Gazyva
obinutuzumab
Species
Monkey
Longest study
26 wk
Genotox
Not conducted Not conducted
Carcinogenicity
Not conducted Not conducted
Repro
Partial / alternative Partial / alternative
First dose
Not conducted Not stated publicly
Speciesopen answer page →
Species
Cynomolgus monkey only
“Toxicology studies were conducted solely using cynomolgus monkeys because other species available for toxicity testing are not pharmacologically responsive to obinutuzumab.”
Why that species
Binds cynomolgus (not rodent) CD20 with affinity and ADCC potency similar to human CD20
“Obinutuzumab binds to Cynomolgus monkey (but not rodent) CD20 with an affinity and ADCC potency similar to that of human CD20; consequently, the Cynomolgus monkey was considered the only appropriate species in which to assess the safety of obinutuzumab.”
Surrogate molecule
No surrogate; the clinical antibody was tested in cynomolgus monkeys
“Toxicology studies were conducted solely using cynomolgus monkeys because other species available for toxicity testing are not pharmacologically responsive to obinutuzumab.”
Study lengthopen answer page →
Longest pivotal study
26 weeks
“The route of application was IV (9, 13 and 26-weeks duration) and SC (4-week), thus reflecting the clinical route of administration in the pivotal 26-week study.”
Pivotal GLP studies
Weekly-dosed monkey studies: IV 9, 13 and 26 weeks (37 weeks of recovery after the 13- and 26-week studies); SC 4 weeks
“The route of application was IV (9, 13 and 26-weeks duration) and SC (4-week), thus reflecting the clinical route of administration in the pivotal 26-week study. A 37-week treatment free period was included after the 13 week and 26 week IV studies, respectively.”
Route in tox
IV (pivotal); SC in a 4-week study
“Repeat dose toxicology studies of 13-week or 26-week duration with extended recovery periods were conducted using IV administration of obinutuzumab. A separate 4-week study that evaluated subcutaneous (SC) administration was also completed.”
Skipped studiesopen answer page →
Genotoxicity
Not conducted (ICH S6/S9)
“Evaluation of the genotoxicity, carcinogenicity and dedicated safety pharmacology studies were not conducted and were not needed for this application.”
Carcinogenicity
Not conducted; acceptable under ICH S6
“The lack of carcinogenicity studies is considered acceptable based ICH S6 guidance.”
Reproductive & developmental
No fertility study; no reproductive organ effects in repeat-dose studies. Monkey ePPND: no teratogenicity; complete infant B-cell depletion, recovered within 6 months
“With regard to the offspring, a complete depletion of B-lymphocytes was observed at both tested dose-levels. B-lymphocyte counts and immunologic function (TDAR) in the infants returned to almost normal levels within 6 months following birth.”
Safety pharmacology
Incorporated into 13- and 26-week monkey studies; no CNS, respiratory, blood pressure or ECG effects
“The potential effect of obinutuzumab on CNS, respiratory and cardiovascular systems was evaluated as part of the IV 26-week repeat-dose toxicity study in Cynomolgus monkeys (Report 1036190).”
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 Gazyva 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 monoclonal antibodies (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: Hypersensitivity at all doses (≥5 mg/kg) in 26-week study: immune-complex glomerulonephritis, arteritis, deaths; expected B-cell depletion; no off-target toxicity (FDA pharmacology/toxicology review, p. 12)
NOAEL / key findings
Hypersensitivity at all doses (≥5 mg/kg) in 26-week study: immune-complex glomerulonephritis, arteritis, deaths; expected B-cell depletion; no off-target toxicity
“Hypersensitivity reactions were noted at all doses (≥5 mg/kg) in the 26-week study and were attributed to cross-species reactivity to a foreign protein.”
Risksopen answer page →
Immune & cytokine safety
In vitro whole-blood assays: cytokine release (IL-6, IL-8, TNF) predicting first-infusion reactions; monkey ADA with hypersensitivity; opportunistic infections
“In vitro analysis of obinutuzumab using whole blood from healthy human donors indicated that obinutuzumab can cause first-infusion cytokine release in patients.”
Biodistribution & persistence
Unexpected TCR in human and monkey liver epithelium, salivary gland and lung endothelium; crosses placenta; very low milk levels
“Unexpected tissue cross-reactivity staining using obinutuzumab was observed localized in the membrane of human and monkey liver epithelium, salivary glands and lung endothelium (refer to Section 11).”
Modality-specific risk
Infection from B-cell depletion-mediated immunosuppression; infusion-related cytokine release; fetal B-cell depletion
“Suspected opportunistic infections in an additional three unscheduled deaths from the shorter repeat-dose studies were considered a secondary result of obinutuzumab-mediated immunosuppression.”