After AZ Combination Therapy Fails, Alnylam Pushes Back: “Silencer Works With Stabilizer”

AstraZeneca failed in a combination-therapy trial for cardiac amyloidosis, but Alnylam Pharmaceuticals is pushing back with new data showing that its silencing drug is effective when used with standard treatment.

According to U.S. pharmaceutical trade publication Fierce Pharma on the 1st (local time), AstraZeneca appears to have effectively abandoned its combination-therapy approach after the Phase 3 trial of Wainua, co-developed with Ionis, failed (CARDIO-TTRansform). Alnylam, meanwhile, has entered the debate over monotherapy versus combination treatment with a silencer and stabilizer by releasing new data defending its approved cardiomyopathy treatment, Amvuttra.

The debate was sparked in early July by the failure of Wainua to meet the trial’s primary endpoint. Wainua (eplontersen), Alnylam’s Amvuttra (vutrisiran) and the late-stage RNA interference asset nucresiran are all classified as transthyretin (TTR) silencers.

The issue is that more than half of trial participants were also taking a stabilizer in Pfizer’s blockbuster tafamidis class. By the end of the study, that proportion had exceeded 80%. “Unfortunately, we realized there was no benefit to adding a second mechanism,” said Mina Makar, AstraZeneca’s executive vice president of global cardiovascular, renal and metabolism.

But Alnylam Chief Medical Officer (CMO) Pushkal Garg maintained confidence in Amvuttra and nucresiran, saying, “Not all TTR silencers or clinical trial designs are the same.”

Stifel analysts said Alnylam’s Phase 3 trial of nucresiran (TRITON-CM) could succeed if it focuses on patients with early-stage disease. They cited the fact that Wainua outperformed placebo in patients with stage 1 disease, about 60% of whom were also taking Pfizer’s stabilizer Vyndamax.

Citi analysts were optimistic, noting that nucresiran suppresses TTR by more than 92%, exceeding Wainua’s 70% and Amvuttra’s 81%. Evercore ISI also reported that experts were receptive to the view that RNA interference is “meaningfully differentiated” from antisense oligonucleotides.

Jefferies analysts, by contrast, said the value proposition for silencers had “somewhat weakened” and that the likelihood of TRITON-CM’s success remained “questionable.” They noted that the data show silencers do not add substantial cardiovascular benefit to stabilizers.

“We believe the degree of TTR reduction achieved by a silencer matters,” Garg said, emphasizing that the difference in suppression rates between HELIOS-B and CARDIO-TTRansform is “clinically meaningful and an important factor in understanding the difference in outcomes.”

At the European Society of Cardiology (ESC) Congress, Alnylam also presented a subgroup analysis of HELIOS-B, the pivotal trial of Amvuttra. The results were also published in the Journal of the American College of Cardiology (JACC). The company said Amvuttra’s effects were consistent regardless of baseline tafamidis use. It added, however, that HELIOS-B was not designed to separately assess the drug’s effects in patients taking tafamidis at baseline.

“Unlike eplontersen, vutrisiran showed consistent efficacy across all subgroups, including patients taking a stabilizer at baseline,” Garg said.