Bavencio
avelumab
Species
Monkey
Longest study
13 wk
Genotox
Not conducted Not conducted
Carcinogenicity
Not conducted Not conducted
Repro
Not conducted Not conducted
First dose
Not conducted Not stated publicly
Speciesopen answer page →
Species
Cynomolgus monkey only
“Thus, the toxicity of avelumab was evaluated in a GLP-compliant, 13-week toxicology study in cynomolgus monkeys.”
Why that species
Similar binding affinity to monkey and human PD-L1 and comparable tissue cross-reactivity
“The cynomolgus monkey was, however, a pharmacologically relevant species for toxicity testing based on a similar avelumab binding affinity to cynomolgus monkey and human PD-L1 and the comparable cross-reactivity of avelumab across cynomolgus monkey and human tissues.”
Surrogate molecule
No surrogate; avelumab itself binds mouse and cynomolgus PD-L1
“Avelumab shows similar binding affinity for human, mouse and cynomolgus PD-L1.”
Species: general tox
Cynomolgus monkey (13-week GLP study)
“Thus, the toxicity of avelumab was evaluated in a GLP-compliant, 13-week toxicology study in cynomolgus monkeys.”
Species: DART
Not conducted; literature-based assessment of reproductive risk instead
“Reproductive and developmental toxicology studies were not conducted with avelumab. Instead, the Applicant submitted a non-product specific literature based assessment of the potential for avelumab to affect reproduction.”
Species: carcinogenicity
Not conducted (ICH S6, S1, S9)
“Not conducted per ICH S6, ICH S1, and ICH S9.”
Surrogate used in
No surrogate used; avelumab binds human, mouse and cynomolgus PD-L1 similarly
“Avelumab shows similar binding affinity for human, mouse and cynomolgus PD-L1.”
Study lengthopen answer page →
Longest pivotal study
13 weeks
“Thus, the toxicity of avelumab was evaluated in a GLP-compliant, 13-week toxicology study in cynomolgus monkeys.”
Pivotal GLP studies
13-week cynomolgus monkey IV study, once weekly 20, 60 or 140 mg/kg, 2-month recovery; plus 1-month monkey study
“Non-clinical data reveal no special hazard for humans based on conventional studies of repeated dose toxicity in Cynomolgus monkeys administered intravenously doses of 20, 60 or 140 mg/kg once a week for1 month and 3 months, followed by a 2-month recovery period after the 3-month dosing period.”
Route in tox
IV infusion (over 90 minutes)
“Route of administration: IV infusion over 90 minutes”
Skipped studiesopen answer page →
Genotoxicity
Not conducted (ICH S6)
“Not conducted per ICH S6.”
Carcinogenicity
Not conducted (ICH S6, S1 and S9)
“Not conducted per ICH S6, ICH S1, and ICH S9.”
Reproductive & developmental
Not conducted; literature-based assessment of reproductive risk submitted instead
“Reproductive and developmental toxicology studies were not conducted with avelumab. Instead, the Applicant submitted a non-product specific literature based assessment of the potential for avelumab to affect reproduction.”
Safety pharmacology
Incorporated into 4- and 13-week monkey studies; heart rate, ECG, blood pressure, respiration, CNS and temperature unaffected at 140 mg/kg
“In both studies the heart rate, electrocardiogram, arterial blood pressure, respiratory rate, CNS parameters, and body temperature were unaffected by treatment with avelumab at the high dose level of 140 mg/kg weekly.”
Genotox: Ames
Not conducted (ICH S6)
“Not conducted per ICH S6.”
Genotox: in vitro mammalian
Not conducted (ICH S6)
“Not conducted per ICH S6.”
Genotox: in vivo
Not conducted (ICH S6)
“Not conducted per ICH S6.”
Carcinogenicity model
Not conducted (ICH S6, S1, S9)
“Not conducted per ICH S6, ICH S1, and ICH S9.”
Carcinogenicity timing
Not required for biotechnology-derived monoclonal antibodies (ICH S9)
“Genotoxicity and carcinogenicity studies are generally not required for biotechnology-derived monoclonal antibodies such as avelumab (ICH S9).”
hERG / QT
No hERG assay; heart rate, ECG, blood pressure, respiration unaffected in monkeys at 140 mg/kg weekly
“In both studies the heart rate, electrocardiogram, arterial blood pressure, respiratory rate, CNS parameters, and body temperature were unaffected by treatment with avelumab at the high dose level of 140 mg/kg weekly.”
