality (including either death or cardiac transplantation, 8.5%) and cardiovascular-related hospitalizations (25.5%) observed in an exploratory analysis of participants in this study following a median of 15 months since Phase 2 initiation were lower than those observed at 15 months in placebo-treated patients in the ATTR-ACT study (all-cause mortality including death or cardiac transplantation, 15.3%;

cardiovascular-related hospitalizations, 41.8%).

Stabilization of TTR, as measured using established ex vivo assays, was maintained >90% on average at all study visits in actively treated patients.

Stabilization of TTR, as measured using established ex vivo assays, was maintained greater than 90% on average at all study visits in actively treated patients.

(1) Reported occupancy >100% caused by background protein fluorescence.

Mean serum TTR levels, a prognostic indicator of survival in a published cohort of wild-type ATTR-CM patients, were elevated upon AG10 treatment and were maintained in the normal range throughout the study duration.

Mean serum TTR levels, a prognostic indicator of survival in a published cohort of wild-type ATTR-CM patients, were elevated upon acoramidis treatment and were maintained in the normal range throughout the study duration.

Mean serum TTR levels were increased from baseline by 39% and 56% in wild-type and variant-carrying ATTR-CM patients, respectively, at OLE Visit Day 180.

400mg and 800mg BID AG10 groups pooled during randomized portion

400mg and 800mg BID acoramidis groups pooled during randomized portion

Defined as the lower limit of the reference interval for the serum prealbumin (TTR) clinical laboratory assay

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Clinical Development Plan

In November and December of 2018, we met with the FDA to discuss a potential regulatory path for BBP-265 in ATTR-CM.

Following these discussions, we initiated a randomized, global Phase 3 study of BBP-265 in ATTR-CM patients (ATTRibute-CM).

ATTRibute-CM will enroll approximately 510 subjects with symptomatic ATTR-CM, including both wild-type and mutant TTR carriers with New York Heart Association Class I-III symptoms.

Subjects will be randomized 2:1 between treatment (AG10 800 mg twice daily) and placebo.

In Part A, change in six-minute walk distance (6MWD) at 12 months will be compared between treatment and placebo groups as a potential registrational endpoint.

We anticipate reporting 12-month 6MWD data from Phase 3 ATTRibute study in patients with ATTR-CM in 2021.

If the change in 6MWD is highly statistically significant, we anticipate submitting an NDA for ATTR-CM.

We are conducting a randomized, global Phase 3 study of acoramidis in ATTR-CM patients, or ATTRibute-CM.

ATTRibute-CM enrolled 632 subjects with symptomatic ATTR-CM, including both wild-type and variant TTR carriers with NYHA Class I-III symptoms.

Subjects were randomized 2:1 between treatment (acoramidis 800 mg twice daily) and placebo.

In Part A, change in 6MWD at 12 months will be compared between treatment and placebo groups as a potential registrational endpoint.

We anticipate reporting 12-month 6MWD data from Part A of the Phase 3 ATTRibute-CM study in late 2021 or early 2022, and from Part B in 2023.

If the change in 6MWD is highly statistically significant, we anticipate submitting an NDA for ATTR-CM in 2022.

In Part B, the study will continue for a total duration of 30 months, at which point all-cause mortality and cardiovascular hospitalizations will be compared between treatment and control groups.

A schematic of the trial is shown below:

Secondary endpoints include:

Kansas City Cardiomyopathy Questionnaire, serum TTR, TTR stabilization

As local standard of care evolves, concomitant use of approved, indicated therapies may be allowed

6MWD = Six minute walk distance;

NYHA = New York Heart Association;

99mTc = Technetium labeled pyrophosphate (PYP) or bisphosphonate (e.g., DPD);

dx = diagnosis;

CV hosp = cardiovascular-related hospitalizations

We believe the safety and tolerability data of BBP-265 in healthy volunteers and in ATTR-CM patients will also be relevant for the ATTR-PN patient population.

We anticipate initiating a Phase 3 clinical trial of BBP-265 in ATTR-PN in 1H 2020.

Our Phase 3 study in ATTR-PN (ATTRibute-PN) is expected to enroll approximately 145 subjects with symptomatic ATTR-PN.

Eligible subjects will be randomized in a 2:1 ratio to AG10 800 mg or matching placebo administered twice daily.

The primary endpoint of the study is to evaluate the efficacy of AG10 based on the difference between the AG10 and placebo groups in Modified Neuropathy Impairment Score + 7 at 18 months of treatment relative to baseline.

Market Opportunity

We believe that the total market for ATTR therapeutic interventions will continue to grow for the foreseeable future as the population of diagnosed patients increases as a result of heightened disease awareness and the adoption of non-invasive diagnostic techniques.

As such, if BBP-265 is approved, we believe that there could be a significant population of newly diagnosed patients who can be treated with BBP-265 who have not previously been treated with a disease-modifying therapy.

If approved, we believe that BBP-265 could have meaningful commercial potential.

Further, we believe that BBP-265, if approved, has the potential to demonstrate benefit as a best-in-class stabilizer for the treatment of ATTR.

In the area of ATTR, we expect to face competition from competitors targeting three distinct mechanisms of action:

TTR stabilization, TTR knockdown, and TTR clearance, each of which is expected to compete with BBP-265, if approved.

Among TTR stabilizers, we will face competition from Pfizer Inc.’s tafamidis, an oral TTR stabilizer that is approved for ATTRwt-CM and ATTRm-CM in the United States, Europe, and Japan and is marketed as VYNDAQEL and VYNDAMAX.

Tafamidis is also approved in select geographies outside of the United States for Stage 1 (early stage) ATTR-PN.

Corino Therapeutics Inc./SOM Innovation Biotech, S.L.

is developing SOM0226 (tolcapone, CRX-1008), an oral, small molecule TTR stabilizer for ATTR and has completed a Phase 2a trial in ATTR-PN.

Tolcapone is a generic drug that is FDA-approved for the treatment of Parkinson’s disease.

Diflunisal, a generic, non-steroidal anti-inflammatory drug (NSAID) indicated for mild to moderate pain and arthritis, may also be considered a competitor, having been shown to significantly slow development of ATTR-PN in a randomized Phase 2/3 trial.

Diflunisal’s label contains a boxed warning for cardiovascular, renal and gastrointestinal risks.

Potentially competitive TTR knockdown approaches are being pursued by multiple companies.

In 2018, Alnylam Pharmaceuticals Inc., or Alnylam, received marketing authorization from both the FDA and EMA for Onpattro (patisiran), an intravenously administered RNAi therapeutic for the treatment of hereditary ATTR with polyneuropathy.

Alnylam is also developing ALN-TTRsc02 (vutrisiran), a subcutaneously administered RNAi therapeutic for ATTR.

Alnylam has reportedly completed a Phase 1 clinical trial of ALN-TTRsc02 in healthy volunteers and initiated a Phase 3 trial in patients with hereditary ATTR with polyneuropathy.

Ionis Pharmaceuticals Inc./Akcea Therapeutics, Inc.

received marketing approval from both the FDA and EMA in 2018 for Tegsedi (inotersen), an antisense oligonucleotide (ASO) drug, for hereditary ATTR with polyneuropathy.

Both Alnylam and Ionis/Akcea have initiated Phase 3 trials in ATTR-CM.

Intellia’s program is currently in preclinical development.

Therapeutics targeting TTR clearance may also be competitive to BBP-265.

Prothena Therapeutics plc is developing PRX004, a monoclonal antibody, for ATTR that is currently in a Phase 1 clinical trial.

Neurimmune Holding AG is developing NI006, a monoclonal human antibody for ATTR that is in Phase 1 clinical trial.

Proclara Biosciences, Inc.

is developing NPT189, an immunoglobulin fusion, for ATTR and amyloid light chain amyloidosis and has completed a Phase 1a clinical trial.

BBP-831/Infigratinib:

FGFR-Driven Cancers

We are developing infigratinib, an oral FGFR1-3 selective tyrosine kinase inhibitor, or TKI, for the treatment of FGFR-driven cancers.

Specifically we are developing infigratinib in three oncologic indications:

(i) cholangiocarcinoma, or CCA, with FGFR2 fusions or translocations, (ii) urothelial carcinoma, or UC, with FGFR genomic alterations, and (iii) other cancers with FGFR fusions or translocations.

We are currently preparing an NDA submission in advanced CCA, as a second-line or later therapy and have initiated a Phase 3 clinical trial in advanced CCA as a first-line therapy as well as an Investigator-initiated trial in certain cancers involving FGFR fusions or translocations.

We received Fast Track Designation in adults with first-line advanced or metastatic cholangiocarcinoma and Orphan Drug Designation for infigratinib for treatment of cholangiocarcinoma.

We anticipate submitting an NDA for the treatment of advanced CCA as a second-line or later therapy in 2020.

We also anticipate enrolling our first patient in a Phase 3 clinical trial in adjuvant UC in 2020.

Disease Overview

FGFRs are a family of genes that regulate multiple biological processes including cell proliferation, angiogenesis, and tissue repair.

Amplifications, mutations, and fusions/translocations in FGFR genes are present in multiple cancers, and it is believed that they are key drivers in certain cancer types.

FGFR genomic alterations have been shown to be present in approximately 7% of cancers.

FGFR fusions or translocations, more specifically, have been shown to be present in approximately 0.6% of solid tumors.

Below is a table showing the frequency of certain FGFR genomic alterations in different tumor types:

Occurrence of

alteration(s)

Cholangiocarcinoma

FGFR2 fusions or

translocations

Urothelial carcinoma

Non-muscle invasive bladder cancer

FGFR3 mutations

Muscle invasive bladder cancer

FGFR3 mutations

Non-invasive upper tract urothelial carcinoma

FGFR3 mutations

Invasive upper tract urothelial carcinoma

FGFR3 mutations

Gastric adenocarcinoma

FGFR2 amplifications,

FGFR2 fusions or

translocations

FGFR3 fusions or

translocations, FGFR1

amplifications

Head and neck squamous cell carcinoma

FGFR1 genomic

Carcinoma of unknown primary

FGFR2/3 fusions or

translocations

Endometrial adenocarcinoma

FGFR2 fusions or

translocations

Approximate percentages

Cholangiocarcinoma

CCA is a rare and aggressive epithelial malignancy of the bile ducts of the liver.

Approximately 20,000 new cases are diagnosed each year in the United States and European Union.

The majority of newly diagnosed cases are non-resectable, meaning the malignancy cannot be removed completely through surgery.

CCA, including resectable and non-resectable cases, has a median overall survival, or OS, between 20 and 28 months from diagnosis, and a five-year survival rate of approximately 25%.

Currently, no product has been specifically approved for the treatment of non-resectable CCA.

Standard of care in locally advanced (i.e., non-resectable) and/or metastatic disease for first-line treatment is platinum-based chemotherapy, which has median with a progression-free survival, or PFS, of approximately eight months and an OS of approximately 12 months.

Approximately 85% of these patients will move on to receive a second-line of treatment.

Second-line treatment for advanced and/or metastatic CCA is alternative single or combination agent chemotherapy;

however, second-line chemotherapy has shown only single-digit response rates on average.

In a comprehensive review of 25 studies, median PFS was 3.2 months and overall response rate, or ORR, was 7.7% for patients receiving second-line treatment.

As a result, the National Comprehensive Cancer Network, or NCCN, guidelines for the treatment of CCA currently do not recommend any specific regimen for second-line treatments.

Further, there are currently no targeted therapies approved for the treatment of CCA.

Urothelial Carcinoma

UC is a cancer of the lining of the urinary tract with approximately 200,000 new cases diagnosed each year in the United States and European Union.

UC can be categorized as bladder cancer, or BC, and upper tract urothelial carcinoma, or UTUC.

In BC, patients are typically segmented into muscle-invasive, or MIBC, and non-muscle invasive, or NMIBC disease.

UTUC, in turn, can be classified as invasive or non-invasive disease.

We are initially focused on developing infigratinib for the 45,000 MIBC and 15,000 invasive UTUC cases that occur annually in the United States and European Union.

Patients that present with MIBC or invasive UTUC are typically candidates for surgical resection, specifically radical cystectomy or radical nephroureterectomy, respectively, as an initial treatment.

However, upon resection, approximately 50% of cases will recur within two years of surgery.

Following surgical resection there is no standard of care for adjuvant treatment, especially for cisplatin ineligible patients.

There are limited clinical data suggesting that cisplatin-based adjuvant regimens may increase disease-free survival.

And, as renal function is impaired in many patients due to age and surgical removal of the bladder, ureter and/or kidney, many patients are not candidates for cisplatin-based therapy.

Data suggests that approximately 40% to 50% of MIBC patients and 70% to 80% of invasive UTUC patients are cisplatin ineligible after radical cystectomy and radical nephroureterectomy, respectively.

Our Product Concept

Signaling via FGFR genes is thought to be a key driver of certain cancers, including CCA and UC.

As an FGFR1-3 specific inhibitor, infigratinib abrogates signaling via the FGFR1-3 pathways, interfering with oncogenic signaling and cancer growth.

Infigratinib has shown clinical activity in advanced and/or metastatic CCA with FGFR2 fusions or translocations, with an ORR of 26.9%, in a Phase 2 clinical trial as described below.

In advanced and/or metastatic CCA, limited treatment options make FGFR-directed therapies particularly attractive potential treatment options.

Infigratinib has also shown clinical activity in advanced and/or metastatic UC with FGFR3 genomic alterations in a Phase 1 expansion cohort, with an ORR of 25.4%, as described below.

The majority of patients with invasive UC undergo surgical resection;

however, there is no standard of care for adjuvant treatment post-surgery, especially for cisplatin-ineligible patients.

While there is limited evidence for the use of cisplatin-based chemotherapy as an adjuvant treatment, many patients are cisplatin ineligible due to poor renal function.

We believe that infigratinib could play a meaningful role as an adjuvant treatment for patients with UC driven by FGFR3 genomic alterations.

Clinical Data

Infigratinib has been studied in fifteen clinical trials that include eight Phase 1 clinical trials in healthy volunteers, one mass balance and exertion study, three Phase 1 clinical trials in cancer patients, and three Phase 2 clinical trials in certain cancer patients, and has demonstrated clinical proof of concept in CCA and UC.

To date, infigratinib has been tested in over 700 subjects, including healthy volunteers and cancer patients, and has demonstrated acceptable tolerability.

In the studies described below, the following revised RECIST guideline version 1.1, or RECIST 1.1, criteria, which are the accepted criteria by the scientific community for the tumor type discussed, were used to define responses:

ORR, which is defined as the proportion of patients with a best overall response of partial response, or PR, plus those with complete response, or CR.

Response duration, which is measured from the time of initial response until documented tumor progression.

Disease control rate, or DCR, which is defined as the proportion of patients who have achieved a best overall response of CR, PR, or stable disease, or SD.

Progression free survival, or PFS, which is defined as the time from randomization/start of treatment until objective tumor progression or death, whichever occurs first.

Overall survival, or OS, which is defined as the time from randomization until death from any cause.

CCA Phase 2 Clinical Trial

Infigratinib is being studied in an open-label, single-arm, Phase 2 clinical trial in patients with advanced and/or metastatic CCA.

The study initially enrolled patients with any FGFR genomic alterations and was later amended to enroll only patients with FGFR2 fusions or translocations, who represented patients showing the strongest response.

To date, we have reported interim data in 71 CCA patients with FGFR2 fusions or translocations, who had previously received a cisplatin-and gemcitabine-containing regimen, or a gemcitabine-containing regimen (for those who are considered intolerant to cisplatin) and are continuing to enroll patients in the trial.

