Ukoniq
umbralisib
Species
MouseDog
Longest study
39 wk
Genotox
Conducted Conducted
Carcinogenicity
Not conducted Not conducted
Repro
Conducted Conducted
First dose
Not conducted Not stated publicly
Speciesopen answer page →
Species
Mouse and dog
“The tolerability, potential toxicities, target organs, and toxicokinetics of umbralisib were evaluated in repeat-dose toxicity studies up to 26 weeks in mice and 39 weeks in dogs.”
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
“In the 26-week mouse study, umbralisib was administered by oral gavage at 30, 100, and 300 mg/kg/day with 4 weeks of recovery.”
Study lengthopen answer page →
Longest pivotal study
39 (39-week dog)
“The tolerability, potential toxicities, target organs, and toxicokinetics of umbralisib were evaluated in repeat-dose toxicity studies up to 26 weeks in mice and 39 weeks in dogs.”
Pivotal GLP studies
26-week mouse and 39-week dog oral studies
“The tolerability, potential toxicities, target organs, and toxicokinetics of umbralisib were evaluated in repeat-dose toxicity studies up to 26 weeks in mice and 39 weeks in dogs.”
Route in tox
Oral (gavage in mice, capsule in dogs)
“The studies were conducted using the oral route of administration, which is consistent with the intended clinical route of administration.”
Skipped studiesopen answer page →
Genotoxicity
Negative in Ames, in vitro TK6 micronucleus and in vivo mouse micronucleus assays
“Umbralisib was not mutagenic in a bacterial mutagenicity (Ames) assay. Umbralisib was not clastogenic in an in vitro micronucleus assay using human (TK6) lymphoblast cells or in an in vivo micronucleus assay in mice at doses up to 1000 mg/kg.”
Carcinogenicity
Not conducted; not warranted for the indication
“No carcinogenicity studies have been conducted or are warranted to support the marketing of umbralisib for the current indications.”
Reproductive & developmental
Mouse EFD: cleft palate at 200 and 400 mg/kg/day, nasopharyngeal fistula at 400 mg/kg/day
“Malformations were observed at doses of 200 mg/kg/day (cleft palate) and 400 mg/kg/day (cleft palate and nasopharyngeal fistula).”
Safety pharmacology
hERG IC50 above 100 µM, the highest concentration tested
“An in vitro hERG channel inhibition study (Study # CYP0358-R10) with hERG-expressing cells incubated with umbralisib at concentrations up 100 M showed that the test article had an IC50 greater than the highest dose tested.”
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 Ukoniq 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: Main target organs: liver in mice, gastrointestinal tract in dogs (FDA multi-discipline review, p. 39)
NOAEL / key findings
Main target organs: liver in mice, gastrointestinal tract in dogs
“The liver was identified as the main target organ in mice and the gastrointestinal tract in dogs.”
Risksopen answer page →
Immune & cytokine safety
Decreased white blood cells and lymphoid depletion
“Drug-related findings included decreased white blood cells (WBCs) and differentials, increased liver weights and alkaline phosphatase (ALP) levels, and lymphoid depletion.”
Biodistribution & persistence
Wide distribution in mice; lowest concentration in brain, limited CNS passage
“In mice, umbralisib was widely distributed, with the highest concentrations in the gastrointestinal, metabolic/excretory, fatty, secretory, and endocrine tissues and the lowest concentration in brain, demonstrating penetration of umbralisib occurred in richly perfused organs, while passage to the CNS was limited.”
Modality-specific risk
Embryo-fetal toxicity (malformations at exposures comparable to clinical)
“In animal reproduction studies, administration of umbralisib to pregnant mice during organogenesis resulted in adverse developmental outcomes, including alterations to growth, embryo-fetal mortality, and structural abnormalities at maternal exposures (AUC) comparable to those in patients at the recommended dose of 800 mg (see Data ) .”