Mark

Mark inquired whether additional mitigation strategies beyond those implemented in MAGNITUDE-2 would be necessary to resolve the MAGNITUDE study clinical hold, and sought confirmation on the number of liver enzyme elevation instances (only two others besides the patient who passed away).

Answer

President and CEO John Leonard stated that the incidence of Grade 4 elevations was less than 1% in the entire MAGNITUDE patient population. He indicated that it's premature to detail exact additional mitigation strategies for MAGNITUDE, but they are thinking broadly. He confirmed that they are very far along in discussions with the FDA for MAGNITUDE.

Mark inquired whether additional mitigation strategies beyond those implemented in MAGNITUDE-2 would be necessary for the MAGNITUDE study clinical hold resolution, and sought confirmation on the number of liver enzyme elevation instances besides the patient who passed away.

Answer

President and CEO John Leonard stated that the incidence of Grade 4 elevations was less than 1% in the entire MAGNITUDE patient population. He indicated that Intellia is broadly addressing this with the FDA and that while the PN study is progressing, it is premature to detail the exact path for MAGNITUDE, though commonalities and differences between the two populations are being considered.

Mark asked about the EMA's comfort with imperfect clinical data in rare diseases, referencing Skyclarys and trofinetide as analogs, and the anticipated timing for receiving Day 180 questions for the EU marketing authorization application.

Answer

Anish Bhatnagar, Chairman and CEO, acknowledged that rare disease datasets are rarely perfect and that EMA decisions are custom. He noted that the key questions centered on efficacy proof from the randomized control study and potential for bias, similar to FDA inquiries. He anticipated receiving Day 180 questions imminently, around February 26th.

Mark inquired about Mirum's perspective on the optimal endpoint for Fragile X studies, given recent comments from Shionogi, and the implications for Mirum's newly initiated program. He also asked about potential safety risks, specifically GI side effects, for Volixibat in PSC patients who often have inflammatory comorbidities, and whether blinded data showed any material differences compared to PBC or Alagille.

Answer

CEO Chris Peetz deferred to CMO Joanne Quan for details. CMO Joanne Quan expressed confidence in Mirum's Fragile X program, citing strong preclinical data, successful engagement with the community and FDA, and awareness of endpoint validation requirements. Regarding PSC safety, she noted that the data monitoring committee has raised no issues or suggested protocol modifications, indicating comfort with the current safety profile, which is consistent with known IBAT inhibitor effects.