Roche’s letter to the Huntington’s disease community this month confirmed what analysts had been bracing for: tominersen is dead, again. GENERATION HD2, the Phase 2 trial Roche built from the wreckage of the failed Phase 3 GENERATION HD1, lowered its target biomarkers over 16 months of dosing but posted no separation from placebo on the disease-severity readouts that actually count.
Rodman & Renshaw’s read, in a note to investors, put the blame on mechanism: tominersen knocks down both mutant and wild-type huntingtin, and losing the healthy copy for over a year likely erased whatever benefit came from clearing the toxic one.
That reasoning is what’s propping up Wave Life Sciences. WVE-003 targets SNP3, a polymorphism that exists only on the mutant allele, and Wave’s SELECT-HD data, a 46% CSF mHTT reduction at 24 weeks with wild-type protein preserved, is now the analysts’ exhibit A.
I’ve watched this old-yardstick-versus-new-yardstick argument play out before in HD: total knockdown looked like the more aggressive lever until it wasn’t. Selectivity was the theoretical advantage on paper for a decade; tominersen’s autopsy is what turns it into the market’s working assumption. It doesn’t make WVE-003 work. Rodman & Renshaw’s own note admits SELECT-HD “was not powered to demonstrate clinical benefit.”
Wave still needs a partner before it files its IND for a registrational Phase 2/3 study, the same slot Takeda walked away from in October 2024 without explanation. uniQure’s AMT-130 got FDA’s blessing for an accelerated BLA in June; Wave hasn’t gotten that letter yet.
Worth reading Rodman & Renshaw’s note before pricing in a Wave rerate this quarter.
— Rebecca Lauren