Alnylam's next-gen RNA drug Amvuttra wins FDA approval—and a Pfizer showdown may await

Alnylam’s closely watched Onpattro follow-on therapy, vutrisiran, has snagged a much-anticipated FDA green light. The approval tees up a possible showdown with Pfizer’s blockbuster Vyndaqel franchise in an increasingly competitive rare disease field.

Vutrisiran, to be marketed under the brand name Amvuttra, has won an FDA approval to treat hereditary transthyretin amyloidosis (hATTR) polyneuropathy, a rare debilitating disease that damages nerves. Alnylam said it expects to make the drug available to U.S. doctors in early July.

Based on Amvuttra’s potential to treat another form of ATTR that affects the heart, Evaluate Vantage recently said the drug could reach $1.8 billion in global sales by 2026. That indication, called ATTR cardiomyopathy, represents the key battleground between Alnylam and Pfizer, plus other players.

Amvuttra marks Alnylam’s first FDA approval under newly minted CEO Yvonne Greenstreet, who officially took over from founder John Maraganore, Ph.D., in January. The drug belongs to an emerging class of RNA interference therapeutics, which Alnylam is best known for. It’s a small interfering RNA that targets the transthyretin mRNA to block the protein from forming into toxic clumps.

Alnylam already sells an RNAi therapy, Onpattro, for ATTR polyneuropathy. While Onpattro is given via intravenous infusion once every three weeks, Amvuttra can be administered less frequently via under-the-skin injections once every three months thanks to its high metabolic stability.

Alnylam is offering Amvuttra at an annual list price of $463,500, consistent with Onpattro’s sticker, Chief Commercial Officer Tolga Tanguler told investors during a Tuesday.

In the phase 3 HELIOS-A study, Amvuttra helped ATTR polyneuropathy patients achieve an average 2.2-point improvement on a modified neuropathy impairment score after nine months; half of the patients experienced some level of improvement. In the same study, Onpattro takers got 1.4 points better. By comparison, patients who took placebo in a historical Onpattro clinical trial called APOLLO experienced disease worsening of an average 17 points.

New ATTR patients will likely start on Amvuttra thanks to its convenience edge, Alnylam Chief Financial Officer Jeff Poulton said during an SVB Securities conference in February, according to an SVB note. But for existing Onpattro patients, compliance has been high, and they may prefer to stick with the older med that they’ve been on for years, Poulton reportedly said.

Hereditary ATTR, including polyneuropathy and a small portion of cardiomyopathy cases, is a rare condition that affects about 50,000 people worldwide. But non-inherited ATTR, which is mainly cardiomyopathy, is estimated to affect 200,000 to 300,000 people globally, and some suspect the prevalence is even higher because of underdiagnosis. That makes ATTR cardiomyopathy the more important indication commercially.

Last year, Pfizer’s pair of ATTR therapies Vyndaqel and Vyndamax posted $2 billion in total sales, with $909 million coming from the U.S., where the drugs are only approved for ATTR cardiomyopathy. The drugs have polyneuropathy labels in other parts of the world. Despite being a year earlier to the U.S. market, Onpattro’s total 2021 sales were $475 million based on its polyneuropathy indication.

As for the ATTR cardiomyopathy use, Alnylam is running the HELIOS-B study for Amvuttra and is expecting patient survival data in 2024. For now, investors are waiting anxiously for the phase 3 APOLLO-B readout later this year for Onpattro in this heart disease setting.

Industry watchers largely fear that APOLLO-B will fail on its primary endpoint, which measures change in six-minute walk distance after 12 months of treatment. The unusually strong performance on that marker observed in the placebo arm for BridgeBio’s rival ATTR candidate, acoramidis, in the phase 3 ATTRibute-CM study raised that concern.

In a May note to clients, Berenberg analyst Zhiqiang Shu, Ph.D., said his team’s calculation indicated Onpattro’s APOLLO-B study has a low probability of success. But he noted that experts believe Amvuttra’s HELIOS-B trial is more likely to succeed, and positive data should be practice-changing.

Other large drugmakers are also vying for a piece of the ATTR market. AstraZeneca recently partnered with Tegsedi maker Ionis, and Novo Nordisk has bought a late-stage program from Prothena.