Rezlidhia
olutasidenib
Species
MonkeyRat
Longest study
13 wk
Genotox
Conducted Conducted
Carcinogenicity
Not conducted Not conducted
Repro
Conducted Conducted
First dose
Not conducted Not stated publicly
Speciesopen answer page →
Species
Rat and cynomolgus monkey
“Repeat-dose studies in rats and monkeys were conducted to assess the general toxicology of olutasidenib.”
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 drug was administered for 13 weeks in rats and monkeys via oral administration, which is consistent with the intended clinical route of administration.”
Species: general tox
Rat and monkey (13-week oral)
“The drug was administered for 13 weeks in rats and monkeys via oral administration, which is consistent with the intended clinical route of administration.”
Species: DART
Rat and rabbit (EFD only)
“Animal studies with olutasidenib have been conducted in rats and rabbits to evaluate effects on embryofetal development.”
Species: carcinogenicity
Not conducted (ICH S9)
“Carcinogenicity of olutasidenib was not evaluated in accordance with ICH S9.”
Surrogate used in
No surrogate used; clinical compound tested in rat and monkey
“The drug was administered for 13 weeks in rats and monkeys via oral administration, which is consistent with the intended clinical route of administration.”
Study lengthopen answer page →
Longest pivotal study
13 (13-week rat and monkey)
“The drug was administered for 13 weeks in rats and monkeys via oral administration, which is consistent with the intended clinical route of administration.”
Pivotal GLP studies
13-week oral rat and monkey studies
“The drug was administered for 13 weeks in rats and monkeys via oral administration, which is consistent with the intended clinical route of administration.”
Route in tox
Oral
“The drug was administered for 13 weeks in rats and monkeys via oral administration, which is consistent with the intended clinical route of administration.”
Skipped studiesopen answer page →
Genotoxicity
Negative in Ames, in vitro human lymphocyte micronucleus and in vivo rat bone marrow micronucleus assays
“Olutasidenib was not genotoxic in the in vitro bacterial reverse mutation (Ames), in vitro human lymphocyte micronucleus, and in vivo rat bone marrow micronucleus assays.”
Carcinogenicity
Not conducted (advanced cancer indication, ICH S9)
“Carcinogenicity of olutasidenib was not evaluated in accordance with ICH S9.”
Reproductive & developmental
Rat and rabbit EFD: embryo-fetal death and altered fetal growth at up to 10x and 0.7x human exposure
“In embryo-fetal development studies, oral olutasidenib resulted in embryo-fetal death and altered fetal growth when administered to pregnant rats and rabbits during the period of organogenesis at exposures up to 10 times and 0.7 times, respectively, the human exposure at the recommended daily dose”
Safety pharmacology
hERG inhibition; progressive QTc prolongation at the high dose in the 28-day monkey study
“The in vivo cardiovascular assessments were conducted as part of a 28-day repeat-dose general toxicology study in monkeys (2336-008). Consistent with hERG inhibition, olutasidenib was associated with a significant increase in corrected QT (QTc) interval duration at the high dose (300/200/100 mg/kg/day), which became progressively longer with repeated dosing.”
Genotox: Ames
Negative
“Olutasidenib was not genotoxic in the in vitro bacterial reverse mutation (Ames), in vitro human lymphocyte micronucleus, and in vivo rat bone marrow micronucleus assays.”
Genotox: in vitro mammalian
In vitro human lymphocyte micronucleus: negative
“Olutasidenib was not genotoxic in the in vitro bacterial reverse mutation (Ames), in vitro human lymphocyte micronucleus, and in vivo rat bone marrow micronucleus assays.”
Genotox: in vivo
Rat bone marrow micronucleus: negative
“Olutasidenib was not genotoxic in the in vitro bacterial reverse mutation (Ames), in vitro human lymphocyte micronucleus, and in vivo rat bone marrow micronucleus assays.”
Carcinogenicity model
Not conducted (ICH S9)
“Carcinogenicity of olutasidenib was not evaluated in accordance with ICH S9.”
Carcinogenicity timing
Not conducted; not required for advanced cancer under ICH S9 (FDA agreed)
“Carcinogenicity of olutasidenib was not evaluated in accordance with ICH S9.”
hERG / QT
hERG IC50 11.8 µM, 17-fold free Cmax at 150 mg BID
“Olutasidenib inhibited hERG potassium channels with an IC50 value of 11.8 μM, which is 17-fold the free Cmax of 711 nM at the recommended clinical dose of 150 mg BID.”
