Alnylam Reports Positive Phase 3 Results 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 the polyneuropathy associated with hereditary transthyretin-mediated (hATTR) amyloidosis, met all secondary endpoints measured at 18 months, suggesting that the positive results observed at nine months were maintained.

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

The secondary endpoints that were met include statistically significant improvements in neuropathy as measured by the modified Neuropathy Impairment Score (mNIS+7), quality of life (QOL), gait speed, nutritional status and overall disability, relative to external placebo data from the APOLLO phase 3 study of patisiran.

The final secondary endpoint, reduction in serum TTR levels with vutrisiran, demonstrated non-inferiority relative to the within-study patisiran arm, as expected. In addition, patients treated with vutrisiran showed improvements in exploratory endpoints, including the biomarker NT-proBNP and certain echocardiographic parameters, relative to placebo, and an improvement in technetium uptake relative to baseline in a majority of patients in a planned cohort, providing potential evidence for reduced cardiac amyloid burden.

Vutrisiran continued to demonstrate an encouraging safety and tolerability profile. Alnylam previously announced that HELIOS-A met its primary and secondary endpoints at nine months and study results were presented at the 2021 American Academy of Neurology (AAN) Virtual Annual Meeting. Alnylam intends to present HELIOS-A 18-month results at a medical congress in early 2022.

“These results build on the positive vutrisiran data shared earlier this year and suggest that the reduction of neurologic impairment and improvement in quality of life in patients with hATTR amyloidosis with polyneuropathy observed as early as nine months are maintained at 18 months. We are also encouraged by the hypothesis-supporting, exploratory endpoints and cardiac amyloid imaging results,” said Rena Denoncourt, vice president, TTR Franchise lead at Alnylam. “Vutrisiran is currently under review by multiple regulatory authorities around the world, bringing this low-dose, once-quarterly, subcutaneously administered investigational therapy with a highly-attractive profile one step closer to being a potentially available therapeutic option for patients living with this progressive, life-threatening, multi-system disease.”

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. Variants 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. Vutrisiran utilizes Alnylam’s Enhanced Stabilization Chemistry (ESC)-GalNAc-conjugate delivery platform, designed for increased potency and high metabolic stability that may allow for infrequent subcutaneous injections.

At 18 months, patients treated with vutrisiran showed quantitative improvement across a number of exploratory endpoints. Compared to placebo, patients in the vutrisiran arm demonstrated improvement in the cardiac biomarker endpoint, NT-proBNP, a measure of cardiac stress. In addition, patients treated with vutrisiran also demonstrated improvement in certain echocardiographic parameters, relative to placebo. Finally, in a planned cohort of 48 patients, treatment with vutrisiran was associated with an improvement in technetium uptake in the heart in a majority of patients, providing potential evidence for reduced cardiac amyloid burden.

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

Author: Rare Daily Staff