Vutrisiran for ATTR-CM: Exploring an RNAi Therapeutic

Investigating Vutrisiran in Patients with ATTR-CM
Transthyretin amyloidosis, also known as ATTR amyloidosis, is a life-threatening disease caused by the misfolding of transthyretin (TTR), a tetrameric protein. In both wild-type and hereditary ATTR amyloidosis, when the molecular bonds stabilizing TTR break, the monomers can misfold and aggregate into amyloid fibrils, depositing in tissues and organs throughout the body. Multisystemic amyloid deposition can lead to polyneuropathy, cardiomyopathy, or a mixed phenotype in patients with the disease.

Patients with transthyretin amyloid cardiomyopathy (ATTR-CM) are often misdiagnosed with hypertensive heart failure, and the median survival after diagnosis is just two to six years. Increasing awareness of ATTR-CM may help address diagnostic challenges, but patients continue to face significant unmet needs due to limited treatment options.

What is vutrisiran?
Vutrisiran, an RNA interference (RNAi) therapeutic that targets the liver to suppress the production of TTR protein, brings new hope for patients with ATTR-CM. Already FDA-approved for treating hereditary ATTR amyloidosis with polyneuropathy, vutrisiran is currently under FDA review for ATTR-CM.

The phase 3 HELIOS-B trial evaluated the safety and efficacy of vutrisiran in 654 patients with wild-type or hereditary ATTR-CM. The double-blind trial randomized patients to receive either vutrisiran (326) or placebo (328) subcutaneously every 12 weeks for up to 36 months. Patients were stratified by tafamidis use at baseline. However, they could initiate tafamidis during the trial if needed. Consequently, the results were analyzed for the overall population (patients with or without tafamidis use at baseline) and the monotherapy population (patients not on tafamidis at baseline). 

The primary composite endpoint was all-cause mortality and recurrent cardiovascular (CV) events, including hospitalization due to a CV event and urgent heart failure visits. Secondary endpoints included all-cause mortality at 42 months, functional capacity, and quality of life.

Promising findings in ATTR-CM patients
Vutrisiran demonstrated significant benefits in reducing mortality and recurrent CV events compared to placebo. Findings included:

• A 28 percent reduction in the risk of all-cause death and recurrent CV events in the overall population
• A 33 percent reduction in the risk of all-cause death and recurrent CV events among patients not receiving tafamidis at baseline (i.e. monotherapy population)
• Lower risk of all-cause death at 42 months, both in the overall population and in monotherapy patients
• Better preservation of functional capacity and quality of life.
• Prevention of heart failure symptom progression compared to placebo
• Comparable adverse event profiles between vutrisiran and placebo trial arms, and a lower rate of serious adverse events in the vutrisiran group (62 percent) compared to placebo (67 percent)

RNAi therapeutics are advancing the treatment landscape for transthyretin amyloidosis. Vutrisiran emerges as a promising option for patients with wild-type or hereditary ATTR-CM, lowering the risk of mortality and recurrent CV events while preserving patient quality of life. If approved, it may set a new standard of care for patients facing this progressive and debilitating disease.

References:
Alnylam Pharmaceuticals, Inc. (2024, November 25). Alnylam announces U.S. Food and Drug Administration acceptance of supplemental New Drug Application for vutrisiran for the treatment of ATTR amyloidosis with cardiomyopathy [Press release]. https://investors.alnylam.com/press-release?id=28546

Fontana, M., Berk, J. L., Gillmore, J. D., Witteles, R. M., Grogan, M., Drachman, B., Damy, T., Garcia-Pavia, P., Taubel, J., Solomon, S. D., Sheikh, F. H., Tahara, N., González-Costello, J., Tsujita, K., Morbach, C., Pozsonyi, Z., Petrie, M. C., Delgado, D., Van der Meer, P., Jabbour, A., … HELIOS-B Trial Investigators and Collaborators (2025). Vutrisiran in Patients with Transthyretin Amyloidosis with Cardiomyopathy. The New England Journal of Medicine, 392(1), 33–44. https://doi.org/10.1056/NEJMoa2409134

Keam S. J. (2022). Vutrisiran: First Approval. Drugs, 82(13), 1419–1425. https://doi.org/10.1007/s40265-022-01765-5

American Heart Association. (2024, May 29). Transthyretin amyloid cardiomyopathy (ATTR-CM). https://www.heart.org/en/health-topics/cardiomyopathy/what-is-cardiomyopathy-in-adults/transthyretin-amyloid-cardiomyopathy-attr-cm