Padcev (enfortumab vedotin): how was the first human dose set?

Precedia/Antibody-drug conjugates/Padcev/First dose

Padcev: how was the first human dose set?

enfortumab vedotin · Nectin-4

First-in-human starting dose

Not stated in public reviews

Why it's blank

The public FDA and EMA reviews of Padcev 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 ADCs

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: Monkey HNSTD/MTD 3 mg/kg, rat MTD 5 mg/kg; skin, injection site, bone marrow, liver, eye, male reproductive organs (FDA multi-discipline review, p. 56)

Full method, every step sourced →

NOAEL / key findings

Monkey HNSTD/MTD 3 mg/kg, rat MTD 5 mg/kg; skin, injection site, bone marrow, liver, eye, male reproductive organs

“In the 4-week monkey study (# 20005664), AGS-22M6E systemic exposure at 3 mg/kg (MTD/HNSTD) was 2450 µg.hr/mL (Day 1) and 903 µg.hr/mL (Day 22).”

✓ VerifiedFDA multi-discipline review, p. 56Source ↗

Summary across all 14 ADCs →

Padcev: how was the first human dose set?

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