In one of the most highly anticipated clinical trial readouts this year, an RNA silencing treatment developed by Alnylam Pharmaceuticals reduced the risk of death, heart-related hospital visits and hospitalizations by 28% compared to placebo in patients with a heart muscle disease.
The results, announced Monday, pave the way for Alnylam’s therapy vutrisiran to become the first RNA silencing therapy on the market for ATTR amyloidosis with cardiomyopathy, a condition in which misfolded proteins build up in the heart and can result in heart failure. If approved, Alnylam could enter a multibillion-dollar market currently dominated by Pfizer.
Vutrisiran is already approved as Amvuttra for ATTR amyloidosis with polyneuropathy, where the misfolded proteins affect the nerves. Alnylam believes that it can potentially reach 10 times more patients in the expanded indication, as the heart manifestation of the disease has been estimated to impact as many as 500,000 globally.
“We believe with the data we have in hand, this will become the new standard of care in patients with ATTR cardiomyopathy,” Alnylam CEO Yvonne Greenstreet told Endpoints News on Saturday. “This is really, really tremendous data and clearly a huge opportunity for Alnylam.”
Alnylam was worth $6 billion more Monday morning after the data were released, as the company’s shares $ALNY were up nearly 30%.
In the Phase 3 HELIOS-B trial, 655 patients with ATTR amyloidosis received either a vutrisiran or placebo injection once every three months. At 33 months, the primary endpoint results — the drug’s impact on risk of death and heart-related hospital events — were measured.
The primary endpoint result was statistically significant in the overall study population, resulting in a p-value of 0.0118.
Roughly 40% of patients in the study also took Pfizer’s ATTR amyloidosis drug, which is known generically as tafamidis and marketed as Vyndamax or Vyndaqel. It is currently the only drug approved to treat ATTR amyloidosis that impacts the heart and generated $3.3 billion in sales last year.
Wall Street analysts have estimated that Alnylam’s therapy could generate $2 billion to $4 billion in annual sales, depending on the Phase 3 data.
In contrast to Alnylam’s approach of blocking the production of transthyretin, or TTR, Pfizer’s drug is known as a stabilizer and works by binding the protein and slowing it from breaking down and depositing in the heart. BridgeBio is also awaiting an FDA decision on its own stabilizer, acoramidis, by Nov. 29.
AstraZeneca and its partner Ionis are studying an RNA therapy for the heart muscle disease in a Phase 3 trial, which is expected to read out in 2025, according to a federal clinical trials database.
The FDA rejected Alnylam’s other ATTR amyloidosis treatment Onpattro in the heart condition.
A monotherapy market
In the 60% of patients in the Phase 3 study who received only vutrisiran, there was a 33% reduction in the risk of death, heart-related hospitalizations, and hospital visits for heart failure. The p-value was 0.0162.
Showing the effect of vutrisiran alone is important for Alnylam because insurers are unlikely to cover a combination of two pricey drugs. The company changed its Phase 3 trial in February to add that subgroup to the primary analysis and also to shift the primary endpoint from 30 to 33 months, stirring up a flurry of questions at the time about the upcoming readout.
Both Pfizer and BridgeBio reported 30-month data in their studies.
“The opportunity from a payer perspective for combination use is going to be somewhat constrained until tafamidis goes off-patent,” Greenstreet said. “We certainly have the clinical data to support combinations.”
Vutrisiran hit all secondary endpoints, including the 6-minute walk test, in both the overall population and the vutrisiran-alone group. Notably, it reduced the risk of death in both of these groups by 36% and 35%, respectively.
Pushkal GargOn the other subgroups in the study — including the 40% of patients who received both vutrisiran and Pfizer’s drug — Alnylam said that the study showed “consistent effects.” When asked whether the results in that subgroup were statistically significant, Alnylam’s medical chief Pushkal Garg said that “this was a topline release.”
There were no serious safety concerns raised in the study, and rates of adverse events in the treatment and placebo arm were similar.
Alnylam said detailed data from the HELIOS-B study were submitted to the European Society of Cardiology, which is hosting its annual meeting in London in late August and early September.
Alnylam plans to take the results to the FDA and other regulatory authorities to expand the label of vutrisiran to include patients who have ATTR amyloidosis with cardiomyopathy. At the FDA, the company plans to file by the end of the year and use a priority review voucher to speed the process.
Editor’s note: This story was updated with changes in Alnylam’s stock and market value.