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

Precedia/Monoclonal antibodies/Unituxin/Tox package

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

dinutuximab · GD2

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 Unituxin 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 oncology monoclonal antibodies (ICH S9)

HNSTD/STD10 is the method used for anticancer drugs in patients: the start dose is one-sixth of the highest non-severely toxic dose (HNSTD) in non-rodents, or one-tenth of the dose severely toxic to 10% of rodents (STD10), scaled by body surface area. The aim is a dose that is pharmacologically active yet reasonably safe.

“A common approach for many small molecules is to set a start dose at 1/10 the Severely Toxic Dose in 10% of the animals (STD 10) in rodents. If the non-rodent is the most appropriate species, then 1/6 the Highest Non-Severely Toxic Dose (HNSTD) is considered an appropriate starting dose.”

✓ VerifiedICH 2009: ICH S9: Nonclinical Evaluation for Anticancer Pharmaceuticals, p. 13Source ↗

This product's starting point

NOAEL / key findings: Rat NOAEL below 5 mg/kg/day; liver changes, decreased erythrocyte parameters, increased hematopoiesis (EMA assessment report, p. 33)

Full method, every step sourced →

Longest repeat-dose systemic studies

Longest repeat-dose study and recovery

4-week rat (4 days on, 3 days off weekly) with 6-week recovery

“Rats were administered dinutuximab at doses significantly higher than the clinically recommended dose for 4 weeks (4 days on, 3 days off/week) with a 6-week recovery period.”

✓ VerifiedFDA pharmacology/toxicology review, p. 2Source ↗

Pivotal GLP studies

GLP 4-week IV rat study (4 days on, 3 days off weekly) with 6-week recovery

“Rats were administered dinutuximab at doses significantly higher than the clinically recommended dose for 4 weeks (4 days on, 3 days off/week) with a 6-week”

✓ VerifiedFDA pharmacology/toxicology review, p. 2Source ↗

DART package

Species: DART

Not conducted: not required for paediatric population (90% under 5 years)

“Based on the median age of the proposed patient population (90% of patients less than 5 years of age), the Agency agreed that reproductive and developmental toxicology studies would not be required to support the BLA for Unituxin for the treatment of high risk neuroblastoma.”

✓ VerifiedFDA pharmacology/toxicology review, p. 12Source ↗

Reproductive & developmental

Not conducted (pediatric population); no reproductive organ effects in rat repeat-dose study at high exposures

“In the repeat-dose toxicity studies, administration of dinutuximab in male and female rats resulted in no adverse effects on reproductive organs at exposures that were at least 60 fold higher than those observed clinically.”

✓ VerifiedEMA assessment report, p. 39Source ↗

PPND / ePPND: when

Not conducted: reproductive toxicology not required because 90% of patients are under 5 years (median age 18 months)

“Because the median age of the proposed patient population is 18 months and 90% of the cases occur in children under the age of 5, reproductive toxicology studies of dinutuximab were not required to support the submission of the Unituxin BLA.”

✓ VerifiedFDA pharmacology/toxicology review, p. 3Source ↗

Carcinogenicity

Species: carcinogenicity

Not conducted

“No carcinogenicity studies have been conducted.”

✓ VerifiedEMA assessment report, p. 34Source ↗

Carcinogenicity model

Not conducted (advanced cancer indication)

“Carcinogenicity studies were not required to support the licensing application for a product intended to treat advanced human cancer and are neither planned nor expected as post-marketing requirements at this time.”

✓ VerifiedFDA pharmacology/toxicology review, p. 3Source ↗

Carcinogenicity timing

Not required for advanced cancer; not planned as a postmarketing requirement

✓ VerifiedFDA pharmacology/toxicology review, p. 3Source ↗

Summary across all 117 monoclonal antibodies →

Unituxin: 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