Crenessity
crinecerfont
Species
RatDog
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
“TK results from pivotal 6-month rat and 12-month dog studies are presented in Table 97 and Table 98 below.”
Why that species
Metabolism similar across species, with no unique or disproportionate human metabolites
“The metabolism of crinecerfont was similar among species, with no unique or disproportionate human metabolites (Figure 29).”
Surrogate molecule
No surrogate; the clinical compound (free base) was tested
“Subsequently, the tosylate salt formulation was replaced with a free base form of crinecerfont for evaluation in the pivotal chronic toxicology, carcinogenicity, prenatal and postnatal and juvenile nonclinical studies, and for the clinical studies.”
Species: general tox
Rat (6-month) and dog (12-month)
“TK results from pivotal 6-month rat and 12-month dog studies are presented in Table 97 and Table 98 below.”
Species: DART
Rat and rabbit (fertility, embryo-fetal and juvenile development)
“The effects of crinecerfont on fertility, reproduction, early embryonic and embryo-fetal development, and juvenile development were evaluated in rat and rabbit toxicology studies.”
Species: carcinogenicity
Rat (2-year) and transgenic mouse (6-month)
“The Applicant evaluated the oncogenic potential of crinecerfont by conducting 2-year rat and 6-month transgenic mouse carcinogenicity studies.”
Surrogate used in
No surrogate used; clinical free base tested in pivotal studies
“Subsequently, the tosylate salt formulation was replaced with a free base form of crinecerfont for evaluation in the pivotal chronic toxicology, carcinogenicity, prenatal and postnatal and juvenile nonclinical studies, and for the clinical studies.”
Study lengthopen answer page →
Longest pivotal study
52 (12-month dog)
“TK results from pivotal 6-month rat and 12-month dog studies are presented in Table 97 and Table 98 below.”
Pivotal GLP studies
6-month rat and 12-month dog oral studies
“The assessment of the pivotal chronic 6-month rat and 12-month dog studies are summarized in Sections 19.1.7.1.1 and 19.1.7.1.3, respectively.”
Route in tox
Oral (gavage)
“The 6-month rat study was conducted with a once-daily oral gavage dose of 0, 50, 250 or 1250 mg/kg crinecerfont free base.”
Skipped studiesopen answer page →
Genotoxicity
Negative in Ames, in vitro chromosomal aberration and in vivo rat bone marrow micronucleus assays
“Crinecerfont was not mutagenic in the in vitro bacterial reverse mutation test (Ames) or clastogenic in the in vitro mammalian chromosomal aberrations assay in human peripheral blood lymphocytes or in the in vivo rat bone marrow micronucleus assay.”
Carcinogenicity
Transgenic mouse: no oncogenic effects; 2-year rat: thyroid follicular adenoma/carcinoma in females at 4-fold MRHD exposure
“Crinecerfont did not show oncogenic effects in transgenic mice. In the 2-year rat study, crinecerfont increased the incidence of thyroid gland follicular cell adenoma and carcinoma in females at 100 mg/kg crinecerfont (4-fold MRHD exposure).”
Reproductive & developmental
No developmental toxicity in rats; low-incidence craniofacial poly-malformations in rabbits at 2-fold MRHD exposure
“No developmental toxicity was observed in rats at 4-fold higher than human exposure at the maximum recommended human dose (MRHD) based on area under the concentration-time curve (AUC). Crinecerfont was associated with a low incidence of poly-malformations (craniofacial defects) in rabbits at 2-fold higher than human exposure at the MRHD.”
Safety pharmacology
No arrhythmia risk: <5% hERG inhibition and no Purkinje fiber action potential effects at 10 µM
“Crinecerfont showed no potential for clinical arrhythmia risk based on human ether-à-go-go-related gene (hERG) current (<5% inhibition) or isolated rabbit Purkinje fiber action potential assays at up to 10µM crinecerfont concentrations.”
Genotox: Ames
Negative (5 Salmonella strains, ±S9)
“Negative for mutagenic potential in five Salmonella typhimurium strains (TA98, TA100, TA1535, TA102 and TA1537) at 50-2500 µg/plate concentration (±S9 metabolic activation).”
