Palsonify
paltusotine
Species
RatDog
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 dog
“These studies included repeat-dose toxicology studies in rats (up to 26 weeks) and dogs (up to 39 weeks), and reproductive and developmental toxicology studies in rats and rabbits.”
Why that species
Metabolic profiles similar to human; both species pharmacologically relevant
“The rat and dog were selected as the species for non-clinical toxicity studies based on similarity in the metabolic profiles compared to humans. Both species are also pharmacologically relevant.”
Surrogate molecule
No surrogate; the clinical compound was tested
“In the pivotal 26-week chronic study, rats were administered paltusotine at doses of 25, 75, or 500 mg/kg/day.”
Species: general tox
Rat (up to 26 weeks) and dog (up to 39 weeks)
“These studies included repeat-dose toxicology studies in rats (up to 26 weeks) and dogs (up to 39 weeks), and reproductive and developmental toxicology studies in rats and rabbits.”
Species: DART
Rat (fertility, EFD, pre/postnatal) and rabbit (EFD)
“DART program is composed with a GLP fertility and early embryonic development study in rats, embryo-foetal development studies in rats and rabbits and a pre- and postnatal study in rats.”
Species: carcinogenicity
Rat (2-year) and Tg.rasH2 mouse (26-week)
“Paltusotine did not elicit any treatment-related increase in the incidence of tumors in a 2-year study in rats or a 26-week study in Tg.rasH2 transgenic mice.”
Surrogate used in
No surrogate used; rat and dog are pharmacologically relevant
“The rat and dog were selected as the species for non-clinical toxicity studies based on similarity in the metabolic profiles compared to humans. Both species are also pharmacologically relevant.”
Study lengthopen answer page →
Longest pivotal study
39 (9-month dog)
“These studies included repeat-dose toxicology studies in rats (up to 26 weeks) and dogs (up to 39 weeks), and reproductive and developmental toxicology studies in rats and rabbits.”
Pivotal GLP studies
26-week rat and 39-week dog studies with recovery
“The pivotal toxicity studies were performed up to 26 weeks in rats and up to 39 weeks in dogs with appropriate recovery periods.”
Route in tox
Oral gavage
“CRN00808-HCL: 26-Week Oral Gavage Toxicity and Toxicokinetic Study in the Rat With 4-Week Recovery/2018-TX-050”
Skipped studiesopen answer page →
Genotoxicity
Negative in Ames, in vitro CHO micronucleus and in vivo rat bone marrow micronucleus assays
“Paltusotine was negative in the bacterial mutagenicity assay (Ames test) with Salmonella and Escherichia coli, the in vitro micronucleus test in Chinese hamster ovary cells, and the in vivo micronucleus test in rat bone marrow.”
Carcinogenicity
2-year rat and 26-week Tg.rasH2 mouse: no drug-related tumors
“Paltusotine did not elicit any treatment-related increase in the incidence of tumors in a 2-year study in rats or a 26-week study in Tg.rasH2 transgenic mice.”
Reproductive & developmental
Rat: preimplantation loss and fewer live embryos; rabbit: delayed fetal development and sporadic malformations
“Findings in rats included preimplantation loss and reduced number of live embryos, and findings in rabbits included delayed fetal development and sporadic malformations.”
Safety pharmacology
No significant ECG changes (PR, QRS, QT, QTc), morphology or rhythm in dog telemetry
“No biologically significant changes in ECG parameters (PR, QRS, QT, QTc intervals), ECG gross morphology and rhythm were noted.”
Genotox: Ames
Negative
“Paltusotine was negative in the bacterial mutagenicity assay (Ames test) with Salmonella and Escherichia coli, the in vitro micronucleus test in Chinese hamster ovary cells, and the in vivo micronucleus test in rat bone marrow.”
Genotox: in vitro mammalian
In vitro micronucleus: equivocal; overall judged non-genotoxic
“In vitro micronucleus test was considered as equivocal. The in vivo micronucleus test was negative. Paltusotine was considered to be a non-genotoxic compound.”
