Evaluating Transthyretin Stabilizers and Silencers in ATTR-CM

In ‘Evaluating Transthyretin Stabilizers and Silencers in ATTR-CM,’ our panel delves into the segment by asking Dr. Alexander to explain the differences between transthyretin stabilizers and silencers. Dr. Alexander begins with a brief overview of ATTR-CM pathophysiology, explaining that transthyretin is normally secreted by the liver as a tetramer, but in amyloidosis, the tetramers dissociate into unstable monomers that misfold and aggregate into amyloid fibrils. TTR stabilizers, such as tafamidis and acoramidis, are small molecules that bind to the tetramer to prevent dissociation, while vutrisiran, a silencer, uses small interfering RNA to reduce liver production of transthyretin by approximately 80%, thereby limiting the supply of protein available to form amyloid.

When asked about clinically meaningful differences between these therapy classes, Dr. Alexander notes that no head-to-head trials exist, making direct comparisons difficult. Each trial studied progressively healthier patient populations over time, and the background use of tafamidis in the later trials further complicates cross-trial analysis. Both physicians agree that matching patients to trial inclusion criteria remains the most practical approach for informing treatment decisions in the absence of comparative data.

Dr. Alexander then reviews the three pivotal trials chronologically. The ATTR-ACT trial studied tafamidis in 441 patients over 30 months, demonstrating strong benefits across a hierarchical composite endpoint including mortality and cardiovascular hospitalizations. The ATTRibute-CM trial evaluated acoramidis in over 600 patients with a similar design, also showing clear statistical benefit, with clinician discretion allowing tafamidis to be added after 12 months. Finally, Helios-B assessed vutrisiran over 36 to 42 months, with approximately 30% of patients on background tafamidis, and similarly demonstrated strong improvements in the composite endpoint, mortality, and cardiovascular hospitalizations.

Our next episode, ‘Key Efficacy and Safety Considerations for Payers in ATTR-CM,’ further explores ATTR-CM, highlighting long-term efficacy and safety data from the tafamidis and acoramidis extension studies, key clinical takeaways from all three pivotal trials, and the generally favorable safety profiles of each therapy with select management considerations.