Filspari
sparsentan
Species
MonkeyRatMouse
Longest study
39 wk
Genotox
Conducted Conducted
Carcinogenicity
Conducted Conducted
Repro
Conducted Conducted
First dose
Not conducted Not stated publicly
Speciesopen answer page →
Species
Mouse, rat and cynomolgus monkey
“General toxicity studies were conducted for durations up to 13 weeks in mice, 26 weeks in rats, and 39 weeks in monkeys.”
Why that species
Monkey ETA and AT1 receptors closely homologous to human; pharmacology, metabolism and toxicity consistent with rat
“As sequence similarity of monkey ETAR and AT1R to human ETAR and AT1R is relatively high, anticipated pharmacology is observed in the monkey safety pharmacology and repeat dose toxicity studies, and considering that pharmacological activity, metabolic profile, and toxicological findings in monkeys are consistent with observations in the rat”
Surrogate molecule
No surrogate; the clinical compound was tested
“Following 26 weeks of treatment in rats, minimal to mild renal tubular degeneration was noted at the 320 mg/kg/day dose with increased incidence/severity compared to the control, and it was fully reversible.”
Study lengthopen answer page →
Longest pivotal study
39 (39-week monkey)
“General toxicity studies were conducted for durations up to 13 weeks in mice, 26 weeks in rats, and 39 weeks in monkeys.”
Pivotal GLP studies
13-week mouse, 26-week rat and 39-week cynomolgus monkey oral studies
“General toxicity studies were conducted for durations up to 13 weeks in mice, 26 weeks in rats, and 39 weeks in monkeys.”
Route in tox
Skipped studiesopen answer page →
Genotoxicity
Negative in Ames, in vitro chromosomal aberration and in vivo rat micronucleus assays
“There was no evidence of mutagenicity or clastogenicity for sparsentan in in vitro bacteria reverse mutation and chromosomal aberration assays or in an in vivo rat micronucleus study.”
Carcinogenicity
2-year rat: no increased neoplasia (males 15 mg/kg/day, limited by tolerability; females up to 240 mg/kg/day)
“In the 2-year rat carcinogenicity study, there was no evidence of an increased incidence of neoplasia in male rats orally administered 15 mg/kg/day (dose limited by tolerability) and in female rats orally administered up to 240 mg/kg/day, which provides an exposure approximately 0.7 times and 26 times the AUC at the MRHD, respectively.”
Reproductive & developmental
Rat EFD: craniofacial and skeletal malformations, embryo-fetal lethality and reduced fetal weight at all doses (≥80 mg/kg/day)
“In pregnant rats treated with sparsentan at doses of 80, 160, and 240 mg/kg/day, dose-dependent toxicity and teratogenicity marked by craniofacial malformations, skeletal abnormalities, embryo-fetal lethality, and reduced fetal weight were observed at all doses.”
Safety pharmacology
No relevant cardiovascular (monkey), respiratory or CNS (rat) effects at doses up to 1000 mg/kg
“Sparsentan, at doses up to 1000 mg/kg, did not show statistically significant or biologically relevant AEs on the CVS (monkeys) or the respiratory and CNS (rats).”
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 Filspari 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: 9-month monkey NOAEL 50 mg/kg/day; changes reversible or reversing after 1–2-month recovery (EMA assessment report, p. 24)
NOAEL / key findings
9-month monkey NOAEL 50 mg/kg/day; changes reversible or reversing after 1–2-month recovery
“All sparsentan-related changes were reversible or reversing at the end of the 1-or 2-month recovery periods. The NOAEL in the monkeys in the 9-month study was 50 mg/kg/d.”
Risksopen answer page →
Immune & cytokine safety
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.
Biodistribution & persistence
Rat QWBA: no melanin affinity, none in eye lens; elimination complete in all tissues by 168 h
“No affinity for tissues containing melanin was noted and no quantifiable amount was detected in the eye lens. In all tissues, the elimination of radioactivity was complete by 168 hours postdosing.”
Modality-specific risk
Embryofetal toxicity (teratogenicity) consistent with ETA and AT1 receptor blockade
“In embryo-fetal developmental toxicity studies in pregnant rats and rabbits, teratogenicity and developmental toxicity were observed. The findings were consistent with the pharmacologic class of compounds that inhibit ETA and angiotensin II type 1 (AT1) receptors.”