Patients received infigratinib 125 mg once daily for 21 days followed by seven days off in 28-day cycles until disease progression.

The primary endpoint of the study is ORR.

Secondary endpoints include PFS, best overall response, or BOR, DCR, OS, safety and PK.

The median age of enrolled subjects is 53 years, 62.0% are female, 100.0% are FGFR2 fusion or translocation positive, and 7.0% have co-existing FGFR2 mutations.

A significant majority of patients enrolled in the trial were pretreated, with 65.1% having received at least two prior lines of antineoplastic therapy.

At an interim analysis based on a data cut-off date of August 8, 2018, we observed the following results for FGFR2 fusion or translocation positive patients.

The data presented in the table below are based on patients with potential for confirmation (n=67;

patients who had completed or discontinued prior to six cycles).

All responses were investigator-assessed.

ORR, % (95% CI)

26.9 (16.8-39.1)

ORR in patients receiving prior lines of treatment, %

BOR ‡ (confirmed and unconfirmed PRs)*, %

DCR, % (95% CI)

83.6 (72.5-91.5)

Median duration of response, months (95% CI)

5.4 (3.7-7.4)

Median PFS, months (95% CI)

6.8 (5.3-7.6)

Median OS, months (95% CI)

12.5 (9.9-16.6)

Three patients received no prior systemic therapy for advanced or metastatic CCA

BOR defined per RECIST1.1:

patients with one scan with greater than 30% change from baseline in target lesions, without confirmation from a second scan

The ORR as of the interim analysis was observed to be higher in the subsegment of patients who had received only one prior line of therapy (39.3% versus 26.9% for all patients).

Urothelial Carcinoma Phase 1 Clinical Trial Expansion Cohort

In a Phase 1 open-label, single arm expansion cohort of the ‘2101 study, patients with UC harboring FGFR3 genomic alterations (n=67) received infigratinib 125 mg once daily for 21 days followed by seven days off in 28-day cycles until progression.

Patients enrolled in the trial had a median age of 67 years, and 68.7% were male.

92.5% of patients had FGFR3 mutations and 7.5% had FGFR3 fusions or translocations.

The primary objective of the ‘2101 study was to determine the maximum tolerated dose, or MTD, and thus the recommended Phase 2 clinical trial dose and schedule of single agent oral BGJ398 in patients with advanced solid tumors.

The key secondary objective of the expansion cohort in this study was to assess preliminary anti-tumor activity in patients treated with infigratinib.

Other secondary objectives included safety, tolerability and PK analyses.

Patients enrolled in the trial were heavily pre-treated, 70% of enrolled patients having received two or more prior lines of therapy.

The endpoint assessment of patients from this trial follows:

25.4 (15.5-37.5)

BOR (confirmed and unconfirmed PRs), %

64.2 (51.5-75.5)

Median duration of response, months (95% CI)

5.6 (2.3-11.0)

Median PFS, months (95% CI)

3.8 (3.1-5.4)

Median OS, months (95% CI)

7.8 (5.7-11.9)

Of the 67 patients treated in this expansion cohort, eight were diagnosed as having UTUC.

In these eight patients, ORR was 50% and DCR was 100%.

Infigratinib has been studied in over 700 subjects to date, including 222 healthy volunteers, 433 oncology patients treated with infigratinib monotherapy, and 62 oncology patients treated with infigratinib in combination with BYL719, a phosphoinositide 3-kinase, or PI3K inhibitor.

To date, at the dose of 125mg daily (three weeks on, one week off), the dose being used in our ongoing and planned Phase 2 and Phase 3 clinical trials, infigratinib has shown acceptable tolerability with expected on-target class effects.

The table below show safety data for all oncology patients (n=433) exposed to infigratinib monotherapy across all studies, dosing levels, and dosing schedules, and provides a summary of the most frequently observed AEs in ≥ 25.0% of oncology patients:

The most commonly reported treatment emergent adverse event of any grade was hyperphosphatemia, occurring in 61.2% of patients.

Hyperphosphatemia is an on-target AE based on FGFR1 inhibition.

Other frequently reported AEs included fatigue (40.4%), constipation (36.7%), stomatitis (34.9%), decreased appetite (29.8%), nausea (28.9%), diarrhea (27.0%), and alopecia (26.8%).

Other Grade 3+ AEs occurring in >5% of patients included hypophosphatemia (7.6%), hyponatremia (6.9%), and increased lipase (6.2%).

In total, 37.9% (n=164/433) of oncology patients across all trials with monotherapy treatment experienced SAEs.

SAEs occurring in greater than 1.0% of patients included pyrexia (2.8%), dyspnea (2.3%), general physical health deterioration (2.1%), pyrexia (2.1%), sepsis (2.1%), vomiting (2.1%), abdominal pain (1.8%), anemia (1.8%), hypercalcemia (1.8%), pneumonia (1.8%), , acute kidney injury (1.4%), constipation (1.4%), dehydration (1.4%), nausea (1.4%), and urinary tract infection (1.4%).

In healthy volunteers (n=222), no SAEs were reported.

Clinical Development Plans

We intend to file an NDA with the FDA for second line and later advanced CCA with FGFR2 fusions or translocations in 2020 with the data that have been generated to date from clinical trials of infigratinib, after meetings with the FDA in 2019, including a pre-submission meeting with the Center for Drug Evaluation and Research and the Center for Devices and Radiological Health to discuss analytical validation and clinical bridging to support the marketing authorization pathway for the companion diagnostic we are developing with FMI.

We believe that approval of this companion diagnostic via the premarket approval, or PMA, pathway will be required for approval of an NDA for infigratinib;

however, based on our interactions with the FDA to date, we do not expect to have to perform any additional clinical work specifically related to the companion diagnostic we are developing with FMI.

We have fully enrolled the cohort that will be used for the primary efficacy analysis to support our planned NDA submission.

First-line CCA

A Phase 3 randomized, open-label clinical trial of infigratinib as a first-line therapy for CCA compared to gemcitabine and cisplatin in advanced and/or metastatic CCA with FGFR2 fusions or translocations is currently enrolling.

The trial has a target enrollment of approximately 384 patients globally.

Adjuvant Urothelial Carcinoma

We anticipate enrolling the first patient in a Phase 3 randomized, double-blind, placebo controlled clinical trial in cisplatin-ineligible adjuvant UC with FGFR3 genomic alterations in 2020.

Other Cancers with FGFR Fusions or Translocations

We are exploring potential clinical development paths for infigratinib in additional FGFR fusion or translocation-driven cancers, as we believe that fusions or translocations are the most likely FGFR genomic alterations to be sensitive to infigratinib monotherapy, based on available data.

To date, infigratinib has shown responses in FGFR fusion or translocation-driven CCA and UC, as well as gallbladder cancer, carcinoma of unknown primary, and glioblastoma.

An investigator initiated trial has been initiated at the Ohio State University to study infigratinib in patients with multiple tumor types exhibiting FGFR fusions or translocations to further explore the activity of infigratinib in FGFR fusion or translocation-driven solid tumors.

Key Competitors

There are six other FGFR targeted assets currently known to be in clinical development.

These product candidates have not been compared with infigratinib in head-to-head studies.

However, efficacy and tolerability data of competitive compounds appears to be in-line with the data from clinical studies of infigratinib.

Key competitors include pemigatinib, an FGFR TKI under Phase 2 and Phase 3 clinical development by Incyte Corporation, futibatinib (TAS-120), an FGFR TKI under Phase 2 clinical development by Taiho Oncology, Inc., derazantinib, an FGFR TKI under Phase 2 and Phase 1/2 clinical development by ArQule, Inc.

in collaboration with Basilea Pharmaceutica International Limited, erdafitinib (BALVERSA), an FGFR TKI under development by Janssen Pharmaceuticals, Inc., which has been approved by FDA for the treatment of adult patients with locally advanced or metastatic urothelial carcinoma that has susceptible FGFR3 or FGFR2 genetic alterations and who have progressed during the following at least one line of prior platinum-containing therapy, vofatamab, an FGFR3 monoclonal antibody under Phase 1/2 clinical development by Rainier Therapeutics, Inc.

and rogaratinib, an FGFR TKI under Phase 2/3 clinical development by Bayer AG.

BBP-831/Infigratinib:

As such, if acoramidis is approved, we believe that there could be a significant population of newly diagnosed patients that can be treated with acoramidis who have not previously been treated with a disease-modifying therapy.

If approved, we believe that acoramidis could have meaningful commercial potential.

Further, we believe that acoramidis, if approved, has the potential to demonstrate benefit as a best-in-class stabilizer for the treatment of ATTR.

If acoramidis is approved as a treatment for ATTR-CM, we expect to face competition primarily from Vyndaqel / Vyndamax (tafamidis meglumine/tafamidis), which is approved in the United States, European Union and Japan as a treatment for ATTR-CM.

Additionally, there are a number of RNAi, antisense oligonucleotide and gene editing product candidates that are currently in development as potential treatments for ATTR-CM.

Low-dose Infigratinib:

Achondroplasia

We are developing infigratinib, an oral FGFR1-3 selective TKI for the treatment of achondroplasia at a significantly lower dose than those doses studied in our oncology programs for infigratinib.

We are currently enrolling patients in PROPEL, a prospective observational study in children with achondroplasia.

We anticipate both initiating our Phase 2 PROPEL 2 trial in Australia and submitting our IND to the FDA in 2020 to expand the study to the United States.

We are developing low-dose infigratinib, an oral FGFR1-3 selective tyrosine kinase inhibitor, or TKI, for the treatment of achondroplasia.

While we are also investigating infigratinib as a potential treatment for certain oncology indications, we are utilizing a significantly lower dose in children with achondroplasia than we are for our oncology programs.

We are currently enrolling patients in PROPEL, a prospective observational study in children with achondroplasia and PROPEL 2, a Phase 2 dose-escalation and expansion study of infigratinib in children with achondroplasia.

We anticipate that we will report initial data from PROPEL 2 in the second half of 2021.

Condition Overview

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FGFR3 is expressed in osteoblasts and chondrocytes where it plays a critical role in regulating bone growth through the MAPK pathway, which drives hypertrophic differentiation, and through the STAT1 pathway, which drives chondrocyte proliferation.

Apart from growth hormones, which are approved in Japan, we are not aware of any other medicines approved for marketing by the FDA or the EMA for the treatment of achondroplasia.

Apart from growth hormones, which are approved in Japan, we are not aware of any other medicines approved for marketing by the FDA or the European Medicines Agency, or the EMA, for the treatment of achondroplasia.

Our Product Concept

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We are currently enrolling patients in PROPEL, a prospective observational study in children with achondroplasia.

The study will establish annualized growth velocity (AGV) for each child of a minimum period of six months.

PROPEL is designed to provide baseline measurements for children that we anticipate enrolling in PROPEL 2, a planned Phase 2 study of low-dose infigratinib, that we anticipate initiating in 2020.

We anticipate that we will report initial data from PROPEL 2 in 2021.

The study will establish annualized growth velocity, or AGV, for each child for a minimum period of six months.

PROPEL is designed to provide baseline measurements for children that we anticipate enrolling in PROPEL 2, an ongoing Phase 2 study of low-dose infigratinib.

PROPEL 2 is designed as an open-label, dose-escalation and expansion trial in children with achondroplasia prior to growth plate closure.

The primary objective of this study will be to assess safety and tolerability in children with achondroplasia.

The primary objective of this study is to assess safety and tolerability in children with achondroplasia.

Secondary objectives will include PK analyses, change in growth velocity, and assessment of quality of life.

We anticipate that we will report initial data from PROPEL 2 in the second half of 2021.

Key Competitors

Infigratinib is the only oral direct FGFR1-3 inhibitor that has been publicly disclosed in development for the treatment of achondroplasia.

There are three other identified companies developing compounds for the treatment of achondroplasia using alternative mechanistic approaches:

There are four other identified companies developing compounds for the treatment of achondroplasia using alternative mechanistic approaches:

BioMarin Pharmaceutical Inc.

(vosoritide), Ascendis Pharma A/S (TransCon CNP), and Pfizer Inc.

(recifercept).

(vosoritide), Ascendis Pharma A/S (TransCon CNP), Pfizer Inc.

(recifercept) and Sanofi S.A.

Congenital Adrenal Hyperplasia

We are developing BBP-631, a preclinical AAV gene transfer product candidate, for the treatment of CAH, caused by 21OHD.

BBP-631 was granted orphan drug designation from both FDA for the treatment of congenital adrenal hyperplasia 21-hydroxylase deficiency and EMA for the treatment of congenital adrenal hyperplasia in 2018.

We are currently conducting GLP toxicity studies and anticipate submitting an IND to the FDA in 2020.

BBP-631 was granted orphan drug designation from both the FDA for the treatment of congenital adrenal hyperplasia 21-hydroxylase deficiency and the EMA for the treatment of congenital adrenal hyperplasia in 2018.

We anticipate initiating a Phase 1/2 first-in-human clinical trial of BBP-631 in the second half of 2021, with initial data from this study anticipated in late 2021 or early 2022.

Disease Overview

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Hormonal changes during puberty compound the CAH deficiencies.

Females often suffer from limited fertility and require intensive treatment before, during, and after pregnancy, and up to 40% of adult males will have adrenal rest tumors which can lead to gonadal dysfunction and infertility, occasionally requiring surgery.

Females often suffer from limited fertility and require intensive treatment before, during and after pregnancy, and up to 40% of adult males will have adrenal rest tumors that can lead to gonadal dysfunction and infertility, occasionally requiring surgery.

Over 90% of CAH cases are caused by 21OHD, a genetic defect in the CYP21A2 gene coding for the enzyme 21OH.

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We are primarily focused on treating classic patients, who have the more severe phenotype and that can be categorized into simple virilizing (approximately 25% of patients) and salt-wasting (approximately 75%) by the severity of aldosterone deficiency and level of residual 21OH enzyme activity.

Patients with the salt-wasting form of disease have residual enzyme activity of 0-1% of normal and patients with the simple virilizing phenotype have 1-10% enzyme activity.

Patients with the salt-wasting form of disease have residual enzyme activity of 0% to 1% of normal and patients with the simple virilizing phenotype have 1% to 10% enzyme activity.

All patients with the classic form require treatment at birth, as cortisol deficiency can lead to adrenal crisis as early as one to four weeks of life and can quickly lead to death.

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BBP-631 was granted both FDA and EMA orphan drug designation in 2018 for the treatment of CAH caused by 21OHD.

Development Status

Preclinical Data

Initial preclinical activity was explored in a Cyp21 knockout mouse model using AAVrh10.

An IV injection of vector genomes was observed to improve multiple disease-related factors over a 15-week duration window, including an increase in body weight, a decrease in urinary progesterone (the main substrate of 21OH), and an increase in renin expression (signaling an increased capacity for salt retention).

A study in nonhuman primates (NHP) comparing evaluated AAV serotypes 1, 5, and 6 identified AAV5 as the optimum serotype.

An intravenous, or IV, injection of vector genomes was observed to improve multiple disease-related factors over a 15-week duration window, including an increase in body weight, a decrease in urinary progesterone (the main substrate of 21OH), and an increase in renin expression (signaling an increased capacity for salt retention).

A study in non-human primates, or NHP, comparing evaluated AAV serotypes 1, 5 and 6 identified AAV5 as the optimum serotype.

We observed significant transfection in the adrenals where 21OH is synthesized.

Additionally, AAV5 has relatively low seroprevalence in the human population limiting potential immunogenicity issues.

Additionally, AAV5 has relatively low seroprevalence in the human population, which may limit potential immunogenicity issues.