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 Rezlidhia 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: Target organs: GI tract, liver, cardiovascular system, kidneys, hematopoietic system; altered glucose and lipid metabolism, inflammation, electrolyte imbalance (FDA multi-discipline review, p. 33)
NOAEL / key findings
Target organs: GI tract, liver, cardiovascular system, kidneys, hematopoietic system; altered glucose and lipid metabolism, inflammation, electrolyte imbalance
“Overall, adverse findings included altered glucose and lipid metabolism, inflammation, electrolyte imbalance, and toxicities in the GI tract, liver, cardiovascular system, kidneys, and hematopoietic system.”
Risksopen answer page →
Immune & cytokine safety
Lymph node cellular depletion and increased white blood cells
“hematopoietic system (reduced RBCs and lineages, increased WBCs and differentials, increased platelets, and lymph node cellular depletion).”
Biodistribution & persistence
Highest QWBA levels in small intestine, cecum and liver; crosses blood-brain barrier in rats
“A QWBA distribution study in rats demonstrated tissues with the highest radioactivity concentrations were small intestines, cecum, and liver. Olutasidenib crossed the blood brain barrier in rats with unbound ratios of cerebrospinal fluid to plasma and brain to plasma of 0.29 and 0.1, respectively.”
Modality-specific risk
Phototoxicity linked to melanin binding
“Distribution studies showed binding of olutasidenib to melanin-containing tissues and a follow up phototoxicity study in rats showed erythema in the skin of animals after 48 hours of exposure to UV light that persisted for 72 hours.”
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
Not applicable; not assessed or expected
“Not applicable as this was not assessed or expected.”
Label warnings
Boxed warning: Differentiation syndrome
- Differentiation Syndrome
- Hepatotoxicity
Hepatotoxicity
US prescribing information, Boxed Warning and Warnings and PrecautionsDailyMed ↗
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 Rezlidhia 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: Target organs: GI tract, liver, cardiovascular system, kidneys, hematopoietic system; altered glucose and lipid metabolism, inflammation, electrolyte imbalance (FDA multi-discipline review, p. 33)
Longest repeat-dose systemic studies
Longest repeat-dose study and recovery
13-week rat and monkey (oral), each with 4-week recovery
“In the 13-week rat study, olutasidenib was administered at 25, 100, or 250 mg/kg BID, (50, 200, or 500 mg/kg/day) with a 4-week recovery period.”
Pivotal GLP studies
13-week oral rat and monkey studies
“The drug was administered for 13 weeks in rats and monkeys via oral administration, which is consistent with the intended clinical route of administration.”
DART package
Species: DART
Rat and rabbit (EFD only)
“Animal studies with olutasidenib have been conducted in rats and rabbits to evaluate effects on embryofetal development.”
Reproductive & developmental
Rat and rabbit EFD: embryo-fetal death and altered fetal growth at up to 10x and 0.7x human exposure
“In embryo-fetal development studies, oral olutasidenib resulted in embryo-fetal death and altered fetal growth when administered to pregnant rats and rabbits during the period of organogenesis at exposures up to 10 times and 0.7 times, respectively, the human exposure at the recommended daily dose”
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 (ICH S9)
“Carcinogenicity of olutasidenib was not evaluated in accordance with ICH S9.”
Carcinogenicity model
Not conducted (ICH S9)
“Carcinogenicity of olutasidenib was not evaluated in accordance with ICH S9.”
Carcinogenicity timing
Not conducted; not required for advanced cancer under ICH S9 (FDA agreed)
“Carcinogenicity of olutasidenib was not evaluated in accordance with ICH S9.”
Safety marginopen answer page →
Safety margin at NOAEL
Toxicology-study AUC margins 1- to 12-fold vs pivotal clinical study (unbound drug)
“Comparisons between the AUC values observed in the toxicology studies and those in the pivotal clinical study show that the safety margins range between 1- and 12-fold for unbound olutasidenib.”
NOAEL / key findings
Target organs: GI tract, liver, cardiovascular system, kidneys, hematopoietic system; altered glucose and lipid metabolism, inflammation, electrolyte imbalance
“Overall, adverse findings included altered glucose and lipid metabolism, inflammation, electrolyte imbalance, and toxicities in the GI tract, liver, cardiovascular system, kidneys, and hematopoietic system.”
Efficacy evidenceopen answer page →
Efficacy evidence
Mouse xenografts of cell lines engineered to express mutant IDH1 (tumor 2-HG measured)
“The in vivo activity of olutasidenib was assessed by measuring 2-HG in xenograft models of cell lines engineered to express mutated IDH1.”
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
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.
Flexibilityopen answer page →
Flexibility accepted
No departure named in the public reviews.
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