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.”
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.”
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)
In cancer patients the start dose should be pharmacologically active yet reasonably safe. A common small-molecule approach is one-tenth of the dose severely toxic to 10% of rodents, or one-sixth of the highest non-severely toxic dose in non-rodents.
“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.”