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BridgeBio Tumbles on Phase 3 ATTR-CM Results

December 27, 2021

Shares of BridgeBio Pharma fell to $11.38 (72 percent) from a previous close of $40.62 on news that topline results from 12 months of an ongoing phase 3 study of its experimental therapy acoramidis for the rare heart condition amyloid cardiomyopathy failed to meet its primary endpoint.

Photo: Neil Kumar, founder and CEO of BridgeBio

Transthyretin amyloidosis (ATTR) is an underdiagnosed and life-threatening disease with limited treatment options that can devastate the heart and nervous system. When the transthyretin (TTR) becomes unstable due to inherited variants or aging, it can accumulate as amyloid fibrils in various organs in the body, causing ATTR. TTR amyloid deposits predominantly in the heart and/or peripheral nerves cause cardiomyopathy (ATTR-CM) and/or polyneuropathy (ATTR-PN). ATTR often dramatically impairs the quality of life, functional independence and life expectancy of patients, as well as impacting caregivers due to the progressive nature of the disease. If left untreated life expectancy from diagnosis is approximately four years.

Acoramidis (AG10) is an investigational, orally administered small molecule designed to potently stabilize tetrameric transthyretin, or TTR, thereby halting at its outset the series of molecular events that give rise to TTR amyloidosis, or ATTR. Acoramidis is currently being evaluated in phase 2 and phase 3 studies in patients with ATTR. Acoramidis was designed to mimic a naturally occurring variant of the TTR gene (T119M) that is considered a “rescue mutation” because it has been shown to prevent or minimize ATTR in individuals carrying pathogenic, or disease-causing, mutations in the TTR gene.

The ATTRibute-CM study did not meet its primary endpoint at Month 12. Mean observed six-minute walk distance (6MWD) decline for the acoramidis arm was 9 meters and the placebo arm was 7 meters. Both declines are similar to healthy elderly adults and less than prior untreated ATTR-CM cohorts. The decline in the ATTRibute-CM placebo group was more than 70 percent lower than the decline observed in the ATTR-ACT treatment group.

“This result is disappointing and baffling. I am, along with many others, searching for answers regarding the 6MWD,” said Neil Kumar, founder and CEO of BridgeBio. “The results do not appear to be due to a baseline imbalance. The hypotheses we are currently evaluating include context bias, training bias, and an evolution in diagnosis and standard of care. The drug does appear to be pharmacologically active and well-tolerated, and we observed improvement on quality of life with promising trends on adverse events leading to death. The drug seems to be doing what we are asking of it. If we observe enough clinical outcome events at Month 30, I am still hopeful that we will demonstrate the benefit of acoramidis treatment.”

The company said it observed improvements at Month 12 on the Kansas City Cardiomyopathy Questionnaire Overall Score, a quality-of-life measurement, N-terminal pro BNP, a cardiac biomarker, and serum TTR concentration, a measure of TTR stabilization.

Acoramidis was generally well-tolerated with no safety signals of clinical concern identified. Some 27 percent fewer treatment emergent adverse events leading to death occurred in participants receiving acoramidis than in participants receiving placebo.

The ATTRibute-CM independent data monitoring committee recommends continuing the study based on unblinded data reviews. Despite the unexpected performance of the six-minute walk test, the trial’s steering committee co-chairs and the company agree that there is potential for acoramidis to demonstrate benefit on the Month 30 endpoint which includes all-cause mortality and cardiovascular hospitalizations. 

ATTRibute-CM enrolled 632 participants with symptomatic ATTR-CM, associated with either wild-type or variant TTR, with New York Heart Association Class I-III symptoms. The study is designed as a two-part study with Part A (Month 12) comparing change from baseline in 6MWD and Part B (Month 30) utilizing a hierarchical comparison including all-cause mortality and cardiovascular hospitalizations.

ATTRibute-CM enrolled a similar patient population as ATTR-ACT, excepting a smaller proportion of U.S. participants and TTR variant carriers. Participants were randomized 2:1 between treatment (acoramidis 800 mg) and placebo twice daily.

BridgeBio said it is well-capitalized through the completion of ATTRibute-CM and remains on track to deliver on additional catalysts in 2022 and 2023. The company said it has $800 million in cash with access to up to $300 million on achieving portfolio milestones through year-end 2022.

It has ongoing clinical trials in multiple genetic diseases, including achondroplasia, autosomal dominant hypocalcemia type 1, limb-girdle muscle dystrophy type 2i, and dystrophic epidermolysis bullosa.

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