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 Bavencio 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: No NOAEL in 13-week monkey study: perivascular mononuclear infiltrates in brain and spinal cord at all doses; LOAEL 1.5-fold human exposure (EMA assessment report, p. 29)
NOAEL / key findings
No NOAEL in 13-week monkey study: perivascular mononuclear infiltrates in brain and spinal cord at all doses; LOAEL 1.5-fold human exposure
“Due to the finding of perivascular mononuclear cell infiltrates in the brain and spinal cord at all dose levels in the 13-week monkey study, there was no NOAEL in this study and accordingly only a LOAEL, which was 1.5-fold above the human therapeutic exposure.”
Risksopen answer page →
Immune & cytokine safety
Human PBMC cytokine release limited to a 5-7 fold TNFα increase at 24 hours
“The results were limited to a 5-7 fold increase in TNFα following 24 hours of exposure to avelumab at concentrations ≥ 14.4 ng/mL.”
Biodistribution & persistence
Human and monkey tissue staining generally comparable
“Overall, except for these differences, avelumab staining of normal human and cynomolgus tissues was generally comparable.”
Modality-specific risk
Immune-related toxicity from loss of PD-L1-mediated self-tolerance
“Avelumab’s mode of action removes the suppressive effects of PD-L1 on T cells, which may lead to decreases in self-tolerance and immune-related effects.”
Anti-drug antibodies: animals
4-week monkey study: 3/12 (25%) ADA-positive; decreased exposure in ADA-positive animals at 20 mg/kg
“Antigenicity: 3/12 (25%) monkeys treated with avelumab tested positive for anti-drug antibodies (ADA). Two were in the low dose and one in the high dose group. At 20 mg/kg, a decrease of exposure was observed in ADA-positive animals.”
Anti-drug antibodies: patients
5.9% (96/1,627) treatment-emergent ADA at 10 mg/kg Q2W
“Of 1,738 patients treated with avelumab 10 mg/kg as an intravenous infusion every 2 weeks, 1,627 were evaluable for treatment-emergent anti-drug antibodies (ADA) and 96 (5.9%) tested positive.”
Label warnings
- Severe and Fatal Immune-Mediated Adverse Reactions
- Infusion-Related Reactions
- Complications of Allogeneic HSCT
- Major Adverse Cardiovascular Events (MACE)
- Embryo-Fetal Toxicity
Immune-mediated reactionsHypersensitivity & infusion reactionsCardiovascularEmbryo-fetal toxicity
US prescribing information, Warnings and PrecautionsDailyMed ↗
Tox packageopen answer page →
Before first-in-human
First-in-human: where
US, Belgium, Czech Republic, France, Germany, Hungary, Korea, Poland, Taiwan, China and UK: first dose-escalation study (EMR100070-001) in patients with solid tumors
“EMR100070-001 Conducted in US, Belgium, Czech Republic, France, Germany, Hungary, Korea, Poland, Taiwan, Republic of China, and UK Phase I, open-label, 2-phase (dose escalation and treatment expansions) in solid tumors”
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 Bavencio 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: No NOAEL in 13-week monkey study: perivascular mononuclear infiltrates in brain and spinal cord at all doses; LOAEL 1.5-fold human exposure (EMA assessment report, p. 29)
Longest repeat-dose systemic studies
Longest repeat-dose study and recovery
13-week GLP cynomolgus monkey (IV infusion) with 8-week recovery
“MSB0010718 (Anti-PD-L1): 13-Week Toxicity Study in Cynomolgus Monkeys by Intravenous Infusion Followed by an 8-Week Recovery Period”
Pivotal GLP studies
13-week cynomolgus monkey IV study, once weekly 20, 60 or 140 mg/kg, 2-month recovery; plus 1-month monkey study
“Non-clinical data reveal no special hazard for humans based on conventional studies of repeated dose toxicity in Cynomolgus monkeys administered intravenously doses of 20, 60 or 140 mg/kg once a week for1 month and 3 months, followed by a 2-month recovery period after the 3-month dosing period.”
