Mark Breidenbach

Mark Breidenbach asked about the key measures Acadia is looking to assess in the upcoming phase I ACP-271 healthy volunteer study, beyond improved sedation levels compared to VMAT2 inhibitors.

Answer

Elizabeth Thompson, EVP and Head of Research and Development, explained that Acadia is interested in understanding the overall human behavior of this novel GPR88 agonist, its PK profile, potential PK/PD disconnect observed in animal models, and the adverse event profile to support its therapeutic hypothesis.

Mark Breidenbach asked for a quantitative perspective on REMS-certified physicians for ACTIVASE in the first few months and the trajectory of certification, and for sickle cell, if accelerated approval is still reasonable or if full approval is more confident, and what a confirmatory trial might entail.

Answer

Tsveta Milanova, Chief Commercial Officer, stated that the REMS is not a barrier, with academic centers certifying first and community physicians certifying simultaneously with prescriptions, noting it's a quick process. Sarah Gheuens, Chief Medical Officer and Head of R&D, expressed confidence in the RISE UP data package for full approval due to its strong anti-hemolytic profile and clinical benefits, noting FDA's view of hemoglobin as a surrogate, and confirmed readiness to discuss various confirmatory trial options if accelerated approval is pursued.

Mark Breidenbach asked about the quantitative perspective on REMS-certified physicians for ACTIVASE in the first few months and the expected trajectory of certified physicians. He also inquired if accelerated approval for mitapivat in sickle cell disease is still a reasonable outcome, given the aim for full approval, and what a confirmatory trial might look like under an accelerated approval scenario.

Answer

Chief Medical Officer and Head of Research and Development Dr. Sarah Gheuens stated that physicians do not see REMS as a barrier, with academic centers certifying early and community physicians certifying simultaneously with first prescriptions. Dr. Sarah Gheuens clarified that the data package supports full approval, but acknowledged that hemoglobin can be a surrogate endpoint for sickle cell disease, making accelerated approval a possibility. She mentioned several options for confirmatory trials, including both established and novel endpoints.

Mark Breidenbach from Oppenheimer & Co. Inc. questioned why IMM-1-104's broad RAS-agnostic activity is unique for a MEK inhibitor and confirmed whether establishing the Recommended Phase 2 Dose (RP2D) is required before starting expansion cohorts.

Answer

President and CEO Benjamin Zeskind and CSO Brett Hall explained that unlike older MEK inhibitors limited by toxicity and adaptive resistance (like CRAF-bypass), IMM-1-104's "deep cyclic inhibition" mechanism and novel engagement avoids these issues, unlocking MEK's potential. Chief Medical Officer Scott Barrett confirmed that the RP2D must be determined before starting Phase 2a expansion cohorts, noting a specific dose evaluation phase is planned to select the optimal dose.

Mark Breidenbach from Oppenheimer & Co. Inc. inquired about the timeline for finalizing the PKU Phase III protocol, its potential for global registration, the manufacturing plan for the study, and the mechanism of action for the new gout candidate, SYNB 2081.

Answer

CEO Aoife Brennan stated that Phase III design details will be shared after the end-of-Phase II FDA meeting, noting a focus on US BLA speed despite global ambitions. COO Tony Awad confirmed that Phase III materials will be supplied by their in-house, expanded manufacturing facility. CSO Dave Hava explained that SYNB 2081 is expected to target uric acid from both dietary sources and systemic recirculation.

Mark Breidenbach from Oppenheimer inquired if baseline plasma Phenylalanine (Phe) levels could skew the treatment effect in PKU patients and asked about the company's plans for engaging with the EMA for a regulatory path in Europe, including the potential for ex-U.S. sites in the Phase III trial.

Answer

CEO Aoife Brennan explained that current modeling and clinical data suggest the absolute Phe reduction is independent of baseline levels for patients above the 600 micromole/liter threshold. She also confirmed that Synlogic is actively engaging with ex-U.S. regulators due to the significant global commercial opportunity. While the intent is to include ex-U.S. sites to accelerate the Phase III trial, a firm commitment awaits clarification of the regulatory pathway to avoid potential delays.