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.”
Species: general tox
Cynomolgus monkey only
“Pivotal 1- and 3-month IV repeat-dose toxicity studies of nivolumab alone were conducted in cynomolgus monkeys.”
Species: DART
Cynomolgus monkey (enhanced pre- and postnatal development)
“In an enhanced pre- and post-natal development study in cynomolgus monkeys, nivolumab was administered to pregnant dams twice weekly at dose levels of 10 or 50 mg/kg”
Species: 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”
Surrogate used in
Yes: murine anti-PD-1 surrogate (4H2) for syngeneic tumor efficacy studies; none in toxicology
“Since nivolumab does not recognize mouse PD-1, a surrogate anti-mouse PD-1 antibody (4H2) was derived to assess the efficacy of PD-1 blockade on tumor growth in syngenic tumor models.”
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”
Genotox: Ames
Not conducted (ICH S6)
“Consistent with the ICH S6 guidance, genetic toxicology studies were not conducted or required for nivolumab.”
Genotox: in vitro mammalian
Not conducted (ICH S6)
“Consistent with the ICH S6 guidance, genetic toxicology studies were not conducted or required for nivolumab.”
Genotox: in vivo
Not conducted (ICH S6)
“Consistent with the ICH S6 guidance, genetic toxicology studies were not conducted or required for nivolumab.”
Carcinogenicity model
Not conducted: not required for advanced cancer indication
“Carcinogenicity studies were not required to support the licensing application for a product to treat advanced human cancer”
Carcinogenicity timing
Not required for advanced cancer indication
“Carcinogenicity studies were not required to support the licensing application for a product to treat advanced human cancer”
hERG / QT
No hERG assay; telemetered monkeys at 10 or 50 mg/kg IV showed no cardiovascular effects
“In the single-dose cardiovascular safety study, groups of 6 telemetered Cynomolgus monkeys (3 per sex) were administered 0 (vehicle control), 10, or 50 mg/kg nivolumab intravenously. Both were well tolerated and there were no nivolumab-related effects on clinical signs, body weights, cardiovascular parameters, or body temperature.”
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”
Anti-drug antibodies: animals
ADA in 4% (2QW), 20-53% (weekly) and 67% (monthly) of monkeys; lower nivolumab concentrations in ADA-positive animals
“ADAs were detected in 4% of monkeys receiving 2QW doses of nivolumab, 20% to 53% of monkeys receiving weekly doses of nivolumab, and 67% of monkeys receiving monthly doses of nivolumab. Nivolumab concentrations were lower in animals with anti-nivolumab antibodies.”
Anti-drug antibodies: patients
Intravenous nivolumab: 7% (15/215) ADA, 0% (0/15) neutralizing (CHECKMATE-67T comparator arm)
“The corresponding incidence of ADA was 7% (15/215) and NAb was 0% (0/15) for intravenous nivolumab in the same study.”
Label warnings
- Severe and Fatal Immune-Mediated Adverse Reactions
- Complications of Allogeneic Hematopoietic Stem Cell Transplantation
- Embryo-Fetal Toxicity
- Increased Mortality in Patients with Multiple Myeloma when Nivolumab Is Added to a Thalidomide Analogue and Dexamethasone
Immune-mediated reactionsEmbryo-fetal toxicity
US prescribing information, Warnings and PrecautionsDailyMed ↗
Tox packageopen answer page →
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 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)
Longest repeat-dose systemic studies
Longest repeat-dose study and recovery
3-month cynomolgus monkey IV study with 28-day recovery
“A 3-month intravenous toxicity study of MDX-1106 With a 28-day recovery period in cynomolgus monkeys”
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.”
DART package
Species: DART
Cynomolgus monkey (enhanced pre- and postnatal development)
“In an enhanced pre- and post-natal development study in cynomolgus monkeys, nivolumab was administered to pregnant dams twice weekly at dose levels of 10 or 50 mg/kg”
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)”
PPND / ePPND: when
ePPND in cynomolgus monkey completed before the marketing application
“The Applicant evaluated potential nivolumab-associated effects on reproduction in an expanded pre- and postnatal development study (EPPND) in the cynomolgus monkey.”
Carcinogenicity
Species: 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”
Carcinogenicity model
Not conducted: not required for advanced cancer indication
“Carcinogenicity studies were not required to support the licensing application for a product to treat advanced human cancer”
Carcinogenicity timing
Not required for advanced cancer indication
“Carcinogenicity studies were not required to support the licensing application for a product to treat advanced human cancer”
Safety marginopen answer page →
Safety margin at NOAEL
Monkey exposures up to 42x clinical AUC at 3 mg/kg Q2W without autoimmune disease
“Though exposures in the monkey studies were up to 42-fold higher than the clinical AUC of 25500 µg*hr/mL determined when nivolumab was administered at the recommended dose of 3 mg/kg on a once every two week schedule, no evidence of autoimmune disease was observed in the monkey toxicology studies.”
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.”
Efficacy evidenceopen answer page →
Efficacy evidence
Murine anti-PD-1 surrogate (4H2) in syngeneic mouse tumor models (MC38, Sa1N, J558 responsive)
“The administration of anti-mouse PD-1 antibody 4H2 resulted in delayed tumor progression in the MC38 colon carcinoma, Sa1N fibrosarcoma, and J558”
Why that model
Nivolumab does not bind rodent PD-1, so a murine surrogate was developed
“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.”
Reviewer's view of the efficacy data
EMA: nonclinical pharmacology, PK and toxicology studies adequate and acceptable
“In conclusion, the non-clinical studies (pharmacology, pharmacokinetics and toxicology), submitted for the marketing authorisation application for nivolumab, were considered adequate and acceptable for the assessment of non-clinical aspects.”
Flexibilityopen answer page →
Flexibility accepted
DARTAccepted
No fertility and early embryonic development study
Why: Not required under ICH S6(R1) and ICH S9 for therapeutics for advanced cancer · Within the guideline · Serious disease
“The applicant did not submit studies for genotoxicity, carcinogenicity as well as fertility and early embryonic development.”
“According to ICH guideline S6(R1) “Preclinical safety evaluation of biotechnology-derived pharmaceuticals” (EMA/CHMP/ICH/731268/1998), these studies are not required and are not warranted to support marketing for therapeutics intended to treat patients with advanced cancer (ICH guideline S9 “Nonclinical evaluation for anticancer pharmaceuticals” EMEA/CHMP/ICH/646107/2008), the lack of studies is acceptable.”
Efficacy modelVerdict not stated
In vivo anti-tumour efficacy shown only with a surrogate anti-mouse PD-1 antibody (4H2) in syngeneic mouse models
Why: Nivolumab does not recognise mouse PD-1 · No relevant species
“Since nivolumab does not recognize mouse PD-1, a surrogate anti-mouse PD-1 antibody (4H2) was derived to assess the efficacy of PD-1 blockade on tumor growth in syngenic tumor models.”
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