We have completed two sets of NHP studies designed to evaluate durability of expression, dosing/transgene expression relationships and preliminary safety.

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We did not observe rapid decreases in vector genome counts and mRNA levels due to adrenal cell turnover between 1.5 and six months, providing preliminary support for sustained transgene expression.

In a second set of experiments, a total of 20 non-human primates (NHPs) were treated with BBP-631 at one of three intravenous (IV) doses.

Vector copy number and transgene mRNA expression in the adrenal glands were analyzed at 4 and 12 weeks post-dosing in the low- and medium-dose arms and at 12 and 24 weeks post-dosing in the high-dose arm.

No dose-related adverse events were observed at any of the doses tested at any time point.

Overall, treatment with BBP-631 resulted in high vector copy number (VCN) and mRNA expression in the adrenal gland, suggesting strong tropism and uptake of BBP-631 for the adrenal gland.

In a second set of experiments, a total of 20 NHPs were treated with BBP-631 at one of three IV doses.

Vector copy number and transgene mRNA expression in the adrenal glands were analyzed at four and 12 weeks post-dosing in the low- and medium-dose arms, and at 12 and 24 weeks post-dosing in the high-dose arm.

No dose-related AEs were observed at any of the doses tested at any time point.

Overall, treatment with BBP-631 resulted in high vector copy number, or VCN, and mRNA expression in the adrenal gland, suggesting strong tropism and uptake of BBP-631 for the adrenal gland.

In the high-dose arm, VCNs were maintained between 12 and 24 weeks.

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Researchers also saw dose-dependent increases in both VCNs and mRNA levels across the three doses tested.

Subject to the successful outcome of ongoing toxicology studies, we anticipate filing an IND for BBP-631 in 2020.

Key Competitors

There are two alternative therapeutic mechanisms being investigated for treatment of CAH.

The first are corticotropin-releasing factor type 1 (CRF1) receptor antagonists.

CRF1 receptor antagonists regulate the release of adrenocorticotropic hormone (ACTH) from the pituitary gland, which stimulates androgen and cortisol synthesis in the adrenal gland.

There are two alternative therapeutic classes being investigated for treatment of CAH.

The first are corticotropin-releasing factor type 1, or CRF1, receptor antagonists.

CRF1 receptor antagonists regulate the release of adrenocorticotropic hormone, or ACTH, from the pituitary gland, which stimulates androgen and cortisol synthesis in the adrenal gland.

In healthy individuals, endogenous cortisol provides negative feedback to the release of ACTH, which keeps androgen synthesis well regulated.

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Therefore, steroid supplementation is still required with CRF1 receptor antagonists.

Two CRF receptor antagonists, NBI-74788 (under development by Neurocrine Biosciences, Inc.) and SPR001 (under development by Spruce Biosciences, Inc.), are currently in Phase 2 clinical trials.

The second alternative therapeutic mechanism is acetyl-coenzyme A acetyltransferase 1 (ACAT-1) inhibition.

Inhibition of this metabolic enzyme induces targeted cell death in the adrenal gland, reducing steroid production and secretion.

However, like CRF1 receptor antagonists, ACAT-1 inhibitors do not address the lack of cortisol or aldosterone production in these patients.

ATR-101, an ACAT1 inhibitor, is currently in Phase 2 clinical development by Millendo Therapeutics, Inc.

Two CRF receptor antagonists, Crinecerfont (under development by Neurocrine Biosciences, Inc.) and Tildacerfont (under development by Spruce Biosciences, Inc.), are currently in Phase 3 and Phase 2b clinical trials, respectively.

The second alternative therapeutic class is ACTH receptor antagonists .

Inhibition of this pathway, which is downstream of the CRF1 pathway, also results in inhibition of androgen and cortisol synthesis in the adrenal gland .

However, like CRF1 receptor antagonists, ACTH inhibitors do not address the lack of cortisol or aldosterone production in these patients.

CRN04904, an oral ACTH antagonist, is currently in Phase 1 clinical development by Crinetics Pharmaceuticals , Inc.

While these alternative therapeutic mechanisms attempt to address meaningful aspects of the disease by potentially reducing the need for exogenous steroids, neither is able to address the disease at its source by targeting the complete set of features that define the disease.

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In contrast, we believe enzymatic replacement by gene therapy has the potential to simultaneously address all facets of the disease by restoring proper flux through the hormonal pathways, reducing androgen production by providing alternative pathways for the precursor molecules to be converted into cortisol or aldosterone.

KRAS-Driven Cancers

We are advancing BBP-454, a preclinical development program focused on novel approaches to inhibit KRAS, for the treatment of KRAS-driven cancers.

BBP-454 is currently in the lead optimization stage of preclinical development.

Pathway Overview

KRAS is a member of the RAS family of oncogenes, which also includes HRAS and NRAS, and together comprises some of the most well-known monogenic drivers of cancer.

Mutations in NRAS are frequently found in leukemia and melanoma, while HRAS is frequently mutated in bladder, thyroid, and head and neck squamous cell carcinoma.

KRAS mutations are a frequent driver of a number of the largest cancer indications with high unmet medical need, including 30% of non-small cell lung cancers, 98% of pancreatic adenocarcinomas, and 45% of colorectal adenocarcinomas.

The most common KRAS mutations involve a change from glycine at position 12 in the protein to aspartic acid (G12D, 36% of all KRAS mutations), valine (G12V, 24%), and cysteine (G12C, 15%) but also include mutations at glycine 13 and glutamine 61.

In aggregate, over 500,000 patients in the United States and Europe are diagnosed with KRAS-driven cancers, annually.

KRAS is a G protein, meaning that it cycles between ON and OFF states when bound to GTP or GDP, respectively.

When active, KRAS interacts with multiple proteins that initiate a series of reactions that collectively cause cells to grow and divide.

Because of its critical position atop multiple pathways, aberrant KRAS activation is a potent driver of unwanted cell growth, resulting in tumors.

Normal KRAS is kept almost entirely in its inactive state by GTPase-activating proteins (GAPs), which cause KRAS to quickly convert GTP into GDP.

All forms of mutant KRAS are insensitive to GAPs and remain bound to GTP long enough to drive oncogenic signaling.

In order to initiate signaling, KRAS is required to be both localized to the cell membrane and bound to GTP.

Historically, KRAS has been viewed as an undruggable target, due to the lack of a clear binding pocket to drug.

KRAS localization to the cell membrane is facilitated by modification to KRAS on the HVR.

This modification consists of addition of a farnesyl or geranylgeranyl group to the cysteine residue at position 185 (C185) by farnesyl transferase or geranylgeranyl transferase.

KRAS can only be modified when the hypervariable region is “open” and accessible to the transferring enzymes.

When the hypervariable region is “closed,” KRAS cannot be modified, preventing its association with the cell membrane and subsequent downstream signaling.

An earlier therapeutic strategy inhibiting farnesyl transferase, which transfers farnesyl group onto HRAS to allow membrane association, has generated effective clinical responses in tumors driven by mutant HRAS.

Though these molecules proved ineffective in KRAS, which has an adaptive capability to utilize an alternative modification (geranylgeranylation), these results for mutant HRAS provide a proof of concept for using a single agent disrupting localization of an oncogenic RAS mutant to treat RAS-driven tumors.

The RAS Signaling Pathway

Autosomal Dominant Hypocalcemia Type 1 and Hypoparathyroidism

Encaleret is an oral small molecule antagonist of the calcium sensing receptor, or CaSR, that we are developing for the treatment of Autosomal Dominant Hypocalcemia Type 1, or ADH1.

We are currently studying encaleret in an ongoing Phase 2b clinical trial as a potential treatment for patients with ADH1, and anticipate reporting early results from this study in the first half of 2021.

Encaleret has been granted orphan drug designation as a treatment for autosomal dominant hypocalcemia, including ADH Type 1 and ADH Type 2.

Hypoparathyroidism, or HP, is a disease in which the parathyroid gland secretes no or abnormally low levels of parathyroid hormone, or PTH, which results in hypocalcemia.

Common presenting symptoms of hypoparathyroidism, related to hypocalcemia, including muscle cramps, carpopedal spasms, tingling and seizures.

ADH1 is a rare, genetic form of HP caused by gain-of-function mutations of the CaSR, and which is characterized by increased sensitivity of the CaSR to calcium level.

Symptoms due to hypocalcemia can be more severe than in other forms of HP, and include severe muscle cramping, seizures and kidney damage resulting from hypercalcuria.

ADH1 has a prevalence of approximately 12,000 variant carriers in the United States.

Chronic hypoparathyroidism has a larger estimated prevalence of approximately 200,000 in the United States and the European Union.

No FDA or EMA approved therapies for ADH1 currently exist, although hypocalcemia is typically managed with calcium and activated vitamin D supplementation.

Natpara (parathyroid hormone) was approved by the FDA in 2015 as an adjunct to calcium and vitamin D to control hypocalcemia in patients with hypoparathyroidism, and has a labeled limitation of its use in patients with ADH1.

Our Product Concept

KRAS-mutant cancers are driven by active, GTP-bound KRAS located at the cell membrane.

We are developing two different strategies that target KRAS through novel, mutation-agnostic mechanisms.

The first involves preventing modification of C185 in the HVR, disrupting the membrane localization process that is required for KRAS signaling.

The second directly reduces concentration of active GTP-bound KRAS by targeting a novel residue to induce degradation.

Frank McCormick, one of our co-founders and leader of the NCI RAS initiative, characterized a novel druggable binding pocket involved in positioning of the HVR on KRAS.

Molecules that bind this eponymous “McCormick” pocket were confirmed to stabilize the KRAS HVR in a “closed” state, where C185 is not accessible for modification to localize KRAS to the membrane, thereby preventing oncogenic signaling.

This mechanism is independent of the specific mutation causing KRAS tumors and is expected to apply to all oncogenic KRAS mutants.

We have identified compounds that bind at this new pocket and covalently modify C185, thus preventing farnesylation and geranylgeranylation and thereby blocking membrane association.

The second approach is another pan-mutant KRAS drug which targets the histidine residue at position 95 (H95), an amino acid unique to KRAS located in the G-domain.

Initial preclinical data have demonstrated that our initial series of compounds are able to downregulate KRAS signaling by degrading GTP-KRAS and thereby reducing the concentration of GTP-bound KRAS.

We believe that degrading fully processed, active KRAS at the plasma membrane is the most direct strategy for eliminating oncogenic signaling across all mutant KRAS cancers.

We believe our approach compares favorably with several other identified competitive approaches, which bind GDP-bound KRAS, which exists only transiently in mutant KRAS cancers.

This mechanism is mutation agnostic, in contrast to competitive molecules, which only target a single mutation.

Development Status

We are advancing our KRAS research program through collaborations with the NCI RAS initiative and with Lawrence Livermore National Labs, where we are utilizing one of the most powerful supercomputers in the world to conduct molecular dynamics simulations.

We blend the knowledge and experimental capabilities of our collaborators with BridgeBio’s drug development expertise to prosecute these targets.

Key Competitors

Due to its high prevalence in cancer, we expect to face competition from other small molecule KRAS inhibitors as well as other modalities, including mRNA vaccines, that target KRAS mutations.

The majority of these product candidates focus on a single version of mutant KRAS, G12C.

This form is particularly accessible for drug development due to the reactivity of the mutant cysteine residue.

However, both compounds we are developing will target a broader set of cancers by pursuing mutation-agnostic mechanisms.

In particular, our competitors may include:

MRTX849, a KRAS inhibitor that only targets KRAS harboring a G12C mutation.

Mirati Therapeutics, Inc., or Mirati, has dosed its first patient in a Phase 1/2 clinical trial enrolling patients with solid tumors harboring a KRAS G12C mutation.

Additionally, Mirati is currently developing a KRAS G12D inhibitor through preclinical testing.

AMG-510, a KRAS inhibitor that only targets KRAS harboring a G12C mutation, is in Phase 1 clinical development by Amgen Inc.

mRNA-5671, an mRNA vaccine targeting the four most common KRAS mutations, is currently under joint development by Moderna, Inc.

and Merck & Co., Inc.

The rationale is to induce a neoantigen response causing T-cells to attack tumors with KRAS mutations.

ARS-1620, a G12C-specific covalent small molecule, is currently in preclinical development by Wellspring Pharmaceutical Corporation in collaboration with Janssen Pharmaceuticals, Inc.

Revolution Medicines, Inc.

is in the hit-to-lead phase of discovery for small molecule inhibitors of KRAS mutations G12C, G12D, and G13C acquired from Warp Drive Bio, Inc.

Encaleret is an investigational small molecule antagonist of the CaSR.

It has been studied in more than 1,200 human subjects and was observed to increase serum calcium in a dose-dependent manner.

The rationale for developing encaleret as a potential treatment for patients with ADH1 is based on both non-clinical and clinical evidence.

Antagonists of the CaSR have been shown, in both in vitro and in vivo models, to shift the aberrant CaSR “set-point” back towards a normal IC 50 for calcium, resulting in increased PTH secretion, elevation of blood calcium concentrations, and reduction of urinary calcium excretion in cellular and animal models of ADH1.

By selectively antagonizing the CaSR, encaleret may restore normal CaSR function in individuals with ADH1 and may address symptoms associated with hypocalcemia and hypercalciuria.

Clinical Development Plan

We have initiated a single-center Phase 2b study investigating encaleret in ADH1 at the National Institutes of Health.

We anticipate reporting early results from this study in the first half of 2021.

Encaleret is the only molecule that has been publicly disclosed in development for the treatment of ADH1.

There are other identified companies developing compounds for the treatment of hypoparathyroidism using

recombinant parathyroid hormone analogs or PTH receptor agonists :

Takeda Pharmaceutical Company (Natpara) , Ascendis Pharma A/S (TransCon PTH ) , Amolyt Pharma (AZP-3601), Chugai Pharmaceutical Company (PCO371), and Extend Biosciences Inc.

OTHER DEVELOPMENT PROGRAMS

MENDELIAN PORTFOLIO

BBP-870 / fosdenopterin:

We are developing BBP-870, also known as fosdenopterin, an IV formulation of synthetic cyclic pyranopterin monophosphate, or cPMP, for the treatment of molybdenum cofactor deficiency, or MoCD, Type A.

Fosdenopterin:

We are developing fosdenopterin, an IV formulation of synthetic cyclic pyranopterin monophosphate, or cPMP, for the treatment of molybdenum cofactor deficiency, or MoCD, Type A.

Fosdenopterin received breakthrough therapy designation from the FDA in 2013 for MoCD, orphan drug designation from the FDA in 2009 and EMA in 2010 for the treatment of MoCD Type A, and rare pediatric disease designation for the treatment of MoCD Type A in June 2017.

We have initiated a rolling NDA submission of fosdenopterin with the FDA in late 2019.

MoCD Type A is an ultra-rare autosomal recessive inborn error of metabolism caused by disruption in molybdenum cofactor (MoCo) biosynthesis which results in deficiencies in multiple enzyme activities, including sulfite oxidase (SOX) and leads to uncontrolled sulfite toxicity in the brain.

The disease typically presents very early in life (median presentation at first day of life).

We filed an NDA for fosdenopterin with the FDA in 2020, which has been granted Priority Review designation.

MoCD Type A is an ultra-rare autosomal recessive inborn error of metabolism caused by disruption in molybdenum cofactor, or MoCo, biosynthesis which results in deficiencies in multiple enzyme activities, including sulfite oxidase, or SOX, and leads to uncontrolled sulfite toxicity in the brain.

The disease typically presents very early in life, with median presentation at first day of life.

