Evrysdi
risdiplam
Species
MonkeyRat
Longest study
39 wk
Genotox
Conducted Conducted
Carcinogenicity
Conducted Conducted
Repro
Conducted Conducted
First dose
Not conducted Not stated publicly
Speciesopen answer page →
Species
Rat and cynomolgus monkey
“Repeated dose toxicity studies included studies in Wistar Hannover rats (adults) and cynomolgus monkeys (sexually immature), with administration of risdiplam, by daily oral gavage, during up to 26 and 39 weeks, respectively.”
Why that species
Secondary mRNA splice targets and metabolism (SMN2 is human-specific)
“The choice of the animal species was justified based on secondary mRNA splice targets and on metabolism. The SMN2 gene is human-specific.”
Surrogate molecule
No surrogate; the clinical compound was tested
“Repeated dose toxicity studies included studies in Wistar Hannover rats (adults) and cynomolgus monkeys (sexually immature), with administration of risdiplam, by daily oral gavage, during up to 26 and 39 weeks, respectively.”
Species: general tox
Rat (Wistar, up to 26 weeks) and cynomolgus monkey (up to 39 weeks)
“Repeated dose toxicity studies included studies in Wistar Hannover rats (adults) and cynomolgus monkeys (sexually immature), with administration of risdiplam, by daily oral gavage, during up to 26 and 39 weeks, respectively.”
Species: DART
Rat (EFD, pre/postnatal, pre- and postweaning juvenile) and rabbit (EFD)
“Embryofetal development in rat and rabbit - Pre- and postnatal development in rat - 4-week preweaning juvenile development in rat - 13-week postweaning juvenile development in rat”
Species: carcinogenicity
Tg rasH2 mouse (6-month)
“A 6-month carcinogenicity study in Tg.rasH2 mice showed no tumorigenic effects at oral doses up to 9 mg/kg/day, which was associated with exposures (AUC) of 15600 and 11800 ng.hr/mL in males and females, respectively.”
Surrogate used in
No surrogate used; transgenic SMA mice judged unsuitable for toxicity testing
“However, the use of the available transgenic mouse models of SMA for toxicity testing was not considered appropriate due to lack of availability in sufficiently large numbers, lack of suitable characterisation of relevant physiological parameters”
Study lengthopen answer page →
Longest pivotal study
39 (39-week monkey)
“Repeated dose toxicity studies included studies in Wistar Hannover rats (adults) and cynomolgus monkeys (sexually immature), with administration of risdiplam, by daily oral gavage, during up to 26 and 39 weeks, respectively.”
Pivotal GLP studies
26-week adult Wistar rat and 39-week young cynomolgus monkey oral gavage studies
“dose range-finding and 4- and 26-week definitive toxicity studies in adult Wistar rats, a 26-week non-GLP toxicity study in Brown Norway rats, dose range-finding and 2- and 39-week definitive toxicity studies in young cynomolgus monkeys”
Route in tox
Oral gavage
“The toxicology package included the following oral (gavage) repeat-dose toxicity studies:”
Skipped studiesopen answer page →
Genotoxicity
Ames negative; clastogenic (micronucleus) in vitro in mouse lymphoma cells and in vivo in rat bone marrow
“RIS was negative for mutagenicity in an in vitro Ames test but positive for clastogenicity (micronucleus (MN) formation) in vitro in mouse lymphoma cells and in vivo in a combined bone marrow micronucleus and comet assay in rat.”
Carcinogenicity
6-month rasH2 mouse: no tumors up to 9 mg/kg/day
“A 6-month carcinogenicity study in Tg.rasH2 mice showed no tumorigenic effects at oral doses up to 9 mg/kg/day”
Reproductive & developmental
Rabbit EFD: embryofetal death and hydrocephaly at maternally toxic 12 mg/kg
“Embryofetal mortality (increased number of late resorptions) and increased incidences of fetal malformations (hydrocephaly) and variations were seen in the rabbit embryofetal development study at the HD (12 mg/kg), which was also maternally toxic.”
Safety pharmacology
No significant hERG inhibition; no hemodynamic or ECG effects in monkeys at single doses up to 7.5 mg/kg
“In safety pharmacology studies, RIS concentrations up to 5 mM (said to correspond to ~18000 ng/mL total plasma concentration in human) produced no significant reduction in the outward K+ current in CHO cells expressing recombinant hERG K+ channels. In cynomolgus monkeys, administration of single oral doses up to 7.5 mg/kg had no effects on hemodynamic or ECG parameters at up to 24 hours postdose.”
