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.”
Species: general tox
Mouse and juvenile cynomolgus monkey
“Toxicity studies of nusinersen were conducted in mice and juvenile cynomolgus monkeys.”
Species: DART
Mouse and rabbit
“Developmental and reproductive toxicity studies in mice and rabbit showed no fetal effects related to treatment with nusinersen.”
Species: carcinogenicity
Mouse (2-year SC study, conducted after approval)
“Administration of nusinersen (0, 5, 15, or 50 mg/kg) to male and female mice by subcutaneous injection, once every two weeks for 2 years, resulted in an increase in the incidence of vascular tumors (combined hemangioma and hemangiosarcoma) at the highest dose tested.”
Surrogate used in
Transgenic models only: human-SMN2 SMA mice for in vivo pharmacology; no surrogate molecule
“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.”
Genotox: Ames
Negative (Ames)
“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.”
Genotox: in vitro mammalian
Chromosomal aberration in CHO cells: negative
“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.”
Genotox: in vivo
Mouse micronucleus: negative
“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 model
2-year SC mouse study: increased vascular tumors (hemangioma/hemangiosarcoma) at the highest dose
“Administration of nusinersen (0, 5, 15, or 50 mg/kg) to male and female mice by subcutaneous injection, once every two weeks for 2 years, resulted in an increase in the incidence of vascular tumors (combined hemangioma and hemangiosarcoma) at the highest dose tested.”
Carcinogenicity timing
No carcinogenicity study before approval; 2-year carcinogenicity study is a postmarketing requirement
“the sponsor should conduct a 2-year carcinogenicity study as a postmarketing requirement.”
hERG / QT
No ECG effects in repeat-dose IT monkey studies; no cardiovascular effects in rats with 25-day IT infusion
“In safety pharmacology studies, there were no pulmonary or cardiovascular effects in rats using continuous intrathecal (IT) infusion for 25 days, or effects on ECG in the repeat-dose IT toxicology studies in monkeys.”
First doseopen answer page →
First-in-human starting dose
Not stated in public reviews
Why it's blank
The public FDA and EMA reviews of Spinraza don't say how the first human dose was chosen. That rationale is in the IND, which is confidential, so it is missing for most approved products.
How it's usually set for oligonucleotides outside oncology
Find the highest dose with no adverse effects (NOAEL) in each animal species, convert it to a human equivalent dose, usually by body surface area, pick the most appropriate species, then divide by a safety factor (default 10) to get the maximum recommended starting dose.
“In general, one should consider using a safety factor of at least 10. The MRSD should be obtained by dividing the HED by the safety factor.”
This product's starting point
NOAEL / key findings: Monkey neurotoxicity NOAEL 0.3 mg/dose; hippocampal neuronal vacuolation/necrosis; no CSF-based safety margin (FDA pharmacology/toxicology review, p. 89)
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.”
Anti-drug antibodies: animals
Not stated in public reviews
Not reported in the public reviews. Reviewers summarise selectively, so this usually means it wasn't discussed publicly, not that it wasn't studied.
Anti-drug antibodies: patients
10% treatment-emergent ADA with low dose regimen (16 transient, 22 persistent)
“Thirty eight patients (10%) developed treatment-emergent ADAs, of which 16 were transient and 22 were considered to be persistent.”
Label warnings
- Thrombocytopenia and Coagulation Abnormalities
- Renal Toxicity
ThrombocytopeniaNephrotoxicity
US prescribing information, Warnings and PrecautionsDailyMed ↗
Tox packageopen answer page →
Before first-in-human
First-in-human: where
Not stated in public reviews
Not reported in the public reviews. Reviewers summarise selectively, so this usually means it wasn't discussed publicly, not that it wasn't studied.
Repeat-dose tox before first-in-human
Not stated in public reviews
Not reported in the public reviews. Reviewers summarise selectively, so this usually means it wasn't discussed publicly, not that it wasn't studied.
First-in-human starting dose
Not stated in public reviews
Why it's blank
The public FDA and EMA reviews of Spinraza don't say how the first human dose was chosen. That rationale is in the IND, which is confidential, so it is missing for most approved products.
How it's usually set for oligonucleotides outside oncology
Find the highest dose with no adverse effects (NOAEL) in each animal species, convert it to a human equivalent dose, usually by body surface area, pick the most appropriate species, then divide by a safety factor (default 10) to get the maximum recommended starting dose.
“In general, one should consider using a safety factor of at least 10. The MRSD should be obtained by dividing the HED by the safety factor.”