The disease is characterized by severe and rapidly progressive acute sulfite-related neurological damage and associated heterogeneous neurological sequelae including seizures, feeding difficulties and in most cases death, with the median survival estimated to be approximately three years.

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BBP-671 is currently in preclinical development.

BBP-671 has received orphan drug designation as a treatment of proprionic acidemia, or PA, and as a treatment of PKAN.

BBP-671 was also designated as a drug for a rare pediatric disease for treatment of both PKAN and PA.

PKAN is a rare genetic disorder with progressive neurodegeneration.

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Later onset disease is heterogeneous, with psychiatric symptoms and progressive parkinsonism developing in late childhood to adulthood.

The prevalence of PKAN is approximately one in 1,000,000, with between 800 to 850 patients in the United States and European Union.

The prevalence of PKAN is approximately one in 1,000,000, with between 800 to 850 patients in the United States and the European Union.

There are currently no approved treatments for PKAN.

Organic acidemias are caused by mutations in enzymes that disrupt amino acid metabolism leading to acute decompensations requiring hospitalization, as well as long term complications involving multiple organ systems, such as the heart, pancreas, kidney, liver, and brain.

The incidence of OAs are approximately 5 in 100,000 births.

OAs are caused by mutations in enzymes that disrupt amino acid metabolism leading to acute decompensations requiring hospitalization, as well as long-term complications involving multiple organ systems, such as the heart, pancreas, kidney, liver and brain.

The incidence of OAs is approximately five in 100,000 births.

The standard of care includes dietary restriction and supplementation, but unmet need remains high due to metabolic decompensations and long-term complications.

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BBP-711 is currently in preclinical development.

Primary hyperoxaluria, or PH1, is a rare, autosomal-recessive inborn error of metabolism driven by a defect in the AGXT gene, which codes for the enzyme alanine-glyoxylate aminotransferase, or AGXT.

BBP-711 has received orphan drug designation from the FDA as a treatment of primary hyperoxaluria type 1, or PH1.

BBP-711 has also been designated as a drug for a rare pediatric disease for treatment of PH1.

PH1 is a rare, autosomal-recessive inborn error of metabolism driven by a defect in the AGXT gene, which codes for the enzyme alanine-glyoxylate aminotransferase, or AGXT.

Deficiencies in the AGXT enzyme translate into the incapacity of PH1 patients to detoxify glyoxylate into glycine.

As a result, glyoxylate is oxidized into oxalate, which cannot be metabolized by humans.

Elevated oxalate levels form calcium oxalate crystals, and subsequently kidney stones, which damage the kidneys, culminating in renal dysfunction.

Prevalence for PH1 is estimated to be 5,000 patients in the United States and EU.

Elevated oxalate levels form calcium oxalate crystals, and

subsequently kidney stones, which damage the kidneys, culminating in renal dysfunction.

Prevalence for PH1 is estimated to be 5,000 patients in the United States and the European Union .

Due to heterogeneous symptom presentation and similarity with other diseases, we believe that the disease is underdiagnosed.

Prevalence for FSF is estimated to be 1.5 million in the United States and European Union.

Prevalence for frequent stone formers is estimated to be 1.5 million in the United States and the European Union.

Standard of care involves symptomatic management through supplementation with vitamin B6, increased fluid intake, and citrate, to intensive dialysis and lithotripsy.

Ultimately, the only curative treatment is a combined liver and kidney transplant.

Leber’s Hereditary Optic Neuropathy

BBP-761 is a preclinical program focused on developing succinate pro-drugs for the treatment of Leber’s Hereditary Optic Neuropathy, or LHON.

LHON is a rare mitochondrial disease of the eye, which manifests as rapidly progressive and severe loss of central vision predominantly in young adults.

Onset occurs most frequently in a single eye and is followed by the second eye, while bilateral presentation occurs in approximately 25% of cases.

Most patients reach legal blindness several months after disease onset.

LHON is caused by mutations in subunits of Complex I of the electron transport chain, a key protein complex for energy metabolism found in mitochondria, which results in mitochondrial dysfunction.

Prevalence is approximately 20,000 patients in the United States and European Union and annual incidence is estimated at approximately 500 new patients.

There are currently no treatments for the disease approved in the United States.

Idebenone (Santhera) was approved in the European Union for LHON in 2015 under exceptional circumstances, as its pivotal trial did not meet its primary endpoint

Limb Girdle Muscular Dystrophy type 2i (LGM2i)

BBP-418 is an orally administered ribitol replacement therapy we are developing for the treatment of Limb Girdle Muscular Dystrophy type 2i (LGDM2i).

BBP-418 is currently in preclinical development.

Limb Girdle Muscular Dystrophy Type 2i

BBP-418 is an orally administered ribitol replacement therapy we are developing for the treatment of Limb Girdle Muscular Dystrophy type 2i, or LGDM2i.

We are currently studying BBP-418 in an ongoing Phase 1 clinical trial.

Subject to successful completion of the Phase 1 clinical trial, we anticipate initiating a Phase 2 clinical trial in 2021 and generating top-line data from this clinical trial in 2022.

LGMD2i is an inherited rare progressive genetic disorder characterized by lower-limb weakness and loss of ambulation, in addition to potential pulmonary and cardiac dysfunction.

LGMD2i has an estimated prevalence of ~4.5 per 1M.

LGMD2i has an estimated prevalence of around 4.5 per 1,000,000.

There is no disease-modifying treatment available.

Standard of care for FKRP dystroglycanopathies is supportive care to alleviate end organ dysfunction.

BBP-305 / encaleret:

Autosomal Dominant Hypocalcemia Type 1 and Hypoparathyroidism

Encaleret is an oral small molecule antagonist of the calcium sensing receptor that we are developing for the treatment of Autosomal Dominant Hypocalcemia Type 1, or ADH1 and hypoparathyroidism, or HP.

Our IND application for the treatment of ADH1 became effective in late 2019.

HP is a disease in which the parathyroid gland secretes no or abnormally low levels of parathyroid hormone, or PTH, which results in hypocalcemia, causing symptoms including muscle cramps, tingling and seizures.

ADH1 is a rare form of HP caused by gain-of-function mutations of the Calcium Sensing Receptor (CaSR), and which is characterized by increased sensitivity of the CaSR to calcium level.

Symptoms due to hypocalcemia can be more severe than in other forms of HP, and include severe muscle cramping, seizures and kidney damage resulting from hypercalcuria.

ADH1 has a prevalence of approximately 2,000 in the US and EU.

Hypoparathyroidism has a larger patient group of approximately 200,000 in the US and EU.

No FDA or EMA approved therapies for ADH1 currently exist, although hypocalcemia is typically managed with calcium and vitamin D supplementation.

Natpara (parathyroid hormone) was FDA approved in 2015 as an adjunct to calcium and vitamin D to control hypocalcemia in patients with hypoparathyroidism, and has a boxed warning for potential risk of osteosarcoma.

BBP-551 / - Zuretinol acetate – Inherited Retinal Disease (Retinitis Pigmentosa and Leber’s Congenital Amaurosis) due to autosomal recessive RPE65 or LRAT mutations

We are developing zuretinol acetate, an oral, small molecule synthetic retinoid as a treatment for inherited retinal disease, or IRD, associated with autosomal recessive mutations in Retinal Pigment Epithelium Protein, or RPE65, or Lecithin:

Retinol Acyltransferase, or LRAT.

We anticipate initiating a Phase 2/3 clinical trial for BBP-551 in 2020.

BBP-551 has been granted Orphan Drug Designation in the United States for the treatment of Leber congenital amaurosis (LCA) due to inherited mutations in RPE65 or LRAT genes and for the treatment of retinitis pigmentosa and in the European Union for the treatment of retinitis pigmentosa and for the treatment of Leber’s congenital amaurosis.

BBP 551 has also received Fast Track Designation in the United States for the treatment of LCA due to inherited mutations in LRAT and RPE65 genes, and for the treatment of autosomal recessive RP due to inherited mutations in LRAT and RPE genes.

IRDs, including RP and LCA, are a group of genetically driven retinal degenerations that are characterized by progressive photoreceptor and retinal pigment epithelial cell (RPE) death and dramatic vision loss.

It is estimated that there are approximately 2,000-4,500 people in the US and EU with IRDs due to RPE65 and LRAT mutations.

No FDA or EMA approved therapies for LRAT-associated IRDs currently exist.

Luxturna, a subretinally administered gene therapy, has received FDA approval for the treatment of patients with confirmed biallelic RPE65 mutation-associated retinal dystrophy.

BBP-472 – PI3KB Inhibitor for Autism-Spectrum Disorder characterized by loss of PTEN protein

BBP-472 is a series of small molecule PI3KB inhibitors being designed to balance kinase signaling in the brain for the treatment of children with autism-spectrum disorders (ASD) characterized by loss of the PTEN protein.

Standard of care for fukutin-related protein gene dystroglycanopathies is supportive care to alleviate end organ dysfunction.

PI3KB Inhibitor for Autism-Spectrum Disorder Characterized by Loss of PTEN Protein

BBP-472 is a series of small molecule PI3KB inhibitors being designed to balance kinase signaling in the brain for the treatment of children with autism-spectrum disorders characterized by loss of the PTEN protein.

BBP-472 is currently in preclinical development.

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We have received breakthrough therapy designation from the FDA, as well as orphan drug designation from both the FDA and EMA, for BBP-009 for the treatment of Gorlin Syndrome.

Basal Cell Carcinomas, or BCCs, a form of skin tumor, are universally driven by overactivation of the hedgehog pathway.

Gorlin Syndrome is caused by a genetic mutation in Patched1, or PTCH1, the primary inhibitor of the hedgehog signaling pathway.

Uninhibited hedgehog signaling can cause tumorigenesis, leading to the formation of BCCs, particularly on the face and sun-exposed regions.

HF-BCC is the presentation of more than nine BCCs over a period of three years, without having the genetic mutation present in Gorlin Syndrome.

Gorlin Syndrome has a prevalence of approximately 1/31,000 individuals worldwide, approximately 10,000 patients in the United States and 17,000 in the European Union.

HF-BCC has a larger patient group of approximately 1/9,000 individuals, approximately 35,000 patients in the United States and 57,000 in the European Union.

No FDA or EMA approved therapies for Gorlin Syndrome currently exist.

Current treatments involve surgical resection of BCCs, or topical 5-FU or imiquimod, which are effective only in treating superficial BCCs.

In November 2018, through our investment in PellePharm, Inc., or PellePharm, we entered into a partnership with LEO Pharma, pursuant to which LEO has acquired a minority stake in PellePharm and has agreed to provide additional non-dilutive capital to fund the development of topical patidegib, including our planned Phase 3 clinical trial.

In November 2018, through our investment in PellePharm, Inc., or PellePharm, we entered into a partnership with LEO Pharma A/S, or LEO, pursuant to which LEO has acquired a minority stake in PellePharm and has agreed to provide additional non-dilutive capital to fund the development of topical patidegib, including our planned Phase 3 clinical trial.

LEO also acquired an option to purchase all shares in PellePharm at a later date.

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BBP-589/PTR-01:

Recessive Dystrophic Epidermolysis Bullosa (RDEB)

Recessive Dystrophic Epidermolysis Bullosa

We are developing BBP-589, an IV-administered recombinant collagen type VII, or rC7, protein replacement therapy, for the treatment of recessive dystrophic epidermolysis bullosa, or RDEB.

BBP-589 received orphan drug designation from the FDA and EMA in 2014 for the treatment of dystrophic epidermolysis bullosa, or DEB, and we received fast track designation from the FDA in 2019 for the treatment of dystrophic epidermolysis bullosa (DEB).

We are currently conducting a Phase 1/2 clinical trial of BBP-589 in RDEB patients, and anticipate that data readout from this study will occur in 2020.

Disease Overview

DEB is a genetic condition caused by mutations in the COL7A1 gene encoding the protein collagen type VII, a type of collagen protein that plays an important structural function.

Collagen type VII resides in the basement membrane beneath stratified squamous epithelia and forms anchoring fibrils that hold layers of the epithelium together, most notably the epidermal and dermal layers of the skin.

In DEB patients, mutations of the COL7A1 gene lead to deficient anchoring fibrils, resulting in normal physical touch or friction upon the epithelium causing severe blistering, wounds, and scarring of the skin as well as the mucous membranes and gastrointestinal tract, which are lined with epithelial cells.

These patients can also suffer from joint contractures and pseudosyndactyly as a result of this condition as well as many other comorbidities, and they experience a shortened life expectancy often due to squamous cell carcinomas.

RDEB is a subtype of DEB that tends to have more severe symptoms and clinical outcomes.

At present, there is no approved therapy for RDEB.

All of the current standard of care treatment approaches rely on protective or palliative interventions.

These include bandaging and disinfecting of wounds, nutritional supplementation and pain management none of which address the underlying cause of the disease.

We believe there is a significant unmet need for a therapeutic option that can potentially address the cause of disease systemically and offer respite from the effects of the disease.

Our Product Concept

DEB is caused by dysfunctional collagen type VII protein.

BBP-589 is a recombinant version of collagen type VII that is intended to take the place of the patient’s defective protein and reverse the DEB phenotype by forming the anchoring fibrils needed to hold the dermis and epidermis together.

We have successfully generated a Chinese Hamster Ovary, or CHO, cell line to produce rC7 protein for use in further development.

BBP-589, also referred to as PTR-01, has received orphan drug designation for the treatment of DEB in both the United States and European Union, respectively.

As a systemic protein replacement therapy candidate, rC7 is intended for intravenous delivery, a modality that has proven effective at delivering rC7 to the skin’s basement membrane in preclinical animal models.

Preclinical Data

Preclinical studies have shown that rC7 distributes to the basement membrane of the skin.

In COL7A1 knockout mouse models, treatment with intravenously delivered rC7 was observed to restore anchoring fibrils, promote healing and improve survival.

Immunogold electron microscopy of skin obtained from COL7A1 knockout mice injected with rC7 showed formation of anchoring fibrils in the correct location.

A single IV administration of rC7 to neonatal COL7A1 knockout mice was associated with a statistically significant improvement in survival compared to vehicle-treated controls.

In single bolus dose toxicity studies conducted in rats and non-human primates, or NHP, rC7 was shown to be well-tolerated.

In PD studies, the rC7 administered product was detectable at up to four weeks in the tissue of COL7A1 knockout mouse while the serum half-life ranged from one to five hours in mouse, rat, and NHP.

A 28-day repeat dose rat toxicology study and two 28-day NHP repeat-dosing IV toxicology studies included histopathology observations consistent with immune complexes and/or compound deposition.

The NOAEL was determined at 4 mg/kg for NHP only, which was used to inform the starting dose of the Phase 1/2 clinical trial.

Clinical Development Plan

We are studying BBP-589 in a Phase 1/2 randomized, saline-controlled, single-blind, multiple ascending dose, dose-escalation trial that was initiated in the first quarter of 2019.

This first-in human study in adult RDEB patients is evaluating ascending doses of BBP-589 over four cohorts administering a total of three doses of BBP-589 and three doses of saline control IV to all patients in a cross-over design over a 10-week period.

The primary objective of the trial is to evaluate the safety, tolerability and PK of BBP-589 in RDEB patients.

Additionally, the trial will assess the proof of biologic activity through skin biopsy evaluation of C7, and formation of anchoring fibrils.

Wound healing and clinically meaningful patient reported outcomes will also be evaluated at multiple timepoints.

We expect to complete the trial in 2020.

BBP-589 received fast track designation from the FDA in 2019 for the treatment of DEB.