DART package
Species: DART
Not conducted; literature-based assessment of reproductive risk instead
“Reproductive and developmental toxicology studies were not conducted with avelumab. Instead, the Applicant submitted a non-product specific literature based assessment of the potential for avelumab to affect reproduction.”
Reproductive & developmental
Not conducted; literature-based assessment of reproductive risk submitted instead
“Reproductive and developmental toxicology studies were not conducted with avelumab. Instead, the Applicant submitted a non-product specific literature based assessment of the potential for avelumab to affect reproduction.”
PPND / ePPND: when
Not conducted: no DART studies; a literature-based reproductive risk assessment was submitted instead
“Reproductive and developmental toxicology studies were not conducted with avelumab. Instead, the Applicant submitted a non-product specific literature based assessment of the potential for avelumab to affect reproduction.”
Carcinogenicity
Species: carcinogenicity
Not conducted (ICH S6, S1, S9)
“Not conducted per ICH S6, ICH S1, and ICH S9.”
Carcinogenicity model
Not conducted (ICH S6, S1, S9)
“Not conducted per ICH S6, ICH S1, and ICH S9.”
Carcinogenicity timing
Not required for biotechnology-derived monoclonal antibodies (ICH S9)
“Genotoxicity and carcinogenicity studies are generally not required for biotechnology-derived monoclonal antibodies such as avelumab (ICH S9).”
Safety marginopen answer page →
Safety margin at NOAEL
No NOAEL in 13-week monkey study (CNS perivascular infiltrates at all doses); LOAEL 1.5-fold human AUC; high dose 10- to 15-fold
“Plasma exposure (AUC) achieved in the repeat-dose toxicity studies in monkeys exceeded the human therapeutic exposure by 10- to 15-fold. Due to the finding of perivascular mononuclear cell infiltrates in the brain and spinal cord at all dose levels in the 13-week monkey study, there was no NOAEL in this study and accordingly only a LOAEL, which was 1.5-fold above the human therapeutic exposure.”
NOAEL / key findings
No NOAEL in 13-week monkey study: perivascular mononuclear infiltrates in brain and spinal cord at all doses; LOAEL 1.5-fold human exposure
“Due to the finding of perivascular mononuclear cell infiltrates in the brain and spinal cord at all dose levels in the 13-week monkey study, there was no NOAEL in this study and accordingly only a LOAEL, which was 1.5-fold above the human therapeutic exposure.”
Efficacy evidenceopen answer page →
Efficacy evidence
Syngeneic MC38 colon cancer mouse model with avelumab
“To assess the in vivo anti-tumor activity of avelumab, the Applicant utilized a syngeneic mouse model of colon cancer.”
Why that model
Avelumab binds human, mouse and cynomolgus PD-L1 with comparable affinities
“In vitro pharmacology studies demonstrated the ability of avelumab to bind to human, mouse, and cynomolgus monkey PD-L1 with comparable affinities.”
Reviewer's view of the efficacy data
EMA: in vivo ADCC contribution to anti-tumour effect demonstrated in mouse MC38 model
“An in vivo contribution of ADCC to the anti-tumour effect of avelumab was demonstrated in the mouse tumour MC38 model.”
Flexibilityopen answer page →
Flexibility accepted
DARTVerdict not stated
No reproductive or developmental toxicity studies; non-product-specific literature assessment of PD-1/PD-L1 role in pregnancy instead
Why: Literature: the PD-1/PD-L1 pathway preserves pregnancy by maintaining maternal immune tolerance to the fetus · Weight of evidence · Pharmacology or kinetics
“Instead, the Applicant submitted a non-product specific literature based assessment of the potential for avelumab to affect reproduction. Based on the literature, a central function of the PD-1/PD-L1 pathway is to preserve pregnancy by maintaining maternal immune tolerance to the fetus.”
Safety marginVerdict not stated
No NOAEL in the 13-week monkey study (CNS perivascular infiltrates at all doses); LOAEL only 1.5-fold human exposure
“Due to the finding of perivascular mononuclear cell infiltrates in the brain and spinal cord at all dose levels in the 13-week monkey study, there was no NOAEL in this study and accordingly only a LOAEL, which was 1.5-fold above the human therapeutic exposure.”
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