On November 3, 2022 BridgeBio Pharma, Inc. (Nasdaq: BBIO) (BridgeBio or the Company), a commercial-stage biopharmaceutical company focused on genetic diseases and cancers, reported its financial results for the third quarter ended September 30, 2022 and provided an update on the Company’s operations.
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"We remain committed to focused execution across our pipeline, and have continued to deliver exciting data for patients, including in our LGMD2i and KRAS programs, while at the same time materially reducing our operating expenses and putting the Company on safe footing," said Neil Kumar, Ph.D., founder and CEO of BridgeBio.
"The compounds that we have developed in our RAS franchise after years of intensive work now allow us to clinically interrogate the promise of direct inhibition of active KRAS, as well as the potential of breaking PI3Kα:RAS binding," added Frank McCormick, Ph.D., Chairman of Oncology and cofounder of BridgeBio. "RAS and PIK3CA are the two most common oncogenes in human tumors, and we hope that our programs are able to serve the vast unmet need of the patients that they impact."
BridgeBio’s Key Programs
RAS cancer portfolio:
BridgeBio has selected a next-generation KRASG12C dual inhibitor development candidate, BBO-8520, and plans to be in the clinic in 2023.
The Company shared promising preclinical data on BBO-8520, as well as its novel PI3Kα:RAS breaker program in late lead optimization, at the Fourth RAS Initiative Symposium.
BBO-8520 has shown significantly greater potency in KRAS models than first-generation KRASG12C GDP-only inhibitors as measured by its ability to bind and covalently modify KRASG12C, block KRASG12C binding to effector proteins such as RAF, and inhibit downstream signaling.
BBO-8520 was shown to retain potency in the context of receptor tyrosine kinase drive, which renders KRASG12C GDP-only inhibitors inactive and is thought to be a major mechanism of non-response and resistance to first-generation agents.
BBO-8520 showed strong activity in KRASG12C in vivo models including deep regressions and differentiated efficacy compared to a first-generation KRASG12C GDP-only inhibitor.
BridgeBio scientists highlighted rationale and design of compounds targeting PI3Kα:RAS binding, which is a novel and potentially broad MoA to target PI3Kα mutant tumors, RAS mutant tumors and potentially other tumors driven by RTK activation of RAS signaling.
Targeting PI3Kα activity in tumors through its interaction with RAS may spare glucose metabolism, potentially allowing for potent target coverage without displaying the dose-limiting hyperglycemia common to PI3Kα kinase inhibitors.
RAS is the most common oncogenic driver with approximately 30% of all human cancers being driven by RAS mutations, including large proportions of lung, colorectal and pancreatic tumors. PIK3CA is the second most common oncogene in human tumors, being present in more than 30% of breast and endometrial carcinomas.
Low-dose infigratinib – FGFR1-3 inhibitor for achondroplasia and hypochondroplasia:
Earlier this year BridgeBio shared positive interim results from available data in Cohort 4 from a Phase 2 trial of low-dose infigratinib in patients with achondroplasia, which demonstrated an increase in annualized height velocity of 1.52 cm/year in children 5 years of age and older.
Given infigratinib’s profile to date, and after discussions with regulators, BridgeBio started dosing children in Cohort 5; that cohort is now enrolled with no serious adverse events (SAEs), and no adverse events that required dose modifications reported to date.
The Company expects to report an update on Cohort 5 AHV in the first half of 2023, followed by the initiation of a pivotal Phase 3 trial.
With more than 55,000 cases estimated in the United States (US) and Europe, achondroplasia is the most common form of genetic short stature and one of the most common genetic conditions. BridgeBio also expects to evaluate development of infigratinib in other FGFR-driven skeletal dysplasias, which affect more than 50,000 people in the US and Europe.
Encaleret – Calcium-sensing receptor (CaSR) inhibitor for autosomal dominant hypocalcemia type 1 (ADH1):
BridgeBio intends to initiate a Phase 3 pivotal study of encaleret in patients with ADH1 by the end of 2022 and expects to release topline data by year-end 2023.
Positive data from the Company’s Phase 2b study of encaleret in ADH1 were shared earlier this year in an oral presentation at the Endocrine Society’s 2022 ENDO Conference.
The Phase 2b study demonstrated that treatment with encaleret resulted in rapid and sustained restoration of normal mineral homeostasis by day 5 of therapy which sustained at 24 weeks, and encaleret was well-tolerated without any reported SAEs.
