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.”
Species: general tox
Sprague-Dawley rat and Beagle dog (up to 3 months)
“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.”
Species: DART
Rat (preliminary EFD study only); no fertility study
“In a GLP-compliant preliminary embryo-fetal development study, pregnant rats received oral doses of inavolisib up to 6 mg/kg/day during the period of organogenesis from gestational day”
Species: 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.”
Surrogate used in
No surrogate used; inavolisib tested in rats and dogs
“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.”
Genotox: Ames
Negative (not mutagenic in bacterial reverse mutation assay)
“In GLP-compliant genetic toxicology studies, inavolisib was not mutagenic in the bacterial reverse mutation assay.”
Genotox: in vitro mammalian
Positive: clastogenic in in vitro human lymphocyte micronucleus assay
“Inavolisib was clastogenic in an in vitro human lymphocyte micronucleus assay.”
Genotox: in vivo
Negative: rat bone marrow micronucleus and liver alkaline Comet assay
“Inavolisib treatment did not cause a significant increase in micronucleus frequency in polychromatic erythrocytes of the bone marrow and did not induce DNA strand breaks in the liver above the historical control range when evaluated by the alkaline Comet assay.”
Carcinogenicity model
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.”
Carcinogenicity timing
Not required for advanced cancer (ICH S9); none conducted
“FDA agrees that carcinogenicity studies are not warranted to support the proposed indication in patients with advanced cancer in accordance with ICH S9 guidance.”
hERG / QT
hERG IC50 >1700x human unbound Cmax (0.116 µM) at 9 mg
“The IC50 for inhibition of hERG current was > 1700 times higher than the human plasma Cmax [unbound] (0.116 µM) at the 9 mg 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 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)
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: 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.”
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 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.
Label warnings
- Hyperglycemia
- Stomatitis
- Diarrhea
- Embryo-Fetal Toxicity
Metabolic & endocrineGastrointestinalEmbryo-fetal toxicity
US prescribing information, Warnings and PrecautionsDailyMed ↗
Tox packageopen answer page →
Before first-in-human
First-in-human: where
US, Spain, Canada, UK, France: first-in-human dose escalation and expansion in patients with PIK3CA-mutated solid tumors
“13 sitesc 5 countrie s (US, Spain, Canada, UK, France)”
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 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)
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: lymphoid tissues and bone marrow, eye, pancreas, male and female reproductive organs (FDA multi-discipline review, p. 41)
Longest repeat-dose systemic studies
Longest repeat-dose study and recovery
13-week rat (no recovery phase) and 13-week dog (recovery group, males only, length not given)
“Duration: 13 Weeks GLP compliance: Yes Drug, lot#, and % purity: GDC-0077, lot # 68878-287, 98.9% purity Methods Doses: 0, 0.3, 1.5/1.0 mg/kg/day Frequency of dosing: Once daily Number/Sex/Group: 3 (terminal); 3 (recovery at 0 and 1.5/1.0 mg/kg/day only)”
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.”
DART package
Species: DART
Rat (preliminary EFD study only); no fertility study
“In a GLP-compliant preliminary embryo-fetal development study, pregnant rats received oral doses of inavolisib up to 6 mg/kg/day during the period of organogenesis from gestational day”
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”
PPND / ePPND: when
Not conducted: PPND not warranted for advanced cancer (ICH S9)
“The ICH S9 guidance (ICH 2009) states that studies on (1) fertility and early embryonic development and (2) pre- and postnatal toxicology are not warranted to support marketing authorization applications for pharmaceuticals intended for the treatment of patients with advanced cancer, such as inavolisib. Accordingly, such studies were not performed.”
Carcinogenicity
Species: 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.”
Carcinogenicity model
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.”
Carcinogenicity timing
Not required for advanced cancer (ICH S9); none conducted
“FDA agrees that carcinogenicity studies are not warranted to support the proposed indication in patients with advanced cancer in accordance with ICH S9 guidance.”
Safety marginopen answer page →
Safety margin at NOAEL
Rat and dog 4- and 13-week NOAELs generally below clinical AUC; no exposure margin
“The AUC exposure margins NOAELs in the 4- and 13-week repeat-dose rat and dog studies, and in the preliminary EFD study in rats were generally below 1 indicating a lack of exposure margins to the adverse effects observed in the non-clinical studies.”
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.”
Efficacy evidenceopen answer page →
Efficacy evidence
PIK3CA-mutant human breast cancer xenografts in mice (KPL-4, HCC1954X1, MCF7)
“Inavolisib showed anti-tumor effects in xenograft mouse models of human breast cancer using KPL-4, HCC1954X1, and MCF7 cell lines.”
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
EMA: in vitro and in vivo primary pharmacology adequately characterised
“The in vitro and in vivo primary pharmacology of inavolisib have been adequately characterised.”
Flexibilityopen answer page →
Flexibility accepted
Safety marginVerdict not stated
No exposure margins: NOAEL AUC margins in 4- and 13-week rat and dog studies and rat embryo-fetal study generally below 1
“The AUC exposure margins NOAELs in the 4- and 13-week repeat-dose rat and dog studies, and in the preliminary EFD study in rats were generally below 1 indicating a lack of exposure margins to the adverse effects observed in the non-clinical studies.”
RecoveryAccepted with a conditionBeyond the letter
No recovery assessment in the 3-month rat study (reproductive organ findings)
Why: Reversibility shown in the 4-week study; reflected in SmPC section 5.3 · Weight of evidence
“Findings in the uterus, vagina, and estrous cycle observed in the 4-week toxicity study were not observed following a 4-week recovery period. Recovery was not assessed in the 3-month study in rats.”
“Recovery was not assessed in the 3-month study in rats. This is reflected in SmPC section 5.3.”
Impurity or metaboliteAcceptedBeyond the letter
Impurity RO7304403 qualified for genotoxicity without testing (inconclusive in silico); RO7304383 qualified by non-GLP Ames only
Why: Structural similarity to inavolisib, no structural alerts, and presence at 1.1% in batches used in genotoxicity studies · Weight of evidence
“For genotoxicity, one impurity RO7304383 was tested in Ames test in a non-GLP study, whereas the other impurity, RO7304403, was investigated in silico analysis of genotoxicity and is considered qualified.”
“However, considering structural similarity to inavolisib, the absence of structural alerts, as well as the fact that the impurity was present (at 1.1%) in the batch of inavolisib tested in the Ames study and the in vivo genotoxicity study, this impurity is considered qualified for genotoxicity.”
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