Alnylam's two siRNA drugs hit the same liver target. One failed an FDA review in 2023. Two years later the other was approved for both forms of ATTR amyloidosis. The mechanism didn't change. The trial design did.
In September 2023 an FDA advisory committee voted 9-3 that patisiran's benefit supported approval for cardiac ATTR amyloidosis. The FDA rejected it anyway. Eighteen months later it approved vutrisiran — a near-identical Alnylam siRNA against the same liver target — for both forms of ATTR at once. Patisiran's APOLLO-B was 360 patients, 12 months, a six-minute-walk endpoint (+14.7 m, p=0.0162) with a secondary composite that missed at a win ratio of 1.27. Vutrisiran's HELIOS-B was 655 patients, up to 36 months, a hard mortality-plus-CV-events composite cut by 28%. Same mechanism, opposite verdicts — the molecule never changed, the trial did.
Pfizer, Amgen, Lilly, Merck, and Astellas all failed at IGF-1R in cancer. Then a shelved Roche antibody became the only effective treatment for thyroid eye disease. Same receptor, completely different biology.
Five major pharmas spent two decades chasing IGF-1R as a cancer target. Every Phase 3 trial failed. The only IGF-1R drug ever approved is for thyroid eye disease — Tepezza, which generated $1.9 billion in 2024 and 8x exceeded its acquirer's peak forecast. Eleven more IGF-1R-for-TED programs are now in clinical trials, including the literal cancer-graveyard compound being resurrected by Sling Therapeutics. Targets don't travel. Disease context decides.
Sickle cell disease is a single-letter typo in DNA. CRISPR can now edit DNA with precision. You'd think the fix is obvious. It's not. Casgevy uses CRISPR to reactivate fetal hemoglobin instead of correcting the mutation directly — because the indirect approach is proving safer and more effective.
