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

Precedia/Monoclonal antibodies/Yervoy/Tox package

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

ipilimumab · CTLA-4

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 Yervoy 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

ADCs with cytotoxic payloads follow the S9 rules (1/10 STD10 or 1/6 HNSTD of the ADC, scaled by body surface area). For immune agonists, a MABEL-based start dose should be considered instead.

“For example, for cytotoxic payloads, the starting clinical dose can be determined using either 1/10th the Severely Toxic Dose (STD) in 10% of animals (STD10) in rodents or 1/6th the Highest Non- Severely Toxic Dose (HNSTD) in non-rodents, for the ADC based on body surface area, depending on which is the most appropriate and/or sensitive species.”

✓ VerifiedICH 2018: ICH S9 Guideline: Nonclinical Evaluation for Anticancer…, p. 15Source ↗

This product's starting point

NOAEL / key findings: Fatal colitis and persistent dermatitis/rash in two monkeys, considered immune-related adverse events of CTLA-4 blockade (EMA assessment report, p. 21)

Full method, every step sourced →

Longest repeat-dose systemic studies

Longest repeat-dose study and recovery

6-month cynomolgus monkey (IV, 10 mg/kg monthly); recovery phase not stated

“In a 6-month toxicity study in cynomolgus monkeys, ipilimumab in a dose of 10 mg/kg with monthly intervals (4 times over these 6 months) was not associated with adverse drug-related toxicity”

✓ VerifiedEMA assessment report, p. 24Source ↗

Pivotal GLP studies

GLP cynomolgus monkey IV studies: 1-month weekly, 10-week weekly, and 6-month monthly 10 mg/kg

“ipilimumab generally did not result in adverse toxicities in any other monkeys when administered IV at doses up to 30 mg/kg for 1 week, 10 mg/kg administered weekly for 1 month, 1 mg/kg weekly for 10 weeks, or 10 mg/kg monthly for up to 6 months.”

✓ VerifiedEMA assessment report, p. 21Source ↗

DART package

Species: DART

Cynomolgus monkey (combined embryo-fetal and peri-postnatal study)

“In a combined study of embryo-fetal and peri-postnatal development, pregnant cynomolgus monkeys received ipilimumab every 3 weeks from the onset of organogenesis in the first trimester through parturition.”

✓ VerifiedUS prescribing informationSource ↗

Reproductive & developmental

Monkey combined EFD/PPND: third-trimester dose-related increases in abortion, stillbirth, premature delivery and infant mortality

“Beginning in the third trimester, administration of ipilimumab at doses resulting in exposures approximately 2.6 to 7.2 times the human exposure at a dose of 3 mg/kg resulted in dose-related increases in abortion, stillbirth, premature delivery (with corresponding lower birth weight), and an increased incidence of infant mortality.”

✓ VerifiedUS prescribing informationSource ↗

PPND / ePPND: when

Combined embryo-fetal and pre/postnatal development study (ePPND design, cynomolgus monkey) ongoing at the marketing application

“a combined embryofoetal, pre/post-natal development study is ongoing. As indicated in the Risk Management Plan, final results of this study will be submitted when available.”

✓ VerifiedEMA assessment report, p. 24Source ↗

Carcinogenicity

Species: carcinogenicity

Not conducted

“Carcinogenicity studies for ipilimumab were not conducted.”

✓ VerifiedEMA assessment report, p. 21Source ↗

Carcinogenicity model

Not conducted

“Carcinogenicity studies for ipilimumab were not conducted.”

✓ VerifiedEMA assessment report, p. 21Source ↗

Carcinogenicity timing

Not required: rodents not relevant, limited value of homologous studies, advanced disease

“In addition, considering the lack of relevance of the rodent species for ipilimumab, the limited value of short-term carcinogenicity studies with homologous products (as reflected in the draft reviewed version of the guideline), and the advanced condition intended to be treated by ipilimumab, the lack of conventional carcinogenicity studies is acceptable.”

✓ VerifiedEMA assessment report, p. 25Source ↗

Summary across all 117 monoclonal antibodies →

Yervoy: 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