ESC: Alnylam's next-gen silencer sees silver linings after fallout of AZ, Ionis trial in ATTR-CM

Special report: Meet the 2026 Fierce 50 Biotech ESC: Alnylam's next-gen silencer sees silver linings after fallout of AZ, Ionis trial in ATTR-CM By Fraiser Kansteiner, Darren Incorvaia Sep 1, 2026 1:55pm Alnylam RNA interference (RNAi) Clinical Data transthyretin amyloidosis As AstraZeneca appears to close the book on a combo approach following the phase 3 failure of its Ionis-partnered Wainua, several analysts contend it’s too early to count out Alnylam’s silencing drugs in ATTR-CM patients also taking standard-of-care stabilizers. Meanwhile, Alnylam itself has stepped up with new data in defense of its approved cardiomyopathy med Amvuttra, wading into the emerging monotherapy vs. silencer-plus-stabilizer debate.

That line of questioning was sparked in early July on the topline fumble of AZ and Ionis’ CARDIO-TTRansform trial. The trial’s surprise results went on to become one of the most anticipated presentations at the European Society of Cardiology Congress in Munich this past weekend. The issue on doctors and industry watchers’ minds wasn’t just what the results mean for AZ and Ionis’ antisense oligonucleotide Wainua, but the follow-on implications for the silencing approach more generally in a heavily stabilizer-dependent patient population.

Wainua (eplontersen), Alnylam’s approved Amvuttra (vutrisiran) and the late-stage RNA interference asset nucresiran are all considered silencers. Signals earlier this summer suggested that Wainua might have functioned better on its own, whereas more than half of patients—exceeding 80% by the study’s end—in CARDIO-TTRansform were also on a stabilizer drug, a class that includes Pfizer’s juggernaut tafamidis franchise. That common use of stabilizers is not an aberration among patients with transthyretin amyloid cardiomyopathy (ATTR-CM), in which misfolded TTR deposits form in the heart muscle, impairing cardiac function and worsening symptoms of heart failure and recurrent cardiovascular events.

Related Tenaya, Alnylam ink research collab to find gene targets for cardio drugs AZ seems to think that layering such treatments on top of one another is a dead end. CARDIO-TTRansform was designed to answer whether ATTR-CM patients might benefit from the addition of a second mechanism, “[a]nd I think what we’ve realized through this is unfortunately, there isn’t,” Mina Makar, AZ’s SVP of global cardiovascular, renal and metabolism, said in an interview ahead of the company’s ESC presentation. But to hear Alnylam’s R&D chief Pushkal Garg, M.D., tell it, the Wainua study and Amvuttra’s positive Helios-B trial “reinforce that not all TTR silencers or clinical trial designs are the same.” Garg espoused continued confidence in both Amvuttra and nucresiran for ATTR-CM in an emailed statement to Fierce.

For the right patient population With new evidence from ESC in hand, several analysts agreed Alnylam’s next-gen siRNA prospect nucresiran could still succeed in its own ongoing phase 3 test, TRITON-CM. “There is a case that TRITON-CM could be in okay shape to still succeed,” analysts from Stifel wrote in an Aug. 30 note to investors, if Alnylam is focusing more on patients with earlier stages of ATTR-CM.

Wainua did beat placebo in patients with stage 1 disease in the CARDIO-TTRansform trial, the analysts noted, even though about 60% of those patients were also taking Pfizer's stabilizer drug Vyndamax (tafamidis). “This is a notable datapoint and suggests that there was probably benefit on top of tafamidis for eplontersen in the right patients who are milder,” the analysts wrote. “Which would make sense given the progressive nature of TTR-CM.” Garg also highlighted the nominal benefit observed in NAC stage 1 patients in CARDIO-TTRansform, which appeared to have enrolled “a substantially higher proportion of patients with more advanced disease” compared with Amvuttra’s Helios-B study.

That difference, he said, “underscores the importance of understanding which patients are most likely to benefit from TTR silencing.” Unlike transthyretin stabilizers, which bind to the protein and prevent it from breaking apart into its toxic form, silencers like Wainua, Amvuttra and nucresiran operate upstream to destroy the mRNA blueprint used to make transthyretin in the first place. Wainua’s antisense approach is also different from Amvuttra and nucresiran’s RNA-interference method in their enzymatic mechanisms and mRNA-targeting efficiency. More thorough knockdown equals bigger efficacy?

Nucresiran’s chances are also bolstered by its more thorough knockdown of transthyretin, analysts from Citi pointed out in a note Monday. Nucresiran reduced the protein’s levels by more than 92% in phase 1, surpassing Wainua’s 70% and Amvuttra’s 81% marks. Alnylam currently anticipates a 95% or greater knockdown for the newer silencer, according to its R&D chief.

