Omlonti
omidenepag isopropyl
Species
MonkeyRat
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 cynomolgus monkey
“The general toxicology study package spans two species: two topical ocular monkey studies, and a series of subcutaneous-route studies in the Sprague Dawley rat.”
Why that species
Not stated in public reviews
The reviews list the species but not why. For small molecules, ICH M3(R2) expects one rodent and one non-rodent species, chosen with in vitro metabolism, protein binding and exposure data compared with human.
“In vitro metabolic and plasma protein binding data for animals and humans and systemic exposure data (ICH S3A, Ref. 7) in the species used for repeated-dose toxicity studies generally should be evaluated before initiating human clinical trials.”
✓ VerifiedICH 2009: ICH M3(R2): Guidance on Nonclinical Safety Studies for the Conduct…, p. 11Source ↗
Surrogate molecule
No surrogate; the clinical compound was tested
“The GLP rat 26-week subcutaneous toxicity study with omidenepag isopropyl did not identify a NOAEL, because rare tumors were observed with treatment.”
Study lengthopen answer page →
Longest pivotal study
39 (39-week monkey topical ocular)
“The GLP monkey 39-week topical ocular toxicity study with omidenepag isopropyl did not identify a NOAEL.”
Pivotal GLP studies
Two topical ocular monkey studies and a series of subcutaneous rat studies
“The general toxicology study package spans two species: two topical ocular monkey studies, and a series of subcutaneous-route studies in the Sprague Dawley rat.”
Route in tox
Topical ocular (monkey); subcutaneous (rat)
“The general toxicology study package spans two species: two topical ocular monkey studies, and a series of subcutaneous-route studies in the Sprague Dawley rat.”
Skipped studiesopen answer page →
Genotoxicity
Negative in Ames and in vivo micronucleus; positive (mutagenic and clastogenic) in in vitro mouse lymphoma assay
“Omidenepag was not mutagenic in the bacterial reverse mutation (Ames) test and the in vivo mouse micronucleus test. Omidenepag isopropyl was positive (mutagenic and clastogenic) without metabolic activation in the in vitro mouse lymphoma forward mutation assay.”
Carcinogenicity
Lifetime rodent studies not conducted; nephroblastoma and spermatic cord tumor in 26-week rat subcutaneous study
“Lifetime rodent studies have not been performed to evaluate the carcinogenic potential of omidenepag isopropyl or omidenepag. In rats dosed by subcutaneous injection daily for 26 weeks, nephroblastoma and a spermatic cord tumor were found at 0.003 mg/kg/day (33 times the RHOD based on the estimated area under the curve [AUC]).”
Reproductive & developmental
Rabbit EFD: fetal skeletal anomalies at 24x clinical exposure; not teratogenic in rats
“In animal reproduction studies, subcutaneous administration of omidenepag isopropyl to pregnant rabbits throughout the period of organogenesis produced fetal skeletal anomalies at a dose of 24 times the clinical dose, based on estimated plasma C max .”
Safety pharmacology
Dog inhalation study: no CV effect at 0.268 mg/kg/day; at ≥1.02 mg/kg raised heart rate, shortened PR, lowered blood pressure, prolonged QTc
“For in-life cardiovascular safety pharmacology endpoints, 0.268 mg/kg/day did not have an apparent effect. Doses ≥ 1.02 mg/kg of omidenepag caused increased heart rate, shortened PR interval, decreased blood pressure, and prolonged QTc.”
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 Omlonti 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: Monkey 13-week: no NOAEL; LOAEL 0.9 µg/eye/day based on nasal cavity findings (FDA pharmacology/toxicology review, p. 190)
NOAEL / key findings
Monkey 13-week: no NOAEL; LOAEL 0.9 µg/eye/day based on nasal cavity findings
“No NOAEL. The low dose, 0.9 µg/eye/day is the LOAEL, based on two findings in the nasal cavity:”
Risksopen answer page →
Immune & cytokine safety
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.
Biodistribution & persistence
Monkey eye: highest in cornea and conjunctiva, lower in iris, ciliary body and choroid-RPE; plasma and blood lowest
“Distribution was: cornea > bulbar conjunctiva > trabecular meshwork > palpebral conjunctiva > sclera > aqueous humor > iris > ciliary body > choroid-retinal pigmented epithelium (RPE) > plasma > blood.”
Modality-specific risk
Rare tumors in 26-week rat study and nasal cavity metaplasia in monkeys (carcinogenic potential)
“As noted above, the 26-week sc rat study detected rare tumors after dosing with omidenepag isopropyl, and the monkey topical ocular studies detected nasal cavity metaplasia.”