Cyramza
ramucirumab
Species
Monkey
Longest study
39 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
“Ramucirumab binds only to human and non-human primate VEGFR2, thus a single species was used for the toxicological assessment of the antibody.”
Why that species
Binds only human and non-human primate VEGFR2 (not mouse); comparable binding affinity in human and monkey
“The Cynomolgus monkey can be considered an appropriate nonclinical species for ramucirumab toxicity testing given the comparable binding affinity of ramucirumab to its receptor in humans and Cynomolgus monkeys, and the fact that pharmacological effects have been seen in this test species.”
Surrogate molecule
No surrogate in toxicology; rat anti-mouse VEGFR2 antibody DC101 used only for in vivo pharmacology; clinical antibody tested in monkeys
“A rat-anti mouse flk-1 monoclonal IgG1 antibody, DC101, was developed for use in in vivo studies.”
Study lengthopen answer page →
Longest pivotal study
39 weeks
“The Applicant submitted 5-week and 39-week GLP-compliant toxicity studies in cynomolgus monkeys.”
Pivotal GLP studies
GLP monkey 5-week IV (0, 4, 12, 40 mg/kg, Days 1, 15, 22, 29) and 39-week IV weekly (0, 5, 16, 50 mg/kg)
“In the 5-week study, ramucirumab was administered by intravenous infusion on Days 1, 15, 22, and 29 at dose levels of 0, 4, 12, and 40 mg/kg. In the 39-week study, ramucirumab was administered by intravenous infusion weekly at dose levels of 0, 5, 16, and 50 mg/kg.”
Route in tox
Intravenous (bolus or infusion)
“Ramucirumab was administered intravenously (i.v.) as either a slow bolus in the 5-week study, or an approximate 10 minute i.v. infusion in the 39-week study.”
Skipped studiesopen answer page →
Genotoxicity
Not conducted (ICH S6)
“In accordance with ICH S6, the Applicant did not submit genotoxicity studies; routine tests for genotoxicity are not applicable to biotherapeutics”
Carcinogenicity
Not conducted (advanced cancer, ICH S9)
“In accordance with ICH S9 the Applicant did not conduct carcinogenicity studies with ramucirumab because these studies are not warranted to support marketing for therapeutics intended to treat patients with advanced cancer.”
Reproductive & developmental
No dedicated studies; literature-based assessment of VEGFR2 inhibition in pregnancy
“Dedicated reproductive toxicology studies examining the effects of ramucirumab administration to animals during pregnancy have not been conducted. Instead the Applicant submitted a literature based assessment of the potential effects of inhibition of VEGFR2 signaling during pregnancy.”
Safety pharmacology
Incorporated into 5- and 39-week monkey studies; no effects on blood pressure, ECG or body temperature
“No dedicated safety pharmacology studies have been performed with ramucirumab but safety pharmacology parameters were assessed as part of the GLP-compliant 5-and 39-week toxicology studies 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 Cyramza 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 oncology monoclonal antibodies (ICH S9)
In cancer patients the start dose should be pharmacologically active yet reasonably safe. A common small-molecule approach is one-tenth of the dose severely toxic to 10% of rodents, or one-sixth of the highest non-severely toxic dose in non-rodents.
“A common approach for many small molecules is to set a start dose at 1/10 the Severely Toxic Dose in 10% of the animals (STD 10) in rodents. If the non-rodent is the most appropriate species, then 1/6 the Highest Non-Severely Toxic Dose (HNSTD) is considered an appropriate starting dose.”
This product's starting point
NOAEL / key findings: Target organs: kidney (glomerulonephritis), epiphyseal growth plate (thickening, abnormal ossification), ovaries and uterus (decreased weight) (EMA assessment report, p. 27)
NOAEL / key findings
Target organs: kidney (glomerulonephritis), epiphyseal growth plate (thickening, abnormal ossification), ovaries and uterus (decreased weight)
“The target organs identified in repeated dose Cynomolgus monkey toxicity studies were kidney (glomerulonephritis), bone (thickening and abnormal endochondral ossification of the epiphyseal growth plate) and female reproductive organs (decreased weight of ovaries and uterus)”
Risksopen answer page →
Immune & cytokine safety
ADA in 5/7 monkeys at 5 mg/kg and 3/9 at 16 mg/kg; none at the high dose
“In immunogenicity testing, 5 of 7 animals in the 5 mg/kg group tested positive for anti-ramucirumab antibodies, 3 of 9 animals in the 16 mg/kg group tested positive for anti-ramucirumab antibodies, and none tested positive”
Biodistribution & persistence
TCR: vascular endothelium in human and monkey tissues, consistent with VEGFR-2 distribution
“Tissue cross-reactivity was observed in vascular endothelium in both human and Cynomolgus monkey tissues, consistently with the distribution of the molecular target of ramucirumab, VEGFR-2.”
Modality-specific risk
Anti-angiogenic toxicity, notably moderate to severe glomerulonephritis in monkeys at ≥16 mg/kg
“Ramucirumab induced renal toxicity in the 39-week study. Moderate to severe glomerulonephritis occurred in male and female monkeys at ramucirumab doses ≥ 16 mg/kg.”