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, and lowering tau in animal models protects against disease progression.

• No evidence suggests that partial tau lowering is unsafe; full knockout models show protective effects without adverse outcomes.

• Tau pathology can occur early, sometimes presymptomatically, but its timing and impact vary by individual and underlying disease drivers.

• Antibody approaches to tau have shown limited efficacy, likely due to challenges in intercepting tau spread between neurons.

• Phase I/II studies showed reversal of tau PET signals, with up to 60% reduction in the hippocampus, supporting effective brain targeting.

Ongoing and future clinical studies

• The ongoing phase II CELIA study is designed to determine the optimal tau reduction needed for clinical benefit, with both quarterly and biannual dosing arms.

• High-dose tau oligo showed sustained effects for at least six months post-dosing, supporting less frequent administration.

• The phase II study includes comprehensive biomarker and patient subgroup analyses to inform phase III design.

• Patient populations in current studies are consistent with those in major recent Alzheimer's trials.

• Mid-year data readout is anticipated for the tau program.

Angelman syndrome program

• Phase III REVEAL study was refined to focus 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 the Bayley-4, chosen for clinical relevance and regulatory alignment.

• Placebo effect data from a competitor is awaited to inform expectations, but differences in molecule chemistry limit direct comparison.

• Additional studies include an under-two cohort and a CHAMPION study to cover all genotypes and age groups.