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

Precedia/Monoclonal antibodies/Rituxan/Tox package

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

rituximab · 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

Repeat-dose pilot pharmacology/toxicology study in cynomolgus monkeys (16.8 mg/kg doses); duration and recovery not stated

“A repeated pilot pharmacology/toxicology experiment in Cynomolgus monkeys (using 16.8 mg/kg doses) demonstrated the relationship between exposure of multiple injections of rituximab to the degree of B–cell depletion in the peripheral blood and bone marrow, as well as within the lymphatic tissues. This experiment formed the basis for the initial dose escalating study in humans.”

✓ VerifiedEMA assessment report, p. 6Source ↗

First-in-human starting dose

Based on monkey pilot study relating multiple-dose rituximab exposure to B-cell depletion

✓ VerifiedEMA assessment report, p. 6Source ↗

Longest repeat-dose systemic studies

Longest repeat-dose study and recovery

8-week GLP cynomolgus monkey study, weekly IV up to 20 mg/kg; recovery not stated

“Weekly dose of rituximab up to 20 mg/kg (= 276 mg/m2 ) was generally well tolerated over up to 8 weeks of treatment in a further GLP toxicity study in Cynomolgus monkeys.”

✓ VerifiedEMA assessment report, p. 6Source ↗

Pivotal GLP studies

GLP cynomolgus monkey study, weekly IV up to 20 mg/kg for up to 8 weeks

“Weekly dose of rituximab up to 20 mg/kg (= 276 mg/m2 ) was generally well tolerated over up to 8 weeks of treatment in a further GLP toxicity study in Cynomolgus monkeys.”

✓ VerifiedEMA assessment report, p. 6Source ↗

DART package

Species: DART

Cynomolgus monkey (embryo-fetal and subsequent pre- and postnatal studies)

“A subsequent pre-and postnatal reproductive toxicity study in cynomolgus monkeys was completed to assess developmental effects including the recovery of B cells and immune function in infants exposed to rituximab in utero.”

✓ VerifiedUS prescribing informationSource ↗

Reproductive & developmental

Monkey EFD and PPND: decreased B cells and immunosuppression in offspring, restored within 6 months postpartum

“Regardless of the timing of treatment, decreased B cells and immunosuppression were noted in the offspring of rituximab-treated pregnant animals. The B-cell counts returned to normal levels, and immunologic function was restored within 6 months postpartum.”

✓ VerifiedUS prescribing informationSource ↗

PPND / ePPND: when

No reproductive studies at the initial marketing application (lack judged justified); cynomolgus monkey PPND done later

“The lack of reproductive, mutagenic, genotoxic and carcinogenic studies is justified, and SPC has been amended appropriately.”

✓ VerifiedEMA assessment report, p. 6Source ↗

Carcinogenicity

Species: carcinogenicity

Not conducted

“No long-term animal studies have been performed to establish the carcinogenic or mutagenic potential of RITUXAN or to determine potential effects on fertility in males or females.”

✓ VerifiedUS prescribing informationSource ↗

Carcinogenicity model

Not conducted

“No long-term animal studies have been performed to establish the carcinogenic or mutagenic potential of RITUXAN or to determine potential effects on fertility in males or females.”

✓ VerifiedUS prescribing informationSource ↗

Carcinogenicity timing

Not required: lack of carcinogenicity studies justified

“The lack of reproductive, mutagenic, genotoxic and carcinogenic studies is justified, and SPC has been amended appropriately.”

✓ VerifiedEMA assessment report, p. 6Source ↗

Summary across all 117 monoclonal antibodies →

Rituxan: 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