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.”
Species: general tox
Mouse (26-week) and dog (39-week)
“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.”
Species: DART
Mouse (EFD, fertility) and rabbit (EFD)
“TGR-1202: An Embryo Fetal Development Study in Mice via Oral Gavage GD46XG TGR-1202: An Oral (Gavage) Embryo Fetal Development Study in Rabbits WR05CP TGR-1202: Study of Fertility and Early Embryonic Development in the CD-1 Mouse by Oral Gavage Administration”
Species: carcinogenicity
Not conducted (advanced cancer indication, ICH S9)
“In accordance with the International Council for Harmonisation (ICH) guideline ICH S9 (2009), no carcinogenicity studies have been conducted because umbralisib is intended for use in patients with advanced cancer.”
Surrogate used in
No surrogate used
“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.”
Genotox: Ames
Negative
“Umbralisib was not mutagenic in a bacterial mutagenicity (Ames) assay.”
Genotox: in vitro mammalian
In vitro micronucleus in human TK6 lymphoblast cells: negative
“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.”
Genotox: in vivo
Mouse micronucleus up to 1000 mg/kg: negative
“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 model
Not conducted (advanced cancer indication, ICH S9)
“In accordance with the International Council for Harmonisation (ICH) guideline ICH S9 (2009), no carcinogenicity studies have been conducted because umbralisib is intended for use in patients with advanced cancer.”
Carcinogenicity timing
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.”
hERG / QT
hERG IC50 above highest concentration tested; no ECG effects in dogs at 30-250 mg/kg (13-week)
“showed that the test article had an IC50 greater than the highest dose tested. In vivo cardiovascular assessments were conducted as part of a 13-week repeat dose general toxicology study in dogs. ECG examinations showed that umbralisib at doses 30, 100, or 250 mg/kg did not result in any umbralisib-related effects on CV system parameters.”
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)
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: 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 ) .”
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
No immunogenicity data in the application
“There are no immunogenicity data about umbralisib in this application.”
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 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)
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: Main target organs: liver in mice, gastrointestinal tract in dogs (FDA multi-discipline review, p. 39)
Longest repeat-dose systemic studies
Longest repeat-dose study and recovery
39-week dog (oral capsule) with 28-day recovery
“A 39-week Study of TGR-1202 by Oral Capsule in Dogs with a 28- day Recovery Period”
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.”
DART package
Species: DART
Mouse (EFD, fertility) and rabbit (EFD)
“TGR-1202: An Embryo Fetal Development Study in Mice via Oral Gavage GD46XG TGR-1202: An Oral (Gavage) Embryo Fetal Development Study in Rabbits WR05CP TGR-1202: Study of Fertility and Early Embryonic Development in the CD-1 Mouse by Oral Gavage Administration”
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).”
PPND / ePPND: when
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.
Carcinogenicity
Species: carcinogenicity
Not conducted (advanced cancer indication, ICH S9)
“In accordance with the International Council for Harmonisation (ICH) guideline ICH S9 (2009), no carcinogenicity studies have been conducted because umbralisib is intended for use in patients with advanced cancer.”
Carcinogenicity model
Not conducted (advanced cancer indication, ICH S9)
“In accordance with the International Council for Harmonisation (ICH) guideline ICH S9 (2009), no carcinogenicity studies have been conducted because umbralisib is intended for use in patients with advanced cancer.”
Carcinogenicity timing
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.”
Safety marginopen answer page →
Safety margin at NOAEL
No NOAEL margin stated; dog testicular toxicity at ≥100 mg/kg, about 0.1x human AUC at 800 mg
“In a repeat-dose toxicology study in dogs, adverse findings in reproductive organs were observed in males and included findings in the testis (decreased weight, tubular degeneration, tubular atrophy) and epididymis (decreased weight, luminal debris) at doses ≥100 mg/kg, which is approximately 0.1 times the human exposure (AUC) at the recommended dose of 800 mg.”
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.”
Efficacy evidenceopen answer page →
Efficacy evidence
MOLT-4 xenograft mice (150 mg/kg/day oral) plus 13 leukemia/lymphoma cell lines
“The in vivo antitumor activity of umbralisib was evaluated in a MOLT-4 xenograft model. MOLT-4 tumor-bearing mice were dosed orally with umbralisib at 150 mg/kg/day for 25 days, with the measurement of tumor growth continuing until 41 days after dosing initiation.”
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: nonclinical pharmacology and toxicology data adequate to support approval
“The nonclinical pharmacology and toxicology data submitted to this NDA are adequate to support the approval of umbralisib for the proposed indications.”
Flexibilityopen answer page →
Flexibility accepted
Safety marginVerdict not stated
Rabbit embryo-fetal study exposures only 0.03 to 0.08 times clinical exposure, with high variability and no dose-dependence
“The 30, 100, or 300 mg/kg/day doses resulted in exposures that were 0.03, 0.08, and 0.03 times the exposures at the recommended clinical dose based on AUC. There was high inter-animal variability in the toxicokinetic values in this study within each dose group, reduced exposures at high dose, and lack of dose-dependence in exposures observed in rabbits.”
Safety marginVerdict not stated
Dog testicular and epididymal toxicity at about 0.1 times human exposure; no margin
“In a repeat-dose toxicology study in dogs, adverse findings in reproductive organs were observed in males and included findings in the testis (decreased weight, tubular degeneration, tubular atrophy) and epididymis (decreased weight, luminal debris) at doses ≥100 mg/kg, which is approximately 0.1 times the human exposure (AUC) at the recommended dose of 800 mg.”
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