Zanvastro

“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, as well as a 13-week ICV toxicity study in mouse;”

“No meaningful changes in GFAP mRNA levels were observed in brain or spinal cord tissues, likely due to the single mismatch between zilganersen and monkey GFAP mRNA.”

“A parallel group administered the mouse surrogate ASO (ISIS 713812; 0.1 mg ICV) demonstrated locomotor hypoactivity and reductions in bone mineral content in males;”

“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, as well as a 13-week ICV toxicity study in mouse;”

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

“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.”

“A parallel group administered the mouse surrogate ASO (ISIS 713812; 0.1 mg ICV) demonstrated locomotor hypoactivity and reductions in bone mineral content in males;”

“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).”

“In nonclinical toxicology studies, zilganersen was administered via ICV injection in juvenile C57BL/B6Ncrl mouse”

“Zilganersen was negative in the Ames, in vitro chromosomal aberration, and mouse bone marrow micronucleus assays.”

“No new studies were provided. The Division agreed these studies can be completed as post-marketing requirements (PMRs) given the benefit:risk and unmet medical need.”

“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.”

“No zilganersen-related safety pharmacology findings were identified in the 9-month monkey study”

“Zilganersen was negative in the Ames, in vitro chromosomal aberration, and mouse bone marrow micronucleus assays.”

“Zilganersen was negative in the Ames, in vitro chromosomal aberration, and mouse bone marrow micronucleus assays.”

“Zilganersen was negative in the Ames, in vitro chromosomal aberration, and mouse bone marrow micronucleus assays.”

“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.”

“No zilganersen-related safety pharmacology findings were identified in the 9-month monkey study, and hERG inhibition in HEK-293 (human embryonic kidney-293) cells was minimal (IC50>150µM).”

“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 NOAEL in the 9-month ITL study in juvenile monkey was 25 mg.”

“revealed findings consistent with ASO uptake, accumulation, and a proinflammatory response, including basophilic granules in Kupffer cells, mononuclear cell infiltration in the liver, and vacuolated/granular macrophages in multiple tissues”

“Zilganersen concentrations increased in a dose-dependent manner in maternal and paternal liver, but were very low to undetectable in placenta and fetal liver.”

“In the 9-month ITL study in juvenile monkey, transient patellar reflex losses, occasionally accompanied by foot grip impairment, were observed at mid dose and high dose, along with neuronal vacuolation in the brain at high dose”

“Neutralizing ADA assays were not performed. Incidence 28.1% of zilganersen-treated subjects (9/32) were overall ADA positive over the DB and OL and LTE periods. All ADA were treatment-induced; 2 were transient and 7 were persistent.”

“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.”

“Based on doses normalized to CSF volume, the NOAELs in mouse and monkey provide safety margins of 34 and 10, respectively, compared to the (b) (4) human dose of 25 mg, but of 17 and 5, respectively, compared to the proposed human dose of 50 mg.”

“The NOAEL in the 9-month ITL study in juvenile monkey was 25 mg.”

“Specifically, administration of zilganersen reduced GFAP mRNA and AxD-like features in transgenic mice overexpressing human GFAP; additionally, a species surrogate ASO reduced brain GFAP mRNA and decreased GFAP protein in the CSF of a rat model of AxD.”

“Given the lack of cross-reactivity to rodent or monkey GFAP mRNA, pharmacologic effects of zilganersen in vivo were evaluated in”

“These target engagement and mechanistic data confirmed the biologic plausibility of the observed treatment benefit and that the drug is having its intended effect.”