Announcement • Aug 31

Alnylam Pharmaceuticals Presents New Data On Vutrisiran And Zilebesiran At ESC Congress 2026

Alnylam Pharmaceuticals, Inc. announced new data at the European Society of Cardiology (ESC) Congress 2026 demonstrating the strength of RNAi-powered silencing for cardiovascular disease. The findings further reinforce the clinical profile of AMVUTTRA (vutrisiran) across transthyretin amyloidosis (ATTR) patient populations, treatment settings, and manifestations of disease. Additionally, the data expand the potential application of RNAi to uncontrolled hypertension. A late-breaking oral presentation featured a prespecified subgroup analysis of the HELIOS-B Phase 3 clinical trial evaluating the treatment effect of vutrisiran according to baseline tafamidis use. Among 654 randomized and treated patients in HELIOS-B, 259 patients (40%) were receiving tafamidis at baseline. The treatment effect for vutrisiran on the primary composite endpoint of all-cause mortality and recurrent cardiovascular events through 33-36 months was consistent irrespective of baseline tafamidis use, suggesting clinical benefits across broad patient populations, including those receiving stabilizers. All-cause mortality and additional cardiovascular outcomes showed a similar benefit among patients who were receiving tafamidis at baseline (“combination population”) and those who were not (“monotherapy population”). Across both groups, treatment with vutrisiran preserved functional capacity versus placebo, as measured by the Six-Minute Walk Test. Improvement in health status by vutrisiran versus placebo, as measured by the Kansas City Cardiomyopathy Questionnaire-overall summary score, was observed in both the monotherapy and combination populations with an attenuated effect seen among patients receiving tafamidis at baseline. Safety outcomes were generally similar between combination vutrisiran and tafamidis versus tafamidis alone, and between vutrisiran monotherapy versus placebo. HELIOS-B was not powered to establish the benefit of vutrisiran specifically in the population of patients receiving background tafamidis at baseline. These findings reinforce the impact of vutrisiran across contemporary ATTR-CM treatment settings and warrant further evaluation of TTR silencing and stabilization combination strategies. Additional analyses presented at ESC further underscore the multisystemic burden of ATTR-CM and the importance of evaluating measures beyond traditional cardiac endpoints. Real-world evidence from the French National Health Data System showed that patients with ATTR-CM had a significantly higher burden of extra-cardiac manifestations across multiple organ systems compared with matched controls, and multiple manifestations were recorded years before ATTR-CM identification and tended to accumulate over time, suggesting a prolonged pre-diagnostic phase with evolving multisystem involvement. A post hoc analysis of HELIOS-B evaluated the impact of treatment with vutrisiran on intrinsic capacity, a composite measure encompassing locomotion, cognition, vitality, psychological well-being and sensory function aligned with the World Health Organization Integrated Care for Older People framework. In the overall study population, compared with placebo, patients treated with vutrisiran demonstrated 25% less decline from baseline intrinsic capacity score and a 52% reduction in the risk of decline, suggesting that treatment with vutrisiran may help preserve functional reserve and support healthy aging in patients with ATTR-CM. A separate post hoc safety analysis of HELIOS-B showed that patients treated with vutrisiran had fewer adverse events overall compared with placebo across the overall study population, monotherapy population and combination population. Among the most frequent system organ classes in the overall population, the lowest adverse event rate ratios were observed for gastrointestinal disorders and nervous system disorders, with 42% and 41% lower adverse event rates, respectively, with vutrisiran compared with placebo; eye disorders showed a 46% lower event rate with vutrisiran compared with placebo. A pooled analysis of 1,402 patients (203 females, 1,199 males) across four Phase 3 studies of vutrisiran and patisiran further reinforces the clinical benefits of RNAi-mediated TTR silencing across sexes. Despite sex-specific baseline differences in disease presentation, treatment effects were consistent between females and males across both ATTR-CM and the polyneuropathy of hereditary ATTR (hATTR-PN), including clinical, biomarker, functional, health status and echocardiographic measures. The KARDIA-3 Phase 2 study evaluated zilebesiran, an investigational RNAi therapeutic with the potential to provide continuous control of blood pressure (BP) with biannual dosing, in patients with uncontrolled hypertension with high cardiovascular (CV) risk treated with two or more background antihypertensives. In patients who were receiving a background diuretic with an office systolic BP (SBP) =140 mmHg at baseline, zilebesiran achieved greater reductions in mean office and 24-hour ambulatory SBP than in the overall study population. Furthermore, patients treated with zilebesiran experienced SBP reductions across the diurnal cycle, including at nighttime. Similar findings were observed in patients who had impaired nocturnal dipping at baseline. These findings are potentially important given the association between elevated nighttime BP and CV risk. The safety profile in this post hoc subgroup was consistent with the broader zilebesiran Phase 2 program. These findings further support the evaluation of zilebesiran in the ongoing global Phase 3 CV outcomes trial, ZENITH. In the EU, AMVUTTRA (vutrisiran) is indicated for the treatment of hereditary transthyretin amyloidosis in adult patients with stage 1 or stage 2 polyneuropathy (hATTR-PN) and wild-type or hereditary transthyretin amyloidosis in adult patients with cardiomyopathy (ATTR-CM). Vutrisiran treatment can lower serum vitamin A levels, therefore supplementation of approximately, but not exceeding, 2,500 IU to 3,000 IU vitamin A per day is advised for patients. Commonly reported adverse reactions with vutrisiran were injection site reactions and increase in blood alkaline phosphatase and alanine transaminase. In the EU, ONPATTRO (patisiran) is indicated for the treatment of hereditary transthyretin-mediated (hATTR) amyloidosis in adults with stage 1 or stage 2 polyneuropathy. Patisiran treatment can lower serum vitamin A levels, therefore supplementation of approximately, but not exceeding, 2,500 IU to 3,000 IU vitamin A per day is advised for patients. The most common adverse reactions that occurred in patients treated with patisiran were peripheral oedema (30%) and infusion-related reactions (19%). AMVUTTRA (vutrisiran) demonstrates strength in RNAi-powered transthyretin (TTR) silencing, delivering rapid knockdown of TTR at the source of disease to address the underlying cause of transthyretin amyloidosis (ATTR).

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