Itovebi
inavolisib
Species
RatDog
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 dog
“Inavolisib was evaluated in GLP-compliant, repeat-dose toxicology studies in Sprague-Dawley rats and Beagle dogs following once daily oral administration, consistent with the clinical route of administration and intended dosing schedule, for up to 3 months in duration.”
Why that species
Target protein homology, in vivo pharmacodynamics, adequate exposure and human-like metabolic profile
“The rat and dog were selected as the toxicology species based on high protein homology of the target, the demonstration of in vivo pharmacodynamics, adequate in vivo exposure, and comparable in vivo metabolic profile to humans.”
Surrogate molecule
No surrogate; the clinical compound was tested
“Inavolisib was assessed in a series of non-clinical toxicology studies in rats and dogs.”
Study lengthopen answer page →
Longest pivotal study
13 (3-month rat and dog)
“Preliminary and definitive GLP repeat-dose toxicity studies were conducted with inavolisib in rats and dogs up to 13 weeks of duration.”
Pivotal GLP studies
4- and 13-week repeat-dose studies in rats and dogs
“In the 4-week and 13-week repeat-dose toxicology studies with inavolisib in rats and dogs, histopathology changes observed in reproductive organs suggest that inavolisib has the potential to impair male and female fertility.”
Route in tox
Oral, once daily
“Inavolisib was evaluated in GLP-compliant, repeat-dose toxicology studies in Sprague-Dawley rats and Beagle dogs following once daily oral administration, consistent with the clinical route of administration and intended dosing schedule, for up to 3 months in duration.”
Skipped studiesopen answer page →
Genotoxicity
Ames negative; clastogenic in vitro (human lymphocyte micronucleus); negative in vivo rat bone marrow micronucleus and liver comet
“Inavolisib was not mutagenic in the bacterial reverse mutation (Ames) assay. Inavolisib was clastogenic in an in vitro human lymphocyte micronucleus assay. Inavolisib was not genotoxic in an in vivo rat bone marrow micronucleus test and did not induce DNA break in a liver comet assay.”
Carcinogenicity
Not conducted (advanced cancer indication, ICH S9)
“Carcinogenicity studies were not conducted, nor warranted, with inavolisib to support the proposed indication in patients with advanced cancer in accordance with ICH S9 guidance.”
Reproductive & developmental
Rat EFD: reduced fetal weight, post-implantation loss and malformations at ≥2 mg/kg (≥0.9x human AUC)
“Administration of inavolisib resulted in dose dependent effects on embryo-fetal development at ≥2 mg/kg ( ≥ 0.9 times the human exposure at the recommended dose of 9 mg/day based on AUC) that included decreases in fetal body weight and placental weight, post-implantation loss, lower fetal viability, fetal malformations”
Safety pharmacology
Dog telemetry: reversible decreased heart rate, increased arterial pressure and minimal QTc lengthening (+11 msec) at ≥0.3 mg/kg
“In a GLP-compliant single dose safety pharmacology study in telemetry instrumented Beagle dogs, inavolisib-related cardiovascular effects included generally dose-dependent, reversible decreases in heart rate, increases in arterial pressure and contractility, lengthening of PR and QT intervals (likely driven by the decreased heart rates), and minimally lengthened corrected QT (QTc) interval (+11 msec/+5%) at doses ≥ 0.3 mg/kg.”
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 Itovebi 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: Target organs: lymphoid tissues and bone marrow, eye, pancreas, male and female reproductive organs (FDA multi-discipline review, p. 41)
NOAEL / key findings
Target organs: lymphoid tissues and bone marrow, eye, pancreas, male and female reproductive organs
“Overall, the major target organs of toxicity in rats or dogs were the lymphoid tissues (thymus, gut-associated lymphoid tissue/Peyer’s patch, mesenteric and mandibular lymph nodes, spleen, bone marrow), eye, pancreas, and male and female reproductive organs.”
Risksopen answer page →
Immune & cytokine safety
Lymphoid depletion in dogs after 4 weeks of dosing
“Decreases in lymphocytes in lymphoid tissues were observed in dogs administered inavolisib for 4 weeks.”
Biodistribution & persistence
Higher radioactivity in melanin-containing uveal tract and skin of pigmented rats
“In pigmented rats, distribution of inavolisib-derived radioactivity was comparable to that in albino rats, with the exception of melanin containing tissues, such as uveal tract and skin that presented higher levels of radioactivity.”
Modality-specific risk
On-target hyperglycaemia from PI3K inhibition of insulin signalling
“The dose-related and reversible hyperglycaemia is considered related to the pharmacologic effect of PI3K inhibition on insulin signalling.”