Genotox: in vivo
Rat bone marrow micronucleus: negative
“Paltusotine was negative in the bacterial mutagenicity assay (Ames test) with Salmonella and Escherichia coli, the in vitro micronucleus test in Chinese hamster ovary cells, and the in vivo micronucleus test in rat bone marrow.”
Carcinogenicity model
2-year rat; 26-week Tg.rasH2 mouse; no treatment-related tumors
“Paltusotine did not elicit any treatment-related increase in the incidence of tumors in a 2-year study in rats or a 26-week study in Tg.rasH2 transgenic mice.”
Carcinogenicity timing
2-year rat and 26-week Tg.rasH2 mouse studies completed and reviewed with the NDA
“Paltusotine did not elicit any treatment-related increase in the incidence of tumors in a 2-year study in rats or a 26-week study in Tg.rasH2 transgenic mice.”
hERG / QT
hERG IC50 4.8 µM; no ECG changes in dog telemetry
“Paltusotine-HCl inhibited hERG channel tail current in a dose-dependent manner with an IC50 value of 4.8µM, which is significantly higher than the IC50 value of 23.18nM for the positive control, terfenadine, in this study.”
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 Palsonify 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: Dog NOAEL 10 mg/kg/day (3x MRHD) for nervous system effects; tremors only at 75 mg/kg/day (~23x MRHD) (FDA integrated review, p. 87)
NOAEL / key findings
Dog NOAEL 10 mg/kg/day (3x MRHD) for nervous system effects; tremors only at 75 mg/kg/day (~23x MRHD)
“The no-observed-adverse-effect level (NOAEL) (10 mg/kg/day) for nervous system effects in dogs was three-fold the clinical exposures at the MRHD based on area under the concentration-time curve (AUC) and the tremors were observed only at 75 mg/kg/day at approximately 23-fold the MRHD based on AUC.”
Risksopen answer page →
Immune & cytokine safety
No dedicated immunotoxicity study; no immunotoxicity findings in the nonclinical or clinical program
“The Applicant has justified that no dedicated immunotoxicity study was performed, since no immune adverse effects are expected from the pharmacological properties. In addition, no immunotoxicity findings were observed in the non-clinical or clinical program.”
Biodistribution & persistence
Preferential melanin binding (meninges, uveal tract, pigmented skin); minimal brain penetration in rats
“Minimal brain to plasma ratio of paltusotine (<0.05) was observed in rats. QWBA study demonstrated a preferential binding to melanin containing tissues, namely the meninges, uveal tract, and the pigmented skin.”
Modality-specific risk
Phototoxicity with retinal degeneration in pigmented rats (ocular safety concern), plus neurotoxicity at excessive doses
“Paltusotine demonstrated potential for phototoxicity, with animal studies showing possible signals for retinal and corneal AEs, raising concerns about ocular safety in humans. Animal studies revealed neurotoxicity at excessive doses.”
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
- Cholelithiasis and its Complications
- Hyperglycemia and Hypoglycemia
- Cardiovascular Abnormalities
- Thyroid Function Abnormalities
- Steatorrhea and Malabsorption of Dietary Fats
- Vitamin B12 Deficiency
Metabolic & endocrineCardiovascular
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 Palsonify 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: Dog NOAEL 10 mg/kg/day (3x MRHD) for nervous system effects; tremors only at 75 mg/kg/day (~23x MRHD) (FDA integrated review, p. 87)
Longest repeat-dose systemic studies
Longest repeat-dose study and recovery
39-week beagle dog oral GLP study with 4-week recovery
“CRN00808-HCL: 39-Week Repeated Oral Dose Toxicity and Toxicokinetic Study in Beagle Dogs with 4-Week Recovery/ 2018-TX-051”
Pivotal GLP studies
26-week rat and 39-week dog studies with recovery
“The pivotal toxicity studies were performed up to 26 weeks in rats and up to 39 weeks in dogs with appropriate recovery periods.”
