Ojjaara
momelotinib
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
“The toxicity of momelotinib was assessed in rats for up to 26 weeks and in dogs for up to 39 weeks.”
Why that species
Pharmacologically relevant: similar sensitivity to momelotinib as humans
“Rats and dogs were considered pharmacologically relevant nonclinical species based on similar sensitivity to momelotinib compared to humans.”
Surrogate molecule
No surrogate; the clinical compound was tested
“The toxicity of momelotinib was assessed in rats for up to 26 weeks and in dogs for up to 39 weeks.”
Species: general tox
Rat (26-week) and dog (39-week)
“The toxicity of momelotinib was assessed in rats for up to 26 weeks and in dogs for up to 39 weeks.”
Species: DART
Rat (fertility, EFD, pre/postnatal) and rabbit (EFD)
“Reproductive assessments included fertility and early embryofetal development studies in male and female rats, embryofetal development studies in rats and rabbits, and a pre- and postnatal development study in rats.”
Species: carcinogenicity
Tg rasH2 mouse (6-month) and Sprague-Dawley rat (2-year)
“The potential carcinogenicity of momelotinib was assessed in 6-month rasH2 transgenic mouse and 2-year Sprague-Dawley rat studies.”
Surrogate used in
No surrogate used; rat carcinogenicity mid-dose spiked with human metabolite M21
“Since rats do not generate an adequate quantity of human metabolite M21, additional mid dose groups (5 mg/kg/day of momelotinib) were spiked with 25 mg/kg/day of M21.”
Study lengthopen answer page →
Longest pivotal study
39 (39-week dog)
“The toxicity of momelotinib was assessed in rats for up to 26 weeks and in dogs for up to 39 weeks.”
Pivotal GLP studies
26-week rat and 39-week dog oral GLP studies
“The toxicological assessment of orally administered momelotinib was carried out in good laboratory practice (GLP)-compliant nonclinical toxicity studies in rats up to 26 weeks and dogs up to 39 weeks.”
Route in tox
Oral
“The toxicological assessment of orally administered momelotinib was carried out in good laboratory practice (GLP)-compliant nonclinical toxicity studies in rats up to 26 weeks and dogs up to 39 weeks.”
Skipped studiesopen answer page →
Genotoxicity
Negative in Ames, human lymphocyte chromosome aberration and in vivo micronucleus assays
“The genotoxicity of momelotinib was evaluated in a battery of in vitro and in vivo tests (bacterial reverse mutation assay, in vitro mammalian cytogenetic test using human lymphocytes, and in vivo micronucleus assay). Overall, momelotinib was not genotoxic under the test conditions.”
Carcinogenicity
2-year rat: increased testicular Leydig cell tumors at 15 mg/kg/day (17x MRHD)
“Oral administration of the top dose of 15 mg/kg/day of momelotinib (17-times the MRHD) for 2 years significantly increased the incidence of testicular Leydig cell tumors in male rats (11/60 versus 2/60 in control males, Table 32).”
Reproductive & developmental
Rat and rabbit EFD: embryo-fetal toxicity without teratogenicity
“MMB, when administered orally to pregnant rats and rabbits during organogenesis showed evidence of embryo-fetal toxicities, but no teratogenicity.”
Safety pharmacology
Weak hERG inhibitor (IC50 >10 µM), not clinically relevant
“The cardiovascular in vitro studies showed that MMB was a weak inhibitor of hERG channel K+ current (IC50>10 µM), with no clinical relevance.”
Genotox: Ames
Negative
“Momelotinib was not mutagenic in a bacterial reverse mutation assay, or clastogenic in an in vitro chromosomal aberration assay with human peripheral blood lymphocytes or in vivo in a rat bone marrow micronucleus assay.”
Genotox: in vitro mammalian
Human peripheral blood lymphocyte chromosomal aberration: negative
“Momelotinib was not mutagenic in a bacterial reverse mutation assay, or clastogenic in an in vitro chromosomal aberration assay with human peripheral blood lymphocytes or in vivo in a rat bone marrow micronucleus assay.”
Genotox: in vivo
Rat bone marrow micronucleus: negative
“Momelotinib was not mutagenic in a bacterial reverse mutation assay, or clastogenic in an in vitro chromosomal aberration assay with human peripheral blood lymphocytes or in vivo in a rat bone marrow micronucleus assay.”
