Alnylam was flying high one year ago. The RNAi pioneer’s share price was rising ever closer to $500 apiece amid the rapid growth of its transthyretin-mediated amyloidosis (ATTR) franchise thanks to a March 2025 FDA nod and the progress of late-phase programs. Today, the stock has fallen to around $250.
The company’s share price collapsed when management lowered full-year guidance in July. Sales of TTR silencer Amvuttra for the second quarter fell short of analyst expectations and Alnylam reduced its full-year guidance by about $200 million. The news raised doubts about the RNAi product’s prospects in a market served by small-molecule TTR stabilizers from BridgeBio Pharma and Pfizer.
Alnylam’s revenue cut “may create a near term credibility overhang and could “raise questions on peak sales potential, even if there’s tailwinds in the competitive landscape,” according to Stifel.
Guggenheim Securities analysts set out the concerns raised by the revised guidance in a July 31 note to investors. The cut, which happened despite Amvuttra being the “sole, differentiated modality” in ATTR cardiomyopathy (ATTR-CM), suggested that the commercial opportunity is smaller than expected, the drug is mispriced or TTR stabilizers are becoming the preferred modality, the analysts said.
Alnylam’s stock has yet to recover. However, while the Guggenheim team was “on the sidelines on the stock” even before the guidance cut, other analysts have retained faith in a comeback. TD Cowen assigned a $482 price target to Alnylam back in November 2025, when the stock traded above $430. The analysts reiterated the target last month, even as Alnylam traded below $250.
The debates driving Alnylam’s stock
BMO Capital Markets analysts, who began covering Alnylam in August with a $318 price target, set out three key debates about the biotech’s prospects in an Aug. 18 note to investors. Alnylam bulls and bears are split on multiple questions, the analysts said—about the size of the ATTR market, whether the company’s next-generation RNAi candidate nucresiran creates value and the likelihood of gene silencing becoming a major drug modality.
The BMO team sided with the bulls on each point, arguing that Alnylam cut its guidance because the population of patients that Amvuttra served most urgently—those for whom stabilizers hadn’t worked—”exhausted sooner than expected.” Through that perspective, the guidance cut changed the shape of the sales ramp, not the size of the opportunity.
“The path to $10 billion+ in franchise sales was never through the second-line,” the analysts wrote, “it always ran through front-line starts and expansion of the diagnosed population.”
AstraZeneca and Ionis Pharmaceuticals’ data drop divulging more details from its highly watched Phase 3 transthyretin silencer trial “further confuses the picture” for Wainua when combined with the standard of care for ATTR-CM, analysts say.
As the analysts acknowledge, there is another way to view the guidance cut. An Alnylam bear may argue that cutting sales guidance two quarters into the ATTR-CM launch says something about the size of the pool. Another skeptical reading is that, having burned through the second-line market, Alnylam faces the harder challenge of competing with Pfizer’s Vyndamax and BridgeBio’s Attruby for first-line patients.
Alnylam is running Phase 3 trials of nucresiran in ATTR-CM and ATTR with polyneuropathy (ATTR-PN)—the indication for which Amvuttra was first approved, back in 2022. The late-stage failure of AstraZeneca and Ionis’ Wainua in ATTR-CM in July raised questions about nucresiran, but after the dust settled, analysts became more comfortable with Alnylam’s prospects.
In a Sept. 3 note, Stifel analysts said endpoint selection and patient enrollment drove Wainua’s failure. That view, which was echoed by BMO analysts, suggests Alnylam “is positioned for success with their event-driven study that is enriched for earlier-stage patients,” the Stifel team said.
The broadening RNAi pipeline
Beyond ATTR, Alnylam is applying its technology to big markets including hypertension and Alzheimer’s disease. BMO analysts compared gene silencing today to where monoclonal antibodies were in the late 1990s. Antibody developers ignored doubters and established a new, major modality. If gene silencing biotechs do the same, “Alnylam will own the success” more than any other company, BMO analysts said.
A Phase 3 cardiovascular outcomes trial of blood pressure prospect zilebesiran “tests whether RNAi can be delivered to a population-scale chronic indication,” BMO analysts said. A successful readout “could unlock a significant commercial opportunity and highlight the value of Alnylam’s ex-ATTR franchise,” the analysts added in a Sept. 17 note.
Still, skepticism abounds.
Stifel analysts, also writing on Sept. 17, said they “remain cautious on the safety profile and continue to question whether the modest [blood pressure] reductions observed in [Phase 2] are sufficient to drive a clinically meaningful [cardiovascular outcomes trial] benefit.” Alnylam is betting that consistent, modest blood pressure reductions can cut the risk of cardiovascular events.
BridgeBio Pharma’s transthyretin amyloidosis medicine Attruby is off to a strong launch, while Alnylam lowered full-year sales guidance for competitor Amvuttra.
If that bet pays off, Alnylam could cement its position at the forefront of RNAi therapeutics. ADARx Pharmaceuticals’ $446.3 million IPO in September and the 2025 deal between Novartis and China’s Argo Biopharmaceutical illustrate the growing and increasingly global nature of the sector. But Alnylam was the pioneer, and its market cap is several-fold larger than its closest biotech rivals.
Having turned its first-mover advantage into a $3.3 billion cash cushion, Alnylam is considering striking deals for drug candidates and technologies for delivering therapies to new tissues, Stifel analysts said. Alnylam is looking at areas that are complementary to what it is already working on from a commercial and R&D perspective, the analysts added.
Alnylam also has opportunities to reignite enthusiasm for its internal pipeline. This year, the biotech is set to publish Phase 2 data on a bleeding disorder drug candidate, as well as Phase 1 results on Huntington’s disease and obesity programs. Alnylam is aiming to report five or more key readouts in 2027 and in 2028.
