Ocrevus
ocrelizumab
Species
Monkey
Longest study
24 wk
Genotox
Not conducted Not conducted
Carcinogenicity
Not conducted Not conducted
Repro
Conducted Conducted
First dose
Not conducted Not stated publicly
Speciesopen answer page →
Species
Cynomolgus monkey only
“Toxicology studies of ocrelizumab were conducted in cynomolgus monkey, the only pharmacologically relevant species”
Why that species
Binds CD20 in humans and nonhuman primates, not in rodents
“Ocrelizumab specifically binds CD20 in humans and nonhuman primates. It does not bind CD20 in rodents. Therefore, cynomolgus monkey was selected as the relevant species for nonclinical investigation.”
Surrogate molecule
No surrogate; the clinical antibody was tested in cynomolgus monkeys
“Toxicology studies of ocrelizumab were conducted in cynomolgus monkey, the only pharmacologically relevant species”
Species: general tox
Cynomolgus monkey only
“Toxicology studies of ocrelizumab were conducted in cynomolgus monkey, the only pharmacologically relevant species”
Species: DART
Cynomolgus monkey (male and female fertility, embryofetal, pre- and postnatal development)
“Reproductive and developmental toxicology (fertility assessments [male, female] and embryofetal and pre- and postnatal development studies in monkey)”
Species: carcinogenicity
Not conducted (deemed not feasible; waiver granted)
“Assessment of carcinogenic potential was deemed not feasible and the sponsor’s waiver request was granted.”
Surrogate used in
No surrogate molecule; huCD20 transgenic mice used for tissue distribution/clearance studies
“Tissue distribution studies in mice engineered to express huCD20 (huCD20 transgenic mice) demonstrated that, while ocrelizumab does not recognize CD20 in wild-type mice, there was clear binding of ocrelizumab with B cells in huCD20 transgenic mice.”
Study lengthopen answer page →
Longest pivotal study
24 weeks
“In the longest duration study (Study #04-0192-0134), monkeys received ocrelizumab every three weeks for 24 weeks (total of 8 total doses) at doses of 50 or 100 mg/kg IV.”
Pivotal GLP studies
Chronic monkey study 04-0192-0134: IV bolus 0, 50 or 100 mg/kg every 3 weeks, with recovery groups
“In the pivotal chronic toxicity study (04-0192-0134), ocrelizumab was administered to cynomolgus monkeys (4/sex/group for main study; 2/sex C and HD for recovery) by IV bolus injection at doses of 0, 50, and 100 mg/kg every 3 weeks”
Route in tox
Intravenous
“ocrelizumab was administered to cynomolgus monkeys (4/sex/group for main study; 2/sex C and HD for recovery) by IV bolus injection”
Skipped studiesopen answer page →
Genotoxicity
Not conducted (ICH S6)
“Genetic toxicology studies were not conduct for ocrelizumab, consistent with ICH S6 guidance.”
Carcinogenicity
Not conducted; carcinogenicity assessment waiver granted
“The sponsor submitted a carcinogenicity assessment waiver request under IND 100593 (Serial No. 0675, February 4, 2016). The waiver was granted”
Reproductive & developmental
Monkey study: effect on gestation length; neonatal stillbirths, deaths, B-cell depletion, kidney and bone marrow changes
“The results of this study demonstrate an effect on gestation length in dams and adverse effects of ocrelizumab on the neonate, including an increase in stillbirths and neonatal death, B-cell depletion, and microscopic changes in kidney and bone marrow.”
Safety pharmacology
Endpoints included in repeat-dose monkey studies
“Safety pharmacology endpoints were included in repeat dose studies in monkey.”
Genotox: Ames
Not conducted (ICH S6)
“Genetic toxicology studies were not conduct for ocrelizumab, consistent with ICH S6 guidance.”
Genotox: in vitro mammalian
Not conducted (ICH S6)
“Genetic toxicology studies were not conduct for ocrelizumab, consistent with ICH S6 guidance.”
Genotox: in vivo
Not conducted (ICH S6)
“Genetic toxicology studies were not conduct for ocrelizumab, consistent with ICH S6 guidance.”
Carcinogenicity model
Not conducted; carcinogenicity assessment deemed not feasible
“Assessment of carcinogenic potential was deemed not feasible and the sponsor’s waiver request was granted.”