If approved, encaleret could be the first therapy indicated for the treatment of ADH1, a condition caused by gain of function variants of the CASR gene estimated to be carried by 12,000 individuals in the United States alone.
BBP-418 – Glycosylation substrate for limb-girdle muscular dystrophy type 2i (LGMD2i):
The Company shared updated positive Phase 2 data in a presentation at the World Muscle Society (WMS) 27th International Hybrid Annual Congress
BridgeBio engaged with regulatory health bodies to align on a Phase 3 trial design and intends to initiate a Phase 3 clinical trial in the first half of 2023
Phase 2 results indicate the potential for BBP-418 to increase glycosylation of alpha-dystroglycan (αDG), which is directly linked to the underlying disease mechanism, and to drive consistent improvements of muscle function in patients as measured by the reduction of creatine kinase, a key marker of muscle breakdown
12-month data show improvements from baseline on 10-meter walk test and North Star Assessment for Dysferlinopathy, which BridgeBio believes suggests a potential impact on clinical function and on the rate of disease progression
If proven to be successful, BBP-418 could be the first approved therapy for patients with LGMD2i
Acoramidis (AG10) – Transthyretin (TTR) stabilizer for transthyretin amyloid cardiomyopathy (ATTR-CM):
The Phase 3 ATTRibute-CM trial is progressing with topline data from the Month 30 primary endpoint, a hierarchical composite including all-cause mortality and cardiovascular hospitalizations, expected in mid-2023
The Company presented updated results of the Phase 2 open-label extension of acoramidis in ATTR-CM, demonstrating near-complete TTR stabilization and stable or improving serum NT-proBNP levels at month 30
BBP-631 – AAV5 gene therapy candidate for congenital adrenal hyperplasia (CAH):
The Phase 1/2 study is ongoing with an update anticipated late in 2022 or early in 2023.
With more than 75,000 patients estimated in the US and EU, CAH is one of the most prevalent genetic diseases potentially addressable with adeno-associated virus (AAV) gene therapy
The disease is caused by deleterious mutations in the gene encoding an enzyme called 21-hydroxylase, leading to a lack of endogenous cortisol production
BBP-631 is designed to provide a functional copy of the 21-hydroxylase-encoding gene (CYP21A2) and potentially address many aspects of the disease course
If successful, BridgeBio’s investigational gene therapy would be the first therapy for CAH to restore the body’s hormone and steroid balance by enabling people with CAH to make their own cortisol and aldosterone
Recent Corporate Updates
Updated positive data for investigational AAV9 gene therapy in Canavan disease: Promising pharmacodynamic data from the first three participants dosed in the Phase 1/2 clinical trial of BBP-812 for the treatment of Canavan disease. Results showed unprecedented decreases in N-acetylaspartate (NAA) in the brain and urine, suggesting the therapy is producing functional ASPA enzyme. Affecting approximately 1,000 children in the United States and European Union, Canavan disease is an ultra-rare, disabling and fatal disease with no approved therapy.
Approvals in Israel and EU for NULIBRY (fosdenopterin): The European Commission (EC) granted marketing authorization for NULIBRY Powder for Solution for Injection as the first therapy for the treatment of patients with molybdenum cofactor deficiency (MoCD) Type A in Europe, and the State of Israel Ministry of Health approved NULIBRY for Injection as a treatment for MoCD Type A patients in Israel. These decisions are based on the efficacy and safety data collected compared to data from a natural history study. NULIBRY is the first and only approved therapy in either region to treat patients with MoCD Type A, an ultra-rare, life-threatening genetic disorder that often progresses rapidly in infants with a median overall survival age of about four years. NULIBRY was BridgeBio’s first FDA-approved and EC-approved therapeutic. Medison Pharma acquired commercialization rights to NULIBRY in Israel in December 2019. Sentynl Therapeutics, Inc. acquired global rights to NULIBRY in March 2022.
First patient dosed in Phase 1/2 combination trial of BridgeBio’s SHP2 inhibitor BBP-398 with Amgen’s LUMAKRAS: First lung cancer patient was dosed in a Phase 1/2 trial of BridgeBio’s SHP2 inhibitor BBP-398 in combination with Amgen’s LUMAKRAS (sotorasib) in advanced solid tumors with the KRASG12C mutation; additionally, FDA Fast Track Designation was obtained for BBP-398 in combination with LUMAKRAS for adult patients with previously treated, KRASG12C mutated, metastatic non-small-cell lung cancer (NSCLC). BridgeBio has a non-exclusive clinical collaboration with Amgen to evaluate the combination of BBP-398 with LUMAKRAS in patients with advanced solid tumors with the KRASG12C mutation. BridgeBio is party to an exclusive license agreement with Bristol Myers Squibb (BMS) to develop and commercialize BBP-398 in oncology worldwide, except for in mainland China and other Asian markets, which are part of BridgeBio’s strategic collaboration with LianBio. BridgeBio and BMS are also investigating the combination of BBP-398 with OPDIVO (nivolumab) in patients with advanced solid tumors with KRAS mutations.
