Ogsiveo
nirogacestat
Species
RatDog
Longest study
13 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 nirogacestat was assessed in GLP‐compliant 3‐month repeated‐dose toxicity studies in rats and dogs.”
Why that species
Rat and dog chosen based on nirogacestat PK and metabolism compared across species
“The rat and dog were selected as the toxicology species based on nirogacestat PK and metabolism properties compared across species.”
Surrogate molecule
No surrogate; the clinical compound was tested
“Rats received up to 25 mg/kg (50 mg/kg/day) oral nirogacestat, twice per day, for 3 months, resulting in mean exposure levels (AUC) up to 3.4 times the AUC of 6740 ng.h/mL in patients with desmoid tumors at the 150 mg BID dose.”
Study lengthopen answer page →
Longest pivotal study
13 (3-month rat and dog)
“The toxicity of nirogacestat was assessed in GLP‐compliant 3‐month repeated‐dose toxicity studies in rats and dogs.”
Pivotal GLP studies
GLP 3-month repeat-dose studies in rats and dogs
“The toxicity of nirogacestat was assessed in GLP‐compliant 3‐month repeated‐dose toxicity studies in rats and dogs.”
Route in tox
Oral
“The oral route of exposure was selected for these studies since the oral route is the intended clinical route of administration.”
Skipped studiesopen answer page →
Genotoxicity
Negative in Ames, in vitro human chromosome aberration and in vivo rat bone marrow micronucleus assays
“Nirogacestat was not considered genotoxic since it was not mutagenic in a bacterial reverse mutation (Ames) assay and was not clastogenic in an in vitro human chromosome aberration assay or in vivo rat bone marrow micronucleus assay.”
Carcinogenicity
rasH2 mouse: non-significant increase in hemangiosarcomas in 100 mg/kg/day males; negative in females
“The results showed an increased incidence of whole body hemangiosarcomas in 100 mg/kg/day males that was above the historical control value for the test facility but did not reach statistical significance for trend and pairwise comparisons. The study was negative for drug‐related neoplasms in female mice.”
Reproductive & developmental
Preliminary rat EFD: decreased fetal weight, post-implantation loss and fetal subcutis edema at ≥20 mg/kg/day
“Daily oral administration of nirogacestat to pregnant rats resulted in decreased fetal body weights, post‐ implantation loss, and fetal subcutis edema at doses ≥ 20 mg/kg/day (approximately 0.85 times the exposure in patients with desmoid tumors based on AUC at the 150 mg BID dose).”
Safety pharmacology
No CNS, respiratory or cardiovascular effects up to 500 mg/kg; hERG IC50 1 µM, >100x free human Cmax
“There were no nirogacestat‐related adverse effects on the central nervous system, pulmonary function, or the cardiovascular system at single doses up to 500 mg/kg. Nirogacestat blocked the hERG channel with an IC50 of 1 μM; however, this IC50 is greater than 100 times the free Cmax in humans at the 150 mg BID 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 Ogsiveo 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: No NOAEL in 3-month dog study: oocyte mineralization at the lowest dose (2 mg/kg/day) (EMA assessment report, p. 35)
NOAEL / key findings
No NOAEL in 3-month dog study: oocyte mineralization at the lowest dose (2 mg/kg/day)
“Due to oocyte mineralization at the lowest dose in the 3-month dog study, a NOAEL was not identified. The lowest dose in the dog was 2 mg/kg/day (human equivalent dose of 70 mg/day).”
Risksopen answer page →
Immune & cytokine safety
Decreased cellularity of gut-associated lymphoid tissue and mesenteric lymph nodes in rats
“In the 3‐month rat study, ovarian atrophy, alterations in the estrous cycle and decreased cellularity in gut‐associated lymphoid tissue (GALT) in females, and decreased cellularity of mesenteric lymph nodes in males and females at 5 mg/kg/day was observed.”
Biodistribution & persistence
Highest in uveal tract, liver, adrenal, spleen, pituitary; binds melanin in pigmented ocular tissues
“Excluding excreta, the highest Cmax levels of radiolabeled [14C] nirogacestat were uveal tract, liver, adrenal gland, spleen, and pituitary gland. Radiolabeled [14C] nirogacestat exhibited an affinity for pigmented ocular tissues containing melanin.”
Modality-specific risk
Notch-mediated ovarian toxicity (degeneration, atrophy, oocyte mineralization)
“Regarding ovarian dysfunction in humans, ovarian degeneration/necrosis/atrophy and oocyte mineralization occurred in animals administered nirogacestat and was consistent with Notch regulation of mammalian folliculogenesis (Vanorny and Mayo, 2014).”