Opdivo
nivolumab
Species
Monkey
Longest study
13 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
“The nonclinical toxicity studies of nivolumab were performed in a battery of nonGLP studies, and GLP- and ICH-compliant in vitro tissue binding studies in multiple species and in vivo toxicology studies in cynomolgus monkeys.”
Why that species
Binds human and cyno PD-1 to a similar extent; no binding to rodent or rabbit PD-1
“Nivolumab bound to PD-1 from humans and cynomolgus monkeys to a similar extent and blocked the interaction of PD-1 with its ligands. Nivolumab did not bind to PD-1 from rodents or rabbits.”
Surrogate molecule
No surrogate in toxicology studies; a murine anti-PD-1 surrogate was used to study effects on tumor growth
“Because nivolumab was unable to bind to PD-1 from rodents, the Applicant developed a murine surrogate anti-PD-1 antibody to investigate the effects of PD-1 pathway inhibition on tumor growth.”
Study lengthopen answer page →
Longest pivotal study
13 weeks
“In the 3-month toxicity study in cynomolgus monkeys, IV doses of nivolumab were administered 2QW (for a total of 27 doses) at dose levels of 0 (vehicle control), 10, or 50 mg/kg.”
Pivotal GLP studies
Pivotal 1- and 3-month IV repeat-dose studies in cynomolgus monkeys
“Pivotal 1- and 3-month IV repeat-dose toxicity studies of nivolumab alone were conducted in cynomolgus monkeys.”
Route in tox
Intravenous
“Pivotal 1- and 3-month IV repeat-dose toxicity studies of nivolumab alone were conducted in cynomolgus monkeys.”
Skipped studiesopen answer page →
Genotoxicity
Not conducted (ICH S6)
“Consistent with the ICH S6 guidance, genetic toxicology studies were not conducted or required for nivolumab.”
Carcinogenicity
Not conducted; not required for a product to treat advanced cancer
“Carcinogenicity studies were not required to support the licensing application for a product to treat advanced human cancer”
Reproductive & developmental
Monkey ePPND: dose-dependent third-trimester fetal losses (12.5% and 33.3% at 10 and 50 mg/kg vs 7.1% in controls)
“maternal nivolumab administration at both doses was associated with fetal/neonatal mortality characterized by: 1) dose-dependent increases in third trimester fetal losses (12.5% and 33.3% at 10 and 50 mg/kg, respectively, relative to 7.1% in controls)”
Safety pharmacology
Limited to a single-dose cardiovascular safety study in cynomolgus monkeys
“specific safety pharmacology studies were limited to a single-dose cardiovascular safety study in Cynomolgus monkeys”
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 Opdivo 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.”
This product's starting point
NOAEL / key findings: Well tolerated up to 50 mg/kg in 4- and 13-week monkey studies (FDA pharmacology/toxicology review, p. 13)
NOAEL / key findings
Well tolerated up to 50 mg/kg in 4- and 13-week monkey studies
“Nivolumab was evaluated in 4- and 13-week repeat dose studies in the cynomolgus monkey and was well-tolerated at doses of up to 50 mg/kg.”
Risksopen answer page →
Immune & cytokine safety
No CDC, ADCC or direct cytokine release in the absence of TCR activation
“Nivolumab did not mediate complement dependent cytotoxicity, antibody dependent cellular cytotoxicity, or to directly elicit cytokine release from cells in the absence of TCR activation.”
Biodistribution & persistence
Low volume of distribution (0.046-0.071 L/kg); antibody mostly remains in the bloodstream
“The low volume of distribution ranging between 0.046-0.071 L/kg at steady state suggests that most of the monoclonal antibody remains in the bloodstream.”
Modality-specific risk
Autoimmune disturbances, the most commonly reported adverse events in patients
“In patients receiving nivolumab, autoimmune disturbances are the most commonly reported adverse events”