Key Competitors

A number of companies are developing potentially competitive products for RDEB.

Krystal Biotech, Inc.

is developing KB103, a topical HSV-1 gene therapy currently in a Phase 1/2 clinical trial.

Abeona Therapeutics, Inc.

is developing EB-101, a topical therapy consisting of ex vivo autologous gene-corrected keratinocytes which has completed a Phase 1/2 clinical trial.

ProQR Therapeutics N.V.

is developing QR-313, an RNA oligonucleotide therapy for DEB exon 73.

Fibrocell Science, Inc., acquired by Castle Creek, is developing FCX-007, a COL7A1 gene therapy which has completed a Phase 1/2 clinical trial.

We have completed enrollment in both a Phase 1/2 clinical trial and a Phase 2 clinical trial in patients with RDEB.

We anticipate that we will provide data from the ongoing Phase 2 study in late 2021 or early 2022.

Venous and Lymphatic Malformations

BBP-681 is a transdermal PI3K inhibitor that we are developing for the treatment of cutaneous venous and lymphatic malformations.

BBP-681 is currently in preclinical development.

We are currently studying BBP-681 in an ongoing Phase 1/2 clinical trial and anticipate providing initial data from this study in 2022.

Venous malformations, or VMs, are large, disorganized veins that can cause significant morbidity due to functional impairment, pain, bleeding and disfigurement.

Lymphatic malformations, or LMs, involve the lymphatic vessels and cause functional impairment and pain similar to VM, lymphatic leakage and disfigurement.

The prevalence of VMs and LMs is greater than 75,000 and 42,000, respectively, in the United States and EU in the skin.

The prevalence of VMs and LMs is greater than 75,000 and 42,000, respectively, in the United States and the European Union in the skin.

Standard of care is generally non-disease-modifying and invasive and ranges from compression bandages and aspirin, to laser ablation, surgical resection and sclerotherapy.

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It can additionally lead to chronic problems including allergy, infection and inflammation.

The prevalence is approximately 4,000 – 17,000 patients in the United States and European Union.

The prevalence is approximately 4,000 to 17,000 patients in the United States and the European Union.

No disease-modifying therapy exists.

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TARGETED ONCOLOGY

Infigratinib:

FGFR-Driven Cancers

We are developing infigratinib, an oral FGFR1-3 selective TKI for the treatment of FGFR-driven cancers.

Specifically, we are developing infigratinib in three oncologic indications:

(i) cholangiocarcinoma, or CCA, or bile duct cancer, with FGFR2 fusions or translocations, (ii) urothelial carcinoma, or UC, with FGFR genomic alterations, and (iii) other cancers with FGFR fusions or translocations.

We filed an NDA with the FDA in late 2020 for infigratinib as a second-line or later therapy in patients with advanced and/or metastatic CCA with FGFR2 fusions or translocations.

The FDA has granted our NDA for infigratinib in cholangiocarcinoma Priority Review designation and it is being reviewed under the Real-Time Oncology Review, or RTOR, pilot program, which is an initiative of the FDA’s Oncology Center of Excellence designed to expedite the delivery of safe and effective cancer treatments to patients.

We are studying infigratinib as a potential treatment for FGFR-driven cancers in multiple ongoing clinical trials:

a Phase 3 randomized, open-label clinical trial of infigratinib as a first-line therapy for CCA compared to gemcitabine and cisplatin in advanced and/or metastatic CCA with FGFR2 fusions or translocations;

a Phase 2 single-arm clinical trial in patients with advanced or metastatic cholangiocarcinoma with FGFR alterations;

a Phase 3 randomized, double-blind, placebo-controlled clinical trial in cisplatin-ineligible adjuvant UC with FGFR3 genomic alterations;

a Phase 2 single-arm clinical trial in patients with advanced or metastatic solid tumors harboring FGFR1-3 gene fusions or genetic alterations.

We received Fast Track Designation in adults with first-line advanced or metastatic cholangiocarcinoma and the FDA and EMA have granted orphan drug designation for infigratinib as a treatment of cholangiocarcinoma.

Targeting Multiple Oncology Indications

BBP-398 is a small molecule inhibitor of SHP2 that we are developing as a potential treatment of cancers driven by hyperactive receptor tyrosine kinase, or RTK, or MAPK signaling.

BBP-398 is currently in preclinical development.

We are currently enrolling patients in a Phase 1 dose escalation and expansion clinical trial in patients with RAS and RTK mutations.

SHP2 is a phosphatase that acts downstream of receptor tyrosine kinases in the MAPK signaling pathway.

SHP2 is critical in signaling in these pathways.

Increased MAPK signaling is a hallmark of a number of cancer types, including:

cancers driven by RTK genetic alterations, cancers with RTK fusion mutations, and cancers with constitutively active MAPK signaling.

Increased MAPK signaling is a hallmark of a number of cancer types, including cancers driven by RTK genetic alterations, cancers with RTK fusion mutations, and cancers with constitutively active MAPK signaling.

Additionally, SHP2 is implicated as a downstream mediator of PD-1 signaling, a key target of immuno-oncology treatment.

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Preclinical data generated by us and third parties suggest many of the most common cancers are sensitive to GPX4 inhibition, both in monotherapy and combination with standard anti-cancer agents such as kinase inhibitors and chemotherapy.

We believe that GPX4 may be potentially applicable to a number of common solid and hematologic cancers, including:

non-small cell lung cancer, breast cancer, melanoma, pancreatic adenocarcinoma, renal cell carcinoma and Non-Hodgkin’s lymphoma, among others.

We believe that GPX4 may be potentially applicable to a number of common solid and hematologic cancers, including non-small cell lung cancer, breast cancer, melanoma, pancreatic adenocarcinoma, renal cell carcinoma and Non-Hodgkin’s lymphoma, among others.

KRAS-Driven Cancers

BBP-454 is a preclinical development program focused on approaches to inhibit KRAS through novel selective mechanisms, for the treatment of KRAS-driven cancers.

KRAS is a member of the RAS family of oncogenes, which also includes HRAS and NRAS, and together comprises some of the most well-known monogenic drivers of cancer.

Mutations in NRAS are frequently found in leukemia and melanoma, while HRAS is frequently mutated in bladder, thyroid, and head and neck squamous cell carcinoma.

The most common KRAS mutations involve a change from glycine at position 12 in the protein to aspartic acid (G12D, 36% of all KRAS mutations), valine (G12V, 24%), and cysteine (G12C, 15%), but also include mutations at glycine 13 and glutamine 61.

In aggregate, over 500,000 patients in the United States and Europe are diagnosed with KRAS-driven cancers, annually.

KRAS-mutant cancers are driven by active, GTP-bound KRAS located at the cell membrane.

We are developing multiple strategies that target KRAS through novel, mutation-agnostic mechanisms.

We anticipate nominating our first development candidate from this discovery program in 2022.

Canavan Disease

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

We currently depend on third-party contract manufacturing organizations (“CMOs”), for all of our requirements of raw materials, drug substance and drug product for our preclinical research and our ongoing clinical trials of our product candidates.

We currently depend on third-party contract manufacturing organizations, or CMOs, for all of our requirements of raw materials, drug substance and drug product for our preclinical research and our ongoing clinical trials of our product candidates.

Aside from a manufacturing agreement that we entered into in December 2019 through our subsidiary, BridgeBio Gene Therapy, LLC, we have not entered into long-term agreements with our current CMOs.

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We seek to obtain domestic and international patent protection and, in addition to filing and prosecuting patent applications in the United States, we may file counterpart patent applications in additional countries where we believe such foreign filing is likely to be beneficial, including Australia, Canada, Europe, China, Japan, and Mexico.

We have entered

into various license agreements to obtain the rights to use certain patents for the development and commercialization of our product candidates.

We have entered into various license agreements to obtain the rights to use certain patents for the development and commercialization of our product candidates.

See “—Our Material Agreements.” We also rely on trade secrets to protect aspects of our business that are not amenable to, or that we do not consider appropriate for, patent protection.

Our success will depend on our ability to obtain and maintain patent and other proprietary rights protecting our commercially important technology, inventions and know-how related to our business, defend and enforce our current and future issued patents, if any, preserve the confidentiality of our trade secrets and operate without infringing the valid and enforceable patents and proprietary rights of third parties.

infringing the valid and enforceable patents and proprietary rights of third parties.

We continually assess and refine our intellectual property strategy in order to best fortify our position, and file additional patent applications when our intellectual property strategy warrants such filings.

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Moreover, we may have to participate in interference proceedings or derivation proceedings declared by the United States Patent and Trademark Office, or USPTO, to determine priority of invention.

As of February 28, 2020, our intellectual property portfolio is composed of over 33 issued patents and over 56 patent applications that we license from academic and research institutions and other third parties, and over 37 issued patents or pending patent applications that we own, including through our subsidiaries.

As of February 15, 2021, our intellectual property portfolio is composed of 65 issued patents and 135 patent applications that we license from academic and research institutions and other third parties, and 25 issued patents and 220 pending patent applications that we own, including through our subsidiaries.

These patents and patent applications generally provide us with the rights to develop our product candidates in the United States and worldwide.

Our intellectual property portfolios for each of the programs that we consider to be our key value drivers are further described below.

Our intellectual property portfolios for each of the programs that we consider to be our core value drivers are further described below.

QED Therapeutics, Inc.

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patent, granted patent in Europe, and the pending patent application, if issued, are expected to expire in 2032.

In addition, QED Therapeutics, Inc.

owns one pending U.S.

provisional patent application and two pending PCT patent applications that are directed to methods of treating various cancers using BBP-831.

If any patents issue from these patent applications, such patents would be expected to expire in 2040 or 2041.

Eidos Therapeutics, Inc.

For our subsidiary Eidos Therapeutics, Inc., we license rights from the Board of Trustees of the Leland Stanford Junior University, or Stanford, to six issued U.S.

patents with claims directed to composition of matter and methods of use relating to BBP-265.

For our subsidiary Eidos Therapeutics, Inc., we license rights from the Board of Trustees of the Leland Stanford Junior University, or Stanford, to nine issued U.S.

patents with claims directed to composition of matter and methods of use relating to acoramidis.

These patents are expected to expire in 2031 or 2033.

We also license rights from Stanford to two pending U.S.

patent applications, one issued European patent, one pending European patent application, and one issued Japanese patent with claims directed to composition of matter and methods of use relating to BBP-265.

These patents and patent applications, if issued, are expected to expire in 2031 or 2033.

In addition, we own one issued U.S.

patent, two pending U.S.

patent applications, a pending PCT patent application, and over 12 related foreign patent applications pending in various jurisdictions, including Australia, Canada, Europe, China, Japan, and Mexico with claims directed to salt and solid forms, methods of manufacturing, dosing methods, and formulations relating to BBP-265.

patent, three pending U.S.

patent applications, and 50 related foreign patent applications pending in various jurisdictions, including Australia, Canada, Europe, China, Japan, and Mexico with claims directed to salt and solid forms, methods of manufacturing, dosing methods, and formulations relating to acoramidis.

The issued U.S.

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The pending U.S.

patent applications, any patent applications claiming the benefit of and priority to the PCT patent application, and the foreign patent applications, if issued, are expected to expire in 2038 or 2039.

and foreign patent applications, if issued, are expected to expire in 2038 or 2039.

Adrenas Therapeutics, Inc.

For our subsidiary Adrenas Therapeutics, Inc., we own one pending PCT patent application with claims directed to recombinant AAV vectors relating to BBP-631.

Any patent applications claiming the benefit of this PCT patent application, if issued, are expected to expire in 2039.

For our subsidiary Adrenas Therapeutics, Inc., we own one pending U.S.

patent application and six related foreign patent applications pending in various jurisdictions including Canada, China, Europe, Japan, and Korea with claims directed to recombinant AAV vectors relating to BBP-631.

These patent applications, if issued, are expected to expire in 2039.

Phoenix Tissue Repair, Inc.

For our subsidiary Phoenix Tissue Repair, Inc., we license rights from the University of Southern California, or USC, to one issued U.S.

patent with claims directed to polypeptides comprising functional fragments of collagen 7, and five pending U.S.

patent with claims directed to polypeptides comprising functional fragments of collagen 7, and three pending U.S.

patent applications with claims directed to methods of use, including treating epidermolysis bullosa with collagen 7.

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patent applications, if issued, are expected to expire between 2027 and 2035.

We also license rights from USC to over four related foreign patents issued in various jurisdictions including Australia, Europe and Japan, and over seven related foreign patent applications pending in various jurisdictions including Australia, Canada, Europe, and Japan.

We also license rights from USC to five related foreign patents issued in various jurisdictions including Australia, Europe and Japan, and three related foreign patent applications pending in various jurisdictions including Australia.

The foreign patents and patent applications, if issued, are expected to expire between 2027 and 2035.

We also own an issued U.S.

patent with claims directed to collagen 7 modification for enhancing the degradability of collagen, and related issued patents in the United Kingdom, France and Germany.

These issued patents are expected to expire in 2022.

We also own one pending U.S.

patent application with claims directed to methods of treating epidermolysis and chronic skin wounds with collagen 7, with one related issued patent in Australia, and over three related foreign patent applications pending in various jurisdictions including Australia, Canada, and Europe.

The issued patent and related patent applications, if issued, are expected to expire in 2033.

We also own a pending U.S.

patent application with claims directed to formulations comprising collagen 7 and over seven related foreign patent applications pending in various jurisdictions, including Canada, China, Europe, Japan, and Mexico.

These patent applications, if issued, are expected to expire in 2036.

For our subsidiary TheRas, Inc., we license rights from The Regents of the University of California, or the University of California, and Leidos Biomedical Research, Inc., or Leidos, to two pending U.S.

We also own six issued U.S.

patents, four pending U.S.

patent applications, one pending PCT patent application, seven foreign patents, and over 20 foreign patent applications pending in various jurisdictions with claims relating to collagen 7 materials and methods relating to the same.

These include issued U.S.

patents in the United Kingdom, France and Germany with claims directed to collagen 7 modification for enhancing the degradability of collagen that are expected to expire in 2022.

This portfolio also includes pending and/or issued claims relating to collagen 7 detection assays, methods of making and purifying collagen 7, methods of treating subjects having age-related disorders with collagen 7, collagen 7 compositions, and methods of treating epidermolysis bullosa with collagen 7.

These patents and patent applications, if issued, are expected to expire between 2025-2040.

patent and two pending U.S.

patent applications with claims directed to modulators of K-RAS, which include claims to the modulators as composition of matter and their use in therapy, including the treatment of cancer, and over twenty related foreign patent applications pending in various jurisdictions, including Australia, Canada, China, Europe, Japan, and Mexico.

patent application and foreign patent applications, if issued, are expected to expire in 2036 and 2038.

We also co-own with, and license rights from, the University of California and Leidos, three pending PCT applications.

If issued, any patent applications claiming the benefit of these PCT applications are expected to expire in 2039.

patent and the U.S.

and foreign patent applications, if issued, are expected to expire in 2036 and 2038.

We also co-own with, and license rights from, the University of California and Leidos, three pending Taiwanese patent

applications.

If issued, any patent applications claiming the benefit of these applications are expected to expire in 2039.

In addition, TheRas co-owns with Leidos and Lawrence Livermore National Security, LLC, or Livermore, one pending U.S.

patent application with claims directed to modulators of K-RAS, which include claims to the modulators as composition of matter and their use in therapy, including the treatment of cancer.

Any patents issuing from this application are expected to expire in 2042.

