On October 12, 2021BridgeBio Pharma, Inc. (Nasdaq: BBIO), a commercial-stage biopharmaceutical company that focuses on genetic diseases and cancers, reported that meaningful progress in its KRAS cancer portfolio, new programs in gene therapy, and advancements in cardiorenal and early-stage Mendelian programs at its second annual R&D Day today (Press release, BridgeBio, OCT 12, 2021, View Source [SID1234591107]). BridgeBio will also discuss how it is broadening the scope of its R&D engine with the launch of its new early-stage research institute, BridgeBioX.
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BridgeBio’s R&D Day will feature presentations by Neil Kumar, Ph.D., BridgeBio founder and CEO; Richard Scheller, Ph.D., chairman of R&D at BridgeBio; Charles Homcy, M.D., chairman of pharmaceuticals at BridgeBio; Uma Sinha, Ph.D., chief scientific officer at BridgeBio; and scientists and physicians leading BridgeBio’s drug discovery and development programs.
BridgeBio has more than 30 programs in its pipeline for patients living with genetic diseases and genetically-driven cancers. Fourteen of those programs are being advanced in the clinic or commercial setting, and earlier this year BridgeBio received its first two U.S. Food and Drug Administration (FDA) drug approvals.
R&D Day pipeline news and updates:
BridgeBio Precision Oncology
KRAS inhibitors for KRAS cancers: BridgeBio announces its discovery of next-generation G12C dual inhibitors, the first-known compounds that directly bind and inhibit KRAS in both its active (GTP bound) and inactive (GDP bound) conformations driven by insights from its molecular dynamics platform. This unique mechanism of action (MOA) is differentiated in preclinical models from first generation compounds, which only bind inactive KRAS. RAS is one of the most well-known oncogenic drivers with approximately 30% of all cancers being driven by RAS mutations, including large proportions of lung, colorectal and pancreatic tumors.
In preclinical models, BridgeBio compounds showed rapid and complete modification of active (GTP bound) KRAS, which is not observed with first generation compounds. BridgeBio compounds were shown to be >500 fold more potent in inhibiting KRAS:RAF effector binding and more potent at inhibiting downstream signaling than first generation inhibitors.
In cellular resistance models, BridgeBio’s dual KRAS inhibitors were shown to be >35x more potent at blocking the emergence of resistance clones than first generation inhibitors, suggesting the potential for more durable efficacy in the clinic.
PI3Ka:RAS breaker: The company will discuss the discovery of multiple PI3Ka:RAS breakers, a potential therapeutic approach developed to block RAS driven PI3Kα activation with the potential to avoid adverse effects on glucose metabolism that limit the potential of PI3Ka kinase inhibitors.
BridgeBio will also announce its novel G12D inhibitor research program.
BridgeBio expects to select a RAS development candidate in 2022.
BridgeBio Gene Therapy
BBP-818 – New adeno-associated virus (AAV) gene therapy program for classic galactosemia (severe GALT deficiency): Classic galactosemia, which is caused by a severe deficiency of the enzyme galactose-1-phosphate uridylyltransferase (GALT), affects approximately 7,000 patients in the United States and the European Union. Studies in more than 500 patients with galactosemia have shown that despite early detection and strict adherence to diet, children with ≤1% of GALT enzyme levels may experience language delay, speech defects, learning disabilities, cognitive impairment, osteopenia, and in females, primary ovarian insufficiency.
BBP-818 is designed to enable production of the GALT enzyme and to enable the body’s natural ability to metabolize galactose. Preclinical studies in a mouse model of classic galactosemia have shown that BridgeBio’s BBP-818 therapy restored up to 72% of wild-type levels of GALT enzyme in the brain following a single dose.
In addition to the GALT program, BridgeBio Gene Therapy is advancing clinical candidates for Canavan disease and congenital adrenal hyperplasia (CAH), and a preclinical program for TMC1 hearing loss. BridgeBio will also announce at R&D Day preclinical gene therapy programs targeting tuberous sclerosis, cystinuria, and a genetic dilated cardiomyopathy, as well as collaborations to identify and characterize next generation capsids with tropism for the central nervous system and kidney.
BridgeBio Cardiorenal
BBP-711 – Glycolate oxidase (GO) inhibitor for hyperoxaluria: BridgeBio will share preliminary Phase 1 data in which BBP-711 was well-tolerated and resulted in maximal increases in plasma glycolate exceeding those achieved by any GO-targeting agents reported in healthy adult volunteers. At steady state in multiple ascending dose cohorts, BBP-711 treatment resulted in plasma glycolate concentrations comparable to case reports of individuals with germline HAO1 knockout, the gene encoding GO, suggesting complete inhibition.
BBP-711 is being developed for the treatment of primary hyperoxaluria type 1 (PH1) and hyperoxaluria caused by hepatic overproduction of oxalate in recurrent kidney stone formers. A full readout of Phase 1 data in healthy adult volunteers is expected in 2022, to be followed by initiation of a Phase 2/3 trial in PH1 and a Phase 2 proof-of-concept trial in recurrent kidney stone formers.
