Precedia/Monoclonal antibodies/Penpulimab/Tox package

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

Q: Penpulimab (penpulimab): what was done before first-in-human, and what came after?

Australia: first-in-human study in patients (Source: FDA multi-discipline review, p. 335.)

penpulimab · PD-1

Before first-in-human

First-in-human: where

Australia: first-in-human study in patients

“two different assays were used to characterize the ADAs and NAbs in the Phase 1 study conducted in Australia and the three Phase 2 studies conducted in China, respectively.”

✓ VerifiedFDA multi-discipline review, p. 335Source ↗

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 Penpulimab 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: 13-week monkey NOAEL 60 mg/kg; lymph node increased cellularity and erythrophagocytosis (FDA multi-discipline review, p. 53)

Full method, every step sourced →

Longest repeat-dose systemic studies

Longest repeat-dose study and recovery

13-week cynomolgus monkey IV infusion study with 6-week recovery

“A 13-Week Intravenous Infusion Toxicity Study of AK105 Injection With a 6-Week Recovery Period in Cynomolgus Monkeys”

✓ VerifiedFDA multi-discipline review, p. 53Source ↗

Pivotal GLP studies

GLP monkey IV infusion studies (6-week and 13-week), 4, 15 or 60 mg/kg once every two weeks

“In 6-week repeat-dose toxicity study, no apparent toxicity was observed in cynomolgus monkeys following intravenous infusion of penpulimab at 4, 15, or 60 mg/kg once every two weeks for 6 weeks.”

✓ VerifiedFDA multi-discipline review, p. 52Source ↗

DART package

Species: DART

Not conducted; literature-based assessment of reproductive toxicity instead

“No reproductive or embryo-fetal developmental toxicology studies were conducted with penpulimab. Rather, the Applicant provided a literature-based assessment of the potential reproductive toxicity of penpulimab”

✓ VerifiedFDA multi-discipline review, p. 42Source ↗

Reproductive & developmental

No dedicated studies; literature-based assessment of reproductive toxicity used instead

✓ VerifiedFDA multi-discipline review, p. 42Source ↗

PPND / ePPND: when

Not conducted: not warranted for advanced cancer (ICH S9)

“Pre- and postnatal toxicity studies were not conducted with penpulimab. As described in ICH Guidance S9, pre- and postnatal toxicity study is not warranted for marketing of pharmaceuticals for the treatment of patients with advanced cancer.”

✓ VerifiedFDA multi-discipline review, p. 318Source ↗

Carcinogenicity

Species: carcinogenicity

Not conducted (advanced cancer, ICH S9)

“FDA agrees that carcinogenicity studies are not needed to support the use of penpulimab in the currently proposed indication per ICH S9.”

✓ VerifiedFDA multi-discipline review, p. 57Source ↗

Carcinogenicity model

Not conducted; rodent bioassays inappropriate as penpulimab is not active in rodents

“however rodent bioassays are inappropriate, as penpulimab does not appear to be active in rodents.”

✓ VerifiedFDA multi-discipline review, p. 57Source ↗

Carcinogenicity timing

Not required for the advanced cancer indication (ICH S9)

“FDA agrees that carcinogenicity studies are not needed to support the use of penpulimab in the currently proposed indication per ICH S9.”

✓ VerifiedFDA multi-discipline review, p. 57Source ↗

Summary across all 117 monoclonal antibodies →

Penpulimab: 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