First patient dosed in Phase 1 trial of BBP-671 for propionic acidemia (PA) and methylmalonic acidemia (MMA): An initial data readout of patients with PA and MMA is expected in mid-2023. BridgeBio is also in active discussions with regulators and expects to launch a pivotal Phase 2/3 study of BBP-671 in pantothenate kinase-associated neurodegeneration (PKAN) in 2024. If successful, BBP-671 has potential to be a best-in-class therapy for PA, MMA, and PKAN patients, as well as the first approved oral therapy for the treatment of systemic complications caused by CoA deficiencies. PA, MMA, and PKAN affect an estimated 7,000 patients in the United States and European Union collectively.
Third Quarter 2022 Financial Results:
Cash, Cash Equivalents and Marketable Securities
Cash, cash equivalents and marketable securities, excluding restricted cash, totaled $558.3 million as of September 30, 2022, compared to $787.5 million as of December 31, 2021. The net decrease of $229.2 million in cash, cash equivalents and marketable securities, excluding restricted cash is primarily attributable to net cash used in operating activities of $326.3 million. The net cash used in operating activities for the nine months ended September 30, 2022 was partially offset by a $90.0 million in upfront payment received under the License, Development and Commercialization Agreement between the Company, its affiliate, Navire Pharma, Inc., and
Bristol Myers Squibb (the "Navire-BMS License Agreement"). During the nine months ended September 30, 2022, the Company also received upfront payments of $110.0 million from the sale of its priority review voucher and $10.0 million upon closing of an asset purchase agreement between its affiliate, Origin Biosciences, Inc., and Sentynl Therapeutics, Inc. The Company made a $20.5 million mandatory prepayment of a portion of its term loan obligations under its Amended Loan and Security Agreement in connection with the upfront payment received from BMS.
Cash, cash equivalents and marketable securities, excluding restricted cash, decreased by $130.3 million when compared to the balance as of June 30, 2022 of $688.6 million. Net cash used in operating activities, was $135.2 million for the three months ended September 30, 2022. Net cash used in operating activities was $191.1 million for the six months ended June 30, 2022.
Operating Costs and Expenses
Operating costs and expenses for the three and nine months ended September 30, 2022 were $129.5 million and $458.7 million, respectively, as compared to $151.8 million and $467.8 million for the same periods in the prior year. The overall decrease in operating costs and expenses for the three and nine months ended September 30, 2022 compared to the comparative periods was mainly due to overall decreases in selling, general and administrative expenses and research, development and other (R&D) expenses resulting from the Company’s reprioritization of its R&D programs and streamlining of costs. The effects of the Company’s restructuring initiative that was started in the first quarter of 2022 are now being realized due to reductions of its operating costs and expenses. Restructuring, impairment and related charges for the three and nine months ended September 30, 2022 of $5.0 million and $36.1 million, respectively, were primarily comprised of winding down costs, exit and other related costs, impairments and write-offs of long-lived assets, and severance and employee-related costs. The Company continues to evaluate restructuring alternatives to drive operational changes in business processes, efficiencies, and cost savings.
"We continue to take action to protect the Company, shore up our balance sheet, and preserve capital to read out our upcoming key catalysts," said Brian Stephenson, Ph.D., CFA, Chief Financial Officer of BridgeBio. "We expect that cash burn will continue to decline in the fourth quarter as a result of ongoing potential business development and restructuring activities. Cash on hand provides us with runway into 2024, and we will continue to look for ways to extend runway via potential royalty monetizations, partnerships, and burn reduction."
The Company’s research and development and other expenses have not been significantly impacted by the global COVID-19 pandemic for the periods presented. While BridgeBio experienced some delays in certain of its clinical enrollment and trial commencement activities, it continues to adapt with alternative site, telehealth and home visits, and at-home drug delivery, as well as mitigation strategies with its contract manufacturing organizations. The longer-term impact, if any, of COVID-19 on BridgeBio’s operating costs and expenses is currently unknown.