Alnylam Adds Vutrisiran as Twice Yearly Injection to HELIOS Extension Trial

Alnylam Pharmaceuticals has initiated testing of a twice a year dosing regimen for vutrisiran, its investigational RNA-targeted therapy for familial amyloid polyneuropathy (FAP) and other forms of ATTR amyloidosis.

The new dosing regime is being added to the open-label extension phase of the ongoing Phase 3 HELIOS-A trial (NCT03759379) that is now underway for vutrisiran. Findings from this extension are expected by 2022 and, if positive, will be used to support the submission of a supplemental new drug application requesting U.S. Food and Drug Administration (FDA) of biannual dosing.

A request for vutrisiran’s approval as a 25 mg quarterly (once every three months) injection treatment, based on results from HELIOS-A main trial, was filed with the FDA in April.

Alnylam is also opening a preclinical program for RNA therapies that might be given as a once yearly injection.

“We’re pleased to have now initiated a clinical study of a biannual dosing regimen for vutrisiran. If shown to be safe and efficacious, the new dosing regimen may provide some patients with a treatment option that neatly aligns the frequency of administration with biannual visits to their doctor,” Rena Denoncourt, vice president and leader of the vutrisiran clinical program at Alnylam, said in a press release.

Vutrisiran, formerly known as ALN-TTRsc02, is an RNA-targeted therapy designed to silence the messenger RNA that provides cells with instructions to make transthyretin — the misfolded protein that clumps in amyloid deposits found in people with ATTR amyloidosis — through a process known as RNA interference, or RNAi.

In the HELIOS-A main trial, 164 FAP patients were randomly assigned to either 25 mg of vutrisiran, given through an under-the-skin (subcutaneous) injection once every 12 weeks (once every three months), or to  0.3 mg/kg of Onpattro (patisiran) as a comparative treatment, given directly into the bloodstream once every three weeks. Treatment here lasted 18 months, or about 1.5 years.

Nine-month HELIOS-A data presented by the company at the 2021 American Academy of Neurology (AAN) virtual Annual Meeting showed that vutrisiran safely and effectively eased neurologic impairments and improved patients’ quality of life when given in a quarterly dosing regimen. These findings supported the FDA application requesting its approval as a FAP treatment for adults.

Now, patients who completed the initial 18 months of treatment are being randomly assigned to either 25 mg of vutrisiran four times a year, or to 50 mg twice a year, for an additional 18 months.

Goals include assessing the safety and effectiveness of the 50 mg biannual dosing regimen of vutrisiran at lowering the levels of transthyretin. Treatment effectiveness will again be measured  at nine months and at the end of the treatment period.

This extension phase follows the announcement of pharmacological data showing that a 50 mg, twice a year a dose of vutrisiran leads to a comparable reduction in transthyretin levels — that of more than 80% — as the quarterly 25 mg dose.

A preclinical program, meanwhile, aims to develop new RNA-based therapies able to lower the production of transthyretin by more than 90% with a single annual dose.

Alnylam has developed an extended RNAi platform, called IKARIA, in which its RNA-targeted molecules were designed to achieve a potent and reversible silencing when administered annually.

“Based on continued discoveries from our RNAi therapeutics platform, we’re also advancing a new pre-clinical program that could enable highly potent and reversible TTR [transthyretin] reduction with an annual dosing regimen,” Denoncourt said.

“We believe that once yearly dosing could provide a vaccine-like dosing schedule strategy for management of ATTR amyloidosis, providing meaningful life-cycle management for our ATTR franchise,” she added.

A potential candidate based on this platform, ALN-TTRsc04, is expected to enter clinical testing next year, Alnylam reported. Further details on the IKARIA platform and ALN-TTRsc04 will be presented at a scientific meeting this year.