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.”
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.”
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”