Ocrevus (ocrelizumab): what was done before first-in-human, and what came after?

Precedia/Monoclonal antibodies/Ocrevus/Tox package

Ocrevus: what was done before first-in-human, and what came after?

ocrelizumab · CD20

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.”

✓ VerifiedEMA 2017: Guideline on strategies to identify and mitigate risks for…, p. 11Source ↗

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)

Full method, every step sourced →

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.”

✓ VerifiedFDA pharmacology/toxicology review, p. 130Source ↗

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”

✓ VerifiedFDA pharmacology/toxicology review, p. 9Source ↗

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)”

✓ VerifiedFDA pharmacology/toxicology review, p. 5Source ↗

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.”

✓ VerifiedFDA pharmacology/toxicology review, p. 17Source ↗

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”

✓ VerifiedFDA pharmacology/toxicology review, p. 19Source ↗

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.”

✓ VerifiedFDA pharmacology/toxicology review, p. 19Source ↗

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.”

✓ VerifiedFDA pharmacology/toxicology review, p. 19Source ↗

Carcinogenicity timing

Not required (waiver granted)

“Assessment of carcinogenic potential was deemed not feasible and the sponsor’s waiver request was granted.”

✓ VerifiedFDA pharmacology/toxicology review, p. 19Source ↗

Summary across all 117 monoclonal antibodies →

Ocrevus: what was done before first-in-human, and what came after?

Before first-in-human

Longest repeat-dose systemic studies

DART package

Carcinogenicity

Same question, other monoclonal antibodies