“In view of full CARDIO-TTRansform results at ESC, we believe the outlook for Alnylam’s TTR franchise looks incrementally brighter on both fronts,” the Citi analysts wrote, “with eplontersen more conclusively emerging as weaker on TTR knockdown and CARDIO-TTRansform potentially hurt by enrolling more advanced disease.” Analysts from Evercore ISI agreed, adding in an Aug. 30 note that experts in the field are “receptive to” the growing idea that RNA interference approaches like Amvuttra and nucresiran are “meaningfully differentiated” from an antisense oligonucleotide. “Data and physician feedback this weekend do indeed seem to lend support to a more credible path to TRITON success,” they wrote.

Overall, given those differences between the drugs and their studies, “we don’t see the silencer vs stabilizer clinical debate undermined post ESC in a way that would challenge” Alnylam’s current growth outlook, the Citi team suggested. Still, the mood was markedly more diminished over at Jefferies, where analysts wrote Sunday that a few “incremental positives” for Amvuttra and nucresiran can’t help the fact that the value proposition of silencers has been “somewhat diminished,” and that the probability of the TRITON-CM study’s success remains “in question.” To the Jefferies team, silencers simply “don’t add much CV benefit to stabilizers” in light of the data. Analysts there argued that a lot hinges now on the belief that TTR knockdown depth matters, both in terms of Amvuttra’s market positioning and the odds of TRITON-CM serving up a win.

Addressing that point directly, Garg stressed to Fierce that at Alnylam, “we believe that the degree of TTR reduction achieved by a silencer matters,” describing the difference in knockdown between Helios-B and CARDIO-TTRansform as “clinically meaningful and an important factor in understanding differences in results across these trials.” Does trial design matter? Meanwhile, all-cause mortality (ACM) results in patients on background stabilizers in both companies’ trials do point “to a real benefit,” the Jefferies team wrote, and a TRITON-CM endpoint inclusive of ACM could bolster the study’s chances. Still, the overall risk around the trial “remains hard to handicap,” they cautioned.

On the topic of the trial plan, Alnylam’s Garg said that “[w]e remain confident in TRITON-CM as currently designed,” while adding that his company will “continue to evaluate the CARDIO-TTRansform data to assess whether any changes are warranted.” He clarified that the study’s design already reflects goals around “deeper TTR knockdown, an event-driven design focused on all-cause mortality and enrichment of enrollment” to find patients most likely to benefit. He also agreed that, despite the CARDIO-TTRansform miss in the overall population on the primary cardiovascular mortality endpoint, ACM “appeared to favor eplontersen as was the case for Amvuttra in Helios-B.” “We think these findings highlight the complexity of measuring outcomes in a heterogeneous, multisystemic disease like ATTR-CM,” Garg explained. Related Roche sees Alnylam hypertension RNAi drug flunk trial but still plans phase 3 push As for Alnylam’s marketed med Amvuttra (vutrisiran), approved in ATTR-CM patients last March, the company itself used the ESC Congress to trumpet a subgroup analysis in its pivotal Helios-B trial focused on patients according to baseline use of Pfizer’s tafamidis.

In the results, which also went live in the Journal of the American College of Cardiology Sunday, Amvuttra’s performance on the primary composite endpoint of all-cause mortality and recurrent cardiovascular events “was consistent irrespective of baseline tafamidis use,” according to Alnylam, which said suggests “clinical benefits across broad patient populations, including those receiving stabilizers.” That said, the company did caveat that its Helios-B trial, which helped earn Amvuttra its cardiomyopathy nod, was not powered to weigh the benefit of the drug specifically in patients receiving background tafamidis from the start. On the commercial front, Jefferies analysts said they believe the CARDIO-TTRansform results have “cast a cloud over the role of silencers in stabilizer-controlled patients,” noting this could challenge share gains enjoyed by silencers. “[I]t’s unclear to us how strong the Amvuttra-stabilizer argument will be to physicians,” they added.

Alnylam appears to contest that thinking, too. Across the company’s ESC data, Garg said, “vutrisiran, unlike eplontersen, delivered consistent efficacy results across all sub-groups in the study, including in patients on background stabilizers, as well as an independent meta-analysis that showed that vutrisiran was associated with better clinical outcomes than eplontersen across every endpoint evaluated.” Alnylam RNA interference (RNAi) Clinical Data transthyretin amyloidosis Tafamidis Cardiology European Society of Cardiology combination therapy AstraZeneca Ionis Pharmaceuticals Clinical Data Biotech