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

Precedia/Monoclonal antibodies/Zynyz/Tox package

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

retifanlimab · 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 Zynyz 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 100 mg/kg per dose, the highest dose evaluated (EMA assessment report, p. 47)

Full method, every step sourced →

Longest repeat-dose systemic studies

Longest repeat-dose study and recovery

13-week GLP cynomolgus monkey (IV, once weekly); no recovery phase

“T18-02-10 (GLP) Cynomolgus monkeys/ 5M 5F 0, 5, 20, 100 mg/kg IV 30 min. infusion 13 weeks, no recovery”

✓ VerifiedEMA assessment report, p. 47Source ↗

Pivotal GLP studies

GLP cynomolgus monkey 4-week (0-150 mg/kg, 10-week recovery) and 13-week (0-100 mg/kg) studies, weekly IV infusion

“Pivotal repeat-dose toxicity studies with retifanlimab in cynomolgus monkeys include a 4-week study (doses: 0, 10, 40, or 150 mg/kg) with a 10-week recovery period (T19-01-03) and a 13 week study (doses: 0, 5, 20, 100 mg/kg; T18 02-10).”

✓ VerifiedEMA assessment report, p. 46Source ↗

DART package

Species: DART

Not conducted; not required for advanced cancer therapeutics (ICH S9)

“Standard fertility and early embryonic development, embryofetal development and pre- and postnatal development studies have not been conducted with retifanlimab as not required for advanced cancer therapeutics (ICH S9 2009).”

✓ VerifiedEMA assessment report, p. 48Source ↗

Reproductive & developmental

Not conducted; weight-of-evidence reproductive risk assessment submitted instead

“Reproductive and developmental toxicology studies were not conducted with retifanlimab. Instead, the Applicant submitted a weight-of-evidence reproductive risk assessment for retifanlimab.”

✓ VerifiedFDA multi-discipline review, p. 40Source ↗

PPND / ePPND: when

Not conducted: not required for advanced cancer therapeutics (ICH S9)

✓ VerifiedEMA assessment report, p. 48Source ↗

Carcinogenicity

Species: carcinogenicity

Not conducted; not warranted

“Carcinogenicity studies were not warranted.”

✓ VerifiedFDA multi-discipline review, p. 40Source ↗

Carcinogenicity model

Not conducted; not warranted

“Carcinogenicity studies were not warranted.”

✓ VerifiedFDA multi-discipline review, p. 40Source ↗

Carcinogenicity timing

Not required

“Carcinogenicity studies were not warranted.”

✓ VerifiedFDA multi-discipline review, p. 40Source ↗

Summary across all 117 monoclonal antibodies →

Zynyz: 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