Despite an affirmative FDA advisory committee vote, the agency declined to approve Alnylam Pharmaceuticals’ Onpattro for treating the heart complications caused by a rare, inherited protein disorder. But Alnylam has other drugs candidates for the disease, including one expected to post Phase 3 data in the first half of 2024.
By FRANK VINLUAN

An Alnylam Pharmaceuticals drug developed to treat a rare disease’s potentially fatal effects on the heart has fallen short in its bid for FDA approval, costing the company a chance to immediately challenge a Pfizer product that has become a blockbuster seller in the indication. But the biotech still has another chance with a different drug in late-stage development that could offer patients a better alternative.
Alnylam was seeking approval of its drug, Onpattro, as a treatment for cardiomyopathy caused by hereditary transthyretin amyloidosis (hATTR). According to the Cambridge, Massachusetts-based company, the FDA’s complete response letter said the application had insufficient evidence to support clinical meaningfulness for the drug. The FDA reached that conclusion despite an advisory committee’s vote in September that the drug’s benefits outweigh its risks.
Onpattro was first approved as a treatment for nerve pain caused by hATTR. The disease stems from a genetic mutation that leads to abnormal versions of transthyretin, a liver protein. The buildup of this protein in organs and tissues leads to a range of complications. In the heart, it can lead to heart failure. The Alnylam drug works by a mechanism called RNA interference, or RNAi. Administered as an intravenous infusion every three weeks, Onpattro targets the liver with small-interfering RNA (siRNA) that stop the culprit gene from producing the disease-causing protein. The 2018 regulatory nod for Onpattro made it the first FDA-approved RNAi treatment.
The only FDA-approved treatment for hATTR cardiomyopathy is Pfizer’s Vyndaqel, a small molecule designed to stabilize the transthyretin protein. The Vyndaqel family of drugs generated more than $2.4 billion in sales in 2022, according to the company’s financial reports.
Alnylam had hoped to expand Onpattro’s approval to include the heart complications caused by hATTR, which would bring the drug to a much larger group of patients. The drug was tested in a Phase 3 study whose main goal was to show improvement measured according to a six-minute walk test. The study also measured health and quality of life changes with a questionnaire.
The six-minute walk test has not been problem free in hATTR cardiomyopathy. Nearly two years ago, BridgeBio Pharma’s shares plunged after the biotech reported preliminary walk test results showing its drug, acoramidis, failed to sufficiently distance itself from a placebo. But those results were at 12 months for a study designed to follow patients for 30 months. The company opted to continue the Phase 3 test, hoping for better results. In July, BridgeBio reported “highly statistically significant” improvement on a composite main endpoint that included measures of death from all causes, frequency of cardiovascular-related hospitalization, and the change from baseline in the six-minute walk test. Detailed results were presented in August during the annual meeting of the European Society of Cardiology. At that time, the company also said it planned an FDA submission for the drug candidate by the end of this year.
The Alnylam drug met the walk test goal of its pivotal test, with results showing that treatment with Onpattro led to a statistically significant improvement from baseline with a 14.7 meters improvement compared to placebo at month 12. But FDA reviewers noted that medical literature reports meaningful differences in cardiomyopathy patients range from 22 meters to 90 meters. The reviewers acknowledged the statistically significant results of Onpattro, but added that the “magnitude of the treatment effect on function and quality of life is small and may not be clinically meaningful.” FDA briefing documents also noted that in patients who were taking Pfizer’s Vyndaqel, treatment with Onpattro did not appear to confer any benefit. During the FDA advisory committee meeting, some panel members expressed similar reservations.
Alnylam said the FDA’s decision did not cite any safety or manufacturing issues associated with Onpattro. Consequently, the rejection of the drug in cardiomyopathy does affect the availability of drug for treating hATTR-caused polyneuropathy.
While the rejection in the cardiomyopathy indication does not preclude Alnylam from trying again, the company said Monday that it will no longer pursue expanded use of the drug in the U.S. Instead, Alnylam will turn its focus to Amvuttra, an RNAi drug that offers patients a less burdensome subcutaneous injection given every three months. The FDA approved Amvuttra last year as a treatment for hATTR nerve pain. The drug is currently in Phase 3 testing as an RNAi therapy for the cardiomyopathy caused by hATTR. Preliminary data from the 655-patient study are expected in early 2024. The Alnylam pipeline also includes ALN-TTRsc04, which uses technology that enables once-a-year dosing.
“We remain confident in the HELIOS-B Phase 3 study of vutrisiran [Amvuttra] and look forward to sharing topline results in early 2024,” Alnylam CEO Yvonne Greenstreet said in a prepared statement. “If successful, we believe vutrisiran will offer convenient, quarterly subcutaneous dosing with a therapeutic profile that may potentially include cardiovascular outcome benefits. Beyond vutrisiran, we are excited about the potential for ALN-TTRsc04, which may allow for greater TTR knockdown and less frequent dosing, providing patients with ATTR amyloidosis an optimized treatment regimen.”
In a note sent to investors on Monday, William Blair analyst Myles Minter said discontinuing further development of Onpattro for cardiomyopathy is prudent, because potential approval would require a large outcomes study. Amvuttro’s Phase 3 study is already doing that. Data from that program’s open-label extension study showed benefit on death from all causes and the six-minute walk test, and Minter believes those trends bode well for the three-year outcomes study. The firm also sees promise in the ALN-TTRsc04 program, whose potential for knocking down transthyretin levels by more than 90% puts it in the ballpark of gene-editing approaches, such as Intellia’s NTLA-2001. That therapy is on track to enter pivotal clinical testing.
More competition could be coming from Ionis and partner AstraZeneca. Their drug, an antisense oligonucleotide drug called eplontersen, is on track to receive an FDA decision in December for treating polyneuropathy caused by hATTR. A pivotal study in the cardiomyopathy caused by the disease is ongoing.
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