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

Precedia/Multispecific antibodies/Ordspono/Tox package

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

odronextamab · CD20 x CD3

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 Ordspono 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 multispecifics

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: Up to 1 mg/kg weekly tolerated; no formal NOAEL/HNSTD stated; B-cell depletion, inflammation, presumed opportunistic infections requiring early euthanasia (EMA assessment report, p. 34)

Full method, every step sourced →

Longest repeat-dose systemic studies

Longest repeat-dose study and recovery

16-week weekly IV cynomolgus monkey GLP study with 14-week recovery

“following once weekly IV infusions of 0.1 and 1 mg/kg for 16 weeks (total of 17 doses) with a 14-week recovery period.”

✓ VerifiedEMA assessment report, p. 34Source ↗

Pivotal GLP studies

GLP cynomolgus single-dose, 4-week (0.01/0.1/1 mg/kg) and 16-week (0.1/1 mg/kg) weekly IV studies with recovery

“once weekly IV infusions of 0.01, 0.1, and 1 mg/kg for 4 weeks (total of 5 doses) with a 12-week recovery period”

✓ VerifiedEMA assessment report, p. 34Source ↗

DART package

Species: DART

Fertility endpoints within repeat-dose monkey study (no findings up to 1 mg/kg/week); EFD not conducted (limited value in advanced cancer)

“There were no odronextamab-related findings in fertility endpoints or microscopic assessment of reproductive organs at doses of up to and including 1 mg/kg/week IV. Embryo-fetal developmental toxicology studies with odronextamab were not conducted as such studies are expected to have limited value in further understanding and communicating risks to patients with advanced cancer.”