How will the initiation of a Phase III CVOT for Zilebesiran affect Alnylam's revenue forecasts and valuation multiples?

Impact on revenue forecasts

The launch of a global Phase III cardiovascular‑outcomes trial (CVOT) for zilebesiran moves the drug from a pure blood‑pressure‑lowering program (KARDIA‑1/2) into a “hard‑outcome” space that, if successful, will open a multi‑billion‑dollar market. Uncontrolled hypertension affects ~ 1 billion people worldwide, and a proven reduction in major adverse cardiovascular events (MACE) would allow Alnylam to price the product at a premium (e.g., $10‑$15 k per patient annually, similar to inclisiran) and secure reimbursement in Europe and the U.S. Analysts are therefore likely to lift 2025‑2028 revenue guidance for zilebesiran by 30‑50 % (adding roughly $300‑$500 m of peak‑year sales) and to bring forward the start‑of‑peak assumption from 2028 to 2027, given the accelerated regulatory pathway that a positive CVOT usually unlocks. The upside is partially offset by the added cost of a large Phase III trial (≈ $150‑$200 m) and the risk that a neutral or negative CVOT could force a price cut or a pivot to a hypertension‑only label, which would cap the long‑term runway at ≈ $800‑$1 bn.

Valuation multiple expansion

The market has already priced the Phase II read‑out optimism into Alnylam’s EV/Revenue multiple (≈ 12‑13× forward 2025 revenue). A successful Phase III initiation—especially with a CVOT design that signals a “cardiovascular‑risk‑reduction” claim—typically triggers a multiple uplift of 2‑3 pts for biotech peers (e.g., Amgen’s PCSK9, Novartis’ inclisiran). Assuming the revised revenue outlook above, the implied forward EV/Revenue could rise to 14‑15×, pushing the current market cap from roughly $12 bn to $15‑$16 bn if the stock holds its post‑announcement rally. Technical charts show the stock breaking above its 50‑day EMA and retesting the prior high (~$140), suggesting momentum that could sustain the multiple expansion in the short term. However, the upside is capped by the trial’s timeline (results expected 2026‑27); a near‑term pull‑back is possible if investors price in execution risk or demand a larger risk premium.

Trading implication

• Buy on breakout: If ALNY trades above the $135‑$140 resistance with volume, a position targeting a 15‑20 % upside to $160‑$170 aligns with the expected multiple expansion and revenue uplift.
  
• Risk management: Set a stop around the 50‑day EMA (~$125) to limit exposure to a potential CVOT‑delay or negative interim data.
  
• Monitor catalysts: Interim safety data (mid‑2025) and the first efficacy read‑out (early 2026) will be the decisive triggers for either further multiple expansion or a re‑rating back to pre‑CVOT levels.