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.”
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.”
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.”