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.”
Species: general tox
Cynomolgus monkey
“Toxicology studies were conducted solely using cynomolgus monkeys because other species available for toxicity testing are not pharmacologically responsive to obinutuzumab.”
Species: DART
Cynomolgus monkey (enhanced pre- and postnatal development study)
“An enhanced pre and postnatal development (ePPND) toxicity study in pregnant Cynomolgus monkeys showed no evidence of teratogenic effects.”
Species: carcinogenicity
Not conducted
“Evaluation of the genotoxicity, carcinogenicity and dedicated safety pharmacology studies were not conducted and were not needed for this application.”
Surrogate used in
No surrogate antibody; huCD20 transgenic mice used in vaccination pharmacology studies
“Vaccination studies in huCD20 mice and Cynomolgus monkeys showed that the enhanced efficacy in terms of B-cell depletion of obinutuzumab translated into stronger suppression of de novo antibody responses, but left the protective humoral memory responses intact (Report 1053638).”
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).”
Genotox: Ames
Not conducted (ICH S6)
“Evaluation of the genotoxicity, carcinogenicity and dedicated safety pharmacology studies were not conducted and were not needed for this application.”
Genotox: in vitro mammalian
Not conducted (ICH S6)
“Evaluation of the genotoxicity, carcinogenicity and dedicated safety pharmacology studies were not conducted and were not needed for this application.”
Genotox: in vivo
Not conducted (ICH S6)
“Evaluation of the genotoxicity, carcinogenicity and dedicated safety pharmacology studies were not conducted and were not needed for this application.”
Carcinogenicity model
Not conducted; acceptable under ICH S6
“The lack of carcinogenicity studies is considered acceptable based ICH S6 guidance.”
Carcinogenicity timing
Not needed for this application
“Evaluation of the genotoxicity, carcinogenicity and dedicated safety pharmacology studies were not conducted and were not needed for this application.”
hERG / QT
No hERG assay; no ECG rhythm abnormalities in the 26-week monkey study
“No rhythm abnormalities or qualitative ECG changes attributed to obinutuzumab were observed on Day 78 or 169 of the dosing phase or Day 254 of the recovery phase as part of the qualitative assessment of the ECGs.”
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)
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: 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.”
Anti-drug antibodies: animals
ADA prevalent in monkeys and associated with rapid clearance of obinutuzumab
“ADA formation was prevalent and was associated with rapid clearance of obinutuzumab.”
Anti-drug antibodies: patients
Seven percent (18/271) of CLL patients in CLL11 tested ADA-positive
“Seven percent (18/271) of patients with CLL tested positive for anti-GAZYVA antibodies at one or more time points in CLL11.”
Label warnings
Boxed warning: HEPATITIS B VIRUS REACTIVATION and PROGRESSIVE MULTIFOCAL LEUKOENCEPHALOPATHY
- Hepatitis B Virus Reactivation
- Progressive Multifocal Leukoencephalopathy
- Infusion-Related Reactions
- Hypersensitivity Reactions Including Serum Sickness
- Tumor Lysis Syndrome
- Serious, Including Fatal, Infections
- Neutropenia
- Thrombocytopenia
- Disseminated Intravascular Coagulation (DIC)
- Immunization
- Embryo-Fetal Toxicity
HepatotoxicityInfectionsNeurotoxicityHypersensitivity & infusion reactionsSecondary malignancyCytopeniasThrombocytopeniaEmbryo-fetal toxicity
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 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)
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: 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)
Longest repeat-dose systemic studies
Longest repeat-dose study and recovery
26-week IV cynomolgus monkey with 37-week treatment-free period
“Repeat-dose toxicity studies applying weekly dosing were conducted in Cynomolgus monkeys (Table 6). 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.”
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.”
DART package
Species: DART
Cynomolgus monkey (enhanced pre- and postnatal development study)
“An enhanced pre and postnatal development (ePPND) toxicity study in pregnant Cynomolgus monkeys showed no evidence of teratogenic effects.”
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.”
PPND / ePPND: when
ePPND in cynomolgus monkey: completed before the marketing application (complete B-cell depletion in infants)
“An enhanced pre- and post-natal development (ePPND) toxicity study was conducted. Administration of obinutuzumab to pregnant cynomolgus monkeys resulted in a complete depletion of B lymphocytes in infants.”
