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

Precedia/Monoclonal antibodies/Lucentis/Tox package

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

ranibizumab · VEGF-A

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 Lucentis 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: No NOAEL: all doses (0.25-2 mg) caused dose-related ocular inflammation; also perivascular sheathing, retinal haemorrhages, cataracts (EMA assessment report, p. 11)

Full method, every step sourced →

Longest repeat-dose systemic studies

Longest repeat-dose study and recovery

26-week cynomolgus monkey study (bilateral intravitreal); recovery phase length not stated

“All repeat-dose toxicity studies were performed in Cynomolgus monkeys, a reasonable choice of species, in studies up to 26-weeks duration.”

✓ VerifiedEMA assessment report, p. 10Source ↗

Pivotal GLP studies

GLP monkey studies up to 26 weeks; bilateral 50 µl intravitreal injections every 2 weeks, up to 2.0 mg/eye

“Ranibizumab was administered bilaterally by 50 µl IVT injections every 2nd week at doses of up to 2.0 mg/eye.”

✓ VerifiedEMA assessment report, p. 10Source ↗

DART package

Species: DART

Cynomolgus monkey (embryo-fetal development, intravitreal)

“An embryo-fetal developmental toxicity study was performed on pregnant cynomolgus monkeys.”

✓ VerifiedUS prescribing informationSource ↗

Reproductive & developmental

Monkey EFD (intravitreal, organogenesis): low incidence of fetal skeletal abnormalities at 13x predicted human exposure

“Administration of ranibizumab to pregnant monkeys throughout the period of organogenesis resulted in a low incidence of skeletal abnormalities at intravitreal doses 13-times the predicted human exposure”

✓ VerifiedUS prescribing informationSource ↗

PPND / ePPND: when

Not conducted: low systemic exposure and elderly AMD population

“No reproduction toxicology studies were performed. This was justified by the low systemic exposure of a compound for which the mechanism of action is well characterised during development, and the median age of the AMD-population (over 70 years).”

✓ VerifiedEMA assessment report, p. 12Source ↗

Carcinogenicity

Species: carcinogenicity

Not conducted

“Animal studies have not been conducted to determine the carcinogenic potential of ranibizumab.”

✓ VerifiedUS prescribing informationSource ↗

Carcinogenicity model

Not conducted

“Animal studies have not been conducted to determine the carcinogenic potential of ranibizumab.”

✓ VerifiedUS prescribing informationSource ↗

Carcinogenicity timing

Not required; acceptable due to the nature of the compound

“There were no studies on genotoxicity or carcinogenicity. This is acceptable due to the nature of the compound.”

✓ VerifiedEMA assessment report, p. 12Source ↗

Summary across all 117 monoclonal antibodies →

Lucentis: 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