TTR Cardiomyopathy Trial of ‘Silencer’ Drug Fails, Sending Alnylam Shares Lower

Clinical results suggest that drugs in the “silencer” class may provide less additional benefit on top of standard treatment for TTR cardiomyopathy than previously expected.

According to results published on the 28th in the medical journal The New England Journal of Medicine (NEJM), eplontersen, jointly developed by AstraZeneca and Ionis Pharmaceuticals, failed to demonstrate a significant benefit over placebo in patients with TTR cardiomyopathy.

The drug is already approved under the name Wainua to treat a rare form of transthyretin amyloidosis that affects the nerves. The two companies conducted the CARDIO-TTRansform study to expand its indication to patients with TTR cardiomyopathy.

More than 1,400 people receiving standard treatment participated in the trial. Half received eplontersen, and the other half received placebo.

After 140 weeks, no statistically significant reduction in the risk of cardiovascular events or death was observed. Cardiovascular events or death occurred in 29% of the eplontersen group and 32% of the placebo group.

The results also raise questions about Amvuttra from Alnylam Pharmaceuticals, a drug in the silencer class that was approved last year for TTR cardiomyopathy.

Silencer-class drugs prevent the mutant gene from producing misfolded TTR protein. By contrast, Pfizer’s Vyndamax and BridgeBio’s Attruby are established standard treatments that “stabilize” TTR protein.

The patient populations in the two trials also differed. In Alnylam’s HELIOS-B study, 53% of participants were taking a stabilizer, compared with 81% in CARDIO-TTRansform.

Michael Leuchten, an analyst at Jefferies, said the “negative result raises the possibility that the incremental benefit of combining a silencer with a stabilizer is smaller than what was seen in HELIOS-B, rather than indicating that the study was poorly designed.”

“It is difficult to see a path to a regulatory filing based on these results,” wrote Paul Matteis, an analyst at Stifel.

According to the researchers’ account in NEJM, heart failure management evolved during the trial, leading to increased use of stabilizers and other treatments. The broad eligibility criteria also included patients across the full spectrum of the disease.

The researchers added that “treatments that reduce the production of new amyloid, such as eplontersen, may be less effective in these patients.”

Alnylam shares fell as much as 5% intraday. They are down about 30% since AstraZeneca and Ionis announced the results.

Matteis said he did not expect the results to change Amvuttra’s commercial outlook. He explained that use of Amvuttra in combination with a stabilizer is “quite limited,” while the main driver of growth is expansion among patients receiving monotherapy.

Alnylam generated $1.9 billion in revenue from Amvuttra in the first half of this year, accounting for 86% of its total revenue.

Analysts said the greater concern is the potential impact on development of nucresiran, a next-generation treatment for TTR amyloidosis. The pivotal trial of nucresiran allows the use of stabilizers and heart failure drugs, leading investors to worry that it could produce a negative result.

Matteis suggested that Alnylam could adjust the design of the nucresiran study. He said there are “several potential inflection points,” such as increasing enrollment of patients receiving monotherapy or making the effect of monotherapy the primary endpoint.

Leuchten noted that a new class of drugs called “depleters,” which bind to and remove amyloid deposits, could produce better results. AstraZeneca, Novo Nordisk and startup Attralus have advanced such drugs into clinical trials.