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.”
Species: general tox
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.”
Species: DART
Not conducted (ICH S9, advanced gastric cancer)
“Genotoxicity, carcinogenicity, developmental or reproductive toxicology studies were not conducted with ramucirumab in line with available guidance [ICH S9 (EMEA/CHMP/ICH/646107/2008)] as ramucirumab is indicated for the treatment of patients with advanced gastric cancer.”
Species: carcinogenicity
Not conducted (ICH S9, advanced cancer)
“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.”
Surrogate used in
Yes: rat anti-mouse VEGFR2 (flk-1) antibody DC101 for in vivo pharmacology studies
“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.”
Genotox: Ames
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 as it is not expected that monoclonal antibodies will react with DNA or other chromosomal material.”
Genotox: in vitro mammalian
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 as it is not expected that monoclonal antibodies will react with DNA or other chromosomal material.”
Genotox: in vivo
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 as it is not expected that monoclonal antibodies will react with DNA or other chromosomal material.”
Carcinogenicity model
Not conducted: not warranted for therapeutics for 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.”
Carcinogenicity timing
Not required for an advanced-cancer product
“Carcinogenicity studies were not required to support the licensing application for a product to treat advanced human cancer”
hERG / QT
No hERG or stand-alone safety pharmacology; no ECG or blood pressure changes in monkey toxicity studies
“There were no ramucirumab-related changes in ECG measurements or in blood pressure in either study, though hypertension is a clinical finding associated with ramucirumab treatment.”
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)
HNSTD/STD10 is the method used for anticancer drugs in patients: the start dose is one-sixth of the highest non-severely toxic dose (HNSTD) in non-rodents, or one-tenth of the dose severely toxic to 10% of rodents (STD10), scaled by body surface area. The aim is a dose that is pharmacologically active yet reasonably safe.
“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.”
Anti-drug antibodies: animals
ADA in monkeys at 5 and 16 mg/kg, not at 50 mg/kg; unlikely to have significantly affected exposure
“Anti-ramucirumab antibodies were detected in animals treated with 5 and 16 mg/kg but not at 50 mg/kg. Given the more than dose proportional exposure to ramucirumab, it is unlikely that the anti-drug antibodies had a significant effect on ramucirumab exposure in this study.”
Anti-drug antibodies: patients
3% (86/2890) treatment-emergent anti-ramucirumab antibodies; neutralizing in 14 of 86
“In clinical trials, 86/2890 (3%) of CYRAMZA-treated patients tested positive for treatment-emergent anti-ramucirumab antibodies by an enzyme-linked immunosorbent assay (ELISA). Neutralizing antibodies were detected in 14 of the 86 patients”
Label warnings
- Hemorrhage
- Gastrointestinal Perforations
- Impaired Wound Healing
- Arterial Thromboembolic Events
- Hypertension
- Infusion-Related Reactions
- Worsening of Pre-existing Hepatic Impairment
- Posterior Reversible Encephalopathy Syndrome
- Proteinuria Including Nephrotic Syndrome
- Thyroid Dysfunction
- Embryo-Fetal Toxicity
BleedingGastrointestinalThrombosis & embolismCardiovascularHypersensitivity & infusion reactionsHepatotoxicityNeurotoxicityNephrotoxicityMetabolic & endocrineEmbryo-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 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)
HNSTD/STD10 is the method used for anticancer drugs in patients: the start dose is one-sixth of the highest non-severely toxic dose (HNSTD) in non-rodents, or one-tenth of the dose severely toxic to 10% of rodents (STD10), scaled by body surface area. The aim is a dose that is pharmacologically active yet reasonably safe.
“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)
Longest repeat-dose systemic studies
Longest repeat-dose study and recovery
39-week IV cynomolgus monkey study, no recovery groups
“Number/Sex/Group: 3/sex/group for 39-week study; 3 females/group for 12-week study; no recovery groups”
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.”
DART package
Species: DART
Not conducted (ICH S9, advanced gastric cancer)
“Genotoxicity, carcinogenicity, developmental or reproductive toxicology studies were not conducted with ramucirumab in line with available guidance [ICH S9 (EMEA/CHMP/ICH/646107/2008)] as ramucirumab is indicated for the treatment of patients with advanced gastric 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.”
PPND / ePPND: when
Not conducted: no developmental or reproductive studies under ICH S9 (advanced gastric cancer)
“Genotoxicity, carcinogenicity, developmental or reproductive toxicology studies were not conducted with ramucirumab in line with available guidance [ICH S9 (EMEA/CHMP/ICH/646107/2008)] as ramucirumab is indicated for the treatment of patients with advanced gastric cancer.”
Carcinogenicity
Species: carcinogenicity
Not conducted (ICH S9, advanced cancer)
“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.”
Carcinogenicity model
Not conducted: not warranted for therapeutics for 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.”
Carcinogenicity timing
Not required for an advanced-cancer product
“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
No NOAEL-based multiple stated; end-of-study 39-week monkey exposures 0.2-5.6x human exposure at 8 mg/kg
“At the end of the 39-week study in monkeys, exposure to ramucirumab ranged from approximately 0.2-5.6 times the exposure after multiple doses in humans at the recommended dose of 8 mg/kg.”
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)”
Efficacy evidenceopen answer page →
Efficacy evidence
Surrogate DC101 in human gastric cancer xenografts (NCI-N87, MKN-45) and primary gastric tumor fragments in athymic mice
“DC101 alone significantly inhibited the in vivo tumor growth of both NCI-N87 and MKN-45 gastric carcinoma cells. In addition, DC101 administered as a monotherapy inhibited 10 of 17 human primary gastric tumor fragments implanted into athymic mice.”
Why that model
Ramucirumab does not cross-react with mouse VEGFR2, so antitumor activity could not be studied in mice
“Since ramucirumab is not cross-reactive with mouse VEGFR2, its antitumor activity and anti-angiogenic mechanism of action could not be studied in the mouse.”
Reviewer's view of the efficacy data
FDA: surrogate DC101 data provide proof of concept that anti-VEGFR2 treatment can inhibit growth of multiple tumor types
“The use of its murine surrogate, DC101, provides a proof-of-concept data that treatment with an anti-VEGFR2 antibody such as ramucirumab has the potential to inhibit the growth of a number of tumors derived from different tissues, alone or in combination with other chemotherapeutics.”
Flexibilityopen answer page →
Flexibility accepted
DARTAccepted
No embryo-fetal, fertility or pre/postnatal studies; reproductive risk assessed from non-product-specific literature on VEGFR2 inhibition
Why: Non-human primates the only relevant species; ICH S9 and S6 principles · Within the guideline · No relevant species · Weight of evidence
“As non-human primates were the only relevant species for toxicological assessment of ramucirumab, in accordance with principles outlined in ICH guidances S9 and S6, the Agency agreed that an assessment of reproductive toxicology based on non-product specific literature might be acceptable in the case of ramucirumab.”
“Nonclinical studies investigating the effects of ramucirumab on embryofetal development are not warranted at this time.”
Safety pharmacologyVerdict not stated
No dedicated safety pharmacology studies; endpoints included in 5- and 39-week monkey toxicity studies
“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.”
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