Manoj

Manoj, on behalf of Akash Tewari, asked for expectations regarding the upcoming HORIZON Lp(a) Phase 3 trial, including what would constitute a commercially viable risk reduction. He also inquired if potential deeper risk reductions from other near-term Lp(a) readouts could alter Pelacarsen's commercial outlook and requested an update on Ionis's next-generation Lp(a) targeting asset.

Answer

Brett Monia, CEO, expressed confidence in the HORIZON trial's outcome, citing its role as the first to test the Lp-CVD hypothesis, positive interim analyses, and a high-risk patient population. He emphasized Pelacarsen's first-mover advantage and the lack of superior Lp(a) lowering profiles from competitors. Eric Swayze, Executive Vice President of Research, discussed the next-generation Lp(a) targeting asset, an siRNA designed for extended dosing (6-month or annual), noting promising preclinical data and the success of ION775 (ApoC-III siRNA) as a precedent. Brett Monia added that the Pelacarsen follow-on is currently in IND-supporting toxicology studies.

Manoj inquired about early observations regarding plasma exposure dynamics for ARV-393 in combination with glofitamab, potential dose modifications, and any increased interest in vepdegestrant following recent Roche registration data.

Answer

President and CEO Randy Teel stated that the vepdegestrant partnership process is on track, with Roche data validating the ER therapy hypothesis. Chief Medical Officer Noah Berkowitz noted that dose modifications for ARV-393 with glofitamab are not anticipated due to non-overlapping toxicities, though cautious dose escalation will occur.