Bavencio (avelumab): what was done before first-in-human, and what came after?

Precedia/Monoclonal antibodies/Bavencio/Tox package

Bavencio: what was done before first-in-human, and what came after?

avelumab · PD-L1

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”

✓ VerifiedEMA assessment report, p. 33Source ↗

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.”

✓ VerifiedICH 2018: ICH S9 Guideline: Nonclinical Evaluation for Anticancer…, p. 15Source ↗

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)

Full method, every step sourced →

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”

✓ VerifiedFDA multi-discipline review, p. 49Source ↗

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.”

✓ VerifiedEMA assessment report, p. 30Source ↗

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.”