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

Precedia/Monoclonal antibodies/Nemluvio/Tox package

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

nemolizumab · IL-31RA

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 Nemluvio 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 25 mg/kg every two weeks (high dose) in 26-week monkey study; no significant toxicity (FDA integrated review, p. 105)

Full method, every step sourced →

Longest repeat-dose systemic studies

Longest repeat-dose study and recovery

26-week cynomolgus monkey SC study with 17-week recovery

“26 weeks of nemolizumab treatment (with a 17-week recovery period) using SC dosing was well tolerated in Cynomolgus monkey, and no mortalities or adverse toxicities were noted.”

✓ VerifiedEMA assessment report, p. 42Source ↗

Pivotal GLP studies

GLP cynomolgus monkey SC repeat-dose studies of 3 and 6 months, biweekly dosing

“Pivotal repeat-dose toxicity studies were conducted in cynomolgus monkeys, with treatment durations of 3 and 6 months.”

✓ VerifiedFDA integrated review, p. 105Source ↗

DART package

Species: DART

Cynomolgus monkey: fertility endpoints in 6-month toxicity study; EFD, pre/postnatal and juvenile in ePPND study

“Safety pharmacology endpoints and fertility assessment were incorporated into the 6-month repeat-dose toxicity study. Embryofetal development, pre- and postnatal development, and juvenile toxicity were evaluated in the ePPND study.”

✓ VerifiedFDA integrated review, p. 58Source ↗

Reproductive & developmental

Monkey ePPND: no maternal or embryofetal toxicity up to 25 mg/kg; increased early postnatal death at 25 mg/kg (3 vs 1 control)

“Early postnatal death occurred in the offspring of one control monkey and 3 monkeys at 25 mg/kg (36 times the MRHD for PN and 50 times for AD, based on AUC comparison).”

✓ VerifiedUS prescribing informationSource ↗

PPND / ePPND: when

ePPND in cynomolgus monkey completed before the marketing application

“The toxicity profile of nemolizumab has been adequately evaluated in repeat-dose subcutaneous toxicity studies with treatment durations up to 6 months and an enhanced pre- and postnatal development (ePPND) study in cynomolgus monkeys.”

✓ VerifiedFDA integrated review, p. 58Source ↗

Carcinogenicity

Species: carcinogenicity

Not conducted; ECAC concurred that carcinogenicity studies are not needed

“The Executive Carcinogenicity Assessment Committee provided concurrence on 02/13/2018 that carcinogenicity studies are not needed to support the development of nemolizumab.”

✓ VerifiedFDA integrated review, p. 107Source ↗

Carcinogenicity model

Not conducted; carcinogenicity risk assessment reviewed by ECAC instead

“Carcinogenicity studies were not conducted for the evaluation of the carcinogenic potential of nemolizumab. The Applicant submitted a carcinogenicity risk assessment to the corresponding IND, and it was reviewed by the Executive Carcinogenicity Assessment Committee of Center for Drug Evaluation and Research.”

✓ VerifiedFDA integrated review, p. 107Source ↗

Carcinogenicity timing

Not required (ECAC concurrence)

“The Executive Carcinogenicity Assessment Committee provided concurrence on 02/13/2018 that carcinogenicity studies are not needed to support the development of nemolizumab.”

✓ VerifiedFDA integrated review, p. 107Source ↗

Summary across all 117 monoclonal antibodies →

Nemluvio: 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