This product's starting point
NOAEL / key findings: Monkey neurotoxicity NOAEL 0.3 mg/dose; hippocampal neuronal vacuolation/necrosis; no CSF-based safety margin (FDA pharmacology/toxicology review, p. 89)
Longest repeat-dose systemic studies
Longest repeat-dose study and recovery
53-week (one year) juvenile cynomolgus monkey study with 26-week recovery
“ISIS 396443: 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.”
DART package
Species: DART
Mouse and rabbit
“Developmental and reproductive toxicity studies in mice and rabbit showed no fetal effects related to treatment with nusinersen.”
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.”
PPND / ePPND: when
PPND study ongoing at approval; submission is a postmarketing requirement
“A pre- and postnatal development study is ongoing; submission of the study should be a post-marketing requirement.”
Carcinogenicity
Species: carcinogenicity
Mouse (2-year SC study, conducted after approval)
“Administration of nusinersen (0, 5, 15, or 50 mg/kg) to male and female mice by subcutaneous injection, once every two weeks for 2 years, resulted in an increase in the incidence of vascular tumors (combined hemangioma and hemangiosarcoma) at the highest dose tested.”
Carcinogenicity model
2-year SC mouse study: increased vascular tumors (hemangioma/hemangiosarcoma) at the highest dose
“Administration of nusinersen (0, 5, 15, or 50 mg/kg) to male and female mice by subcutaneous injection, once every two weeks for 2 years, resulted in an increase in the incidence of vascular tumors (combined hemangioma and hemangiosarcoma) at the highest dose tested.”
Carcinogenicity timing
No carcinogenicity study before approval; 2-year carcinogenicity study is a postmarketing requirement
“the sponsor should conduct a 2-year carcinogenicity study as a postmarketing requirement.”
Safety marginopen answer page →
Safety margin at NOAEL
No margin: monkey 53-week neurotoxicity no-effect dose 0.3 mg gave CSF 12 ng/mL, within patient levels (7-35 ng/mL)
“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.”
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.”
Efficacy evidenceopen answer page →
Efficacy evidence
Transgenic SMA mouse models expressing human SMN2 (ICV and IT dosing)
“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.”
Why that model
SMN2 exists only in humans, so in vivo pharmacology required mice with mouse Smn removed and human SMN2 expressed
“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.”
Reviewer's view of the efficacy data
FDA: nusinersen increased SMN2 exon 7 inclusion in cells and animals with beneficial effects in SMA mouse models
“In cell culture and animals, ISIS 396443 increased SMN2 exon 7 inclusion and had beneficial effects in mouse models of SMA.”
Flexibilityopen answer page →
Flexibility accepted
Study lengthAccepted with a conditionBeyond the letter
No chronic rodent toxicity study to assess systemic exposure
Why: Postmarketing carcinogenicity study in one species to provide chronic toxicity data
“A less-than standard battery of nonclinical studies (no chronic toxicity study in rodent [to assess systemic exposure], pre- and postnatal development (PPND) study in rodent, or carcinogenicity studies in mouse and rat) was conducted to support approval of nusinersen.”
“Completion of the ongoing PPND study and a carcinogenicity study in one species (which will provide chronic toxicity data) should be post-marketing requirements.”
CarcinogenicityAccepted with a conditionBeyond the letter
No carcinogenicity studies before approval; waiver requested, parenteral study in one species required postmarketing
Why: Lifetime intrathecal rodent studies infeasible; waiver rejected because of significant systemic exposure in patients · Other reason
“Carcinogenicity studies were not conducted. The sponsor has requested a waiver based on the infeasibility of conducting lifetime studies in rodents by the IT route, but given the significant systemic exposure documented in clinical studies, it is recommended that a parenteral study in one species be conducted postmarketing.”
DARTAccepted with a conditionBeyond the letter
Pre- and postnatal development study incomplete at approval; deferred to postmarketing requirement
“A pre- and postnatal development study is ongoing; submission of the study should be a post-marketing requirement.”
Safety marginCriticised but acceptedBeyond the letter
No CSF-based safety margin for hippocampal neurotoxicity in the 53-week juvenile monkey study
Why: Seriousness of the indication and apparently substantial clinical efficacy · Serious disease
“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.”
“However, considering the seriousness of the indication and the apparently substantial evidence of efficacy in the clinical trials in SMA patients, there is no objection to approval of the NDA from a pharmacology/toxicology standpoint.”
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