Acoramidis (AG10) – TTR stabilizer for transthyretin amyloid cardiomyopathy (ATTR-CM): BridgeBio will cover the company’s most significant near-term catalysts with a focus on upcoming topline results for acoramidis. Topline results from Part A of the Phase 3 ATTRibute-CM trial are expected in late 2021 and from Part B in 2023. The primary endpoint at Part A is the change from baseline in a 6-minute walk distance (6MWD) in trial participants receiving acoramidis or placebo after 12 months. If the change from baseline in 6MWD in Part A is highly statistically significant, BridgeBio expects to submit an application for regulatory approval of acoramidis in 2022 to the FDA. ATTR is a rare heart condition with a progressive and debilitating impact on quality of life likely affecting more than 400,000 patients worldwide.
Encaleret – Calcium-sensing receptor (CaSR) inhibitor for autosomal dominant hypocalcemia type 1 (ADH1): BridgeBio will review updated Phase 2b data for encaleret, which was originally shared in an oral presentation at the American Society of Bone and Mineral Research (ASBMR) 2021 Annual Meeting. Within five days of individualized dose titration in 13 participants, encaleret normalized mean blood calcium levels and 24-hour urine calcium excretion. Achieving simultaneous blood and urine calcium normalization is a challenge for patients with ADH1 due to the limitations of current standard-of-care. Encaleret could be the first approved therapy for ADH1, a condition caused by gain of function variants in the CaSR gene estimated to be carried by 12,000 individuals in the United States alone. BridgeBio plans to engage with regulatory health authorities to discuss the design of a Phase 3 registrational trial in patients with ADH1.
BridgeBioX
BridgeBio will announce BridgeBioX, the company’s new early research discovery engine with a dedicated lab at Stanford University. BridgeBio created BridgeBioX to test earlier scientific hypotheses in discovery research and target large, complex genetic diseases with high unmet need. BridgeBio’s creation comes with cutting edge tools in genetics and molecular biology, along with expanded capabilities across modalities with the goal of advancing therapies rapidly. The research lab was created to foster collaboration between industry and academia, and to build a culture driven by intellectual curiosity and a dedication to patient impact.
BridgeBio Mendelian
BBP-418 – Glycosylation substrate for limb-girdle muscular dystrophy type 2i (LGMD2i): BridgeBio will review Phase 1 data in which BBP-418 was shown to be well-tolerated in healthy volunteers. The Phase 2 trial was initiated in patients with LGMD2i in the first quarter of 2021. With approximately 7,000 patients with potentially treatable mutations, LGMD2i is an inherited recessive muscular dystrophy caused by mutation of fukutin-related protein. A Phase 2 data readout is expected in 2022.
BBP-589 – Recombinant collagen for recessive dystrophic epidermolysis bullosa (RDEB): BridgeBio will discuss BBP-589, the only potential systemic treatment option being developed for patients with RDEB. BBP-589 was previously shown to be well-tolerated in Phase 1 with dose-dependent increase in C7 skin deposition. RDEB is a Mendelian disease that has devastating effects on patients due to the epidermis separating from the dermis and causes blistering, tearing and scarring of the skin, along with severe pain and itching. In the United States, RDEB has a prevalence of approximately 2,000 patients. Phase 2 data are expected in the first half of 2022.
BridgeBio’s R&D Day will be held today from 8:30 am ET – 11:00 am ET and it will be webcast, with a link available in the event calendar on BridgeBio’s investor website, View Source A replay of the webcast will be available for one year following the event.
To register for BridgeBio’s R&D Day, please sign up here.
Agenda:
Welcome and introduction – Grace Rauh, vice president of marketing and communications, BridgeBio
Genetic basis of disease – Richard Scheller, Ph.D., chairman of R&D, BridgeBio
BridgeBio’s endless summer – Neil Kumar, Ph.D., founder and CEO, BridgeBio
Precision cardiorenal introduction – Cameron Turtle, D.Phil., chief strategy officer, BridgeBio
Acoramidis: TTR stabilizer for ATTR – Jonathan Fox, M.D., Ph.D., chief medical officer, BridgeBio Cardiorenal
Encaleret: Calcium sensing receptor (CaSR) inhibitor for autosomal dominant hypocalcemia type 1 (ADH1) – Mary Scott Roberts, M.D., senior director of clinical development, BridgeBio Cardiorenal
Gene therapy platform – Eric David, M.D., J.D., CEO, BridgeBio Gene Therapy
Mendelian programs: Primary hyperoxaluria type 1 (PH1), limb-girdle muscular dystrophy type 2i (LGMD2i), recessive dystrophic epidermolysis bullosa (rDEB) – Uma Sinha, Ph.D., chief scientific officer, BridgeBio
Precision oncology programs: KRAS, SHP2 – Eli Wallace, Ph.D., chief scientific officer, BridgeBio Oncology
BridgeBioX – Charles Homcy, M.D., chairman of pharmaceuticals, BridgeBio
Q&A