ATTR Study Results Baffle BridgeBio
Palo Alto, Calif.-based BridgeBio Pharma reported topline data from Part A (Month 12) of its Phase III ATTRibute-CM study of acoramidis for symptomatic transthyretin (TTR) amyloid cardiomyopathy (ATTR-CM). The drug failed the study arm. Company shares got hammered, dropping more than 70%, although there has been a slight rise today.
ATTR is believed to be underdiagnosed. It is a life-threatening illness with limited treatment options. When transthyretin (TTR) becomes unstable because of aging or inherited variants, it accumulates as amyloid fibrils in various organs, which causes ATTR. TTR amyloid accumulates mainly in the heart and/or peripheral nerves, resulting in cardiomyopathy (ATTR-CM) and/or polyneuropathy (ATTR-PN).
Acoramidis (AG10) is an oral small molecule engineered to stabilize tetrameric transthyretin. It was designed to mimic a naturally occurring variant of the TTR gene (T119M), a so-called “rescue mutation” that has been shown to prevent or minimize ATTR in people carrying disease-causing mutations in the TTR gene.
In the study arm, the mean observed decrease in 6-minute walking distance (6MWD) at Month 12 in patients receiving acoramidis or placebo with baseline eGFR ≥30 mL/min/1.73m2 were 9 meters and 7 meters, respectively.
The decline that was seen was expected in healthy elderly adults and was also significantly less than the >40-meter annual drops seen in previous untreated arms the company analyzed. The decline in the ATTRibute-CM placebo group was more than 70% lower than seen in the AATR-ACT treatment group.
“This result is disappointing and baffling,” said Neil Kumar, founder and Chief Executive Officer of BridgeBio. “I am, along with many others, searching for answers regarding the 6MWD. 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.”
Kumar went on to say, “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 Independent Data Monitoring Committee (IDMC) recommended continuing the trial based on unblinded reviews of the data. The six-minute walk test data was unexpected, but the study’s steering committee co-chairs and BridgeBio agree that the drug shows potential for benefit at the Month 30 endpoint, which includes all-cause mortality and cardiovascular hospitalizations.
The study enrolled 632 patients with symptomatic ATTR-CM that was associated with either wild-type or variant TTR, with New York Heart Association (NYHA) Class I-III symptoms. Part A, evaluated at 12 months, compared change from baseline in 6MWD. Part B, evaluated at Month 30, uses a hierarchical comparison that includes all-cause mortality and cardiovascular hospitalizations.
The drug improved Kansas City Cardiomyopathy Questionnaire Overall Summary Score compared to placebo, improved NT-proBNP relative to placebo, increased serum TTR levels compared to placebo and was generally well-tolerated with no safety signals of clinical concern.
The company’s finances are strong enough to carry them through 2022 and 2023, with $800 million in cash, cash equivalents and marketable securities, with a potential $300 million in portfolio milestones through the end of 2022.
“Although these results were not what we hoped, the most important moment in this trial will be the Part B readout at 30 months, where we will see the effects of acoramidis on all-cause mortality and cardiovascular hospitalizations,” said Dr. Daniel Judge, Professor in the Division of Cardiology at the Medical University of South Carolina, and Co-Chair of the ATTRibute-CM Steering Committee.