Zanvastro
zilganersen
Sources:FDA integrated review ↗
Species
MonkeyMouse
Longest study
39 wk
Genotox
Conducted Conducted
Carcinogenicity
Not conducted Not conducted
Repro
Conducted Conducted
First dose
Partial / alternative Partly stated
Speciesopen answer page →
Species
Mouse (SC and ICV, juvenile) and juvenile monkey (intrathecal); mouse surrogate ASO arm
“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;”
Why that species
Single mismatch to monkey GFAP mRNA gave no knockdown in monkey; mouse surrogate used to probe on-target GFAP reduction
“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.”
Surrogate molecule
Yes: mouse-specific surrogate ASO (ISIS 713812) dosed ICV in parallel juvenile mouse arm
“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;”
Study lengthopen answer page →
Longest pivotal study
39 weeks
“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”
Pivotal GLP studies
Juvenile monkey 9-month ITL Q4W; juvenile mouse 13-week ICV Q6W; juvenile mouse 26-week SC Q2W
“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).”
Route in tox
Intrathecal lumbar (monkey), intracerebroventricular and subcutaneous (mouse)
“In nonclinical toxicology studies, zilganersen was administered via ICV injection in juvenile C57BL/B6Ncrl mouse”
Skipped studiesopen answer page →
Genotoxicity
Conducted: Ames, in vitro chromosomal aberration, mouse micronucleus; all negative
“Zilganersen was negative in the Ames, in vitro chromosomal aberration, and mouse bone marrow micronucleus assays.”
Carcinogenicity
Not conducted pre-approval; Tg.rasH2 mouse and 2-year rat studies required as PMRs
“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.”
Reproductive & developmental
Combined fertility/EFD in mouse (SC), no adverse effects; rabbit EFD and PPND deferred to PMRs
“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.”
Safety pharmacology
Incorporated into 9-month monkey study (no findings); in vitro hERG minimal; auditory startle in juvenile mice
“No zilganersen-related safety pharmacology findings were identified in the 9-month monkey study”
First doseopen answer page →
First-in-human starting dose
Starting-dose rationale not stated; FDA capped clinical IT dose at 25 mg (~1/10 mouse/monkey NOAEL), later 50 mg Q12W
“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”
NOAEL / key findings
NOAEL 25 mg monkey ITL, 0.2 mg mouse ICV; transient patellar reflex loss, neuronal vacuolation at high dose; CSF-volume margins 5-17x
“The NOAEL in the 9-month ITL study in juvenile monkey was 25 mg.”
Risksopen answer page →
Immune & cytokine safety
Low-severity proinflammatory findings (liver mononuclear infiltrates, vacuolated macrophages) in 26-week SC mouse study
“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”
Biodistribution & persistence
SC dosing: dose-dependent maternal/paternal liver accumulation; very low to undetectable in placenta and fetal liver
“Zilganersen concentrations increased in a dose-dependent manner in maternal and paternal liver, but were very low to undetectable in placenta and fetal liver.”
Modality-specific risk
Intrathecal CNS toxicity (reflex loss, neuronal vacuolation), on-target GFAP knockdown neurobehavior, developmental GFAP role
“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”