Alnylam's next-gen ATTR amyloidosis drug hits goals in phase 3, teeing up approval filing

A phase 3 clinical trial of Alnylam’s subcutaneous, long-acting treatment for transthyretin-mediated (ATTR) amyloidosis has met its primary endpoint. The success sets the RNAi specialist up to file for FDA approval early this year, although a lack of data comparing the experimental vutrisiran to Alnylam’s own ATTR incumbent Onpattro make it impossible to tell just how good the results are.

The clinical trial, HELIOS-A, randomized 164 patients with hATTR amyloidosis with polyneuropathy to receive vutrisiran or Onpattro. Three-quarters of participants received vutrisiran. While Alnylam used Onpattro as the comparator, primary and key secondary endpoints compared the vutrisiran results to historical placebo data from a previous clinical trial.

Vutrisiran outperformed the historical placebo control in terms of change in modified Neuropathy Impairment Score at nine months, causing the clinical trial to hit its primary endpoint. The trial also met secondary endpoints that compared the effect of vutrisiran on quality of life and gait speed to the historical control. The p-values for all three endpoints were less than 0.001.

Alnylam plans to file for FDA approval soon. Filings in countries including Brazil and Japan will follow, but the EU will need to wait longer. Alnylam has agreed to hold off on seeking European Medicines Agency approval until it has the 18-month data due late this year.

Critical details that will dictate whether Alnylam can win approval for vutrisiran and make the drug a commercial success are absent from the press release. Alnylam is yet to reveal how vutrisiran fared against the active control Onpattro or to share safety and tolerability data, saying only that the profile is “encouraging.” The availability of Onpattro means beating merely placebo is unlikely to be enough to establish vutrisiran as a major commercial product.  

Onpattro became the first FDA-approved treatment for ATTR when it came to market in 2018. Armed with evidence Onpattro curbs otherwise inevitable declines in the condition of patients, Alnylam has grown the RNAi drug into a product expected to generate sales of around $300 million in 2020.  

There is scope to improve on Onpattro, though. Patients treated with Onpattro undergo an infusion lasting around 80 minutes every three weeks. Vutrisiran has a far more convenient dosing schedule. Patients on the experimental therapy receive a subcutaneous injection every three months. 

If vutrisiran can match or beat the safety and efficacy of Onpattro, the drug will enable Alnylam to tighten its hold on the ATTR market. Alnylam plans to share the full nine-month data early this year. 

Akshay Vaishnaw, M.D., Ph.D., president of R&D at Alnylam, highlighted the fact vutrisiran drove improvements as soon as nine months as positive finding of the phase 3 trial. The pivotal Onpattro clinical trial tracked patients for 18 months, although clear divergence from placebo was evident after nine months.