Alnylam Pharmaceuticals' vutrisiran, an RNAi therapeutic, has shown promising results in treating transthyretin amyloidosis with cardiomyopathy (ATTR-CM), according to new data from the HELIOS-B Phase 3 study. The findings, presented at the Heart Failure Society of America (HFSA) Annual Scientific Meeting 2024, highlight the drug's potential to improve cardiac structure and function, as well as stabilize key cardiac biomarkers in patients with ATTR-CM. These results support regulatory submissions to the U.S. Food and Drug Administration (FDA) and the European Medicines Agency (EMA), with the goal of establishing vutrisiran as a first-line therapy for this debilitating and often fatal disease.
Vutrisiran's Impact on Cardiac Structure and Function
The HELIOS-B study (NCT04153149), a randomized, double-blind, placebo-controlled trial, involved 655 adult patients with ATTR amyloidosis (hereditary or wild-type) with cardiomyopathy. Patients were randomized 1:1 to receive either vutrisiran 25mg or placebo subcutaneously every three months for up to 36 months. The study's primary endpoint was the reduction of all-cause mortality and recurrent cardiovascular events.
Echocardiographic data from the study demonstrated that vutrisiran slowed disease progression across multiple domains of cardiac structure and function compared to placebo. Specifically, significant improvements were observed in:
- Mean Left Ventricular Wall Thickness: -0.04 cm (p=0.03)
- Left Ventricular Mass Index: -10.6 g/m2 (p=0.0047)
- E/A Ratio: -0.29 (p=0.0434)
- E/e' Ratio: -1.82 (p=0.00003)
- TDI Lateral e': 0.55 cm/s (p=0.0005)
- Left Ventricular Ejection Fraction: 2.03% (p=0.02)
- Absolute Global Longitudinal Strain: 1.23% (p=0.000002)
- Left Ventricular Stroke Volume: 4.05 mL (p=0.0007)
These improvements were observed as early as 12 months for diastolic function and 18 months for systolic function in the overall population.
Stabilization of Cardiac Biomarkers
In addition to echocardiographic improvements, vutrisiran demonstrated a notable impact on cardiac biomarkers. At Month 30, patients treated with vutrisiran showed a 32% relative reduction in the fold change in NT-proBNP compared to placebo (p=3.440E-12) and a 32% relative reduction in the fold change of troponin I (p=1.566E-14). These results were even more pronounced in the monotherapy population, with reductions of 43% in NT-proBNP (p=4.339E-12) and 45% in troponin I (p=9.684E-17).
According to Pushkal Garg, M.D., Chief Medical Officer at Alnylam, these data indicate that rapid knockdown of TTR leads to an early impact on cardiac biomarkers and echocardiographic parameters, suggesting a potential disease-modifying effect. He emphasized the benefit of treating patients earlier in the course of the disease.
Regulatory Submissions and Future Outlook
Based on the strength of the HELIOS-B data, Alnylam has submitted a supplemental New Drug Application (sNDA) to the U.S. FDA and a Type II Variation to the European Medicines Agency (EMA) for vutrisiran to treat ATTR-CM. The company utilized a Priority Review Voucher to accelerate the FDA review timeline. Alnylam anticipates additional global regulatory submissions in the near future.
If approved, vutrisiran has the potential to become a first-line therapy for ATTR amyloidosis with cardiomyopathy, offering a new treatment option for patients with this progressive and life-threatening disease. The detailed results from the HELIOS-B study were published in The New England Journal of Medicine, further validating the drug's efficacy and safety.
Safety and Tolerability
The therapy was generally well-tolerated in the HELIOS-A trial. The most common adverse reactions associated with vutrisiran treatment included pain in an extremity, arthralgia, dyspnea, and decreased vitamin A levels. It is recommended that patients taking vutrisiran receive vitamin A supplementation due to the drug's potential to reduce serum vitamin A levels. Patients should also be monitored for ocular symptoms suggestive of vitamin A deficiency.