Genotox: in vitro mammalian
Mouse lymphoma L5178Y TK assay: negative (±S9)
“In vitro gene mutation assay at the locus TK+/- in mouse lymphoma L5178Y cells/LYM0101 GLP compliance: Yes Valid study: Yes Negative for mutagenic potential at concentration of 12.5- 250 µg/mL (±S9 metabolic activation).”
Genotox: in vivo
Rat bone marrow micronucleus: negative
“No increase in micronucleated polychromatic erythrocytes in bone marrow at oral doses of 500-2000 mg/kg daily for 2 days (at exposure ~3-fold MRHD).”
Carcinogenicity model
2-year rat; 26-week Tg.rasH2 mouse (negative)
“The Applicant evaluated the oncogenic potential of crinecerfont by conducting 2-year rat and 6-month transgenic mouse carcinogenicity studies. Crinecerfont did not increase the incidence of tumors in Tg.rasH2 mice treated for 26 weeks at oral doses of 5, 50, 500 or 1500 mg/kg/day.”
Carcinogenicity timing
2-year rat and 6-month Tg.rasH2 mouse studies completed before the marketing application
“The Applicant evaluated the oncogenic potential of crinecerfont by conducting 2-year rat and 6-month transgenic mouse carcinogenicity studies.”
hERG / QT
<5% hERG inhibition and no Purkinje fiber effects at up to 10 µM
“Crinecerfont showed no potential for clinical arrhythmia risk based on human ether-à-go-go-related gene (hERG) current (<5% inhibition) or isolated rabbit Purkinje fiber action potential assays at up to 10µM crinecerfont concentrations.”
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 Crenessity 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: Target organs: liver, thyroid, GI tract (mouse, rat) and coagulation effects (FDA integrated review, p. 95)
NOAEL / key findings
Target organs: liver, thyroid, GI tract (mouse, rat) and coagulation effects
“The target organs for crinecerfont were liver (mouse, rat, and dog), thyroid gland (rat and dog), gastrointestinal (GI) tract (mouse and rat), and coagulation-associated effects.”
Risksopen answer page →
Immune & cytokine safety
Rat TDAR study: small changes in leukocytes, lymphocyte subsets and T-cell-dependent antibody response (males); no remarkable immunotoxicity
“The changes in leukocytic parameters and lymphocyte subpopulation and T-cell-dependent antibody responses were small in magnitude and occurred in one sex (males) and showed no remarkable evidence of immunotoxicity in rats.”
Biodistribution & persistence
Crosses placenta to fetal liver at low levels; low exposure in brain, skin and testis
“Crinecerfont crossed the placenta and distributed to the fetal liver (at low levels) in pregnant rats and rabbits. Low crinecerfont exposure was observed in brain, skin, and testis.”
Modality-specific risk
Embryofetal toxicity: possible craniofacial malformations in rabbits
“The overall incidence of fetal malformations was low and there was no clear relationship to drug, but absent similar findings in concurrent control fetuses, and with the incidence being outside the historical control range for individual malformations, we cannot rule out a possible effect of crinecerfont treatment on rabbit embryo-fetal development.”
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
Immunogenicity assessment not applicable
“Immunogenicity Assessment—Impact of PK/PD, Efficacy, and Safety Not applicable.”
Label warnings
- Hypersensitivity Reactions
- 2 Risk of Acute Adrenal Insufficiency or Adrenal Crisis w ith Inadequate Concomitant Glucocorticoid Therapy
Hypersensitivity & infusion reactionsNephrotoxicityMetabolic & endocrine
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 Crenessity 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: Target organs: liver, thyroid, GI tract (mouse, rat) and coagulation effects (FDA integrated review, p. 95)
Longest repeat-dose systemic studies
Longest repeat-dose study and recovery
12-month (52-week) oral dog study with 8-week recovery
“12-Month Oral Toxicity Study in Dogs With an 8-Week Recovery Period, Study TXC1204”
Pivotal GLP studies
6-month rat and 12-month dog oral studies
“The assessment of the pivotal chronic 6-month rat and 12-month dog studies are summarized in Sections 19.1.7.1.1 and 19.1.7.1.3, respectively.”
