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”
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.”
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 outside oncology
Find the highest dose with no adverse effects (NOAEL) in each animal species, convert it to a human equivalent dose, usually by body surface area, pick the most appropriate species, then divide by a safety factor (default 10) to get the maximum recommended starting dose.
“In general, one should consider using a safety factor of at least 10. The MRSD should be obtained by dividing the HED by the safety factor.”
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.”