Carcinogenicity
Species: carcinogenicity
Not conducted
“Evaluation of the genotoxicity, carcinogenicity and dedicated safety pharmacology studies were not conducted and were not needed for this application.”
Carcinogenicity model
Not conducted; acceptable under ICH S6
“The lack of carcinogenicity studies is considered acceptable based ICH S6 guidance.”
Carcinogenicity timing
Not needed for this application
“Evaluation of the genotoxicity, carcinogenicity and dedicated safety pharmacology studies were not conducted and were not needed for this application.”
Safety marginopen answer page →
Safety margin at NOAEL
No off-target toxicity in monkeys at AUC up to 6-fold human exposure at 1000 mg
“No off-target toxicity was observed in Cynomolgus monkeys following IV and SC administration of obinutuzumab at AUC exposures up to 6-fold those observed in humans following administration of the maximum recommended dose of 1000 mg.”
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.”
Efficacy evidenceopen answer page →
Efficacy evidence
Human B-cell lymphoma xenografts (DLBCL, NHL, MCL) in SCID beige mice
“IV Q7D obinutuzumab displayed superior anti-tumour efficacy in SCID mice carrying tumours derived from SUDHL-4 DLBCL, OCI-Ly-18 NHL, Z138 MCL, RL NHL and WSU-DLCL2 B cell lymphoma cell lines when compared to rituximab.”
Why that model
Binds cynomolgus monkey but not rodent 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.”
Reviewer's view of the efficacy data
CHMP: potent B-cell depletion and antitumour efficacy demonstrated in animal models
“In animal models obinutuzumab mediated potent B-cell depletion and antitumour efficacy.”
Flexibilityopen answer page →
Flexibility accepted
Safety marginVerdict not stated
Hypersensitivity reactions in the 26-week monkey study at all doses, at 0.7-6 times clinical exposure
Why: Attributed to foreign recognition of the humanised antibody in monkeys · No relevant species
“In a 26 week cynomolgus monkey study, hypersensitivity reactions were noted and attributed to the foreign recognition of the humanised antibody in cynomolgus monkeys (0.7-6 times the clinical exposure based on Cmax and AUC at steady state after weekly administration of 5, 25, and 50 mg/kg).”
GLPAccepted
Bioanalytical method validation for monkey serum not performed under GLP
Why: Method validated per FDA bioanalytical guidance and best industry practice valid at the time · Within the guideline
“The validations of the bioanalysis methods used for quantification of obinutuzumab in Cynomolgus monkey serum were not performed according to GLP.”
“However, the analytical method was validated according to the guidance valid at the time of study performance, which was consistent with the FDA Guidance on Bioanalytical Method Validation and best industry practices (Kelley M et al. 2007, Viswanathan CT et al. 2007) with regards to the tested validation parameters and pre-defined acceptance criteria; thus, the lack of GLP compliance of the bioanalysis validation was considered acceptable.”
BiodistributionAcceptedBeyond the letter
In vivo distribution of obinutuzumab not studied
Why: CD20 tissue expression characterised; limited distribution beyond plasma; no off-target binding in human tissue cross-reactivity · Pharmacology or kinetics
“The in vivo distribution of obinutuzumab has not been studied. This is deemed acceptable due to 1) the fact that obinutuzumab is specific for CD20 whose tissue expression is characterized 2) the fact that pharmacokinetic data indicate limited distribution beyond the plasma compartment and 3) the human cross-reactivity study indicates no potential for off-target binding.”
OtherAccepted
No dedicated single-dose toxicity studies; acute effects assessed after the first dose in repeat-dose monkey studies
Why: Repeat-dose study results address acute toxicity per ICH M3(R2) · Within the guideline
“According to ICH guidance M3(R2), the results of these studies are considered appropriate to address acute toxicity aspects. Therefore, the lack of dedicated single-dose toxicity studies was considered acceptable.”
OtherQuestioned
In vitro cytokine release assay did not test immobilized antibody
“Reviewer’s comment: This assay did not include a set of experiments using immobilized antibodies. By not doing, the assay may not adequately mimic the in vivo conditions that may give rise to cytokine release.”
Similar precedents
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