Our Material Agreements

License Agreement with Alexion

In September 2019, through our subsidiary Eidos Therapeutics, Inc., or Eidos, we entered into a license agreement (the “Alexion License Agreement”) with Alexion Pharma International Operations Unlimited Company, a subsidiary of Alexion Pharmaceuticals, Inc.

(together, “Alexion”) to develop and commercialize BBP-265 in Japan.

In September 2019, through our subsidiary Eidos Therapeutics, Inc., or Eidos, we entered into a license agreement, or the “Alexion License Agreement, with Alexion Pharma International Operations Unlimited Company, a subsidiary of Alexion Pharmaceuticals, Inc.

, or together, Alexion, to develop and commercialize acoramidis in Japan.

Additionally, in September 2019, Eidos entered into a stock purchase agreement with Alexion, pursuant to which Eidos sold to Alexion 556,173 shares of its common stock for aggregate cash proceeds of $25.0 million.

Under the terms of the Alexion License Agreement, Eidos granted Alexion an exclusive license to certain of our intellectual property rights to develop, manufacture and commercialize BBP-265 in Japan.

Under the terms of the Alexion License Agreement, Eidos granted Alexion an exclusive license to certain of our intellectual property rights to develop, manufacture and commercialize acoramidis in Japan.

In consideration for the license grant, Eidos received an upfront payment of $25.0 million, with the potential for an additional one-time payment of $30.0 million subject to the achievement of a regulatory milestone.

In addition, Eidos is entitled to receive royalties in the low double-digits on net sales by Alexion of BBP-265 in Japan.

The royalty rate is subject to reduction if Alexion is required to obtain intellectual property rights from third parties to develop, manufacture or commercialize BBP-265 in Japan, or upon the introduction of generic competition into the market.

In addition, Eidos is entitled to receive royalties in the low double-digits on net sales by Alexion of acoramidis in Japan.

The royalty rate is subject to reduction if Alexion is required to obtain intellectual property rights from third parties to develop, manufacture or commercialize acoramidis in Japan, or upon the introduction of generic competition into the market.

License Agreement with the Board of Trustees of the Leland Stanford Junior University

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Asset Purchase Agreement with Alexion Pharma Holding Unlimited Company

In June 2018, through our subsidiary Origin Biosciences, Inc., we entered into an asset purchase agreement with Alexion Pharma Holding Unlimited Company, or Alexion, pursuant to which we acquired Alexion’s right, title and interest in certain assets relating to fosdenopterin, including patents and other intellectual property rights.

In the event that a Priority Review Voucher, or PRV, is granted to us by the FDA, we have agreed to pay Alexion a percentage in the mid-teens of any proceeds received by us from our sale of the PRV to a third party.

If we do not sell the PRV to a third party within 180 days after our receipt of the PRV, we are obligated to pay Alexion $18.8 million, which amount is creditable against any amounts otherwise due to Alexion in accordance with the preceding sentence upon any future sale by us of the PRV.

In June 2018, through our subsidiary Origin Biosciences, Inc., we entered into an asset purchase agreement with Alexion Pharma Holding Unlimited Company, or Alexion Pharma, pursuant to which we acquired Alexion’s right, title and interest in certain assets relating to fosdenopterin, including patents and other intellectual property rights.

In the event that a Priority Review Voucher, or PRV, is granted to us by the FDA, we have agreed to pay Alexion Pharma a percentage in the mid-teens of any proceeds received by us from our sale of the PRV to a third

If we do not sell the PRV to a third party within 180 days after our receipt of the PRV, we are obligated to pay Alexion Pharma $18.

8 million, which amount is creditable against any amounts otherwise due to Alexion Pharma in accordance with the preceding sentence upon any future sale by us of the PRV.

We are obligated to make contingent milestone payments totaling $3.0 million upon achievement of certain development milestones and $17.0 million upon achievement of certain sales milestones for products containing the fosdenopterin molecule.

We also agreed to pay Alexion tiered royalties ranging from the low-to mid-teens on net sales of products containing the fosdenopterin molecule.

We also agreed to pay Alexion Pharma tiered royalties ranging from the low-to mid-teens on net sales of products containing the fosdenopterin molecule.

We are obligated to use commercially reasonable efforts to obtain a PRV, achieve specified milestone events and commercialize at least one product containing the fosdenopterin molecule after receipt of regulatory approval.

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Option Agreement with LEO Pharma A/S

In November 2018, through PellePharm, Inc., or PellePharm, we entered into an option agreement with LEO Pharma A/S, or LEO Pharma, and LEO Spiny Merger Sub, Inc., pursuant to which LEO Pharma was granted an exclusive, irrevocable option to acquire PellePharm.

In November 2018, through PellePharm, we entered into an option agreement with LEO Pharma, or LEO Pharma, and LEO Spiny Merger Sub, Inc., pursuant to which LEO Pharma was granted an exclusive, irrevocable option to acquire PellePharm.

The option is exercisable by LEO Pharma on or before the occurrence of certain events relating to PellePharm’s clinical development programs, and in no event later than July 30, 2021.

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or Lotus, pursuant to which we acquired from Shire and Lotus the right, title and interest in certain assets relating to recombinant human collagen type VII, including patents and other intellectual property rights, as well as data and regulatory filings, relating to the treatment of DEB, and assumed certain liabilities with respect thereto.

In connection with the acquisition of such assets, (1) Shire and Lotus granted to us a non-exclusive, worldwide, irrevocable, perpetual, royalty-free, sublicensable license under certain intellectual property related to the acquired assets but retained by Shire and Lotus, for the exploitation of certain recombinant human collagen type VII products in all fields, and (2) we granted to Shire and Lotus a non-exclusive, worldwide, irrevocable, perpetual, royalty-free, sublicensable license under certain of the acquired intellectual property assets to exploit products other than recombinant human collagen type VII products and other than for the treatment of DEB in humans.

In connection with the acquisition of such assets, (i) Shire and Lotus granted to us a non-exclusive, worldwide, irrevocable, perpetual, royalty-free, sublicensable license under certain intellectual property related to the acquired assets but retained by Shire and Lotus, for the exploitation of certain recombinant human collagen type VII products in all fields, and (ii) we granted to Shire and Lotus a non-exclusive, worldwide, irrevocable, perpetual, royalty-free, sublicensable license under certain of the acquired intellectual property assets to exploit products other than recombinant human collagen type VII products and other than for the treatment of DEB in humans.

As partial consideration for our acquisition of the assets, we agreed to pay a purchase price of $1.5 million and issued shares of common stock in Phoenix at a nominal value to Lotus.

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Government Regulation of Drug and Biological Products

In the United States, the FDA regulates drugs under the FDCA, and its implementing regulations and biologics under the FDCA and the Public Health Service Act, or PHSA, and their implementing regulations.

In the United States, the FDA regulates drugs under the Federal Food, Drug and Cosmetic Act, or FDCA, and its implementing regulations and biologics under the FDCA and the Public Health Service Act, or PHSA, and their implementing regulations.

Both drugs and biologics also are subject to other federal, state and local statutes and regulations, such as those related to competition.

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

The process of obtaining regulatory approvals and the subsequent

compliance with appropriate federal, state, and local statutes and regulations requires the expenditure of substantial time and financial resources.

Failure to comply with the applicable U.S.

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Any agency or judicial enforcement action could have a material adverse effect on our business, the market acceptance of our products and our reputation.

Our product candidates must be approved by the FDA through either an NDA, or a BLA, process before they may be legally marketed in the United States.

Our product candidates must be approved by the FDA through either an NDA or a Biologics License Application, or BLA, process before they may be legally marketed in the United States.

The process generally involves the following:

completion of extensive preclinical studies in accordance with applicable regulations, including studies conducted in accordance with GLP, requirements;

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

approval by an IRB, or independent ethics committee at each clinical trial site before each human trial may be initiated;

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

completion of extensive preclinical studies in accordance with applicable regulations, including studies conducted in accordance with Good Laboratory Practices, or GLP, requirements;

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

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

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

submission to the FDA of an NDA or BLA;

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Information about certain clinical trials, including clinical trial results, must be submitted within specific timeframes for publication on the www.clinicaltrials.gov website.

In addition to the submission of an IND to the FDA before initiation of a clinical trial in the United States, certain human clinical trials involving recombinant or synthetic nucleic acid molecules had historically been subject to review by the RAC, of the NIH Office of Biotechnology Activities, or the OBA, pursuant to the NIH Guideline.

In addition to the submission of an IND to the FDA before initiation of a clinical trial in the United States, certain human clinical trials involving recombinant or synthetic nucleic acid molecules had historically been subject to review by the NIH Recombinant DNA Advisory Committee, or the RAC, of the NIH Office of Biotechnology Activities, or the OBA, pursuant to the NIH Guideline.

On August 17, 2018, the NIH issued a notice in the Federal Register and issued a public statement proposing changes to the oversight framework for gene therapy trials, including changes to the applicable NIH Guidelines to modify the roles and responsibilities of the RAC with respect to human clinical trials of gene therapy products, and requesting public comment on its proposed modifications.

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In April 2019, NIH announced the updated guidelines, which reflect these proposed changes, and clarify that these trials will remain subject to the FDA’s oversight and other clinical trial regulations, and oversight at the local level will continue as set forth in the NIH Guidelines.

Specifically, under the NIH Guidelines, supervision of human gene transfer trials includes evaluation and assessment by an IBC, a local institutional committee that reviews and oversees research utilizing recombinant or synthetic nucleic acid molecules at that institution.

Specifically, under the NIH Guidelines, supervision of human gene transfer trials includes evaluation and assessment by an Institutional Biosafety Committee, or an IBC, a local institutional committee that reviews and oversees research utilizing recombinant or synthetic nucleic acid molecules at that institution.

The IBC assesses the safety of the research and identifies any potential risk to public health or the environment, and such review may result in some delay before initiation of a clinical trial.

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The FDA does not always meet its PDUFA goal dates for standard and priority NDAs or BLAs, and the review process is often extended by FDA requests for additional information or clarification.

The FDA has developed the Oncology Center of Excellence RTOR pilot program to facilitate a more efficient review process for certain oncology product candidates.

Although this program allows FDA to begin reviewing clinical data prior to submission of a complete NDA or BLA, the program is not intended to change the PDUFA review timelines.

Before approving an NDA or BLA, the FDA will conduct a pre-approval inspection of the manufacturing facilities for the new product to determine whether they comply with cGMP requirements.

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If a Complete Response Letter is issued, the applicant may either resubmit the NDA or BLA, addressing all of the deficiencies identified in the letter, or withdraw the application or request an opportunity for a hearing.

Even if such data and information are submitted, the FDA may decide that the NDA or BLA does not satisfy the criteria for approval.

Even if such data and information are submitted, the FDA may decide that the

NDA or BLA does not satisfy the criteria for approval.

Data obtained from clinical trials are not always conclusive and the FDA may interpret data differently than we interpret the same data.

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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 the potential for PRVs to be granted through September 30, 2026.

Expedited Development and Review Programs

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Fast track designation applies to both the product and the specific indication for which it is being studied.

For a fast track-designated product, the FDA may consider sections of the NDA or BLA for review on a rolling basis before the complete application is submitted, if the sponsor provides a schedule for the submission of the sections of the application, the FDA agrees to accept sections of the application and determines that the schedule is acceptable and the sponsor pays any required user fees upon submission of the first section of the application.

For a fast track-designated product, the FDA may consider sections

of the NDA or BLA for review on a rolling basis before the complete application is submitted, if the sponsor provides a schedule for the submission of the sections of the application, the FDA agrees to accept sections of the application and determines that the schedule is acceptable , and the sponsor pays any required user fees upon submission of the first section of the application.

The sponsor can request the FDA to designate the product for fast track status any time before receiving NDA or BLA approval, but ideally no later than the pre-NDA or pre-BLA meeting.

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This program is intended to facilitate efficient development and expedite review of regenerative medicine therapies, which are intended to treat, modify, reverse, or cure a serious or life-threatening disease or condition and qualify for RMAT designation.

A drug sponsor may request that FDA designate a drug as a RMAT concurrently with or at any time after submission of an IND.

FDA has 60 calendar days to determine whether the drug meets the criteria, including whether there is preliminary clinical evidence indicating that the drug has the potential to address unmet medical needs for a serious or life-threatening disease or condition.

sponsor may request that the FDA designate a drug as a RMAT concurrently with or at any time after submission of an IND.

The FDA has 60 calendar days to determine whether the drug meets the criteria, including whether there is preliminary clinical evidence indicating that the drug has the potential to address unmet medical needs for a serious or life-threatening disease or condition.

A BLA for a regenerative medicine therapy that has received RMAT designation may be eligible for priority review or accelerated approval through use of surrogate or intermediate endpoints reasonably likely to predict long-term clinical benefit, or reliance upon data obtained from a meaningful number of sites.

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or post-approval monitoring of all patients treated with such therapy prior to its approval.

The FDA has also announced the availability of the RTOR pilot program for oncology product candidates that are likely to demonstrate substantial improvements over available therapy, which may include drugs previously granted breakthrough therapy designation for the same or other indications and candidates meeting other criteria for other expedited programs, such as fast track and priority review.

Submissions for RTOR consideration should also have straightforward study designs and endpoints that can be easily interpreted (such as overall survival or progression free survival).

Acceptance into the RTOR pilot does not guarantee or influence approvability of the application, which is subject to the usual benefit-risk evaluation by FDA reviewers, but the program allows FDA to review data earlier, before an applicant formally submits a complete application.

The RTOR pilot program does not affect FDA’s PDUFA timelines.

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

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Post-Marketing Requirements

Following approval of a new product, the manufacturer and the approved product are subject to continuing regulation by the FDA, including, among other things, monitoring and record-keeping activities, reporting of adverse experiences, 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.

adverse experiences, 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.

The FDA and other agencies actively enforce the laws and regulations prohibiting the promotion of off-label uses, and a company that is found to have improperly promoted off-label uses may be subject to significant liability, including investigation by federal and state authorities.

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identify patients likely to be at increased risk for serious side effects as a result of treatment with a particular therapeutic product;

or monitor response to treatment with a particular

therapeutic product for the purpose of adjusting treatment to achieve improved safety or effectiveness.

or monitor response to treatment with a particular therapeutic product for the purpose of adjusting treatment to achieve improved safety or effectiveness.

Companion diagnostics are regulated as medical devices by the FDA.

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A reference biological product is granted four and twelve year exclusivity periods from the time of first licensure of the product.

FDA will not accept an application for a biosimilar or interchangeable product based on the reference biological product until four years after the date of first licensure of the reference product, and FDA will not approve an application for a biosimilar or interchangeable product based on the reference biological product until twelve years after the date of first licensure of the reference product.

The FDA will not accept an application for a biosimilar or interchangeable product based on the reference biological product until four years after the date of first licensure of the reference product, and the FDA will not approve an application for a biosimilar or interchangeable product based on the reference biological product until twelve years after the date of first licensure of the reference product.

“First licensure” typically means the initial date the particular product at issue was licensed in the United States.

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Other Regulatory Matters

Manufacturing, sales, promotion and other activities following product approval are also subject to regulation by numerous regulatory authorities in the United States in addition to the FDA, including the CMS, including the Office of Inspector General and Office for Civil Rights, other divisions of the Department of HHS, the Department of Justice, the Drug Enforcement Administration, the Consumer Product Safety Commission, the Federal Trade Commission, the Occupational Safety & Health Administration, the Environmental Protection Agency and state and local governments.

