Alnylam’s Amvuttra Scores FDA Nod as First RNAi Drug in ATTR-CM While Setting to Take on Pfizer’s Vyndaqel

Alnylam Pharmaceuticals announced the FDA approval of its RNA interference (RNAi) therapy, Amvuttra (vutrisiran), last week, expanding its label to include the treatment of transthyretin amyloid cardiomyopathy (ATTR-CM). With the approval, it has become the first RNAi treatment approved for the indication.

The approval sets the stage for a commercial battle with Pfizer, whose blockbuster drug Vyndaqel (tafamidis) currently dominates the space.

ATTR-CM is a rare, progressive and life-threatening condition caused by the buildup of misfolded transthyretin (TTR) proteins in the heart. This leads to stiffening of the heart muscle, impaired cardiac function and eventually heart failure. It can be hereditary or age-related (wildtype) and is often underdiagnosed due to nonspecific symptoms.

The condition affects an estimated 150,000 people in the US and more than 300,000 globally.

The majority of patients remain undiagnosed and untreated. Moreover, many of those receiving commonly used therapies still experience disease progression.

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Amvuttra induces rapid knockdown of both the wildtype and mutant forms of the TTR gene to reduce the production of TTR protein in the liver. It was first approved for the polyneuropathy form of hereditary transthyretin-mediated amyloidosis (hATTR-PN).

The latest FDA approval makes Amvuttra the first and only FDA-approved treatment for both ATTR-CM and hATTR-PN in adults.

And with the new approval, Amvuttra becomes a direct competitor to Pfizer’s Vyndaqel. The med, which is part of a family of TTR stabilizer drugs, has had a strong hold on the ATTR-CM market since its FDA approval in 2019.

Alnylam’s chief commercial officer, Tolga Tanguler, acknowledged Pfizer’s tafamidis franchise for pioneering the ATTR-CM category and driving improvements in diagnosis rates, but emphasized that significant unmet needs remain.

“I think what Pfizer has done in terms of education and increasing diagnosis — in terms of developing the infrastructure and ecosystem — has been phenomenal,” Tanguler said.

He expressed confidence that Amvuttra, with its novel mechanism of action for the indication, has the potential to be a transformative therapy in the space.

Related: The FDA approval was based on positive data from the HELIOS-B Phase III trial. In the trial, Amvuttra met all 10 of its primary and secondary endpoints.

The treatment significantly reduced all-cause mortality (ACM) and recurrent cardiovascular events (CV) by 28% in patients with ATTR-CM compared to placebo in the trial treatment period, which lasted up to 36 months.

Importantly, the trial included both hereditary and wildtype forms of the disease, making the therapy a broad-spectrum option for patients.

The approval positions Amvuttra as a strong alternative in a market estimated to reach several billion dollars in annual revenue by the end of the decade.

“This is a transformative moment not only for Alnylam but for patients suffering from ATTR-CM,” said Alnylam CEO Yvonne Greenstreet. “We now have the opportunity to bring a powerful, innovative RNAi therapeutic to a broader group of patients.”

Pfizer’s Vyndaqel raked in over $5.4 billion globally in 2024, a 64% increase from 2023.

However, with Amvuttra’s new approval, Alnylam could challenge that lead. It could have an edge if it can convert Vyndaqel users or attract newly diagnosed patients who prefer less frequent dosing and a different mode of action.

Vyndaqel and BridgeBio’s recently approved ATTR-CM drug Attruby (acoramidis) are oral treatments. Like Vyndaqel, Attruby is a TTR stabilizer, but it requires twice-daily dosing compared to Vyndaqel’s once-daily regimen.

Tanguler argued that Amvuttra offers more convenient dosing as it is administered just four times a year via subcutaneous injection.

Analysts expect aggressive marketing from both companies as they battle for cardiologist mindshare.

Analyst Expectations for Amvuttra

Alnylam estimates there are approximately 9,000 patients in the US eligible for first-line ATTR-CM treatment. And another 10,000 second-line patients could potentially switch from tafamidis. Moreover, the overall patient pool could grow significantly if diagnosis rates improve.

According to analysts at Citi, Amvuttra will cost about $450,000 annually for cardiomyopathy before discounts. While aligning with the current price for polyneuropathy, it significantly exceeds the costs of Vyndaqel and Attruby.

According to the analysts, Alnylam said Amvuttra’s net price could decrease over time through rebates and other discounts as revenue from the cardiomyopathy indication begins to grow.

Alnylam said it offers multiple programs to support “broad and seamless patient access.” The company expects most patients will pay $0 out of pocket.

Alnylam will likely pursue global regulatory submissions in key markets such as the European Union (EU) and Japan. It will also continue to gather real-world evidence to support broader adoption.

Alnylam isn’t stopping with Amvuttra. The company is advancing nucresiran, a third-generation RNAi therapy designed to target TTR with deeper, faster knockdown. It also has potential for twice-yearly dosing.

In November 2024, Alnylam shared Phase I data showing a rapid and sustained reduction in TTR levels six months after a single dose. Tanguler said a Phase III trial is slated to begin in the first half of the year.