Carcinogenicity timing
Not required (waiver granted)
“Assessment of carcinogenic potential was deemed not feasible and the sponsor’s waiver request was granted.”
hERG / QT
No respiratory, cardiovascular or CNS findings in monkey studies up to 100 mg/kg
“No treatment related observations in either respiratory, cardiovascular or CNS observations were noted following doses of up to 100 mg/kg ocrelizumab.”
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 Ocrevus 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 monoclonal antibodies
Use pharmacology data (target binding, receptor occupancy, in vitro human cells, PK/PD modelling) to estimate the lowest dose expected to have any biological effect (MABEL) and the active dose (PAD), and, for healthy volunteers, start at an exposure below the PAD unless robustly justified.
“these data should be used to determine the minimal anticipated biological effect level (MABEL) in humans and an estimation of the pharmacologically active dose (PAD) and/or anticipated therapeutic dose range (ATD) in humans.”
This product's starting point
NOAEL / key findings: NOAEL 100 mg/kg; B-cell repopulation at all dose levels (FDA pharmacology/toxicology review, p. 95)
NOAEL / key findings
NOAEL 100 mg/kg; B-cell repopulation at all dose levels
“Repopulation of B cells was demonstrated at all dose levels. NOAEL is100 mg/kg.”
Risksopen answer page →
Immune & cytokine safety
ADAs at all dose levels, most evident at 10 mg/kg or lower
“Results of TK analyses confirmed the immunogenicity of ocrelizumab at all doses levels, but ADAs were most evident at doses of 10 mg/kg or lower.”
Biodistribution & persistence
Transplacental exposure in monkey fetuses
“These data demonstrate trans-placental exposure to ocrelizumab in monkey fetuses.”
Modality-specific risk
Opportunistic infections from B-cell depletion-induced immune suppression (neonatal deaths in monkeys)
“Both of these deaths were due to opportunistic infection (one case involved transfer from the dam), which could have been related to ocrelizumab via the immune suppression induced by the B cell depletion.”
Anti-drug antibodies: animals
ADA in most monkey studies; reduced exposure in some low-dose animals, minimal impact above 10 mg/kg
“Anti-drug antibodies (ADAs) to ocrelizumab were detected in most studies in cynomolgus monkeys and were discussed by the Applicant. The presence of ADAs to ocrelizumab did impact exposure in some low-dose animals but there was only minimal impact in ocrelizumab exposure in animals given doses above 10 mg/kg.”
Anti-drug antibodies: patients
ADA in 12 of 1131 adult MS patients (~1%), 2 neutralizing; 2/90 pediatric (2.2%)
“In Studies 1, 2, and 3, 12 (~1%) out of 1131 adult patients tested positive for ADAs, of which 2 patients tested positive for neutralizing antibodies. In Study 5, two out of 90 pediatric patients (2.2%) had treatment emergent ADAs.”
Label warnings
- Infusion Reactions
- Infections
- Progressive Multifocal Leukoencephalopathy
- Reduction in Immunoglobulins
- Malignancies
- Immune-Mediated Colitis
- Liver Injury
Hypersensitivity & infusion reactionsInfectionsNeurotoxicitySecondary malignancyImmune-mediated reactionsHepatotoxicity
US prescribing information, 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 Ocrevus 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 monoclonal antibodies
Use pharmacology data (target binding, receptor occupancy, in vitro human cells, PK/PD modelling) to estimate the lowest dose expected to have any biological effect (MABEL) and the active dose (PAD), and, for healthy volunteers, start at an exposure below the PAD unless robustly justified.
“these data should be used to determine the minimal anticipated biological effect level (MABEL) in humans and an estimation of the pharmacologically active dose (PAD) and/or anticipated therapeutic dose range (ATD) in humans.”
This product's starting point
NOAEL / key findings: NOAEL 100 mg/kg; B-cell repopulation at all dose levels (FDA pharmacology/toxicology review, p. 95)
Longest repeat-dose systemic studies
Longest repeat-dose study and recovery
24-week cynomolgus monkey IV study (every 3 weeks, 8 doses) with 23-week recovery
“In the longest duration study (Study #04-0192-0134), monkeys received IV doses every three weeks for 24 weeks (total of 8 total doses) at doses of 50 or 100 mg/kg followed by a 23-week recovery period.”