Genotox: Ames
Negative
“RIS was negative for mutagenicity in an in vitro Ames test but positive for clastogenicity (micronucleus (MN) formation) in vitro in mouse lymphoma cells”
Genotox: in vitro mammalian
Micronucleus in mouse lymphoma cells: positive (clastogenic)
“RIS was negative for mutagenicity in an in vitro Ames test but positive for clastogenicity (micronucleus (MN) formation) in vitro in mouse lymphoma cells”
Genotox: in vivo
Rat bone marrow micronucleus + comet assay: positive (micronucleus formation)
“positive for clastogenicity (micronucleus (MN) formation) in vitro in mouse lymphoma cells and in vivo in a combined bone marrow micronucleus and comet assay in rat.”
Carcinogenicity model
6-month Tg rasH2 mouse: no tumors up to 9 mg/kg/day
“A 6-month carcinogenicity study in Tg.rasH2 mice showed no tumorigenic effects at oral doses up to 9 mg/kg/day, which was associated with exposures (AUC) of 15600 and 11800 ng.hr/mL in males and females, respectively.”
Carcinogenicity timing
rasH2 mouse study completed; 2-year rat study ongoing at approval as a post-approval commitment
“A two-year carcinogenicity study in rats is planned to be conducted post-approval. This is acceptable and in agreement with feedback received from CHMP and PDCO. Reference to the ongoing carcinogenicity study in rats is presented in SmPC section 5.3.”
hERG / QT
No significant hERG current reduction up to 5 mM (~18000 ng/mL human plasma equivalent)
“In safety pharmacology studies, RIS concentrations up to 5 mM (said to correspond to ~18000 ng/mL total plasma concentration in human) produced no significant reduction in the outward K+ current in CHO cells expressing recombinant hERG K+ channels.”
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 Evrysdi 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 small molecules 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: 39-week monkey NOAEL 1.5 mg/kg/day (AUC 1870/2060 ng·h/mL, males/females) (FDA pharmacology/toxicology review, p. 8)
NOAEL / key findings
39-week monkey NOAEL 1.5 mg/kg/day (AUC 1870/2060 ng·h/mL, males/females)
“The NOAEL (1.5 mg/kg/day) was associated with RIS exposures of 414 / 396 ng/mL (Cmax) and 1870 / 2060 ng·hr/mL (AUC0-24 h) during Week 39 of the dosing phase for males / females.”
Risksopen answer page →
Immune & cytokine safety
Decreased B lymphocytes in juvenile rats
“Decreases in the B lymphocyte relative percentages and absolute counts were observed in HD males and females at all doses.”
Biodistribution & persistence
Strong melanin binding: high, persistent levels in choroid/RPE, iris and sclera in rats and monkeys
“Substantial distribution into melanin-containing parts of the eye (choroid + retinal pigment epithelium [RPE], iris, sclera) was demonstrated in rats and monkeys, and ocular RIS concentrations remained high for considerable periods after the end of dosing.”
Modality-specific risk
Retinal degeneration in monkeys of unknown mechanism
“The data suggest that retinal effects are seen only in monkeys, the exact mechanism for the delayed type of retinal toxicity being at present unknown”
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
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.
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 Evrysdi 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 small molecules 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: 39-week monkey NOAEL 1.5 mg/kg/day (AUC 1870/2060 ng·h/mL, males/females) (FDA pharmacology/toxicology review, p. 8)
Longest repeat-dose systemic studies
Longest repeat-dose study and recovery
39-week oral cynomolgus monkey study with 22-week recovery phase
“Skin changes fully recovered within the 22-week recovery phase in monkeys treated for 39 weeks with the high dose of risdiplam.”
Pivotal GLP studies
26-week adult Wistar rat and 39-week young cynomolgus monkey oral gavage studies
“dose range-finding and 4- and 26-week definitive toxicity studies in adult Wistar rats, a 26-week non-GLP toxicity study in Brown Norway rats, dose range-finding and 2- and 39-week definitive toxicity studies in young cynomolgus monkeys”
DART package
Species: DART
Rat (EFD, pre/postnatal, pre- and postweaning juvenile) and rabbit (EFD)
“Embryofetal development in rat and rabbit - Pre- and postnatal development in rat - 4-week preweaning juvenile development in rat - 13-week postweaning juvenile development in rat”
Reproductive & developmental
Rabbit EFD: embryofetal death and hydrocephaly at maternally toxic 12 mg/kg
“Embryofetal mortality (increased number of late resorptions) and increased incidences of fetal malformations (hydrocephaly) and variations were seen in the rabbit embryofetal development study at the HD (12 mg/kg), which was also maternally toxic.”
