Dive Brief:

• Alnylam Pharmaceuticals is delaying the readout of a closely watched Phase 3 trial in the heart disease transthyretin amyloidosis with cardiomyopathy, revealing Thursday changes to the study’s plan.
• In a quarterly earnings report, Alnylam said it updated the primary and secondary goals of the trial, called HELIOS-B, and extended it by three months. The changes were made after discussions with regulators and will enable the “best demonstration” of vutrisiran, the drug it’s testing in the trial, CEO Yvonne Greenstreet said on a conference call.
• Still, the adjustments led analysts to question whether the study, which is critical to Alnylam’s future, isn’t going as well as expected. Results are now anticipated in June or July, instead of early 2024. Alnylam shares fell by nearly double digits in early trading Thursday.

Dive Insight:

For Alnylam, a lot is riding on the outcome of HELIOS-B.

Analysts think positive results could make vutrisiran a multibillion-dollar product and Alnylam a profitable company. While the drug is already sold as Amvuttra for a rarer form of transthyretin, or ATTR, amyloidosis that affects nerves, the cardiomyopathy type is far more common. The only drug available, Pfizer’s Vyndamax, generated $3.3 billion in sales last year.

Success would also help Alnylam rebound from the rejection of another one of its drugs, Onpattro, in ATTR cardiomyopathy, a setback that has shaved off one-fifth of the company’s value. Another drug from BridgeBio Pharma could be approved by the end of the year, heightening pressure on Alynlam.

No surprise, then, that changes to the trial’s design caused shares to fall. Alnylam’s executive team spent the entire earnings call Thursday defending their decision.

There are three main changes. First, Alnylam is lengthening the study’s minimum follow-up from 30 months to 33 months. A longer study has more statistical power, and the tail end is when Alnylam expects to see the greatest number of “events” — deaths or heart-related hospitalizations — in the trial’s placebo arm, executives said.

Additionally, the trial now has two “parallel” main study goals, instead of one. Previously, researchers were measuring whether vutrisisran could reduce the risk of death or cardiovascular events in the overall study population. Alnylam is adding a measurement of the drug’s impact in the 60% of participants who weren’t already on Vyndamax at the trial’s start. The company can declare success if both groups reach statistical significance, or if just one meets a lower statistical threshold. The change “allows us to demonstrate the true impact of vutrisiran,” said chief medical officer Pushkal Garg.

Alnylam also trimmed the study’s secondary goals, claiming the ones it has prioritized will better prove whether vutrisiran stops disease-related decline, something Pfizer’s and BridgeBio’s drugs haven’t yet been shown to do.

“We have reiterated our confidence over and over again in the study,” said Alnylam president Akshay Vaishnaw. The alterations “further enhance the robustness of what we’re going to share with the world.”

Analysts questioned whether Alnylam’s adjustments were the result of a review of blinded data from the study, which might be suggestive of an outcome. However, the company claims its motivation for making the changes was to incorporate lessons from follow-up testing of Onpattro, as well as from BridgeBio’s recent Phase 3 trial.

“We have teams that are looking at the blinded data,” but “that’s not the driver here,” said Garg. “The primary drivers here are what we understand about science, biology and prior precedent from clinical medicine and clinical trials.“

BridgeBio shares climbed 13% by mid-day, while Pfizer’s rose by more than 1%.