Carcinogenicity model
2-year SD rat (benign Leydig cell tumors at 15 mg/kg/day, 17x); 26-week rasH2 mouse negative up to 100 mg/kg/day
“There was no evidence of tumorigenicity in male or female mice that received momelotinib doses up to 100 mg/kg/day for 26 weeks. In a 2‑year oral carcinogenicity study in Sprague‑Dawley rats, momelotinib caused benign Leydig cell tumors at a dose of 15 mg/kg/day (17 times the maximum recommended dose”
Carcinogenicity timing
104-week rat and 26-week transgenic mouse completed before the marketing application
“In the 26-week carcinogenicity study in transgenic mice, there were no MMB-related neoplasms in animals administered up to 100 mg/kg/day, although there was a clear carcinogenic response in animals administered the positive control article.”
hERG / QT
Weak hERG inhibition (IC50 >10 µM), ~21x human Cmax at 200 mg; QRS unaffected in dogs
“The QRS values were unaffected by momelotinib in dogs despite a very weak inhibition of hERG channel potassium (IC50 of >10 µM) observed in the hERG assay. It should be noted that the weak effect observed in the hERG assay was about 8-times the Cmax in dogs (30 mg/kg, Cmax 1174 ng/mL) and 21-times the Cmax (479 ng/mL) in humans at 200 mg dose”
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 Ojjaara 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 oncology small molecules (ICH S9)
HNSTD/STD10 is the method used for anticancer drugs in patients: the start dose is one-sixth of the highest non-severely toxic dose (HNSTD) in non-rodents, or one-tenth of the dose severely toxic to 10% of rodents (STD10), scaled by body surface area. The aim is a dose that is pharmacologically active yet reasonably safe.
“A common approach for many small molecules is to set a start dose at 1/10 the Severely Toxic Dose in 10% of the animals (STD 10) in rodents. If the non-rodent is the most appropriate species, then 1/6 the Highest Non-Severely Toxic Dose (HNSTD) is considered an appropriate starting dose.”
This product's starting point
NOAEL / key findings: Rat NOAEL 5 mg/kg/day (renal tubular degeneration at ≥15); 5-10x MRHD (FDA integrated review, p. 104)
NOAEL / key findings
Rat NOAEL 5 mg/kg/day (renal tubular degeneration at ≥15); 5-10x MRHD
“Based on adverse renal tubular degeneration at ≥15 mg/kg/day, the low dose of 5 mg/kg/day was considered the no observed adverse effect level (NOAEL) in rats (5x to 10x the maximum recommended human dose (MRHD) based on combined clinical momelotinib and M21 AUC).”
Risksopen answer page →
Immune & cytokine safety
Hematopoietic and lymphoid tissue targets: bone marrow, spleen, lymph node and thymus
“Consistent with drug pharmacology as a JAK inhibitor, momelotinib targeted hematopoietic tissues, i.e., bone marrow, spleen, lymph node and thymus.”
Biodistribution & persistence
Low penetration across blood-brain and blood-testis barriers; not quantifiable in bone, brain, spinal cord, testis
“Radioactivity was nonquantifiable in bone, brain, spinal cord, and testis at all sampling times suggesting low penetration of 14C-MMB-derived radioactivity across the blood-brain and blood-testis barriers.”
Modality-specific risk
Rat testicular Leydig cell tumors and potential cyanide exposure
“Potential concerns for testicular Leydig cell tumors in rats and cyanide exposure were identified during the review.”
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
- Risk of Infections
- Thrombocytopenia and Neutropenia
- Hepatotoxicity
- Severe Cutaneous Adverse Reactions (SCARs)
- Major Adverse Cardiovascular Events (MACE)
- Thrombosis
- Malignancies
- Symptom Exacerbation Following Interruption or Discontinuation of Treatment
InfectionsThrombocytopeniaCytopeniasHepatotoxicitySkin reactionsCardiovascularThrombosis & embolismSecondary malignancy
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 Ojjaara 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 oncology small molecules (ICH S9)
HNSTD/STD10 is the method used for anticancer drugs in patients: the start dose is one-sixth of the highest non-severely toxic dose (HNSTD) in non-rodents, or one-tenth of the dose severely toxic to 10% of rodents (STD10), scaled by body surface area. The aim is a dose that is pharmacologically active yet reasonably safe.
“A common approach for many small molecules is to set a start dose at 1/10 the Severely Toxic Dose in 10% of the animals (STD 10) in rodents. If the non-rodent is the most appropriate species, then 1/6 the Highest Non-Severely Toxic Dose (HNSTD) is considered an appropriate starting dose.”
This product's starting point
NOAEL / key findings: Rat NOAEL 5 mg/kg/day (renal tubular degeneration at ≥15); 5-10x MRHD (FDA integrated review, p. 104)
Longest repeat-dose systemic studies
Longest repeat-dose study and recovery
39-week dog (oral) with 6-week recovery
“GS-0387: 39-Week Oral Toxicity Study in Dogs With a 6-Week Recovery Period”
Pivotal GLP studies
26-week rat and 39-week dog oral GLP studies
“The toxicological assessment of orally administered momelotinib was carried out in good laboratory practice (GLP)-compliant nonclinical toxicity studies in rats up to 26 weeks and dogs up to 39 weeks.”
DART package
Species: DART
Rat (fertility, EFD, pre/postnatal) and rabbit (EFD)
“Reproductive assessments included fertility and early embryofetal development studies in male and female rats, embryofetal development studies in rats and rabbits, and a pre- and postnatal development study in rats.”
