Alnylam's Phase 3 ATTR Data Cast Doubt on Standard Care Goals

Alnylam Pharmaceuticals is advancing its efforts to position vutrisiran as the preferred treatment for transthyretin amyloid cardiomyopathy (ATTR-CM), a heart muscle disease affecting over 120,000 individuals in the U.S. The drug, marketed under the brand name Amvuttra, received FDA approval in 2022 for treating a rare neurological condition. Alnylam aims to expand its use for ATTR-CM, a market currently dominated by Pfizer’s Vyndaqel since 2019, with competition from BridgeBio's acoramidis.

In June, Alnylam presented topline data from the Phase 3 HELIOS-B trial, describing the results as potentially game-changing for ATTR-CM treatment. However, deeper analysis of patient outcomes and survival rates in the monotherapy subgroup suggests that the competitive landscape remains uncertain. According to Angela Dispenzieri, a consultant in the division of hematology at Mayo Clinic, it may be challenging for doctors to choose between Alnylam’s vutrisiran and Pfizer’s Vyndaqel based on the latest data.

At the European Society of Cardiology annual meeting in London, the trial’s co-primary endpoints were discussed, focusing on freedom from cardiovascular events and all-cause mortality. Initially, patients on placebo seemed to fare better than those on vutrisiran in the monotherapy group, but this trend reversed after the first three months. Dispenzieri noted that while the separation of outcomes in favor of vutrisiran could widen over time, the initial crossing of the curves is unusual.

In a key secondary endpoint, patients on vutrisiran monotherapy exhibited a 30% risk reduction in all-cause mortality at up to 36 months, compared to placebo. For comparison, Vyndaqel's registrational trial reported a 30% risk reduction in mortality at 30 months, though that study included slightly sicker patients at baseline. Dispenzieri suggested that cost could be a decisive factor for prescribing decisions, with Vyndaqel likely having a cost advantage as a small-molecule medicine compared to the siRNA nature of vutrisiran.

The potential benefit of combining vutrisiran with Vyndaqel has also been a point of focus. An analysis of patients in the HELIOS-B trial who were already taking Vyndaqel showed a 41% reduction in all-cause mortality by 42 months when vutrisiran was added. Alnylam's Chief Medical Officer, Pushkal Garg, indicated that these results suggest additive efficacy, highlighting unmet needs in current patient treatments. However, the combination analysis wasn’t powered for statistical significance, which raises questions about the robustness of these findings. Bianca Rocca, associate professor of pharmacology at the Catholic University of Rome, mentioned that while the subgroup data are promising, confirmation in a larger patient population is needed.

Raj Dasgupta, chief medical advisor for Fortune Recommends Health, expressed skepticism about the real-world adoption of combination therapy, citing unclear efficacy and likely insurance hurdles.

The HELIOS-B trial achieved its co-primary endpoints, showing that vutrisiran reduced the risk of death, heart-related hospital visits, and hospitalizations by 28% at 33 months compared to placebo. In the monotherapy subgroup, the drug reduced these risks by 33%. Alnylam introduced changes to the trial’s primary endpoint timeframe in February, extending it to 33 months, which impacted stock prices at the time.

Alnylam plans to submit a label expansion application for ATTR-CM in the U.S. by year-end, aiming for potential approval in the first half of 2025. Despite existing familiarity with Amvuttra for treating hereditary transthyretin-mediated amyloidosis, the company will continue educating prescribers about its use in ATTR-CM to ensure a smooth rollout.

BridgeBio's acoramidis has also shown promising results in ATTR-CM, including a 50% reduction in hospitalization rates and a 25% reduction in mortality risk at 30 months. Bayer recently acquired European rights to acoramidis, and regulatory decisions are anticipated both in Europe and the U.S. in the near future. Analysts project that acoramidis could achieve peak sales of $3 billion.

Amvuttra generated $230 million in the second quarter of this year, with potential annual sales estimated between $2 billion and $4 billion by Wall Street analysts.

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