Amondys 45
casimersen
Species
MonkeyRatMouse
Longest study
39 wk
Genotox
Conducted Conducted
Carcinogenicity
Not conducted Not conducted
Repro
Not conducted Not conducted
First dose
Not conducted Not stated publicly
Speciesopen answer page →
Species
Adult male mouse and cynomolgus monkey; juvenile male rat
“The pivotal (GLP) general toxicity studies were conducted in adult male C57BL/6NCrl mouse and cynomolgus monkey.”
Why that species
No relevant animal models for species-/mutation-specific PMO; pharmacology in human cells only, tox species for exposure
“The pharmacological activity of casimersen was tested in vitro using human rhabdomyosarcoma cells and normal primary myoblasts, as there are no relevant animal models due to the species- and mutation-specific nature of PMO ASOs.”
Surrogate molecule
No surrogate for casimersen; proof of concept from murine exon 23 PMO AVI-4225 (eteplirsen IND)
“Proof of concept for the exon-skipping mechanism was demonstrated in studies conducted under IND 77429 using the MDX mouse model of muscular dystrophy.”
Study lengthopen answer page →
Longest pivotal study
39 weeks
“Title: SRP-4045: A 39-week intravenous infusion toxicity study in male cynomolgus monkeys with an 8-week recovery period”
Pivotal GLP studies
12-wk IV, 22-wk IV (terminated) and 26-wk SC mouse; 12-wk and 39-wk IV monkey; 10-wk IV juvenile rat
“general toxicology (12-, 22-, and 26-week IV in mouse; 12- and 39-week IV in monkey) studies”
Route in tox
IV bolus/30-min infusion; SC for 26-week mouse because chronic IV infeasible (injection-site toxicity)
“Although the clinical route of administration is IV, the adverse effects at the injection site in the 22-week mouse IV study, indicated that the IV route for the 26-week duration is not feasible.”
Skipped studiesopen answer page →
Genotoxicity
Conducted; negative (Ames, CHO chromosomal aberration, mouse micronucleus)
“Casimersen was tested in a standard battery of in vitro (bacterial reverse mutation, chromosomal aberration in CHO cells) and in vivo (mouse micronucleus) genetic toxicology assays. The studies were adequately conducted and negative.”
Carcinogenicity
Not conducted pre-approval (deferred to PMR); Tg mouse and rat dose-ranging studies done
“Carcinogenicity assessments are deferred to post-marketing for the DMD indication.”
Reproductive & developmental
Not conducted (patients extremely rare in females); male reproductive endpoints in tox studies; juvenile rat
“Reproductive and developmental toxicology studies were not required because of the intended patient population (extremely rare in females), and carcinogenicity studies may be conducted post-approval”
Safety pharmacology
Standalone monkey CV/neurological study (4 weekly IV doses up to 320 mg/kg) plus hERG; no adverse effects
“Cynomolgus monkeys received IV injections of SRP-4045 weekly for 4 total doses of 0, 5, 40, or 320 mg/kg.”
First doseopen answer page →
First-in-human starting dose
Not stated in public reviews
NOAEL / key findings
Kidney tubular basophilia/vacuolation, degeneration; juvenile rat NOAEL 300 mg/kg (4x AUC); no kidney no-effect dose in mouse/rat
“Due to the observation of degeneration and necrosis in renal tubular epithelium in a significant number of HD animals, the NOAEL for this study was the MD of 300 mg/kg”
Risksopen answer page →
Immune & cytokine safety
Dose-related complement activation (Bb, C3a) in 12-week monkey; no immune function effects in juvenile rat
“Activation of complement, dose-related in magnitude, was observed in all SRP-4045 dose groups, as evidenced by increases in Bb and C3a.”
Biodistribution & persistence
Extensive tissue distribution; highest kidney, lowest brain; urinary elimination complete by 336 h; low protein binding
“Protein binding was low (<37%) in animal and human plasma, and there was extensive tissue distribution, with highest and lowest levels of radioactivity in kidney and brain, respectively”
Modality-specific risk
Renal tubular toxicity (class PMO effect, monitorable); less severe than golodirsen
“The pivotal nonclinical studies indicate that renal impairment can result from chronic exposure to casimersen . However, because kidney function is monitorable, the nonclinical data are considered adequate”