Ponvory
ponesimod
Species
RatMouseDogRabbit
Longest study
52 wk
Genotox
Conducted Conducted
Carcinogenicity
Conducted Conducted
Repro
Conducted Conducted
First dose
Not conducted Not stated publicly
Speciesopen answer page →
Species
Rat and dog (mouse for carcinogenicity, rabbit for EFD)
“The pivotal nonclinical studies were conducted in CD-1 mouse, Wistar rat, beagle dog, and New Zealand White rabbit.”
Why that species
Rat considered pharmacologically relevant despite 5-fold lower S1P3 potency than human
“In in vitro PD studies ACT-128800 was found to have a 5-fold reduced potency on rat S1P3 receptor as compared to the human counterpart. Nevertheless, the rat is considered a relevant species for the evaluation of the safety of ACT-128800.”
Surrogate molecule
No surrogate; the clinical compound was tested
“In rat, oral administration of ponesimod (0, 3, 10, or 30 mg/kg/day in males and 0, 10, 30, or 100 mg/kg/day in females) did not result in an increase in tumors.”
Species: general tox
Rat (26-week) and dog (26- and 52-week)
“After chronic treatment for 26 weeks, NOAELs for systemic toxicity were established at 30 mg/kg/day in rats and at 2 mg/kg/day in dogs. In the 52-week toxicity study in dogs, the applicant derived a NOAEL at 3 mg/kg/day.”
Species: DART
Rat (fertility, EFD) and rabbit (EFD)
“In the reproductive and development studies with oral ponesimod, fertility was not affected in F or M (NOAEL was 100 mg/kg/day), but teratogenicity and fetal lethality was observed in both rats and rabbits.”
Species: carcinogenicity
CD-1 mouse and Wistar rat (2-year)
“The carcinogenic potential of ponesimod was tested in 2-year oral carcinogenicity studies in CD-1 mouse and Wistar rat.”
Surrogate used in
No surrogate used; ponesimod itself tested
“In rat, oral administration of ponesimod (0, 3, 10, or 30 mg/kg/day in males and 0, 10, 30, or 100 mg/kg/day in females) did not result in an increase in tumors.”
Study lengthopen answer page →
Longest pivotal study
52 (52-week dog)
“Study title: ACT-128800: 52-Week Follow-up Oral (Gavage) Toxicity Study in the Beagle Dog”
Pivotal GLP studies
26-week rat and 26- and 52-week dog oral studies
“After chronic treatment for 26 weeks, NOAELs for systemic toxicity were established at 30 mg/kg/day in rats and at 2 mg/kg/day in dogs. In the 52-week toxicity study in dogs, the applicant derived a NOAEL at 3 mg/kg/day.”
Route in tox
Oral (gavage)
“Route of administration: Oral by gavage”
Skipped studiesopen answer page →
Genotoxicity
Negative in Ames, in vitro chromosomal aberration and rat micronucleus assays
“Ponesimod was negative in in vitro (Ames, chromosomal aberration in mammalian cells) and in vivo (micronucleus in rat) assays.”
Carcinogenicity
2-year rat: no drug-related tumors; mouse: hemangiomas/hemangiosarcomas at all doses in males and high-dose females
“In the 2-year rat carcinogenicity study, there were no drug-related increases in neoplasms in M or F. The mouse study was positive for hemangiomas and hemangiosarcomas, with an increase in incidences at all doses in M and in HDF.”
Reproductive & developmental
Fertility unaffected in rats (NOAEL 100 mg/kg/day); rat and rabbit EFD: teratogenicity and fetal lethality
“In the reproductive and development studies with oral ponesimod, fertility was not affected in F or M (NOAEL was 100 mg/kg/day), but teratogenicity and fetal lethality was observed in both rats and rabbits.”
Safety pharmacology
Single dose decreased heart rate and blood pressure and caused first- to third-degree AV block in guinea pigs
“In cardiovascular safety pharmacology studies, a single oral dose of ponesimod decreased heart rate, blood pressure, and caused first-, second-, and third-degree AV block in guinea pigs.”
Genotox: Ames
Negative (Ames)
“Ponesimod was negative in in vitro (Ames, chromosomal aberration in mammalian cells) and in vivo (micronucleus in rat) assays.”