Pivotal GLP studies
Chronic monkey study 04-0192-0134: IV bolus 0, 50 or 100 mg/kg every 3 weeks, with recovery groups
“In the pivotal chronic toxicity study (04-0192-0134), ocrelizumab was administered to cynomolgus monkeys (4/sex/group for main study; 2/sex C and HD for recovery) by IV bolus injection at doses of 0, 50, and 100 mg/kg every 3 weeks”
DART package
Species: DART
Cynomolgus monkey (male and female fertility, embryofetal, pre- and postnatal development)
“Reproductive and developmental toxicology (fertility assessments [male, female] and embryofetal and pre- and postnatal development studies in monkey)”
Reproductive & developmental
Monkey study: effect on gestation length; neonatal stillbirths, deaths, B-cell depletion, kidney and bone marrow changes
“The results of this study demonstrate an effect on gestation length in dams and adverse effects of ocrelizumab on the neonate, including an increase in stillbirths and neonatal death, B-cell depletion, and microscopic changes in kidney and bone marrow.”
PPND / ePPND: when
PPND in cynomolgus monkey completed before the marketing application; FDA recommended an additional ePPND with immune function assessment
“The lack of an adequate TDAR evaluation in the pre- and postnatal development (PPND) study precluded an evaluation of potential adverse effects on immune function. It is recommended that an expanded pre- and postnatal development (ePPND) study in cynomolgus monkey be conducted”
Carcinogenicity
Species: carcinogenicity
Not conducted (deemed not feasible; waiver granted)
“Assessment of carcinogenic potential was deemed not feasible and the sponsor’s waiver request was granted.”
Carcinogenicity model
Not conducted; carcinogenicity assessment deemed not feasible
“Assessment of carcinogenic potential was deemed not feasible and the sponsor’s waiver request was granted.”
Carcinogenicity timing
Not required (waiver granted)
“Assessment of carcinogenic potential was deemed not feasible and the sponsor’s waiver request was granted.”
Safety marginopen answer page →
Safety margin at NOAEL
Monkey doses tested were 2x and 10x the human 600 mg dose (mg/kg basis); no developmental no-effect dose identified
“A no-effect dose for adverse developmental effects was not identified; the doses tested in monkey are 2 and 10 times the recommended human dose of 600 mg, on a mg/kg basis.”
NOAEL / key findings
NOAEL 100 mg/kg; B-cell repopulation at all dose levels
“Repopulation of B cells was demonstrated at all dose levels. NOAEL is100 mg/kg.”
Efficacy evidenceopen answer page →
Efficacy evidence
Human-derived cell lines in vitro; in vivo studies in cynomolgus monkeys only
“Because ocrelizumab binds only to human and non-human primate CD20, in vitro studies were conducted using human-derived cell lines and in vivo studies were conducted in cynomolgus monkey.”
Why that model
Ocrelizumab binds human and nonhuman primate CD20 but not rodent CD20
“Ocrelizumab specifically binds CD20 in humans and nonhuman primates. It does not bind CD20 in rodents. Therefore, cynomolgus monkey was selected as the relevant species for nonclinical investigation.”
Reviewer's view of the efficacy data
EMA: nonclinical PD studies support mode of action as a reversible B-cell depleting antibody
“The non-clinical studies presented by the Applicant to demonstrate the pharmacodynamic properties of ocrelizumab support its mode of action as a reversible B-cell depleting molecule.”
Flexibilityopen answer page →
Flexibility accepted
OtherCriticised but acceptedBeyond the letter
Pivotal chronic toxicity and embryo-fetal studies used early drug substance not shown comparable to the marketed product
Why: Available clinical data make a repeat chronic toxicity study unnecessary · Human data
“The adequacy of the nonclinical program has been called into question by a lack of sufficient comparability between the drug material used in the nonclinical studies and the to-be-marketed drug product.”
“Repeat of the chronic toxicity study was not considered necessary given the available clinical data.”
DARTQuestioned
Pre-/postnatal development study lacked adequate T-cell-dependent antibody response evaluation of offspring immune function
“The lack of an adequate TDAR evaluation in the pre- and postnatal development (PPND) study precluded an evaluation of potential adverse effects on immune function.”
“It is recommended that an expanded pre- and postnatal development (ePPND) study in cynomolgus monkey be conducted (cf. Stewart J. Repro Toxicol 28:220-225, 2009), to include assessment of immune function.”
CarcinogenicityAcceptedBeyond the letter
Carcinogenicity assessment waived for a chronic multiple sclerosis indication
Why: Carcinogenicity assessment deemed not feasible · Other reason
“Genetic toxicology studies were not required or conducted. Assessment of carcinogenic potential was deemed not feasible and the sponsor’s waiver request was granted.”
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