Dawnzera: what flexibility did regulators accept, and why?

“The Applicant previously sought CHMP Scientific Advice on the necessity for studies in rabbits and it was agreed that studies may not be required on the basis that neither donidalorsen nor the unconjugated PS-only compound, ISIS 546254, were pharmacologically active in the rabbit.”

“This justification is well supported in the literature and is accepted by the CHMP.”

“At the pre-NDA meeting, the Division agreed that it would be acceptable to submit the report of the 6-month carcinogenicity study in Tg.rasH2 mice and a summary of the in-life data for the 2-year carcinogenicity study in rats at the time of the NDA submission and to submit the final report as a PMR (Refer to IND 142564 pre-NDA Meeting Preliminary Comments dated 04/10/2024).”

“While this may provide an explanation for the observations, there was an absence of plasma exposure data in this study to allow a direct derivation of safety to the clinical exposure.”

“Thus, based on the weight of evidence the carcinogenicity assessment to date is acceptable for the CHMP.”

“No AUC data was available for the juvenile mouse study. The lack of AUC data from the juvenile mouse study prevents a quantitative assessment of potential increased sensitivity in younger subjects.”

“It is agreed that additional study data would not provide further useful information for this procedure, and overall sufficient data are available for adolescents (≥12 years), thus this issue was not pursued from a nonclinical perspective.”