Genotox: in vitro mammalian
Chromosomal aberration in mammalian cells: negative
“Ponesimod was negative in in vitro (Ames, chromosomal aberration in mammalian cells) and in vivo (micronucleus in rat) assays.”
Genotox: in vivo
Rat micronucleus: negative
“Ponesimod was negative in in vitro (Ames, chromosomal aberration in mammalian cells) and in vivo (micronucleus in rat) assays.”
Carcinogenicity model
2-year CD-1 mouse (hemangiomas/hemangiosarcomas) and 2-year Wistar rat (negative)
“In the 2-year rat carcinogenicity study, there were no drug-related increases in neoplasms in M or F. The mouse study was positive for hemangiomas and hemangiosarcomas, with an increase in incidences at all doses in M and in HDF.”
Carcinogenicity timing
2-year CD-1 mouse and 2-year Wistar rat studies completed and reviewed in the NDA
“The carcinogenic potential of ponesimod was tested in 2-year oral carcinogenicity studies in CD-1 mouse and Wistar rat.”
hERG / QT
hERG minimally inhibited (22% at 3 µM); metabolite M13 25% and 46% at 10 and 100 µM
“The hERG tail current, expressed in CHO cells, was minimally reduced by ponesimod (22% at 3 µM). The major metabolite M13 (ACT-338375) dose-dependently decreased the hERG tail current by 25% and 46% at 10 and 100 µM, respectively.”
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 Ponvory 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: Lung toxicity NOAELs: 90/30 mg/kg (male/female mouse), 4 mg/kg (rat), 3 mg/kg (dog) (FDA pharmacology/toxicology review, p. 11)
NOAEL / key findings
Lung toxicity NOAELs: 90/30 mg/kg (male/female mouse), 4 mg/kg (rat), 3 mg/kg (dog)
“The NOAELs for lung toxicity were 90 and 30 mg/kg in M and F mice, respectively, 4 mg/kg in rats, and 3 mg/kg in dogs.”
Risksopen answer page →
Immune & cytokine safety
Reversible suppression of T-cell dependent antibody response during dosing
“The TDAR results suggest that there is immune suppression during the dosing of ponesimod that recovers when dosing is stopped.”
Biodistribution & persistence
Wide tissue distribution; highest in GI tract and liver; brain and spinal cord above blood levels
“In albino rats, radioactivity was widely distributed into most tissues and was maximal at 1-4 hours post-dose. The highest exposures were found in GI tract and liver but was also observed in the brain and spinal cord at higher levels than blood at 1-4 hours post-dose.”
Modality-specific risk
Cardiovascular and lung toxicity, and serious teratogenic effects
“The pivotal nonclinical studies of ponesimod were adequately conducted and identified target organs for toxicity (including cardiovascular and lung) and serious developmental (teratogenic) effects.”
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
- Infections
- Bradyarrhythmia and Atrioventricular Conduction Delays
- Respiratory Effects
- Liver Injury
- Increased Blood Pressure
- Cutaneous Malignancies
- Fetal Risk
- Macular Edema
- Posterior Reversible Encephalopathy Syndrome
- Unintended Additive Immunosuppressive Effects From Prior Treatment With Immunosuppressive or Immune-Modulating Therapies
- Severe Increase in Disability After Stopping PONVORY
- Immune System Effects After Stopping PONVORY
InfectionsCardiovascularPulmonary toxicityHepatotoxicitySecondary malignancySkin reactionsEmbryo-fetal toxicityOcular toxicityNeurotoxicity
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 Ponvory 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: Lung toxicity NOAELs: 90/30 mg/kg (male/female mouse), 4 mg/kg (rat), 3 mg/kg (dog) (FDA pharmacology/toxicology review, p. 11)
Longest repeat-dose systemic studies
Longest repeat-dose study and recovery
52-week beagle dog oral study with 13-week recovery (plus a 52-week dog MTD study)
“26 weeks study with 13 weeks recovery (Study T-05.139), 13/26 weeks with daily and bi-daily dosing (Study T-07.186), 52 weeks study with 13 weeks recovery (Study T-06.186), 52 weeks MTD study (Study T-08.357).”
Pivotal GLP studies
26-week rat and 26- and 52-week dog oral studies
“After chronic treatment for 26 weeks, NOAELs for systemic toxicity were established at 30 mg/kg/day in rats and at 2 mg/kg/day in dogs. In the 52-week toxicity study in dogs, the applicant derived a NOAEL at 3 mg/kg/day.”
