Alnylam Pharmaceuticals (ALNY) Investor update summary

Therapeutic rationale and design

• Huntington’s disease is a progressive, fatal inherited neurodegenerative disease with >100K symptomatic people globally; no approved disease-modifying therapy was cited.

• Brezosiran is an investigational intrathecal C16-siRNA targeting a conserved HTT Exon 1 sequence to lower full-length mutant HTT, HTT1a and wild-type HTT in the CNS.

• Preclinical NHP studies showed dose-dependent, widespread CNS HTT lowering sustained for months; no adverse neurological, inflammatory, NfL or histological findings were reported through 12 months, including after >90% wild-type HTT lowering.

HTT1a evidence

• HTT1a is generated from HTT Exon 1 and is implicated alongside full-length mutant HTT in disease; some HTT-lowering approaches may not effectively target HTT1a.

• Mouse studies found that preventing HTT1a generation or lowering it delayed aggregation and improved disease-associated CSF biomarkers and molecular phenotypes; combined targeting of HTT1a and full-length mutant HTT may add benefit.

Phase Ib results

• Ongoing randomized, double-blind, placebo-controlled study assesses safety, tolerability and PK/PD after a single intrathecal dose; initial results covered five dose cohorts through Month 3.

• At Month 3, mean CSF mHTT reduction in the highest cohort was 64% by SMC and 60% by NULISA; maximum individual reductions were 80% and 83%, respectively.

• Safety monitoring found no dose-dependent CSF NfL or inflammatory-marker increases, or ventricular enlargement beyond the placebo range; serious and severe events were limited, no deaths or adverse-event discontinuations were reported, and serious AEs were not assessed as study-drug related.