Spinraza
nusinersen
Species
MonkeyMouse
Longest study
53 wk
Genotox
Conducted Conducted
Carcinogenicity
Not conducted Not conducted
Repro
Conducted Conducted
First dose
Not conducted Not stated publicly
Speciesopen answer page →
Species
Juvenile cynomolgus monkey (IT) and CD-1 mouse (SC, systemic effects)
“Based on the intended patient population (neonates to adolescents), 14- and 53-week repeat dose toxicology studies were conducted in juvenile cynomolgus monkeys using IT dose administration.”
Why that species
No animal has SMN2; monkey used for clinical IT route/CNS exposure, transgenic SMA mice for pharmacology
“Since humans are the only species known to have the SMN2 gene, in vivo pharmacology was examined in mouse models of SMA in which the endogenous mouse gene has been removed and the human SMN2 gene is expressed.”
Surrogate molecule
No surrogate; clinical ASO tested; human-SMN2 transgenic mice used for pharmacology only
“In vivo studies (using intracerebroventricular and intrathecal [IT] administration) were conducted in transgenic mouse models of SMA because only humans are known to have the SMN2 gene.”
Study lengthopen answer page →
Longest pivotal study
53 weeks
“A one year (53 weeks) repeat dose toxicity study in juvenile cynomolgus monkeys with a 26-week recovery phase”
Pivotal GLP studies
14- and 53-week IT bolus juvenile monkey; 13-week SC juvenile mouse; single-dose IT adult monkey
“The toxicity and pharmacokinetics (PK) of ISIS 396443 were evaluated following single IT bolus doses (up to 7 mg) in adult monkeys or following repeated IT bolus doses (weekly or every other week) for 14 (0.3, 1, or 3 mg/dose) and 53 (0.3, 1, or 4 mg/dose) weeks in juvenile monkeys.”
Route in tox
Intrathecal lumbar bolus (monkey, clinical route); subcutaneous (mouse, rabbit) for systemic exposure
“CNS safety was assessed as part of the acute and subchronic toxicity studies in monkeys using IT lumbar bolus injection, the intended route of administration in man.”
Skipped studiesopen answer page →
Genotoxicity
Conducted; negative (Ames, CHO chromosomal aberration, mouse micronucleus)
“ISIS 396443 was negative in an adequately conducted standard battery of in vitro (Ames and chromosomal aberration in CHO) and in vivo (mouse micronucleus) assays.”
Carcinogenicity
Not conducted pre-approval (IT route infeasible); SC carcinogenicity study as postmarketing requirement
“Carcinogenicity studies have not been conducted with nusinersen at this time. The Division has recommended that a carcinogenicity study be conducted after approval.”
Reproductive & developmental
Mouse fertility/EFD and rabbit EFD (SC): no clear toxicity; PPND ongoing as PMR
“No clear evidence of reproductive or developmental toxicity was seen in mouse and rabbit studies, and ISIS 396443 was negative for genotoxicity in a standard battery of in vitro and in vivo assays.”
Safety pharmacology
Rat IT-infusion respiratory/CV study; CNS endpoints incorporated into monkey IT tox studies
“Safety pharmacology consisted of a respiratory and cardiovascular safety pharmacology study in rats treated by continuous intrathecal (IT) infusion.”
First doseopen answer page →
First-in-human starting dose
Not stated in public reviews
NOAEL / key findings
Monkey neurotoxicity NOAEL 0.3 mg/dose; hippocampal neuronal vacuolation/necrosis; no CSF-based safety margin
“The no-effect dose (0.3 mg) for neurotoxicity in the 53-week monkey study was associated with csf levels (12 ng/mL) generally less than that in SMA patients (7-35 ng/mL); therefore, there is no safety margin based on csf levels.”
Risksopen answer page →
Immune & cytokine safety
No complement activation or systemic inflammation in IT monkey studies; proinflammatory effects in mice
“In the 14- and 53-week juvenile monkey studies, no drug-related mortality or effects on body weight, ECG, CSF chemistry/cell counts, clinical pathology, or complement activation (as measured by concentrations of Bb split product) were observed”
Biodistribution & persistence
Substantial CSF-to-systemic transfer; liver/kidney levels similar to spinal cord; CSF t1/2 ~102-111 days
“Concentrations in systemic tissues like liver and kidney following IT administration were similar to those seen in the spinal cord indicating that a substantial proportion of the administered dose was transferred from CSF to the systemic circulation.”
Modality-specific risk
CNS neurotoxicity (hippocampal vacuolation, possible learning deficit) after IT ASO; renal/macrophage PS-oligo accumulation
“Taken together, these considerations as well as the data suggesting a neurobehavioral deficit indicate that the hippocampal vacuolation observed in monkeys following IT administration of ISIS 396443 should be considered an adverse neurotoxic effect.”