Alnylam's Amvuttra launch slows as the RNAi pipeline reaches for bigger diseases

The technology

Alnylam makes small interfering RNA (siRNA) drugs that switch off disease-causing genes. It has six approved medicines and more than 20 years of siRNA data. Its main product, Amvuttra, silences transthyretin (TTR). In the second quarter it made $1.01 billion, up 106%, mostly from its use in ATTR cardiomyopathy.

The company is pushing RNAi into larger diseases and harder tissues. Zilebesiran targets angiotensinogen for hypertension and is in a phase 3 outcomes trial with Roche. Mivelsiran targets APP in the brain and cut amyloid beta 42 in spinal fluid by 70.2% at the top dose in phase 1. In June, Alnylam signed an AI design deal with Inceptive worth up to $2 billion.

Neuroscience is the newest front. Alnylam and Regeneron have seven clinical neuroscience programs together, including the tau-targeting ALN-5288, and the Huntington's drug ALN-HTT02 has phase 1 data due on October 23. The company says it has more than 25 clinical programs and wants over 40 by 2030, which means more spending on early trials before most of them can earn anything.

The odds

TTR silencing is validated. HELIOS-B showed a 28.2% cut in death and recurrent cardiovascular events for vutrisiran. That lowers the risk for nucresiran, the next-generation TTR drug in phase 3. The BIO and Informa base rate for phase 3 to filing is 57.8%, and a program hitting a proven target should do better than the average, though it still has to show an edge over Amvuttra to matter commercially.

Zilebesiran is a harder bet. Outcomes trials in hypertension need large numbers and long follow-up, and the KARDIA-3 subgroup data at ESC came without figures. The same 57.8% base rate applies, with more uncertainty about commercial fit. Mivelsiran sits in phase 2 in cerebral amyloid angiopathy, where the base rate for reaching phase 3 is 28.9% and results are not due until 2028.

The money

Alnylam is now profitable. Second-quarter GAAP net income was $164.5 million on revenue of $1.29 billion, and cash and marketable securities were $3.3 billion on June 30. Guidance calls for $4.7 billion to $5.1 billion in net product revenue in 2026 and $2.7 billion to $2.8 billion in non-GAAP R&D and SG&A. Royalties from Novartis' Leqvio are rising, and Alnylam raised collaboration and royalty guidance to $575 million to $625 million.

The risks

The first risk is the shape of the ATTR-CM launch. Alnylam cut 2026 TTR guidance by $200 million at both ends after second-line US demand moderated. A business this dependent on one drug is exposed to any further slowing.

The second is competition from tafamidis. In HELIOS-B, 40% of patients were already on it, and the quality-of-life benefit was smaller in that group.

The third is reliance on partners. Alnylam names Roche, Novartis, Sanofi and Regeneron as partners it depends on for some development and sales.

Our read

Alnylam has turned into a profitable commercial company on the back of one drug in one large indication. The July guidance cut shows that the easy part of the ATTR-CM launch is over, and the next few quarters will show how fast new diagnoses and second-line switching can carry growth. The pipeline gives the company many shots, from hypertension to Alzheimer's and Huntington's disease, but none of the large ones read out soon. The near-term markers are ALN-HTT02 data on October 23 and third-quarter results on October 29.