The Generative Brain

ALN-6457 (siRNA, Regeneron)

ALN-6457 (also named ALN-PRNP) is Regeneron's PRNP-targeting drug for symptomatic prion disease, inferred but not confirmed to come from the Regeneron-Alnylam RNAi collaboration, in a Phase 1/2 trial planned to start on 23 October 2026. Its registry endpoints differ from the other PrP-lowering trials: plasma NfL is primary and follow-up runs about three years. The modality is not stated on the registry.

Key facts

  • The registry lists the drug as ALN-6457 with the other name ALN-PRNP; it does not state the modality, but the ALN prefix and the Regeneron-Alnylam RNAi collaboration make an Alnylam siRNA the working inference.
  • Sponsor Regeneron (study id ALN-6457-PD-25129); Phase 1/2 open-label with extended follow-up of multiple doses; EU CTIS 2026-526727-21-00; no expanded access.
  • Status not yet recruiting; estimated start 2026-10-23 and estimated completion 2031-02-27; first submitted 2026-09-16.
  • Two arms: dose escalation and cohort expansion.
  • Primary outcomes are treatment-emergent adverse events through Week 156 and percent change in plasma neurofilament light (NfL) through Week 130.
  • Secondary outcomes include CSF PrP concentration and change through Week 130, drug and metabolite concentrations in plasma and CSF, and overall survival at Week 52.
  • Compared with PrProfile and PRiSM, where CSF PrP lowering is the main pharmacodynamic readout, ALN-6457 puts plasma NfL first and tracks participants for three years of repeat dosing; this is a comparison of registry endpoints, not of results.
  • An aggregator lists planned enrollment of 60 and labels the drug a small molecule; the label conflicts with the prefix and the Alnylam collaboration and is unconfirmed.
  • In 2019 Regeneron and Alnylam formed a global collaboration on RNAi therapeutics for eye and CNS targets with a USD 400 million upfront payment.

Timeline

  1. 2019Regeneron and Alnylam begin the collaboration covering CNS targets.
  2. 2026Registry record first submitted.
  3. 2026Estimated start of the Phase 1/2 trial.
  4. 2031Estimated completion.
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