Manufacturing, sales, promotion and other activities following product approval are also subject to regulation by numerous regulatory authorities in the United States in addition to the FDA, including the Centers for Medicare and Medicaid Services, or CMS, including the Office of Inspector General and Office for Civil Rights, other divisions of the Department of HHS, the Department of Justice, the Drug Enforcement Administration, the Consumer Product Safety Commission, the Federal Trade Commission, the Occupational Safety & Health Administration, the Environmental Protection Agency and state and local governments.

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

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Our future marketing and activities relating to the reporting of wholesaler or estimated retail prices for our products, if approved, the reporting of prices used to calculate Medicaid rebate information and other information affecting federal, state and third-party reimbursement for our products, and the sale and marketing of our product candidates, are subject to scrutiny under this law.

HIPAA created new federal criminal statutes that prohibit among other things, knowingly and willfully executing, or attempting to execute, a scheme to defraud or to obtain, by means of false or fraudulent pretenses, representations or promises, any money or property owned by, or under the control or custody of, any healthcare benefit program, including private third party payors, knowingly and willfully embezzling or stealing from a healthcare benefit program, willfully obstructing a criminal investigation of a healthcare offense, and knowingly and willfully falsifying, concealing or covering up by trick, scheme or device, a material fact or making any materially false, fictitious or fraudulent statement in connection with the delivery of or payment for healthcare benefits, items or services.

HIPAA created federal criminal statutes that prohibit among other things, knowingly and willfully executing, or attempting to execute, a scheme to defraud or to obtain, by means of false or fraudulent pretenses, representations or promises, any money or property owned by, or under the control or custody of, any healthcare benefit program, including private third party payors, knowingly and willfully embezzling or stealing from a healthcare benefit program, willfully obstructing a criminal investigation of a healthcare offense, and knowingly and willfully falsifying, concealing or covering up by trick, scheme or device, a material fact or making any materially false, fictitious or fraudulent statement in connection with the delivery of or payment for healthcare benefits, items or services.

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

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The ACA established the Center for Medicare and Medicaid Innovation within CMS to test innovative payment and service delivery models to lower Medicare and Medicaid spending, potentially including prescription drug spending.

Funding has been allocated to support the mission of the Center for Medicare and Medicaid Innovation through 2020.

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.

Various portions of the ACA are currently undergoing legal and constitutional challenges in the Fifth Circuit Court and the United States Supreme Court;

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;

Various portions of the ACA are currently undergoing legal and constitutional challenges in the United States Supreme Court;

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.

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

The United States Supreme Court is expected to rule on a legal challenge to the constitutionality of the ACA in early 2021.

The implementation of the ACA is ongoing, the law appears likely to continue the downward pressure on pharmaceutical pricing, especially under the Medicare program.

Moreover, in May 2018, the Trump administration released its “Blueprint to Lower Drug Prices and Reduce Out-of-Pocket Costs,” or the Blueprint.

The Blueprint contains several potential regulatory actions and legislative recommendations aimed at lowering prescription drug prices, including measures to promote innovation and competition for biologics, changes to Medicare Part D to give plan sponsors more leverage when negotiating prices with manufacturers, and updating the Medicare drug-pricing dashboard to make price increases and generic competition more transparent.

In addition, the Department of HHS released a Request for Information, or RFI, soliciting public input on ways to lower drug pricing.

Together, the recommendations in the Blueprint and RFI, if enacted by Congress and HHS, could lead to changes to Medicare Parts B and D, including the transition of certain drugs covered under Part B to Part D or the offering of alternative purchasing options under the Competitive Acquisition Program that currently applies to selected drugs and biologics covered under Part B.

HHS has already implemented certain of these measures, while others are pending.

For example, in May 2019, the 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.

Additional recommendations in

the Blueprint and RFI, if enacted by Congress and HHS, could lead to changes to Medicare Parts B and D, including the transition of certain drugs covered under Part B to Part D or the offering of alternative purchasing options under the Competitive Acquisition Program that currently applies to selected drugs and biologics covered under Part B.

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

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

While most of the proposed measures will require authorization through additional legislation to become effective, Congress and the Trump administration have each indicated that it will continue to seek new legislative, administrative and/or additional measures to control drug costs.

Although some proposals related to the previous administration’s Blueprint may require additional authorization to become effective, may ultimately be withdrawn, or may face challenges in the courts, Congress has indicated that it will continue to seek new legislative, administrative and/or additional measures to control drug costs.

Likewise, the Biden administration has indicated that lowering prescription drug prices is a priority, but we do not yet know what steps the administration will take or whether such steps will be successful.

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

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This includes aggregate reductions of Medicare payments to providers up to 2% per fiscal year, which went into effect in April 2013, following passage of the Bipartisan Budget Act of 2013, and will remain in effect through 2029 unless additional congressional action is taken.

Further, in January 2013, President Obama signed into law the American Taxpayer Relief Act of 2012, 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.

Any reduction in reimbursement from Medicare or other government programs may result in a similar reduction in payments from private payors, which may adversely affect our future profitability.

Pursuant to 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.

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

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

Any 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.

Any 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.

Prohibitions or restrictions on sales or withdrawal of future products marketed by us could materially affect our business in an adverse way.

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However, an application may be submitted after four years if it contains a certification of patent invalidity or non-infringement.

The FDCA also provides three years of marketing exclusivity for an NDA, 505(b)(2) NDA or supplement to an existing NDA if new clinical investigations, other than bioavailability studies, that were conducted or sponsored by the applicant are deemed by the FDA to be essential to the approval of the application, for example, new indications, dosages or strengths of an existing drug.

The FDCA also

provides three years of marketing exclusivity for an NDA, 505(b)(2) NDA or supplement to an existing NDA if new clinical investigations, other than bioavailability studies, that were conducted or sponsored by the applicant are deemed by the FDA to be essential to the approval of the application, for example, new indications, dosages or strengths of an existing drug.

This three-year exclusivity covers only the conditions of use associated with the new clinical investigations and does not prohibit the FDA from approving ANDAs for drugs containing the original active agent.

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

Although the EU Clinical Trials Directive 2001/20/EC has sought to harmonize the EU clinical trials regulatory framework, setting out common rules for the control and authorization of clinical trials in the European Union, the EU Member States have transposed and applied the provisions of the Directive differently into their national laws.

Although the EU Clinical Trials Directive 2001/20/EC, or Directive, has sought to harmonize the EU clinical trials regulatory framework, setting out common rules for the control and authorization of clinical trials in the EU, the EU Member States have transposed and applied the provisions of the Directive differently into their national laws.

This has led to significant variations in the Member State regimes.

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The EU clinical trials legislation currently is undergoing a transition process mainly aimed at harmonizing and streamlining clinical-trial authorization, simplifying adverse-event reporting procedures, improving the supervision of clinical trials and increasing their transparency.

In April 2014, the EU adopted a new Clinical Trials Regulation (EU) No 536/2014, which is set to replace the current Clinical Trials Directive 2001/20/EC.

In April 2014, the EU adopted a new Clinical Trials Regulation (EU) No 536/2014, or Regulation, which is set to replace the current Clinical Trials Directive 2001/20/EC.

It will overhaul the current system of approvals for clinical trials in the EU.

Specifically, the new Regulation, which will be directly applicable in all Member States, aims at simplifying and streamlining the approval of clinical trials in the EU.

For instance, the new Clinical Trials Regulation provides for a streamlined application procedure via a single entry point and strictly defined deadlines for the assessment of clinical trial applications.

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

For instance, the new Regulation provides for a streamlined application procedure via a single entry point and strictly defined deadlines for the assessment of clinical trial applications.

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

European Union Drug Marketing

Much like the Anti-Kickback Statue prohibition in the United States, the provision of benefits or advantages to physicians to induce or encourage the prescription, recommendation, endorsement, purchase, supply, order or use of medicinal products is also prohibited in the European Union.

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

The provision of benefits or advantages to induce or reward improper performance generally is governed by the national anti-bribery laws of the European Union Member States, and the Bribery Act 2010 in the UK.

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

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

EU Directive 2001/83/EC, which is the EU Directive governing medicinal products for human use, further provides that, where medicinal products are being promoted to persons qualified to prescribe or supply them, no gifts, pecuniary advantages or benefits in kind may be supplied, offered or promised to such persons unless they are inexpensive and relevant to the practice of medicine or pharmacy.

This provision has been transposed into the Human Medicines Regulations 2012 and so remains applicable in the UK despite its departure from the EU.

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

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

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

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

Member States.

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

European Union Drug Review and Approval

In the European Economic Area, or EEA, which is comprised of the 27 Member States of the European Union (including Norway and excluding Croatia), Iceland and Liechtenstein, medicinal products can only be commercialized after obtaining a marketing authorization, or MA.

In the European Economic Area, or EEA, which is comprised of the Member States of the European Union plus Norway, Iceland and Liechtenstein, medicinal products can only be commercialized after obtaining a marketing authorization, or MA.

There are two types of marketing authorizations.

The Community MA is issued by the European Commission through the Centralized Procedure, based on the opinion of the Committee for Medicinal Products for Human Use, or CHMP, of the EMA, and is valid throughout the entire territory of the EEA.

The Centralized Procedure is mandatory for certain types of products, such as biotechnology medicinal products, orphan medicinal products, advanced-therapy medicines such as gene-therapy, somatic cell-therapy or tissue-engineered medicines and medicinal products containing a new active substance indicated for the treatment of HIV, AIDS, cancer, neurodegenerative disorders, diabetes, auto-immune and other immune dysfunctions and viral diseases.

The Centralized Procedure is optional for products containing a new active substance not yet authorized in the EEA, or for products that constitute a significant therapeutic, scientific or technical innovation or which are in the interest of public health in the European Union.

The centralized MA is issued by the European Commission through the centralized procedure, based on the opinion of the Committee for Medicinal Products for Human Use, or CHMP, of the EMA, and is valid throughout the entire territory of the EEA.

The centralized procedure is mandatory for certain types of products, such as biotechnology medicinal products, orphan medicinal products, advanced-therapy medicinal products (gene-therapy, somatic cell-therapy or tissue-engineered medicines) and medicinal products containing a new active substance indicated for the treatment of HIV, AIDS, cancer, neurodegenerative disorders, diabetes, auto-immune and other immune dysfunctions and viral diseases.

The centralized procedure is optional for products containing a new active substance not yet authorized in the EEA, or for products that constitute a significant therapeutic, scientific or technical innovation or which are in the interest of public health in the EEA.

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

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

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

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

The timeframe for the evaluation of a MAA under the accelerated assessment procedure is 150 days, excluding clock stops, but it is possible that the CHMP may revert to the standard time limit for the centralized procedure if it determines that the application is no longer appropriate to conduct an accelerated assessment.

National MAs, which are issued by the competent authorities of the Member States of the EEA and only cover their respective territory, are available for products not falling within the mandatory scope of the centralized procedure.

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Under the decentralized procedure an identical dossier is submitted to the competent authorities of each of the Member States in which the MA is sought, one of which is selected by the applicant as the Reference Member State, or RMS.

The competent authority of the RMS prepares a draft assessment report, a draft summary of the product characteristics, or SPC, and a draft of the labeling and package leaflet, which are sent to the other Member States (referred to as the Member States Concerned) for their approval.

If the Member States Concerned raise no objections, based on a potential serious risk to public health, to the assessment, SPC, labeling, or packaging proposed by the RMS, the product is subsequently granted a national MA in all the Member States (i.e., in the RMS and the Member States Concerned).

The competent authority of the RMS prepares a draft assessment report, a draft summary of the product characteristics, or SmPC, and a draft of the labeling and package leaflet, which are sent to the other Member States (referred to as the Concerned Member States) for their approval.

If the Concerned Member States raise no objections, based on a potential serious risk to public health, to the assessment, SmPC, labeling, or packaging proposed by the RMS, the product is subsequently granted a national MA in all the Member States (i.e., in the RMS and the Concerned Member States).

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

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

All medicinal products with a current centralized MA

were automatically converted to Great Britain MAs on January, 1 2021.

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

A separate application will, however, still be required.

The MHRA also has the power to have regard to MAs approved in EEA Member States through d ecentralized or mutual recognition procedures with a view to more quickly granting a MA in the U nited Kingdom or Great Britain.

European Union New Chemical Entity Exclusivity

In the European Union, new chemical entities, sometimes referred to as new active substances, qualify for eight years of data exclusivity upon marketing authorization and an additional two years of market exclusivity.

The data exclusivity, if granted, prevents regulatory authorities in the European Union from referencing the innovator’s data to assess a generic application for eight years, after which generic marketing authorization can be submitted, and the innovator’s data may be referenced, but not approved for two years.

In the EEA, innovative medicinal products qualify for eight years of data exclusivity upon marketing authorization and an additional two years of market exclusivity.

The data exclusivity, if granted, prevents generic or biosimilar applicants from referencing the innovator’s pre-clinical and clinical trial data contained in the dossier of the reference product when applying for a generic or biosimilar MA in the EEA, for a period of eight years from the date of authorization of the reference product.

During the additional two-year period of market exclusivity, a generic marketing authorization application 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.

The overall ten-year period will be extended to a maximum of 11 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 determined to bring a significant clinical benefit in comparison with currently approved therapies.

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

European Union Orphan Designation and Exclusivity

In the European Union, the EMA’s Committee for Orphan Medicinal Products grants orphan drug designation to promote the development of products that are intended for the diagnosis, prevention or treatment of life-threatening or chronically debilitating conditions affecting not more than five in 10,000 persons in the European Union community (or where it is unlikely that the development of the medicine would generate sufficient return to justify the investment) and for which no satisfactory method of diagnosis, prevention or treatment has been authorized (or, if a method exists, the product would be a significant benefit to those affected).

In the European Union, orphan drug designation entitles a party to financial incentives such as reduction of fees or fee waivers and ten years of market exclusivity is granted following medicinal product approval.

In the EEA, the EMA’s Committee for Orphan Medicinal Products grants orphan drug designation to promote the development of products that are intended for the diagnosis, prevention or treatment of life-threatening or chronically debilitating conditions and either (i) such condition affects not more than five in 10,000 persons in the EEA, or (ii) it is unlikely that the development of the medicine would generate sufficient return to justify the necessary investment in its development.

In either case, the applicant must also demonstrate that no satisfactory method of diagnosis, prevention or treatment has been authorized (or, if a method exists, the product would be a significant benefit to those affected compared to the product available).

In the EEA, orphan drug designation entitles a party to financial incentives such as reduction of fees or fee waivers and ten years of market exclusivity is granted following grant of a marketing authorization.

During this market exclusivity period, neither the EMA nor the European Commission nor any of the competent authorities in the EEA Members States can accept an application or grant a marketing authorization for a “similar medicinal product.” A “similar medicinal product” is defined as a medicinal product containing a similar active substance or substances as contained in an authorized orphan medicinal product, and which is intended for the same therapeutic indication.

This period may be reduced to six years if the orphan drug designation criteria are no longer met, including where it is shown that the product is sufficiently profitable not to justify maintenance of market exclusivity.

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

(ii) the marketing authorization holder consents to such revocation;

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

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

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

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).

European Pediatric Investigation Plan

In the EEA, MAAs for new medicinal products not authorized have to include the results of studies conducted in the pediatric population, in compliance with a pediatric investigation plan, or PIP, agreed with the EMA’s Pediatric Committee, or PDCO.

In the EEA, MAAs for new medicinal products have to include the results of studies conducted in the pediatric population, in compliance with a pediatric investigation plan, or PIP, agreed with the EMA’s Pediatric Committee, or PDCO.

The PIP sets out the timing and measures proposed to generate data to support a pediatric indication of the drug for which marketing authorization is being sought.

