Almost a month ahead of schedule, the U.S. Food and Drug Administrationhas approved Alnylam Pharmaceuticals’ Amvuttra (vutrisiran) for the treatment of hereditary transthyretin-mediated amyloidosis (hATTR) with polyneuropathy in adults.
This early decision came as a surprise for many, as the FDA had originally extended the review period from April to July 14.
The disease is rare, inherited, quickly progressive and fatal, with few treatment options. Polyneuropathy is a malfunction of many peripheral nerves throughout the body, and hATTR is caused by mutations in the TTR gene. The TTR protein is mostly produced in the liver and normally carries vitamin A.
The approval was based on positive nine-month data from the Phase III HELIOS-A trial. In it, Amvuttra improved the signs and symptoms of polyneuropathy. More than 50% of patients receiving the drug had their symptoms stopped or reversed.
Alnylam evaluated the efficacy of the drug by comparing the Amvuttra group in HELIOS-A with the placebo group from the Phase III APOLLO trial of patisiran. This was a randomized, controlled trial in a comparable patient population. Patisiran, under the brand name Onpattro, is Alnylam’s approved drug for polyneuropathy of hATTR.
“Twenty years ago, Alnylam was founded with the bold vision for RNA interference to make a meaningful impact on the lives of people around the world in need of new approaches to address serious diseases with significant unmet medical needs, such as hATTR amyloidosis,” Yvonne Greenstreet, CEO of Alnylam, said in a statement. “Today, Amvuttra has the potential to change the standard of care for people living with the polyneuropathy of this devastating disease.”
The drug is an RNA interference (RNAi) therapeutic. It is made up of a double-stranded small interfering RNA (siRNA) that targets mutant and wild-type transthyretin (TTR) messenger RNA (mRNA). Essentially, it suppresses the expression of a specific gene or gene segment, preventing the production of an abnormal protein. Vutrisiran for polyneuropathy is dosed via subcutaneous injection once every three months.
On Thursday, Alnylam reported that another of its RNAi drugs, cemdisiran, was ready to enter Phase III trials after announcing positive Phase II study results. The drug was co-developed with Regeneron Pharmaceuticals and is designed to treat patients with immunoglobulin A nephropathy (IgAN).
In the Phase II trial, there were 31 patients divided 2:1, placebo to cemdisiran. The patients receiving cemdisiran reported an average 37% decrease in urine protein to creatinine ratio, compared to placebo, recorded over a 24-hour period. The primary endpoint was a change from baseline of the 24-hour urine protein to creatinine ratio.
As BioSpace previously reported, the company announced its five-year strategy, “Alnylam P5x25,” at the 2022 J.P. Morgan Health Care Conference in January. This includes the development of several investigational drugs, including RNAi products for Alzheimer’s disease, Stargardt disease and gout.
At the time, Greenstreet said the company will serve “at least half a million patients around the world, as well as bring forward more marketed medicines – six plus – and continue to build this rich clinical pipeline.”
The Alzheimer’s product, ALN-APP, will begin a Phase I trial this year with data expected before 2023. The company’s gout therapeutic, ALN-XDH, is also expected to report Phase I data this year. Vutrisiran is being developed for several diseases, including hATTR and Stargardt disease, which is expected to start a Phase III trial later this year.
“The FDA approval of Amvuttra is very encouraging for the hATTR amyloidosis community, who need additional therapies to address the polyneuropathy of this progressive, life-threatening, multisystem disease,” Dr. Michael Polydefkis, M.D., MHS, professor, Johns Hopkins Neurology and HELIOS-A study investigator, said in a statement. “Amvuttra is a new therapeutic option that has demonstrated the potential to halt or reverse polyneuropathy progression in patients with an acceptable safety profile, along with an infrequent, subcutaneous dosing regimen that may also help to improve the disease management experience for patients.”
