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

Precedia/Monoclonal antibodies/Tevimbra/Tox package

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

tislelizumab · 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 Tevimbra 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 30 mg/kg Q2W, 4.3-6.6x human exposure at 200 mg; no treatment-related toxicity or histopathology (EMA assessment report, p. 30)

Full method, every step sourced →

Longest repeat-dose systemic studies

Longest repeat-dose study and recovery

13-week IV cynomolgus monkey study (P14-057-CD) with 6-week recovery

“The Applicant performed a first repeat-dose toxicology study in monkeys (P14-057-CD), where 0/3/10/30 mg/kg tislelizumab was administered IV once biweekly for 13 weeks to 6 animals/sex/group followed by a 6-week recovery period”

✓ VerifiedEMA assessment report, p. 27Source ↗

Pivotal GLP studies

Cynomolgus monkey 13-week IV studies, 3-60 mg/kg every 2 weeks (7 doses)

“In repeat-dose toxicology studies in cynomolgus monkeys with intravenous dose administration for 13 weeks at doses of 3, 10, 30 or 60 mg/kg every 2 weeks for 13 weeks (7 dose administrations)”