A pillar of the transthyretin amyloidosis space was shaken last month when AstraZeneca and Ionis Pharmaceuticals’ antisense drug Wainua failed to show significant cardiovascular benefit in a late-stage trial of patients with transthyretin amyloid cardiomyopathy, otherwise known as ATTR-CM.
The Phase 3 flop sent waves across the ATTR space, appearing as an overhang for other developers of similar therapies, while simultaneously boosting those taking alternative approaches to this rare and progressive condition.
Part of the reason the failure was so surprising is that Wainua is already approved to treat transthyretin amyloid polyneuropathy (ATTR-PN).
Affecting around six in a million people in the U.S., ATTR occurs when a protein called transthyretin becomes unstable and misfolds, ultimately depositing as amyloid plaques in various organs across the body.
In ATTR, there are two big “clinical buckets,” ATTR-CM and ATTR-PN, according to Faisal Khurshid, managing director of biotechnology equity research at Jefferies. However, “The same biology manifests very differently depending on where the amyloid is causing the most damage,” he told BioSpace in an email.
ATTR-CM refers to cardiovascular symptoms that arise as amyloid builds up in the heart, causing symptoms of heart failure, while in ATTR-PN, amyloid clumps in peripheral nerves lead to the numbing of the extremities, diarrhea and other symptoms.
Of the two, ATTR-CM is the “much larger” market opportunity, Khurshid said. Indeed, a December 2025 study published in Open Heart showed that 12.7 out of one million people have ATTR-CM, while only 3.5 per million have ATTR-PN.
There can be advantages to targeting ATTR-PN first, however, because this approach can validate biology, Khurshid said, “and in some cases provide a first commercial foothold before [ATTR-CM].”
That was the hope for Wainua, which was first approved in December 2023 for hereditary ATTR-PN. The Phase 3 CARDIO-TTRansform trial was intended to establish the drug in ATTR-CM. With its failure, AstraZeneca and Ionis are unlikely to file for approval in this indication, analysts said.
“ATTR is mechanistically one disease but clinically not one disease,” Khurshid said, explaining why some therapies succeed in one ATTR subtype but not the other. “A drug can be mechanistically rational across ATTR but still show very different clinical results depending on the organ involved, baseline disease stage, endpoint sensitivity, and background therapy.”
The Phase 3 Wainua failure in ATTR-CM leaves in its wake “a highly evolving landscape” of ATTR treatment, Khurshid said—one with many players, but which must also now contend with “big questions” on what will constitute a successful trial in the indication.
BioSpace takes stock of the field here.
AstraZeneca persists with first-in-class candidate
AstraZeneca continues to forge ahead in the ATTR-CM arena with the transthyretin depleter cliramitug.
Originally developed by Neurimmune, cliramitug is an investigational antibody that targets the disease-causing amyloid clumps found in the heart, triggering their removal from the body, according to the biotech’s website. Cliramitug has the potential to be the first agent that not only slows disease progression but also depletes amyloid buildup from the heart, per Neurimmune.
Attracted by this promise, AstraZeneca—through its rare disease outfit Alexion—paid $30 million upfront in 2022 to secure an exclusive global license to develop and commercialize cliramitug. The pharma also put up to $730 million on the line in potential milestone payments.
Long-term data from a first-in-human trial published last month in Nature Medicine showed that continued cliramitug treatment through a median follow-up of nearly 30 months led to sustained reductions in cardiac amyloid burden and biomarker improvements. Outcomes even improved over time in patients who had low initial exposure to cliramitug before doses were ramped up.
There were no serious adverse events or study dropouts related to cliramitug.
AstraZeneca is currently running the Phase 3 placebo-controlled DepleTTR-CM trial of cliramitug, with nearly 1,200 patients enrolled. The study’s primary completion date is around mid-2027, according to a federal clinical trials database.
Novo Nordisk, Prothena deplete problematic proteins with coramitug
Racing against AstraZeneca to bring the first transthyretin depleter to the market is Novo Nordisk, which last year pushed into late-stage development with its investigational therapy coramitug.
Initially developed by Prothena Corp., coramitug is an antibody therapy that specifically targets dysfunctional and misfolded proteins that would otherwise form pathologic clumps, according to the biotech’s website. Coramitug targets deposited amyloid to remove plaques and circulating amyloid to prevent further aggregation.
In July 2021, Novo paid $100 million upfront and earmarked up to $1.2 billion in milestones to take over Prothena’s ATTR business—including coramitug.
Phase 2 data published in November 2025 demonstrated a significant reduction in NT-proBNP levels—a biomarker of heart health—in patients with ATTR-CM taking coramitug versus placebo comparators at 52 weeks. The drug showed no significant benefit on the 6-minute walk test, a measure of exercise capacity and endurance.
