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

Precedia/Monoclonal antibodies/Exdensur/Tox package

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

depemokimab · IL-5

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 Exdensur 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

Use pharmacology data (target binding, receptor occupancy, in vitro human cells, PK/PD modelling) to estimate the lowest dose expected to have any biological effect (MABEL) and the active dose (PAD), and, for healthy volunteers, start at an exposure below the PAD unless robustly justified.

“these data should be used to determine the minimal anticipated biological effect level (MABEL) in humans and an estimation of the pharmacologically active dose (PAD) and/or anticipated therapeutic dose range (ATD) in humans.”

✓ VerifiedEMA 2017: Guideline on strategies to identify and mitigate risks for…, p. 11Source ↗

This product's starting point

NOAEL / key findings: NOAEL 10 mg/kg (EMA, QTc at 100 mg/kg) or 100 mg/kg (applicant); reduced eosinophils; vasculitis in single-dose study (EMA assessment report, p. 55)

Full method, every step sourced →

Longest repeat-dose systemic studies

Longest repeat-dose study and recovery

26-week cynomolgus monkey GLP study with 30-week recovery (off-dosing) period

“once every 3 months for 26 weeks has been performed. The control group and main dose groups contained 3 males and 3 females, but 2 males and 2 females were added to the control group and the group dosed with 10 mg/kg, respectively, for observation during a 30-week off-dosing period.”

✓ VerifiedEMA assessment report, p. 47Source ↗

Pivotal GLP studies

GLP cynomolgus monkey 26-week SC study (10, 100 mg/kg every 13 weeks, 2 doses); 4-week single-dose study

“In the 26-week toxicology study conducted in monkeys, doses of 10 (low dose [LD]) and 100 (high dose [HD]) mg/kg were administered to adult male and female monkeys (4/sex/group) once every 13 weeks for a total of 2 doses.”

✓ VerifiedFDA multi-discipline review, p. 74Source ↗

DART package

Species: DART

Not conducted; DART risk assessed by weight-of-evidence

“No developmental and reproductive toxicity (DART) studies were conducted. The DART risk with depemokimab was assessed using a weight-of-evidence (WoE) approach.”

✓ VerifiedEMA assessment report, p. 48Source ↗

Reproductive & developmental

No DART studies conducted; risk assessed by weight-of-evidence

“No developmental and reproductive toxicity (DART) studies were conducted. The DART risk with depemokimab was assessed using a weight-of-evidence (WoE) approach.”

✓ VerifiedEMA assessment report, p. 48Source ↗

PPND / ePPND: when

Not conducted: monkey ePPND judged unnecessary (hazard identification only; mepolizumab data used)

“After reviewing the nonclinical data, it was decided that conducting an enhanced pre- and postnatal development (PPND) study in monkeys would not be necessary as the study only provides hazard identification.”

✓ VerifiedFDA multi-discipline review, p. 74Source ↗

Carcinogenicity

Species: carcinogenicity

Not conducted

“No carcinogenicity studies were conducted.”

✓ VerifiedEMA assessment report, p. 48Source ↗

Carcinogenicity model

Not conducted; weight-of-evidence assessment

“No carcinogenicity studies were conducted. The applicant conducted a weight-of-evidence (WoE) assessment to evaluate the potential of depemokimab to cause carcinogenicity.”

✓ VerifiedEMA assessment report, p. 48Source ↗

Carcinogenicity timing

Not required: FDA judged a monkey carcinogenicity study unnecessary; mepolizumab data used

“After reviewing the nonclinical data, it was decided that conducting a carcinogenicity study in monkeys for depemokimab would not be necessary. Carcinogenicity information can be taken from the mepolizumab program.”

✓ VerifiedFDA multi-discipline review, p. 75Source ↗

Summary across all 117 monoclonal antibodies →

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

Before first-in-human

Longest repeat-dose systemic studies

DART package

Carcinogenicity

Same question, other monoclonal antibodies