Background
Hereditary transthyretin (ATTR variant) amyloidosis, also called hATTR amyloidosis is a rare, rapidly progressive, debilitating, and fatal disease caused by transthyretin (TTR) gene variants. Misfolded TTR accumulates as amyloid deposits in multiple organs and tissues, resulting in a heterogeneous clinical presentation including sensory, motor, autonomic polyneuropathy, and cardiomyopathy. ATTRv amyloidosis affects approximately 50,000 people worldwide. The study objective was to evaluate the effect of vutrisiran, RNA interference therapeutic that reduces transthyretin (TTR) production, in patients with hereditary transthyretin (ATTRv) amyloidosis with polyneuropathy.
Methods
- HELIOS-A was a phase 3, global, open-label study comparing the efficacy and safety of vutrisiran with an external placebo group.
- Patients were randomized 3:1 to subcutaneous vutrisiran 25 mg every 3 months (Q3M) or intravenous patisiran 0.3 mg/kg every 3 weeks (Q3W) for 18 months.
Results
- HELIOS-A enrolled 164 patients (vutrisiran, n=122; patisiran reference group, n=42); external placebo, n=77.
- Vutrisiran met the primary endpoint of change from baseline in modified Neuropathy Impairment Score +7 (mNIS+7) at 9 months, and all secondary efficacy endpoints.
- Significant improvements versus external placebo were observed in Norfolk Quality of Life-Diabetic Neuropathy, 10-meter walk test, mNIS+7, modified body-mass index and Rasch-built Overall Disability Scale.
- TTR reduction with vutrisiran Q3M was non-inferior to within-study patisiran Q3W.
- Most adverse effects were mild and moderate in severity and there were no drug-related discontinuations or death.
Conclusion
Vutrisiran significantly improved multiple disease-relevant outcomes for ATTRv amyloidosis versus external placebo, with an adequate safety profile.