Novo has nevertheless decided to advance coramitug into Phase 3 studies. The pharma is running the late-stage CLEOPATTRA trial in ATTR-CM, with a primary completion date in mid-2029. The study is currently recruiting patients.
In April, the FDA granted coramitug its Fast Track designation for ATTR-CM, which will expedite the drug’s review once an application has been accepted.
Alnylam’s nucresiran weathers headwinds for silencers
Caught in the downdraft of Wainua’s late-stage stumble is Alnylam’s next-generation ATTR-CM drug nucresiran, an RNA interference therapy that works by suppressing expression of the transthyretin protein, ultimately preventing the pathologic buildup of misfolded versions.
The Wainua failure “raises questions” about nucresiran, another transthyretin silencer, Truist Securities wrote in a July 9 note. In particular, analysts noted that the disappointing outcome raises uncertainties about whether nucresiran could elicit sufficient therapeutic benefit in patients with ATTR-CM amid the current dominance background stabilizer therapy.
In November 2024, Alnylam announced that a 300-mg dose of nucresiran elicited an average reduction of 90.3% in serum transthyretin levels at day 15 in a Phase 1 trial. This effect improved to 96.5% at day 29 before mellowing to 92.6% at day 180. Figures were comparable, if a bit higher, for the 600-mg and 900-mg doses.
Nucresiran is being studied in the Phase 3 TRITON-PN trial for ATTR-PN, with initial data expected in 2027. Alnylam is also running the Phase 3 TRITON-CM study of the asset in ATTR-CM, with primary completion in 2030.
The company said in January that it hopes to launch nucresiran in ATTR-PN by 2028 and in ATTR-CM by 2030.
Aside from nucresiran, Alnylam owns Amvuttra, first approved in June 2022 for hereditary ATTR-PN and then in March 2025 for ATTR-CM. The drug made $890 million in the first quarter of this year.
Intellia takes a gene therapy approach with nex-z
Intellia Therapeutics is taking a similar approach to Wainua and nucresiran, only with a gene therapy. With nexiguran ziclumeran (nex-z), the Massachusetts biotech seeks to lower the overall expression levels of the transthyretin protein.
The asset is being studied in the Phase 3 MAGNITUDE and MAGNITUDE-2 studies for ATTR-CM and ATTR-PN, respectively. Initial data from these two trials could come as soon as the latter half of 2027. Phase 1 data revealed in November 2025 showed that a one-time infusion of nex-z elicited and maintained long-term serum transthyretin reductions. In nine patients followed for 36 months, transthyretin levels were 87% lower on average versus baseline.
Safety, however, seems to be a key concern for nex-z. In 2022, Intellia detected a case of significantly elevated liver enzymes in a Phase 1 study of the therapy, though the patient remained asymptomatic and the episode was “deemed nonserious by the investigator,” the company said at the time. Such a signal appeared again in May last year, with the biotech reporting another case of asymptomatic liver enzyme elevation.
A few months later, in October 2025, the FDA paused both MAGNITUDE and MAGNITUDE-2 after another liver safety issue. This time, the patient needed to be hospitalized. The agency has since released its hold on these trials after Intellia agreed to certain protocol adjustments and stricter safety monitoring strategies.
BridgeBio’s Attruby riding high
For other contenders in the ATTR arena, the Phase 3 failure of Wainua may have removed a formidable competitor. This is the case for BridgeBio, which owns the oral drug acoramidis, sold under the brand name Attruby.
Unlike the transthyretin silencers Wainua and nucresiran, acoramidis is known as a transthyretin stabilizer. Instead of reducing the overall expression levels of the protein, acoramidis instead binds to transthyretin and slows its degeneration, which otherwise would result in the formation of disease-causing plaques.
Acoramidis was approved in 2024 for ATTR-CM.
BridgeBio continues to beef up Attruby’s profile. In May, the biotech presented data from a follow-on analysis of its Phase 3ATTRibute-CM trial. These new findings showed that the drug reduced cardiovascular hospitalization by 34% in ATTR-CM patients as compared with its biggest competitor, Pfizer’s Vyndaqel/Vyndamax, also a transthyretin stabilizer.
All-cause mortality, meanwhile, dropped by 28% in patients on Attruby versus Vyndaqel/Vyndamax, though this benefit was not statistically significant. This additional analysis only indirectly compared the two drugs, and there have been no head-to-head studies pitting the two products against each other.
BridgeBio is also studying Attruby for the prevention of ATTR-CM and ATTR-PN in asymptomatic people who carry pathogenic mutations. The Phase 3 ACT-EARLY trial is ongoing, with primary completion in 2031.
https://www.biospace.com/drug-development/5-companies-advancing-attr-assets-in-the-wake-of-wainuas-fail
