Ionis Pharmaceuticals (IONS) Stifel 2026 Virtual CNS Forum summary

Alzheimer's disease and tau targeting

• Tau pathology correlates more strongly with cognitive decline than amyloid, making it a key target in Alzheimer's disease.

• Lowering tau in animal models protects against disease and excitotoxicity, with no adverse effects seen in knockout models or human genetics.

• Tau pathology can occur early, often downstream of amyloid, but timing and impact vary by individual and disease drivers.

• Antibody approaches to tau have shown limited efficacy, likely due to challenges in blocking intracellular tau spread.

• Intrathecal oligonucleotide therapy showed reversal of tau PET signals in key brain regions, with up to 60% reduction in the hippocampus.

Clinical development and study design

• Ongoing phase II CELIA study is evaluating dosing intervals and the extent of tau reduction needed for clinical benefit.

• Both every-three-month and every-six-month dosing arms are included, with no loading dose for the six-month arm.

• The study is placebo-controlled, includes diverse patient populations, and is designed to inform phase III planning.

• Data readout for the tau program is expected mid-year.

Angelman syndrome program

• Phase III REVEAL study now focuses on the 80mg dose, reducing planned enrollment due to positive phase I/II results.

• Study completion is expected this year, with readout in 2027; FDA Breakthrough Therapy designation has been granted.

• Primary endpoint is expressive communication on Bayley-4, chosen for clinical relevance and regulatory alignment.

• Study design is robust, with a controlled arm and endpoints agreed upon with the FDA.

• Additional studies include an under-two cohort and the CHAMPION study for UPD, ID genotypes, aiming for comprehensive data across all Angelman populations.