How do Vutrisiran’s HELIOS-B results compare with historical standards in ATTR-CM treatment?

Historically, tafamidis (marketed as Vyndamax in the U.S. and Vyndaqel in Europe by Pfizer) has been the primary treatment for transthyretin amyloid cardiomyopathy (ATTR-CM). Approved in 2019, tafamidis became the first FDA-approved therapy to demonstrate mortality and hospitalization benefit in ATTR-CM via the ATTR-ACT trial, which showed a 30% relative reduction in all-cause mortality and a 32% reduction in CV-related hospitalizations over 30 months.

In contrast, Alnylam’s HELIOS-B data at 42 months show that vutrisiran reduces all-cause mortality by 36% and cardiovascular mortality by 33%, suggesting a clinically relevant advantage over tafamidis when viewed through duration-adjusted metrics. Notably, vutrisiran also cut urgent heart failure visits by 46%, a domain where tafamidis had no formal endpoint measure. These figures may mark a paradigm shift, not only in therapeutic efficacy but also in patient convenience, given vutrisiran’s quarterly subcutaneous dosing versus tafamidis’ daily oral administration.

While head-to-head comparative trials are lacking, analysts suggest that vutrisiran’s mechanism—silencing TTR production rather than stabilizing its misfolded tetramers—could result in greater systemic TTR clearance, particularly in patients with rapidly progressing disease. This mechanistic distinction positions AMVUTTRA as a potentially superior disease-modifying treatment, especially when early diagnosis allows for full RNAi benefit before irreversible organ damage occurs.

How Big Is the Commercial Opportunity for Vutrisiran in the ATTR-CM Space?

The market for ATTR-CM therapies is expanding rapidly due to improved disease awareness and diagnostic advancements such as nuclear scintigraphy, which now enables non-invasive diagnosis of wild-type ATTR. Global prevalence estimates suggest that up to 20% of heart failure patients over age 60 may have undiagnosed ATTR-CM, with particularly high incidence among Black and Hispanic populations in the U.S. and Japan’s aging demographic.

Pfizer’s tafamidis achieved blockbuster status in 2022, with global revenues surpassing $2.5 billion, underscoring the market’s potential. Analysts expect the ATTR-CM market to exceed $10 billion by 2030, driven by a shift from symptomatic to disease-modifying treatments. Within this context, AMVUTTRA’s long-acting profile, RNAi mechanism, and newly validated mortality reduction data could allow Alnylam to capture significant market share, particularly in patients who fail or decline tafamidis.

Additionally, AMVUTTRA is already approved for hereditary polyneuropathy, giving Alnylam a multi-indication foothold that Pfizer’s tafamidis lacks. This cross-indication strategy could allow Alnylam to bundle disease education, diagnostics, and prescription pathways across cardiologists and neurologists, accelerating adoption and payer reimbursement support.

Can RNAi Therapeutics Like Vutrisiran Outperform Traditional Small Molecule Drugs?

RNA interference-based medicines like vutrisiran represent a new class of genetic silencers that work upstream of protein production. In contrast to traditional small molecules, which typically bind to proteins post-translation to stabilize or inhibit function, RNAi therapeutics prevent disease proteins from being produced altogether by targeting their mRNA precursors. This difference is significant in diseases like ATTR-CM, where both wild-type and mutant TTR proteins contribute to pathogenesis.

Alnylam’s platform advantage lies in its GalNAc-conjugated delivery technology, which enables precise targeting of liver-expressed genes like TTR with minimal off-target effects. The success of ONPATTRO® (patisiran), GIVLAARI® (givosiran), and OXLUMO® (lumasiran)—all FDA-approved RNAi therapies—has validated this mechanism across multiple rare diseases. AMVUTTRA builds on this legacy with improved dosing frequency and safety margins.

With new RNAi agents like nucresiran entering late-stage trials and expected to require only biannual dosing, RNAi could eventually become the dominant modality for ATTR-CM management, surpassing stabilizers and antisense oligonucleotides (ASOs) like inotersen, which carry higher rates of thrombocytopenia and renal toxicity.

What Is the Regulatory and Competitive Landscape Looking Like in 2025?

In terms of geographic expansion, Alnylam has secured approvals in the U.S. and Brazil and received a positive CHMP opinion from the European Medicines Agency for vutrisiran’s cardiomyopathy indication. A decision from the European Commission is expected in Q3 2025. The Japanese Pharmaceuticals and Medical Devices Agency (PMDA) is also reviewing vutrisiran, making East Asia a critical upcoming battleground for market penetration.

Meanwhile, Ionis Pharmaceuticals, in partnership with AstraZeneca, is advancing eplontersen, an antisense RNA therapy for ATTR. Though eplontersen offers monthly dosing and has shown promising polyneuropathy data, its cardiomyopathy benefit remains under investigation. The absence of head-to-head data between vutrisiran, eplontersen, and tafamidis leaves clinicians and payers in a complex decision-making matrix.

However, with the HELIOS-B 42-month readout showing sustained survival and cardiovascular benefits—even in patients already on TTR stabilizers—AMVUTTRA is arguably the most comprehensively studied ATTR-CM therapy to date. Regulatory agencies are likely to factor this into decision-making, especially in markets where disease burden is high and treatment options limited.

Is Alnylam Stock a Buy After HELIOS-B Update?

Investor sentiment surrounding Alnylam Pharmaceuticals has remained moderately bullish following the HELIOS-B update. The stock (NASDAQ: ALNY) rose modestly post-announcement, with trading volume reflecting increased institutional interest but limited retail volatility. Analysts across JP Morgan, SVB Securities, and Jefferies have reiterated “Buy” or “Outperform” ratings, citing the extended clinical durability, upcoming EMA approval, and pipeline progression with nucresiran.

Institutional flows from biotech-focused funds have reportedly been net positive since the JACC publication. The HELIOS-B update also appears to be triggering options activity ahead of potential catalysts such as TRITON-CM trial enrollment and further regulatory decisions in Asia-Pacific markets.

Buy-side consensus is that Alnylam’s “Alnylam P5x25” strategy—aiming to launch five RNAi therapies into global markets by 2025—remains on track. The vutrisiran label expansion, if approved in Europe and Japan, could become the third major contributor to the company’s long-term revenue stream alongside ONPATTRO and GIVLAARI.