DART package
Species: DART
Rat (fertility, EFD, pre/postnatal) and rabbit (EFD)
“DART program is composed with a GLP fertility and early embryonic development study in rats, embryo-foetal development studies in rats and rabbits and a pre- and postnatal study in rats.”
Reproductive & developmental
Rat: preimplantation loss and fewer live embryos; rabbit: delayed fetal development and sporadic malformations
“Findings in rats included preimplantation loss and reduced number of live embryos, and findings in rabbits included delayed fetal development and sporadic malformations.”
PPND / ePPND: when
PPND in rat completed and assessed with the marketing application
“DART program is composed with a GLP fertility and early embryonic development study in rats, embryo-foetal development studies in rats and rabbits and a pre- and postnatal study in rats.”
Carcinogenicity
Species: carcinogenicity
Rat (2-year) and Tg.rasH2 mouse (26-week)
“Paltusotine did not elicit any treatment-related increase in the incidence of tumors in a 2-year study in rats or a 26-week study in Tg.rasH2 transgenic mice.”
Carcinogenicity model
2-year rat; 26-week Tg.rasH2 mouse; no treatment-related tumors
“Paltusotine did not elicit any treatment-related increase in the incidence of tumors in a 2-year study in rats or a 26-week study in Tg.rasH2 transgenic mice.”
Carcinogenicity timing
2-year rat and 26-week Tg.rasH2 mouse studies completed and reviewed with the NDA
“Paltusotine did not elicit any treatment-related increase in the incidence of tumors in a 2-year study in rats or a 26-week study in Tg.rasH2 transgenic mice.”
Safety marginopen answer page →
Safety margin at NOAEL
Dog 39-week NOAEL (10 mg/kg/day) ~3x human AUC at 60 mg/day
“The NOAEL was determined to be 10 mg/kg/day, which was three-fold the clinical dose of 60 mg/day, based on an AUC0-τ of 2890 ng·h/mL.”
NOAEL / key findings
Dog NOAEL 10 mg/kg/day (3x MRHD) for nervous system effects; tremors only at 75 mg/kg/day (~23x MRHD)
“The no-observed-adverse-effect level (NOAEL) (10 mg/kg/day) for nervous system effects in dogs was three-fold the clinical exposures at the MRHD based on area under the concentration-time curve (AUC) and the tremors were observed only at 75 mg/kg/day at approximately 23-fold the MRHD based on AUC.”
Efficacy evidenceopen answer page →
Efficacy evidence
GHRH-challenged rats: dose-dependent suppression of GH elevation
“Paltusotine orally administered to rats (≥3 mg/kg) significantly and dose-dependently suppressed rat GH elevation induced by growth hormone-releasing hormone (GHRH), with a plasma EC50 of 11 ng/mL.”
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: efficacy demonstrated through pharmacology studies; biased, highly selective SST2 agonist lowering GH, IGF-1 and cAMP
“Paltusotine has demonstrated its efficacy through pharmacology studies. Paltusotine is a biased, highly selective SST2 agonist that decreases levels of GH, IGF-1 and cAMP.”
Flexibilityopen answer page →
Flexibility accepted
CarcinogenicityAcceptedBeyond the letter
Rat carcinogenicity study terminated early (Week 91 males, Week 89 females) due to low control survival
Why: At least 28 animals per sex per group survived to Week 80, enough to evaluate carcinogenicity · Other reason
“Due to low survival of water and vehicle control animals, the study was terminated early during Week 91 for males and Week 89 for females. However, at least 28 animals/sex in each group survived to Week 80, which provided enough animals to adequately evaluate carcinogenicity.”
Safety marginVerdict not stated
Animal-to-human exposure margins uncertain because of large variability in paltusotine bioavailability
“To conclude, animal/human margins of exposure calculated in the whole dossier were taken in consideration with caution, given the large variability of paltusotine bioavailability (see animal PK part of AR).”
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