PPND / ePPND: when
PPND in rat completed and reviewed with the marketing application; dystocia limited the high dose
“In the pre- and postnatal development study in rats in which the highest dose tested (3 mg/kg) was limited by apparent effects on parturition (dystocia), gestation was lengthened at the HD”
Carcinogenicity
Species: carcinogenicity
Tg rasH2 mouse (6-month)
“A 6-month carcinogenicity study in Tg.rasH2 mice showed no tumorigenic effects at oral doses up to 9 mg/kg/day, which was associated with exposures (AUC) of 15600 and 11800 ng.hr/mL in males and females, respectively.”
Carcinogenicity model
6-month Tg rasH2 mouse: no tumors up to 9 mg/kg/day
“A 6-month carcinogenicity study in Tg.rasH2 mice showed no tumorigenic effects at oral doses up to 9 mg/kg/day, which was associated with exposures (AUC) of 15600 and 11800 ng.hr/mL in males and females, respectively.”
Carcinogenicity timing
rasH2 mouse study completed; 2-year rat study ongoing at approval as a post-approval commitment
“A two-year carcinogenicity study in rats is planned to be conducted post-approval. This is acceptable and in agreement with feedback received from CHMP and PDCO. Reference to the ongoing carcinogenicity study in rats is presented in SmPC section 5.3.”
Safety marginopen answer page →
Safety margin at NOAEL
Monkey 39-week NOAEL (1.5 mg/kg/day) AUC identical to targeted patient exposure (no margin)
“the NOAEL was considered to be 1.5 mg/kg/day. At the NOAEL, systemic exposure (AUC0-24h) to risdiplam in males and females was identical to the targeted exposure in patients.”
NOAEL / key findings
39-week monkey NOAEL 1.5 mg/kg/day (AUC 1870/2060 ng·h/mL, males/females)
“The NOAEL (1.5 mg/kg/day) was associated with RIS exposures of 414 / 396 ng/mL (Cmax) and 1870 / 2060 ng·hr/mL (AUC0-24 h) during Week 39 of the dosing phase for males / females.”
Efficacy evidenceopen answer page →
Efficacy evidence
SMNΔ7 and C/C SMA mouse models carrying the human SMN2 transgene
“The in vivo activity of RIS was investigated in 2 different SMA mouse models (SMNΔ7 and C/C), which both carry the human SMN2 transgene”
Why that model
SMN2 exists only in humans, so in vivo models require transgenic mice carrying human SMN2
“The intended pharmacological target, the SMN2 gene, exists only in humans, and thus a pharmacological responder species as requested by existing guidelines does not exist unless studies are conducted in transgenic mouse models.”
Reviewer's view of the efficacy data
EMA: the two SMA mouse models support SMN protein increase in brain and muscle, but the clinical SMN target could not be verified
“Since the applicant did not provide the baseline SMN levels in the two transgenic SMA mouse models, it is not possible to verify such clinical target, However, it is agreed that data from the two mouse SMA models suggest a positive correlation between FL SMN protein increases and increase in the brain and quadriceps.”
Flexibilityopen answer page →
Flexibility accepted
CarcinogenicityAccepted with a conditionBeyond the letter
Only a rasH2 mouse study before approval; 2-year rat carcinogenicity study deferred to a post-approval commitment
Why: Agreed with CHMP and PDCO; ongoing study referenced in SmPC section 5.3 and RMP
“A two-year carcinogenicity study in rats is planned to be conducted post-approval. This is acceptable and in agreement with feedback received from CHMP and PDCO.”
“Furthermore, it is recommended that lack of complete non-clinical data on carcinogenicity is considered in the RMP, and that the reference to the ongoing carcinogenicity study in rats is clearly presented in SmPC section 5.3.”
DARTVerdict not stated
No standard fertility and early embryonic development study; fertility assessed within juvenile and adult repeat-dose studies
Why: Fertility integrated into juvenile rat studies; reproductive organ histopathology examined in adult and juvenile studies · Weight of evidence
“A standard fertility and early embryonic development study was not conducted. The sponsor’s justification was that assessment of fertility was integrated into the juvenile rat toxicity studies and reproductive organ histopathology was examined in the adult and juvenile toxicity studies.”
Safety marginVerdict not stated
No exposure margin at the 39-week monkey NOAEL: AUC identical to targeted patient exposure
“At the NOAEL, systemic exposure (AUC0-24h) to risdiplam in males and females was identical to the targeted exposure in patients.”
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