DART package
Species: DART
Rat and rabbit (fertility, embryo-fetal and juvenile development)
“The effects of crinecerfont on fertility, reproduction, early embryonic and embryo-fetal development, and juvenile development were evaluated in rat and rabbit toxicology studies.”
Reproductive & developmental
No developmental toxicity in rats; low-incidence craniofacial poly-malformations in rabbits at 2-fold MRHD exposure
“No developmental toxicity was observed in rats at 4-fold higher than human exposure at the maximum recommended human dose (MRHD) based on area under the concentration-time curve (AUC). Crinecerfont was associated with a low incidence of poly-malformations (craniofacial defects) in rabbits at 2-fold higher than human exposure at the MRHD.”
PPND / ePPND: when
PPND in rat completed before the marketing application
“A pre- and postnatal development study was conducted with daily oral administration of crinecerfont free base to pregnant rats during the period of organogenesis to weaning from GD7 to lactation day 20 at 0, 15, 150 or 250 mg/kg/day.”
Carcinogenicity
Species: carcinogenicity
Rat (2-year) and transgenic mouse (6-month)
“The Applicant evaluated the oncogenic potential of crinecerfont by conducting 2-year rat and 6-month transgenic mouse carcinogenicity studies.”
Carcinogenicity model
2-year rat; 26-week Tg.rasH2 mouse (negative)
“The Applicant evaluated the oncogenic potential of crinecerfont by conducting 2-year rat and 6-month transgenic mouse carcinogenicity studies. Crinecerfont did not increase the incidence of tumors in Tg.rasH2 mice treated for 26 weeks at oral doses of 5, 50, 500 or 1500 mg/kg/day.”
Carcinogenicity timing
2-year rat and 6-month Tg.rasH2 mouse studies completed before the marketing application
“The Applicant evaluated the oncogenic potential of crinecerfont by conducting 2-year rat and 6-month transgenic mouse carcinogenicity studies.”
Safety marginopen answer page →
Safety margin at NOAEL
NOAEL exposures in pivotal nonclinical studies limited to 1- to 4-fold MRHD
“Thus, clinical exposure multiples at the no-observed-adverse-effect levels (NOAELs) in the pivotal nonclinical studies were limited to one- to fourfold the maximum recommended human dose (MRHD).”
NOAEL / key findings
Target organs: liver, thyroid, GI tract (mouse, rat) and coagulation effects
“The target organs for crinecerfont were liver (mouse, rat, and dog), thyroid gland (rat and dog), gastrointestinal (GI) tract (mouse and rat), and coagulation-associated effects.”
Efficacy evidenceopen answer page →
Efficacy evidence
In vitro CRF1 binding, cAMP and ACTH assays; CRF- and stress-induced ACTH inhibition in normal rats
“These studies demonstrated that crinecerfont inhibits CRF1 receptors and antagonizes CRF-induced cyclic adenosine monophosphate (cAMP) synthesis and ACTH secretion from pituitary, and blocks stress-induced increases in ACTH in rats (Table 99).”
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
Nonclinical pharmacology accepted as supporting the proposed mechanism of action
“The nonclinical pharmacology data were provided to support the proposed mechanism of action of crinecerfont.”
Flexibilityopen answer page →
Flexibility accepted
Safety marginVerdict not stated
Exposure multiples at the NOAELs in pivotal studies limited to one- to fourfold the MRHD because of exposure saturation
“Thus, clinical exposure multiples at the no-observed-adverse-effect levels (NOAELs) in the pivotal nonclinical studies were limited to one- to fourfold the maximum recommended human dose (MRHD).”
OtherAcceptedBeyond the letter
Early toxicology conducted with the tosylate salt, later studies with the free base; data bridged across salt forms
Why: Nonclinical studies adequately bridged tosylate salt and free base data · Pharmacology or kinetics
“Nonclinical studies adequately bridged the data from studies conducted with tosylate salt to those conducted with the free base, and both sets of studies contributed to characterizing the toxicity profile of crinecerfont.”
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