Roche and Ionis bring tominersen back from the dead

Roche is not the first company to persevere with a neuroscience project that previously looked dead and buried, but at least it is going about resurrecting the Huntington’s antisense asset tominersen in the right way. The project, licensed from Ionis, flunked the pivotal Generation HD1 study last year, but Roche now says it has seen a signal in a post-hoc analysis in young adults with a low disease burden. Instead of running another phase 3, or indeed seeking approval, Roche is now going back to phase 2, although details are scant. If the asset is to progress further Roche will need to provide reassurance about worrying findings in Generation HD1: tominersen-treated patients did numerically worse than the placebo group on several clinical measures, with the highest dose performing the worst. And tominersen’s phase 1/2 trial found increases in neurofilament light chain, a marker of neuronal injury; together, these results raise the possibility of toxicity. There is also the theoretical risk that knocking down healthy as well as mutant huntingtin protein might be harmful. Still, with no approved therapies for Huntington’s, and a couple of more recent disappointments, Roche looks justified in trying again.

Selected novel approaches in Huntington's disease
Project Company Description Status/trial details
Phase 3
Pridopidine Prilenia Therapeutics Sigma-1 receptor agonist Proof-HD, topline results due Q1 2023
Phase 2
ANX005 Annexon Bioscience Complement factor C1q antibody NCT04514367, interim data disappointed, full data due Q2 2022
SAGE-718 Sage Therapeutics NMDA receptor regulator NCT05107128 completes Dec 2024
Branaplam Novartis Small-molecule RNA splicing modulator Vibrant-HD completes Feb 2025
PTC518 PTC Therapeutics Small-molecule RNA splicing modulator PIVOT-HD to start Q1 2022
Tominersen Roche/Ionis Huntingtin antisense oligonucleotide Generation HD1 study failed; ph2 to start in younger pts with lower disease burden
Pepinemab (VX15) Vaccinex Semaphorin 4D antibody Ph2 Signal study failed in Sep 2020; Vaccinex looking for partner for ph3
Phase 1/2
AMT-130 Uniqure Gene therapy silencing huntingtin gene NCT04120493, initial data disappointed; full data on cohorts 1 & 2 due H1 2023
WVE-003 Wave Life Sciences* Stereopure huntingtin SNP3 antisense oligonucleotide Select-HD completes Dec 2022
*Takeda has option to co-develop and co-commercialise. Source: Evaluate Pharma &

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