27 October 2021 - - The HELIOS-A Phase 3 study of vutrisiran, an investigational 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, including statistically significant improvements in neuropathy as measured by the modified Neuropathy Impairment Score (mNIS+7), quality of life, gait speed, nutritional status and overall disability, relative to external placebo data from the APOLLO Phase 3 study of patisiran, US-based RNAi therapeutics company Alnylam Pharmaceuticals, Inc. (NASDAQ: ALNY) said.

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.

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 demonstrated an encouraging safety profile. There were three study discontinuations (2.5%) due to adverse events in the vutrisiran arm during the 18 Month treatment period; the single new discontinuation since Month 9 was an event of cardiac failure considered unrelated to study drug by the investigator.

During the 18 Month treatment period, there were two deaths (neither of which was considered related to study drug) and two serious adverse events deemed related to vutrisiran by the study investigator; these deaths and related SAEs all occurred by Month 9 and were previously reported.

Treatment emergent adverse events occurring in 10% 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 were reported in five patients (4.1 %) and were all mild and transient. There were no hepatic safety concerns.

Vutrisiran is under review by the US Food and Drug Administration, the European Medicines Agency, and the Brazilian Health Regulatory Agency (ANVISA). Vutrisiran has been granted Orphan Drug Designation in the US and the European Union for the treatment of ATTR amyloidosis.

Vutrisiran has also been granted a Fast Track designation in the US for the treatment of the polyneuropathy of hATTR amyloidosis in adults. In the US, vutrisiran has received an action date under the Prescription Drug User Fee Act (PDUFA) of April 14, 2022.

The company received Orphan Drug Designation in Japan for transthyretin type familial amyloidosis with polyneuropathy.

Vutrisiran is an investigational, 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 protein before it is made.

Quarterly, and potentially biannual, administration of vutrisiran may help to reduce deposition and facilitate the clearance of TTR amyloid deposits in tissues and potentially restore function to these tissues.

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

The safety and efficacy of vutrisiran have not been evaluated by the US Food and Drug Administration, European Medicines Agency, or any other health authority.

HELIOS-A (NCT03759379) is a Phase 3 global, randomized, open-label study to evaluate the efficacy and safety of vutrisiran. The study enrolled 164 patients with hATTR amyloidosis with polyneuropathy at 57 sites in 22 countries.