After a surprise washout in a recent phase 3 trial of AstraZeneca and Ionis’ antisense oligonucleotide Wainua (eplontersen), the likely reason for the miss is being laid bare, in a potential ill omen for others pursuing silencer drugs in transthyretin-mediated amyloid cardiomyopathy.
The detailed results on CARDIO-TTRansform were among the most anticipated readouts at this year’s European Society of Cardiology Congress in Munich, with industry watchers hungry for more details after AZ and Ionis reported that the Wainua study missed the mark back in July.
At the time, Jefferies analysts noted that the “outright failure” of Wainua to reduce cardiovascular deaths or recurrent heart events came as a shock, with Ionis leadership tying the fumble to the tough realities of treating patients already heavily reliant on standard-of-care stabilizer drugs.
The distinction between patients on background treatment and those who got Wainua as a monotherapy is central to understanding where the trial failed, Mina Makar, SVP of global cardiovascular, renal and metabolism at AstraZeneca, told Fierce in an interview.
“The study performed very well,” Makar said of the results, noting that “the medicine knocks down ATTR exactly as we would expect.”
As a once-a-month RNA-targeted silencer, Wainua is thought to help reduce transthyretin (TTR) amyloid production by the liver. In patients with ATTR-CM—which affects around 300,000 to 500,000 people worldwide—misfolded TTR amyloid deposits form in the heart muscle, which can hamper cardiac function, exacerbating symptoms of heart failure and recurrent cardiovascular events.
“It’s efficacy as a monotherapy is very strong,” Makar said of Wainua, “whether on quality of life, whether on six-minute walk, whether on cardiovascular events—it does what it’s supposed to do as a monotherapy.”
Taking a closer look at the data released ahead of the weekend, a total of 381 primary endpoint events occurred in 210 patients on Wainua, compared to 392 events in 231 patients in the placebo cohort, according to detailed results simultaneously published in The New England Journal of Medicine. The main objective of the study looked at a cumulative composite of death from cardiovascular causes and recurrent cardiovascular events up to 140 weeks.
The study also weighed the effect of non-CV death on the primary analysis with a cumulative composite of death from any cause and cardiovascular events up to the same 140-week cutoff.
On cardiac deaths, a component of the trial’s primary endpoint, 74 occurred in the Wainua group versus 70 in the control arm. Additionally, the study logged 307 cardiovascular clinical events in patients on the study drug, while those on placebo charted 322 such events.
“The hypothesis was always in the clinical community that if you have somebody on a stabilizer and they’re still progressing, adding another mechanism like silencing would add incremental benefit,” Makar explained, “and that was the assumption that everybody made, and that was the hope everybody had, and really, that was what this study was at the end of the day going to answer: Is there additional benefit by adding a second mechanism?”
“And I think what we’ve realized through this,” he continued, “is unfortunately, there isn’t.”
The CARDIO-TTRansform study enrolled 1,432 wild-type or hereditary ATTR-CM patients, with 715 receiving Wainua and 717 on placebo.
Crucially, 57% of patients were using a transthyretin stabilizer therapy—a class dominated by Pfizer’s tafamidis juggernaut Vyndamax—at baseline, with that proportion rising to a little more than 80% by the trial’s end.
But in a silver lining for the ATTR community, knowing that adding a silencing mechanism on top of a stabilizer doesn’t increase the benefit is “very informing in terms of guidelines,” Makar said. “It’s very informing in terms of clinical practice.”
He continued, “It’s not what we were all hoping to see as a clinical community—that we were hoping to be able to give these patients something more than a first-line only—but that’s why you do studies, and that’s why you do this work.”
In its release on the CARDIO-TTRansform data, the ESC echoed AZ and Ionis’ point that Wainua suppressed circulating serum TTR, consistent with the expected effects of TTR gene silencing and confirmed by a prespecified exploratory endpoint.
Meanwhile, in a subgroup analysis, patients who weren’t receiving a stabilizer at baseline charted fewer CV events on the primary composite endpoint than placebo, with the results reaching “nominal statistical significance,” per ESC.
AstraZeneca plans to present more detailed data on baseline stabilizer use Sunday.
While the CARDIO-TTRansform readout offers something of a post-mortem for industry watchers on Wainua specifically—currently approved to treat the related condition ATTR polyneuropathy—the data may have bigger implications down the line for the current crop of ATTR-CM therapies, including stabilizers like Vyndamax and BridgeBio’s second-generation Attruby, plus TTR knockdown therapies like Alnylam’s Amvuttra, analysts at William Blair wrote in a note to clients.
For their part, analysts at Jefferies noted that Wainua’s performance on the trial’s secondary endpoints was “strong although statistically unable to claim significance.” The analysts also qualified the fact that CARDIO-TTRansform enrolled a sicker and more intensively treated patient pool than, for instance, the Helios-B study that won Alnylam’s similarly positioned drug Amvuttra its ATTR-CM approval in March 2025.
All eyes will likely turn to Alnylam now, which is also presenting analysis on background stabilizer use in Amvuttra patients at this year’s ESC Congress. While both Amvuttra and Wainua are considered silencers, Amvuttra uses RNA interference to stop TTR protein creation.
As for implications further afield, the Jefferies team suggested that the AZ-Ionis results could “suggest a higher bar for next-gen silencers in clinical development,” adding that additional cardio benefit measured by hard outcomes could become increasingly challenging for companies to demonstrate.
As for AZ’s cardiovascular and metabolic strategy writ large, the company is “focused now on the interrelatedness of cardiovascular-renal-metabolic diseases, and really focusing on the kidney and the heart and the risks factors that revolve around there,” Makar told Fierce, listing examples like hypertension, dyslipidemia, diabetes and obesity. Those efforts by AZ are “really starting to come to life now,” he added.
The company is currently aiming to launch four new medicines in the space between now and the first half 2028, Makar pointed out.