Alnylam Presents Positive 18-Month Results from Phase 3 Study of Vutrisiran in Patients with hATTR Amyloidosis with Polyneuropathy

Alnylam Pharmaceuticals reported that the HELIOS-A phase 3 study of vutrisiran, an experimental RNAi therapeutic in development for the treatment of transthyretin-mediated (ATTR) amyloidosis, met all secondary endpoints measured at 18 months in patients with hATTR amyloidosis with polyneuropathy.

The positive results included statistically significant improvements in neuropathy impairment, quality of life, gait speed, nutritional status and overall disability, relative to placebo, and non-inferiority of serum TTR reduction relative to the within-study patisiran arm. The results were presented in an oral session at the Société Francophone du Nerf Périphérique (SFNP) Annual Meeting.

Hereditary transthyretin-mediated (hATTR) amyloidosis is an inherited, progressively debilitating, and fatal disease caused by mutations in the TTR gene. TTR protein is primarily produced in the liver and is normally a carrier of vitamin A. Mutations in the TTR gene cause abnormal amyloid proteins to accumulate and damage body organs and tissue, such as the peripheral nerves and heart, resulting in intractable peripheral sensory-motor neuropathy, autonomic neuropathy, and/or cardiomyopathy, as well as other disease manifestations. hATTR amyloidosis, represents a major unmet medical need with significant morbidity and mortality affecting approximately 50,000 people worldwide. The median survival is 4.7 years following diagnosis, with a reduced survival (3.4 years) for patients presenting with cardiomyopathy.

Vutrisiran is an experimental, subcutaneously administered RNAi therapeutic in development for the treatment of ATTR amyloidosis, which encompasses both hATTR and wild-type ATTR (wtATTR) amyloidosis. It is designed to target and silence specific messenger RNA, potentially blocking the production of wild-type and variant transthyretin (TTR) protein before it is made.

In HELIOS-A, patients treated with vutrisiran also showed improvement in exploratory cardiac endpoints including NT-proBNP and echocardiographic parameters relative to placebo, as well as technetium uptake, relative to baseline, in a planned cohort of patients. Vutrisiran also continued to demonstrate an encouraging safety and tolerability profile consistent with the previously reported Month 9 results. Alnylam previously announced that HELIOS-A met its primary and secondary endpoints at 9 months and study results were presented at the 2021 American Academy of Neurology (AAN) Virtual Annual Meeting.

“These HELIOS-A results show that the improvement in neuropathy impairment and quality of life observed with vutrisiran at 9 months is maintained through Month 18, with the treatment effect increasing over time and an encouraging safety profile,” said Rena Denoncourt, vice president, TTR Franchise Lead at Alnylam. “Further, we are encouraged by the exploratory cardiac endpoint results, particularly new data indicating that 18 months of vutrisiran treatment resulted in reduced technetium uptake in the heart compared to baseline in the majority of patients who were in a planned cohort, suggesting the potential for amyloid regression.”

Vutrisiran is under review by the U.S. Food and Drug Administration, the European Medicines Agency, the Brazilian Health Regulatory Agency, and the Japanese Pharmaceuticals and Medical Devices Agency. Vutrisiran has been granted Orphan Drug designation in the United States and the European Union for the treatment of ATTR amyloidosis. Vutrisiran has also been granted Fast Track designation in the United States for the treatment of the polyneuropathy of hATTR amyloidosis in adults. In the United States, vutrisiran has received an action date under the Prescription Drug User Fee Act of April 14, 2022. The company received Orphan Drug Designation in Japan for transthyretin type familial amyloidosis with polyneuropathy.

There were three study discontinuations (2.5 percent) due to adverse events in the vutrisiran arm by Month 18, one due to a non-fatal event of heart failure and two due to deaths, neither of which was considered related to the study drug. During the 18-month treatment period there were two serious adverse events (SAEs) deemed related to vutrisiran by the study investigator, consisting of dyslipidemia and urinary tract infection. The two deaths and the two related SAEs were previously reported at Month 9.

Treatment emergent adverse events (AEs) occurring in 10 percent or more patients included fall, pain in extremity, diarrhea, peripheral edema, urinary tract infection, arthralgia and dizziness; with the exception of pain in extremity and arthralgia, each of these events occurred at a similar or lower rate as compared with external placebo. Injection site reactions (ISRs) were reported in five patients (4.1 percent) and were all mild and transient. There were no clinically significant changes in liver function tests.

Photo: Rena Denoncourt, vice president, TTR Franchise Lead at Alnylam

Author: Rare Daily Staff