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.”
Species: general tox
Mouse (13-week), rat (26-week) and monkey (39-week)
“General toxicity studies were conducted for durations up to 13 weeks in mice, 26 weeks in rats, and 39 weeks in monkeys.”
Species: DART
Rat and rabbit (embryo-fetal development)
“In embryo-fetal developmental toxicity studies in pregnant rats and rabbits, teratogenicity and developmental toxicity were observed.”
Species: carcinogenicity
Transgenic mouse (26-week) and rat (104-week)
“Long-term carcinogenicity studies were conducted in mice (26 -week duration) and one in rats (104- week duration).”
Surrogate used in
No surrogate used; sparsentan binds rat receptors; monkey ETAR/AT1R 99% identical to human
“The affinity of sparsentan for the rat ETAR and AT1R was also demonstrated. Receptor homology ranges from 99% identity to human for both ETAR and AT1R in monkeys and to 92% and 94% identity for ETAR and AT1R, respectively, in mice.”
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).”
Genotox: Ames
Negative
“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.”
Genotox: in vitro mammalian
Negative: in vitro chromosomal aberration assay
“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.”
Genotox: in vivo
Negative: in vivo rat micronucleus
“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 model
2-year rat: no neoplasia (males 15 mg/kg/day, 0.7x; females up to 240 mg/kg/day, 26x MRHD AUC)
“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.”
Carcinogenicity timing
26-week Tg.rasH2 mouse and 104-week rat studies completed before the marketing application
“Long-term carcinogenicity studies were conducted in mice (26 -week duration) and one in rats (104- week duration).”
hERG / QT
No hERG inhibition (margin >2912x); no QTc prolongation in monkeys at 6x clinical exposure
“Sparsentan did not inhibit the hERG channel (hERG safety margin >2912x) and no QTc prolongation was detected in the in vivo QT study in monkeys at 6× the high clinical exposure.”
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.”
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.
Label warnings
Boxed warning: HEPATOTOXICITY and EMBRYO-FETAL TOXICITY
- Hepatotoxicity
- Filspari rems
- Embryo-Fetal Toxicity
- Hypotension
- Acute Kidney Injury
- Hyperkalemia
- Fluid Retention
HepatotoxicityEmbryo-fetal toxicityCardiovascularNephrotoxicityMetabolic & endocrine
US prescribing information, Boxed Warning and 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 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)
Longest repeat-dose systemic studies
Longest repeat-dose study and recovery
39-week oral cynomolgus monkey study with 8-week recovery
“Study title: PS433540: 39- Week Toxicity Study in Cynomolgus Monkeys with an 8-Week Recovery”
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.”
DART package
Species: DART
Rat and rabbit (embryo-fetal development)
“In embryo-fetal developmental toxicity studies in pregnant rats and rabbits, teratogenicity and developmental toxicity were observed.”
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.”
PPND / ePPND: when
PPND in rat completed and reviewed with the marketing application; NOAEL 5 mg/kg/day
“In the pre- and postnatal developmental toxicity study, administration of sparsentan at doses of 5, 20 and 80 mg/kg/day to pregnant rats caused toxicity in offspring”
Carcinogenicity
Species: carcinogenicity
Transgenic mouse (26-week) and rat (104-week)
“Long-term carcinogenicity studies were conducted in mice (26 -week duration) and one in rats (104- week duration).”
Carcinogenicity model
2-year rat: no neoplasia (males 15 mg/kg/day, 0.7x; females up to 240 mg/kg/day, 26x MRHD AUC)
“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.”
Carcinogenicity timing
26-week Tg.rasH2 mouse and 104-week rat studies completed before the marketing application
“Long-term carcinogenicity studies were conducted in mice (26 -week duration) and one in rats (104- week duration).”
Safety marginopen answer page →
Safety margin at NOAEL
9-month monkey NOAEL 50 mg/kg/d: 0.2 (males) and 0.1 (females) times human AUC at 800 mg
“The NOAEL in the monkeys in the 9-month study was 50 mg/kg/d. At the NOAEL, the associated Week 39 AUC0-last values were 16,700 h⋅ng/mL in males and 12,700 h⋅ng/mL in females or 0.2 and 0.1 times, respectively, the AUC0-24 in humans at 800 mg clinical dose.”
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.”
Efficacy evidenceopen answer page →
Efficacy evidence
gddY and passive (EIC-induced) mouse IgAN models; anti-Thy-1 rat mesangioproliferative glomerulonephritis model
“The test article has demonstrated efficacy in 2 rodent models of IgAN (also known as Berger’s disease) - the grouped Deutschland, Denken, and Yoken (gddY) mouse model and an engineered immune complex (EIC)-induced “passive IgAN” mouse model - and in a model of mesangial proliferative glomerular nephritis - the anti-Thymocyte (Thy-1) rat (ATS) model.”
Why that model
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.
Reviewer's view of the efficacy data
EMA: rodent kidney-damage models showed reduced proteinuria, glomerulosclerosis, podocyte loss, inflammation and GFR decline
“In a battery of in vivo PD studies using multiple rodent models of kidney damage, treatment with sparsentan resulted in attenuation of the development of proteinuria, amelioration of glomerulosclerosis, protection of podocytes, reduced TIF, reduction of inflammatory cell infiltrate and mesangial cell activation and attenuation of decline in GFR.”
Flexibilityopen answer page →
Flexibility accepted
Safety marginVerdict not stated
No exposure margin at the 9-month monkey NOAEL: 0.2 (males) and 0.1 (females) times human AUC at 800 mg
“The NOAEL in the monkeys in the 9-month study was 50 mg/kg/d. At the NOAEL, the associated Week 39 AUC0-last values were 16,700 h⋅ng/mL in males and 12,700 h⋅ng/mL in females or 0.2 and 0.1 times, respectively, the AUC0-24 in humans at 800 mg clinical dose.”
CarcinogenicityVerdict not stated
2-year rat study: male dose limited by tolerability, exposure about 0.7 times MRHD AUC
Why: Male dose limited by tolerability
“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.”
OtherAcceptedBeyond the letter
No nonclinical pharmacodynamic drug interaction studies
Why: PD interactions of endothelin antagonists and angiotensin receptor blockers already well characterised · Class precedent
“No non-clinical PD drug interaction studies were performed and a justification that PD interactions of endothelin antagonists and angiotensin receptor blockers with other drugs have been well characterised in the past was provided. The approach is acceptable to the CHMP.”
Impurity or metaboliteVerdict not stated
Bacterial mutagenicity test not performed for one alerting synthetic intermediate; controlled as a Class 2 impurity
Why: Impurity treated as Class 2 (mutagenic) impurity instead of testing
“One was evaluated in a bacterial mutagenicity assay and was negative; reverse bacterial mutagenicity testing was not performed for the second and will be treated as a Class 2 impurity.”
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