Zokinvy: what flexibility did regulators accept, and why?

“As agreed at the pre-IND meeting held on August 22, 2018 (PIND 139923), the Applicant will conduct a carcinogenicity study postapproval.”

“No juvenile toxicity studies were conducted, although lonafarnib is in this application intended for children. The lack of juvenile toxicity studies has previously been agreed upon. In addition, the age of the animals in the toxicological studies corresponded to human ages from approximately 12 years and older and did not cover the ages of the intended paediatric patients (from 12 months and older).”

“In the rat toxicity studies, mainly the M33 is lower than 50% of the human exposure. Since monkeys were not used in the pivotal EFD studies, the low exposure of M33 in rats is uncertain which may impact the results and conclusion of the reproductive toxicity studies.”

“However, since Lonafarnib has shown reproductive toxicity in animals, demonstrating teratogenic potential at clinically relevant exposures, the current recommendation in section 4.6 of the SmPC is considered sufficient.”

“To better investigate the genotoxic potential of Compound W, the substance itself should have been tested and preferably in a bacterial reverse mutation assay.”

“The QSAR analysis report was submitted upon request in the first round of the procedure. The assessment included a statistical and an expert-rule based methodology. It is agreed that Compound W can be considered non-mutagenic.”