Reproductive & developmental
Rat and rabbit EFD: embryo-fetal toxicity without teratogenicity
“MMB, when administered orally to pregnant rats and rabbits during organogenesis showed evidence of embryo-fetal toxicities, but no teratogenicity.”
PPND / ePPND: when
PPND in rat completed before the marketing application
“In a pre- and postnatal development study, pregnant rats (F0) were orally treated daily with 0, 2, 6 or 12 mg/kg/day of momelotinib from GD6 to lactation day (LD) 20.”
Carcinogenicity
Species: carcinogenicity
Tg rasH2 mouse (6-month) and Sprague-Dawley rat (2-year)
“The potential carcinogenicity of momelotinib was assessed in 6-month rasH2 transgenic mouse and 2-year Sprague-Dawley rat studies.”
Carcinogenicity model
2-year SD rat (benign Leydig cell tumors at 15 mg/kg/day, 17x); 26-week rasH2 mouse negative up to 100 mg/kg/day
“There was no evidence of tumorigenicity in male or female mice that received momelotinib doses up to 100 mg/kg/day for 26 weeks. In a 2‑year oral carcinogenicity study in Sprague‑Dawley rats, momelotinib caused benign Leydig cell tumors at a dose of 15 mg/kg/day (17 times the maximum recommended dose”
Carcinogenicity timing
104-week rat and 26-week transgenic mouse completed before the marketing application
“In the 26-week carcinogenicity study in transgenic mice, there were no MMB-related neoplasms in animals administered up to 100 mg/kg/day, although there was a clear carcinogenic response in animals administered the positive control article.”
Safety marginopen answer page →
Safety margin at NOAEL
39-week dog NOAEL 20 mg/kg/day <0.6x MRHD (combined momelotinib + M21 AUC)
“The NOAEL based on mild testicular bilateral spermatocyte degeneration and renal epithelial vacuolation was 20 mg/kg/day in dogs (<0.6x the MRHD on an AUC basis for combined momelotinib + M21).”
NOAEL / key findings
Rat NOAEL 5 mg/kg/day (renal tubular degeneration at ≥15); 5-10x MRHD
“Based on adverse renal tubular degeneration at ≥15 mg/kg/day, the low dose of 5 mg/kg/day was considered the no observed adverse effect level (NOAEL) in rats (5x to 10x the maximum recommended human dose (MRHD) based on combined clinical momelotinib and M21 AUC).”
Efficacy evidenceopen answer page →
Efficacy evidence
Mouse model of myeloproliferative neoplasms and rat model of anemia of chronic disease
“In vivo pharmacological activity of momelotinib has been confirmed in a mouse model of myeloproliferative neoplasms (MPN) and a rat model of anemia of chronic disease (ACD).”
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
FDA: rat ACD data suggest momelotinib reduces hepcidin, raises serum iron and improves anemia
“Oral administration of momelotinib also reduced and normalized “elevated hepcidin” induced by IP administration of streptococcal peptidoglycan-polysaccharide fragment (PG-APS) in rats suggesting that momelotinib is effective in reducing hepcidin, increasing serum iron and improving anemia.”
Flexibilityopen answer page →
Flexibility accepted
Impurity or metaboliteAcceptedBeyond the letter
Major active metabolite M21 not covered by animal exposure; no safety margins for M21
Why: M21 pharmacodynamic activity similar to parent momelotinib · Pharmacology or kinetics
“Although the major active metabolite M21 is not considered qualified based on free exposure in animal species in line with the ICH M3(R2), it can be considered qualified based on pharmacodynamic activities similar to MMB.”
GenotoxicityAcceptedBeyond the letter
No in vitro genotoxicity studies with the major active metabolite M21
Why: M21 present at sufficient exposure in the in vivo rat micronucleus test · Pharmacology or kinetics
“No in vitro genotoxicity studies were performed with the major active metabolite M21.”
“Based on the TK data observed in the repeat-dose toxicity study in rats, the metabolite M21 should has been present at sufficient exposure levels to be considered as qualified.”
Safety marginVerdict not stated
39-week dog NOAEL below 0.6 times the MRHD (combined momelotinib + M21 AUC)
“The NOAEL based on mild testicular bilateral spermatocyte degeneration and renal epithelial vacuolation was 20 mg/kg/day in dogs (<0.6x the MRHD on an AUC basis for combined momelotinib + M21).”
GLPVerdict not stated
Toxicokinetic analyses in several pivotal GLP studies not GLP-compliant
Why: Method validation followed GLP principles
“For some pivotal GLP toxicology studies, toxicokinetics analysis were not performed in compliance with GLP (8283319 4-week in mice; 8336287 4-week impurities in rats ; WIL-604183 Juvenile DRF in rats ; WIL-604256 Juvenile in rats and 8283320 26-week study carcinogenicity in mice), but validation was conducted following the principles of GLP.”
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