DART package
Species: DART
Rat (fertility, EFD) and rabbit (EFD)
“In the reproductive and development studies with oral ponesimod, fertility was not affected in F or M (NOAEL was 100 mg/kg/day), but teratogenicity and fetal lethality was observed in both rats and rabbits.”
Reproductive & developmental
Fertility unaffected in rats (NOAEL 100 mg/kg/day); rat and rabbit EFD: teratogenicity and fetal lethality
“In the reproductive and development studies with oral ponesimod, fertility was not affected in F or M (NOAEL was 100 mg/kg/day), but teratogenicity and fetal lethality was observed in both rats and rabbits.”
PPND / ePPND: when
Rat PPND completed and reviewed in the NDA (delayed sexual maturation in pups at all doses)
“In the pre- and postnatal study, ponesimod was well tolerated in F0 dams and the developmental NOAEL was determined at less than the LD (<1 mg/kg/day) due to delayed sexual maturation in pups from all ponesimod dose groups;”
Carcinogenicity
Species: carcinogenicity
CD-1 mouse and Wistar rat (2-year)
“The carcinogenic potential of ponesimod was tested in 2-year oral carcinogenicity studies in CD-1 mouse and Wistar rat.”
Carcinogenicity model
2-year CD-1 mouse (hemangiomas/hemangiosarcomas) and 2-year Wistar rat (negative)
“In the 2-year rat carcinogenicity study, there were no drug-related increases in neoplasms in M or F. The mouse study was positive for hemangiomas and hemangiosarcomas, with an increase in incidences at all doses in M and in HDF.”
Carcinogenicity timing
2-year CD-1 mouse and 2-year Wistar rat studies completed and reviewed in the NDA
“The carcinogenic potential of ponesimod was tested in 2-year oral carcinogenicity studies in CD-1 mouse and Wistar rat.”
Safety marginopen answer page →
Safety margin at NOAEL
Lung toxicity NOAEL margins: rat 0.7-fold, dog 4.4-fold, mouse 12-/2.4-fold (M/F), based on plasma exposure
“The safety margins for lung toxicity based on plasma exposure were 12- and 2.4-fold in M and F mice, respectively, 0.7-fold in rats, and 4.4-fold in dogs.”
NOAEL / key findings
Lung toxicity NOAELs: 90/30 mg/kg (male/female mouse), 4 mg/kg (rat), 3 mg/kg (dog)
“The NOAELs for lung toxicity were 90 and 30 mg/kg in M and F mice, respectively, 4 mg/kg in rats, and 3 mg/kg in dogs.”
Efficacy evidenceopen answer page →
Efficacy evidence
Mouse MOG-peptide experimental autoimmune encephalomyelitis (EAE) model
“The therapeutic efficacy of ACT-128800 was investigated in a murine Experimental Autoimmune Encephalomyelitis (EAE) model (Study #B-08.460), in which mice were immunised with a peptide derived from myelin oligodendrocyte glycoprotein (MOG)”
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: EAE data show slowed disease progression and increased survival versus vehicle
“Nevertheless, the results from the EAE mouse model indicate that the administration of ponesimod slows down the disease progression and increases survival rate in the mice that received ponesimod comparing to the vehicle-treated animals.”
Flexibilityopen answer page →
Flexibility accepted
Safety marginVerdict not stated
Lung toxicity NOAEL in rats below human exposure (0.7-fold based on plasma exposure)
“The safety margins for lung toxicity based on plasma exposure were 12- and 2.4-fold in M and F mice, respectively, 0.7-fold in rats, and 4.4-fold in dogs.”
DARTVerdict not stated
Fetal NOAEL in rat and rabbit at 0.2-fold clinical plasma exposure (teratogenicity and fetal lethality)
“The fetal NOAEL was 1 mg/kg/day in both rats and rabbits, with a safety margin for fetal toxicity of 0.2-fold in rat and rabbit based on plasma exposure.”
Safety pharmacologyVerdict not stated
Minimal safety margin for acute cardiovascular effects (guinea pig NOAEL) versus the clinical first dose
“The NOAEL for the acute cardiovascular effect in guinea pigs was 0.1 mg/kg (0.8 mg/m2), resulting in a minimal safety margin with the clinical first dose (2 mg; 1.2 mg/m2) on a body surface basis.”
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