The failure of AstraZeneca and Ionis’ Wainua in a late-stage study of ATTR-CM casts doubt on Alnylam’s next-generation candidate but is good news for others in the space, including BridgeBio and Intellia Therapeutics.
The surprising late-stage failure of AstraZeneca and Ionis’ antisense oligonucleotide Wainua in transthyretin amyloidosis cardiomyopathy this week has shaken the field, sowing doubt in certain therapies while building investor confidence in others.
“The study here was expected to work since we know TTR [transthyretin] silencers are effective,” Stifel told investors in a Thursday note, referring to Wainua’s mechanism of suppressing the expression of the TTR protein, which is misfolded in ATTR-CM, leading to pathologic clumps in the heart.
“This is absolutely the most complicated possible outcome” for Alnylam, Stifel analysts wrote, referring to the biotech’s FDA-approved Amvuttra that’s indicated for both hereditary ATTR-CM and polyneuropathy in transthyretin amyloidosis (ATTR). Alnylam is also advancing its RNAi candidate nucresiran for these conditions. Both programs work similarly to Wainua by silencing TTR.
AstraZeneca and Ionis’ setback on Thursday “represents a near-term ‘win’ for ALNY by leaving Amvuttra as the only approved TTR silencer for ATTR-CM,” Truist Securities explained in a Thursday note. But the failure “raises questions about outlook for ALNY’s next-generation silencer, nucresiran, and its ability to demonstrate incremental clinical benefit in a treatment landscape increasingly dominated by background stabilizer therapy.”
Alnylam is studying nucresiran in the Phase 3 TRITON-CM study, which is currently recruiting patients and expected to readout in 2030. The biotech “remains very confident” in nucresiran and TRITON, Oppenheimer wrote Thursday after a Q&A session with the company.
In particular, the firm pointed to three key advantages emphasized by Alnylam: nucresiran is a better molecule than Wainua in potency, durability and onset; TRITON-CM is a larger trial than AstraZeneca and Ionis’ study; and Alnylam has a leadership team with proven experience. “We remain positive on ALNY ahead of TRITON,” Oppenheimer said.
Alnylam ended Thursday’s trading session down 3.3%, while BridgeBio, on the other hand, swelled 15%.
Tailwind for some
AstraZeneca and Ionis’ failure “simplifies the ATTR-CM landscape,” Mizuho Securities wrote in a Thursday note focused on BridgeBio. The biotech owns the TTR stabilizer Attruby, approved in November 2024 for ATTR-CM. Unlike Wainua and Amvuttra, which reduce the expression of TTR, Attruby instead binds to the protein and prevents a crucial step in the formation of the disease-causing clumps.
Earlier this month, BridgeBio presented a post-hoc analysis of Phase 2 and Phase 3 data for Attruby, pointing to the drug’s potential to preserve kidney function in ATTR-CM—a key renal benefit that could set it apart from other therapies in this space.
Another drug that works similarly to Attruby is Pfizer’s Vyndaqel/Vyndamax, which was approved in 2019 and made $1.7 billion worldwide last year. But Phase 3 data in May suggest that Attruby has a survival edge in ATTR-CM.
There has been no direct head-to-head comparison between the two medicines, but Mizuho nevertheless noted that Attruby is a better option in the hospital. “Because ATTR-CM is still a fatal disease, physicians should opt for the more potent stabilizer, BBIO’s Attruby.”
“Peak sales estimates for Attruby may edge higher” with Wainua out of the picture, the group added. The drug brought in $362.4 million in 2025.
Also in the ATTR-CM arena is Intellia Therapeutics, a biotech advancing the CRISPR-based gene therapy nexiguran ziclumeran (nex-z). Two Phase 3 studies of nex-z were subject to an FDA hold last October after a patient in one of the trials developed life-threatening liver enzyme elevations. The agency has since fully lifted the pause.
Nex-z works by deactivating the TTR gene and reducing the overall expression of the protein—much like Wainua and other silencer therapies. What sets Intellia’s candidate apart, however, is that it’s designed to be a one-time therapy. The biotech is advancing nex-z in collaboration with Regeneron.
The Wainua fail delivers an incremental positive to nex-z, Jefferies wrote in a Thursday note, reinforcing the analysts’ view “that achieving deep+consistent TTR knockdown is needed to drive benefit on outcomes.”
“Beyond stabilizer progression, we still expect ATTR [patients] to look for the next best option,” the analysts said.
