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

Precedia/Monoclonal antibodies/Jemperli/Tox package

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

dostarlimab · PD-1

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 Jemperli 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: NOAEL not established in 13-week monkey study due to an immune-type skin finding in one low-dose (10 mg/kg) animal (EMA assessment report, p. 43)

Full method, every step sourced →

Longest repeat-dose systemic studies

Longest repeat-dose study and recovery

13-week cynomolgus monkey (IV, once weekly) GLP study with 8-week recovery

“The study consisted in 13-Week Once Weekly Intravenous Toxicity Study in Cynomolgus Monkeys with an 8-Week Recovery Period (GLP).”

✓ VerifiedEMA assessment report, p. 38Source ↗

Pivotal GLP studies

Cynomolgus monkey 4-week and 13-week once-weekly IV studies at 10, 30 and 100 mg/kg

“The single dose and repeat dose studies of 4- and 13-week duration were all performed with similar dose levels of dostarlimab (10, 30 and 100 mg/kg).”

✓ VerifiedEMA assessment report, p. 42Source ↗

DART package

Species: DART

Not conducted: PD-1/PD-L1 blockade risk to fetomaternal tolerance; fertility not expected for cancer (ICH S9)

“No reproductive and developmental studies were conducted because of potential adverse effects of the blockade of PD‐1/programmed death‐ligand 1 (PD‐L1) pathway on the immune tolerance at the fetomaternal interface. Consistent with the ICH S9 guidance, fertility assessments are not typically expected for products intended for the treatment of patients with cancer.”

✓ VerifiedFDA multi-discipline review, p. 50Source ↗

Reproductive & developmental

No dedicated studies; literature: PD-L1 blockade in murine pregnancy models disrupts fetal tolerance and increases fetal loss

“Blockade of PD-L1 signaling has been shown in murine models of pregnancy to disrupt tolerance to the foetus and to result in an increase in foetal loss.”

✓ VerifiedEMA assessment report, p. 43Source ↗

PPND / ePPND: when

Not conducted: PD-1/PD-L1 blockade risks fetomaternal tolerance; no reproductive and developmental studies

✓ VerifiedFDA multi-discipline review, p. 50Source ↗

Carcinogenicity

Species: carcinogenicity

Not conducted (biotechnology product for advanced cancer)

“No genetic toxicology or carcinogenicity studies were conducted or warranted to support this BLA submission, as dostarlimab‐gxly is a biotechnology‐derived pharmaceutical and the proposed indication is for advanced cancer.”

✓ VerifiedFDA multi-discipline review, p. 37Source ↗

Carcinogenicity model

Not conducted (ICH S6; advanced cancer per ICH S9)

“No studies have been performed to assess the potential of dostarlimab for carcinogenicity or genotoxicity which was considered acceptable based on ICH S6 (R1).”

✓ VerifiedEMA assessment report, p. 43Source ↗

Carcinogenicity timing

Not required (biotechnology product for advanced cancer)

✓ VerifiedFDA multi-discipline review, p. 37Source ↗

Summary across all 117 monoclonal antibodies →

Jemperli: 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