Zanvastro: what was done before first-in-human, and what came after?

“Subjects outside the United States received the IT placebo injection throughout the trial.”

“The FDA placed protocol ION373-CS1 on hold for IT doses of ION373 exceeding 25 mg, which is approximately 1/10th the NOAELs in mouse and monkey, due to unexplained deaths in female mice in the 9-week ICV toxicity study.”

“The FDA placed protocol ION373-CS1 on hold for IT doses of ION373 exceeding 25 mg, which is approximately 1/10th the NOAELs in mouse and monkey”

“The nonclinical package submitted to the NDA included general toxicology studies of up to 26 and 39 weeks' duration in mouse (subcutaneous [SC]) and monkey (intrathecal lumbar [ITL]), respectively”

“In nonclinical toxicology studies, zilganersen was administered via ICV injection in juvenile C57BL/B6Ncrl mouse (13 weeks; 0, 0.05, 0.1, or 0.2 mg every 6 weeks) and via ITL injection in juvenile monkey (9 months; 0, 3, 8, or 25 mg Q4W).”

“The Applicant has completed a combined fertility and developmental toxicology study in the mouse model.”

“No adverse fertility or embryofetal developmental effects were observed in mouse administered zilganersen subcutaneously at doses of 0, 10, 30, or 60 mg/kg once every 2 weeks.”

“5053-4: Conduct a pre- and postnatal development (PPND) study of zilganersen and the mouse surrogate (ISIS 713812) to evaluate maternal and offspring toxicity.”

“5053-1: Conduct a 6-month carcinogenicity study of zilganersen in Tg.rasH2 mice to assess tumorigenic potential. 5053-2: Conduct a 2-year carcinogenicity study of zilganersen in rats to assess tumorigenic potential.”

“Long-term studies to assess the carcinogenic potential of zilganersen have not been conducted.”

“5053-1: Conduct a 6-month carcinogenicity study of zilganersen in Tg.rasH2 mice to assess tumorigenic potential. 5053-2: Conduct a 2-year carcinogenicity study of zilganersen in rats to assess tumorigenic potential.”