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Further, the obligation to provide pediatric clinical trial data can be waived by the PDCO when this data is not needed or appropriate because the product is likely to be ineffective or unsafe in children, the disease or condition for which the product is intended occurs only in adult populations, or when the product does not represent a significant therapeutic benefit over existing treatments for pediatric patients.

Once the marketing authorization is obtained in all Member States of the European Union and trial results are included in the product information, even when negative, the product is eligible for six months’ supplementary protection certificate extension.

If a marketing authorization is obtained and trial results are included in the product information, even when negative, the product is eligible for six months’ supplementary protection certificate extension.

In the case of orphan medicinal products, a two year extension of the orphan market exclusivity may be available.

This pediatric reward is subject to specific conditions and is not automatically available when data in compliance with the PIP are developed and submitted.

Brexit and the Regulatory Framework in the United Kingdom

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

Thereafter, on March 29, 2017, the country formally notified the European Union of its intention to withdraw pursuant to Article 50 of the Lisbon Treaty.

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

A transition period began on February 1, 2020, during which EU pharmaceutical law remained applicable to the United Kingdom.

However this ended on December 31, 2020.

Since the regulatory framework in the United Kingdom covering the quality, safety and efficacy of pharmaceutical products, clinical trials, marketing authorizations, commercial sales, and distribution of pharmaceutical products is derived from EU 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, as the UK legislation now has the potential to diverge from EU legislation.

It remains to be seen how Brexit will impact regulatory requirements for medicinal products and devices in the United Kingdom in the long term.

The MHRA has recently published detailed guidance for industry and organizations to follow now the transition period is over, which will be updated as the United Kingdom’s regulatory position on medicinal products and medical devices evolves over time.

European Data Collection

The collection and use of personal health data in the European Economic Area, or the EEA, is governed by the GDPR, which became effective May 25, 2018.

The GDPR applies to any company established in the EEA and to companies established outside the EEA that process personal data in connection with the offering of goods or services to data subjects in the EU or the monitoring of the behavior of data subjects in the European Union.

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

The GDPR applies to any company established in the EEA and to companies established outside the EEA that process personal data in connection with the offering of goods or services to data subjects in the European Union or the monitoring of the behavior of data subjects in the European Union.

The GDPR enhances data protection obligations for data controllers of personal data, including stringent requirements relating to the consent of data subjects, expanded disclosures about how personal data is used, requirements to conduct privacy impact assessments for “high risk” processing, limitations on retention of personal data, mandatory data breach notification and “privacy by design” requirements, and creates direct obligations on service providers acting as data processors.

The GDPR also imposes strict rules on the transfer of personal data outside of the EEA to countries that do not ensure an adequate level of protection, like the U.S.

Failure to comply with the requirements of the GDPR and the related national data protection laws of the EEA Member States may result in fines up to 20 million Euros or 4% of a company’s global annual revenues for the preceding financial year, whichever is higher.

The GDPR also imposes strict rules on the transfer of personal data outside of the EEA to countries that do not ensure an adequate level of protection, like the United States.

Failure to comply with the requirements of the GDPR and the related national data protection laws of the EEA Member States may result in fines up to €20 million or 4% of a company’s global annual revenues for the preceding financial year, whichever is higher.

Moreover, the GDPR grants data subjects the right to claim material and non-material damages resulting from infringement of the GDPR.

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This may be onerous and adversely affect our business, financial condition, results of operations and prospects.

Further, the United Kingdom’s decision to leave the EU, often referred to as Brexit, has created uncertainty with regard to data protection regulation in the United Kingdom.

In particular, it is unclear how data transfers to and from the United Kingdom will be regulated now that the United Kingdom has left the EU.

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

However, as of

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

The UK GDPR and the UK Data Protection Act 2018 set out the U nited Kingdom ’s data protection regime, which is independent from but aligned to the E uropean U nion ’s data protection regime.

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

The U nited Kingdom , however, is now regarded as a third country under the E uropean U nion ’s GDPR which means that transfers of personal data from the EEA to the U nited Kingdom will be restricted unless an appropriate safeguard, as recogni z ed by the EU’s GDPR, has been put in place.

Although, under the EU-UK Trade Cooperation Agreement it is lawful to transfer personal data between the U nited Kingdom and the EEA for a six- month period following the end of the transition period, with a view to achieving an adequacy decision from the European Commission during that period.

Like the EU GDPR, the UK GDPR restricts personal data transfers outside the U nited Kingdom to countries not regarded by the U nited Kingdom as providing adequate protection (this means that personal data transfers from the U nited Kingdom to the EEA remain free flowing).

Rest of the World Regulation

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The failure to comply with laws governing international business practices may result in substantial civil and criminal penalties and suspension or debarment from government contracting.

The SEC also may suspend or bar issuers from trading securities on U.S.

Securities and Exchange Commission, or the SEC, also may suspend or bar issuers from trading securities on U.S.

exchanges for violations of the FCPA’s accounting provisions.

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However, no uniform policy of coverage and reimbursement for drug products exists among third-party payors and coverage and reimbursement levels for drug products can differ significantly from payor to payor.

Third-party payors may limit coverage to specific products on an approved list or formulary, which might not include all of the FDA-approved products for a particular indication.

Also, third-party payors may refuse to include a particular branded drug on their formularies or otherwise restrict patient access to a branded drug when a less costly generic equivalent or another alternative is available.

Third-party payors are increasingly challenging the prices charged for medical products and services, examining the medical necessity, and reviewing the cost-effectiveness of medical products and services and imposing controls to manage costs.

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

The Medicare Prescription Drug, Improvement, and Modernization Act of 2003, or the MMA, established the Medicare Part D program to provide a voluntary prescription drug benefit to Medicare beneficiaries.

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government agencies, the manufacturer must extend discounts to entities eligible to participate in the 340B drug pricing program.

The required 340B discount on a given product is calculated based on the average manufacturer price, or AMP, and Medicaid rebate amounts reported by the manufacturer.

The required 340B discount on a given product is calculated based on the average

manufacturer price, or AMP, and Medicaid rebate amounts reported by the manufacturer.

As of 2010, the ACA expanded the types of entities eligible to receive discounted 340B pricing, although under the current state of the law these newly eligible entities (with the exception of children’s hospitals) will not be eligible to receive discounted 340B pricing on orphan drugs.

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The American Recovery and Reinvestment Act of 2009 provides funding for the federal government to compare the effectiveness of different treatments for the same illness.

In addition, there have been several changes to the 340B drug pricing program in recent years, which impose ceilings on prices that drug manufacturers can charge for medications sold to certain health care facilities.

Legal challenges to reimbursement formula changes under the 340B drug pricing program are ongoing, and it is unclear how these developments could affect covered hospitals who might purchase our future products and affect the rates we may charge such facilities for our approved products in the future, if any.

The plan for the research was published in 2012 by the Department of HHS, the Agency for Healthcare Research and Quality and the National Institutes for Health, and periodic reports on the status of the research and related expenditures are made to Congress.

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Efforts to control prices and utilization of pharmaceutical products and medical devices will likely continue as countries attempt to manage healthcare expenditures.

As of December 31, 2019, we had 248 full-time employees, including 44 Eidos employees.

Human Capital Management

Our human capital philosophy relies on attracting and retaining team members who consistently demonstrate top performance.

Our culture and our approach to talent reinforces this philosophy, including recruiting, professional development, performance management and total rewards.

We have provided below additional details on some of our core human resources, or People, processes.

As of December 31, 2020, we and our subsidiaries, to which we refer as our affiliates, had 385 full-time employees and 11 part-time employees.

Of these, 268 focus on driving forward research and development programs, either directly or through our affiliates, and 128 work across our affiliates to provide strategic business development, finance and executive leadership expertise, as well as general and administrative services generally across our affiliates.

We have never had a work stoppage, and none of our employees is represented by a labor organization or under any collective-bargaining arrangements.

We consider our employee relations to be good.

In 2020, we established an in-house talent acquisition capability to support our affiliates in hiring the right talent at the right time.

This team of experienced recruiters works closely with hiring managers to understand the required skills and capabilities for an open role, and then supports the interview process and evaluation of candidates.

We strive to hire top talent, and therefore need a high-quality recruiting process and candidate experience.

We endeavor to fill every role with the most qualified candidate possible, which sometimes requires partnership with an external recruitment agency.

We are consistently looking at new opportunities and avenues to recruit talented individuals to work at BridgeBio.

The talent acquisition team’s focus in 2021 is to meet the growth needs across BridgeBio and our affiliates.

We recognize that our current and potential future team members have options for employment opportunities, including with other biotech and pharma companies, research and academic institutions, government entities, and consulting and investment firms.

To attract and retain top performing team members, we focus on creating an environment that allows for autonomy, growth and impact while also offering a competitive total rewards package.

Professional Development and Performance Management

We invest in the professional development of our team members through regular feedback and guidance, as well as targeted learning and development opportunities to meet demonstrated needs.

We established a set of five core attributes that we expect every BridgeBio team member to demonstrate while performing in their roles:

Patient Champion, Entrepreneurial Operator, Truth Seeker, Inspires Excellence and High-Quality Executor.

BridgeBio conducts semi-annual formal performance reviews for all team members to evaluate performance against these attributes.

These reviews include self, peer and manager feedback.

The feedback focuses on strengths and opportunities for improvement to enable the professional development of all team members.

At the end of the year, the performance review also includes a formal rating and informs compensation decisions, including performance bonus, salary adjustments and promotions.

Core Values and Ethics

Millions worldwide are afflicted with genetic diseases, but small patient populations and industry reluctance to conduct early-stage development means that for many, treatments have not been forthcoming.

We are committed to bridging this gap:

between business case and scientific possibility, between patient and hope.

This starts with our first core value:

to put patients first .

We also strive to think independently .

Our goal is to not simply accept the ideas and opinions of others as fact, but instead to ask “why?” and “why not?” We endeavor to bring a rigorous, first-principles mindset to each problem that we take on.

We pride ourselves on being radically transparent .

A commitment to independent thinking requires us to consider the ideas of others and to adopt them if they prove best.

We strive to maintain a culture where any idea is worthy of both consideration and testing.

We know that every minute counts .

Our decentralized model strives to deliver treatments from discovery to patients as fast as humanly possible by utilizing focused teams of experts for each asset.

Big decisions can be taken by people best-equipped to understand them, without wasting time on unnecessary cycles.

And we let Science speak .

Our model was designed to promote the rational assessment of our programs.

Decisions about a program’s fate are driven by its performance against a set of objective criteria, giving each potential medicine’s scientific merits the last word.

All employees are responsible for upholding these values and the BridgeBio Code of Business Conduct and Ethics, which forms the foundation of our policies and practices.

Total Rewards

To attract and retain top talent, we offer a competitive total rewards package.

We peg total direct compensation at the upper end of market.

We link a portion of every employee’s compensation to performance through a performance bonus program.

To create a sense of ownership and align employee incentives with our long-term success, we offer eligible employees equity ownership in the company through stock option or restricted stock unit grants and our employee stock purchase plan.

We also designed a program to incentive affiliate-level employees to achieve specific milestones at core value-inflection points, such as IND or NDA approval.

We focus our benefits offering on areas critical to keeping our employees and their immediate families healthy and productive.

We offer physical and mental health benefits to all employees who work at least 20 hours per week, on average.

We have a flexible paid time off policy to empower team members to take the time they need, when they need it.

Diversity, Equity and Inclusion

We believe that a diverse, equitable and inclusive culture is critical to BridgeBio’s success.

We are proud to promote unique voices within and outside our organization, and are eager to learn from others’ experiences, as we know that a diverse and inclusive workforce is a business imperative and key to our long-term success.

As a starting point of our Diversity, Equity and Inclusion, or DE&I, efforts, a group of employees launched a “Women at Bridge” employee resource group, which receives direct support from executive management.

Women at Bridge is passionate about strengthening opportunities for women and working with others who share enthusiasm for that goal.

In its first few months, the group performed an assessment of diversity and inclusion at BridgeBio, identified potential gaps, and formulated steps to address them.

They facilitate open and direct communication to engage the broader BridgeBio organization, including updates with our Chief Executive Officer, open forums or town hall meetings, often with a guest speaker, regular ongoing update communications, and employee engagement surveys.

Recently, a number of Women at Bridge “chapters” were formed to complement the larger forum and facilitate smaller, more meaningful discussions about strengthening and reinforcing opportunities and engagement of women across the organization.

In 2021, we intend to roll out additional initiatives to guide our DE&I activities.

We formed a volunteer DE&I Steering Committee, comprised of a diverse set of BBP employees, to draft a DE&I vision for BridgeBio, and to establish specific goals and priorities for 2021.

As one of the DE&I Steering Committee’s first initiatives, we intend to launch an Unconscious Bias education program for employees in 2021.

Response to COVID-19

With the emergence of the COVID-19 global pandemic, and prior to the shelter-in-place mandate from the State of California where the majority of our employees are located, we took extra precautions to reduce the risk of virus exposure for all employees.

We encouraged all employees who were able to work from home to do so.

For these newly remote employees, we provided ergonomic evaluations of their workstation, allowed flexible schedules, supported their information technology needs, and provided guidance for managers to ensure that their employees were maintaining their physical, mental and emotional wellbeing.

We provided a monthly financial subsidy from April through August to accommodate for any new or ongoing at-home support that was needed.

We further supported our employees and government efforts to curb the COVID-19 pandemic through a multifaceted communication, infrastructure, and behavior modification and enforcement effort, including:

establishing clear and regular COVID-19 policies, safety protocols, and updates to all employees;

providing/mandating Covid-19 PCR testing protocol for all employees that need or desire to be in the office or lab;

decreasing dens ity and increasing physical distancing in workspaces for employees working onsite by scheduling adjustments;

adjusting attendance polic ies to encourage those who are sick to stay home;

increasing cleaning prot ocols across all locations;

providing additional personal protective equipment and cleaning supplies;

implementing protocols to address actual and suspected COVID-19 cases and potential exposure;

prohibiting all d ome stic and international non-essential travel for all employees; and

requiring masks to be worn in all locations.

Corporate and Other Information

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References to our website address do not constitute incorporation by reference of the information contained on the website, and the information contained on the website is not part of this document or any other document that we file with or furnish to the SEC.

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

As such, we are eligible for exemptions from various reporting requirements applicable to other public companies that are not emerging growth companies, including, but not limited to, not being required to comply with the auditor attestation requirements of Section 404 of the Sarbanes-Oxley Act of 2002 and reduced disclosure obligations regarding executive compensation.

We will remain an emerging growth company until the earliest of (i) December 31, 2024, (ii) the last day of the first fiscal year in which our annual gross revenues are $1.07 billion or more, (iii) the date on which we have, during the previous rolling three-year period, issued more than $1.0 billion in non-convertible debt securities, and (iv) the date on which we are deemed to be a “large accelerated filer” as defined in the Securities Exchange Act of 1934, as amended.

We became a large accelerated filer on December 31, 2020 because our aggregate worldwide market value of the voting and non-voting common equity held by non-affiliates as of June 30, 2020, our most recently completed second fiscal quarter, was greater than $700 million.

Prior to that, we were an “emerging growth company”, or EGC, as defined in the Jumpstart Our Business Startups Act of 2012.

As an EGC, we were eligible for exemptions from various reporting requirements applicable to other public companies that are not emerging growth companies, including, but not limited to, not being required to comply with the auditor attestation requirements of Section 404 of the Sarbanes-Oxley Act of 2002 and reduced disclosure obligations regarding executive compensation.

We can no longer avail ourselves of these exemptions and are now required to comply with the standards and compliance dates for large accelerated filers.

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