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

Precedia/Small molecules/Qulipta/Tox package

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

atogepant · CGRP receptor

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 Qulipta 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 small molecules outside oncology

Find the highest dose with no adverse effects (NOAEL) in each animal species, convert it to a human equivalent dose, usually by body surface area, pick the most appropriate species, then divide by a safety factor (default 10) to get the maximum recommended starting dose.

“In general, one should consider using a safety factor of at least 10. The MRSD should be obtained by dividing the HED by the safety factor.”

✓ VerifiedFDA 2005: Estimating the Maximum Safe Starting Dose in Initial Clinical…, p. 7Source ↗

This product's starting point

NOAEL / key findings: 6-month rat NOAEL 100 mg/kg/day (~33-fold margin over clinical AUC at 60 mg QD) (EMA assessment report, p. 23)

Full method, every step sourced →

Longest repeat-dose systemic studies

Longest repeat-dose study and recovery

9-month GLP rhesus monkey oral study with 3-month interim necropsy; no recovery phase stated

“Study TT #13-1074: Nine-Month Oral Toxicity Study in Rhesus Monkeys with a Three-Month Interim Necropsy”

✓ VerifiedFDA integrated review, p. 129Source ↗

Pivotal GLP studies

6-month rat and 9-month rhesus monkey oral studies

“The toxicologic and toxicokinetic profile of orally administered atogepant was assessed in a series of single and repeat dose studies in rats and monkeys up to 6- and 9-months’ duration, respectively.”

✓ VerifiedFDA integrated review, p. 119Source ↗

DART package

Species: DART

Rat (fertility, EFD, pre/postnatal) and rabbit (EFD)

“2-year carcinogenicity studies in mouse and rat; and reproductive and development studies (fertility and early embryonic, embryofetal development, and pre- and postnatal development studies in rat; embryofetal development study in rabbit).”

✓ VerifiedFDA integrated review, p. 66Source ↗

Reproductive & developmental

Rat and rabbit EFD: embryolethality, lower fetal weight (rats) and fetal variations above clinical exposures

“In animal studies, oral administration of atogepant during organogenesis resulted in embryolethality, adverse effects on embryofetal development (decreased fetal body weight in rats, increased incidences of fetal variations in rats and rabbits) at maternal exposures greater those used clinically.”

✓ VerifiedFDA integrated review, p. 67Source ↗

PPND / ePPND: when

GLP rat PPND completed and included in the marketing application

“In the GLP pre- and postnatal developmental toxicity study in rats, atogepant was administered at dose levels of 0 (vehicle), 15, 45 or 125 mg/kg/day.”

✓ VerifiedEMA assessment report, p. 26Source ↗

Carcinogenicity

Species: carcinogenicity

Mouse and rat (2-year)

✓ VerifiedFDA integrated review, p. 66Source ↗

Carcinogenicity model

2-year mouse and 2-year rat: not carcinogenic; female mouse high dose not adequately justified

“Based on the FDA statistical analysis of the 2-year mouse and rat carcinogenicity studies, atogepant was not carcinogenic. The study in female mice was not adequate because the HD was not adequately justified;”

✓ VerifiedFDA integrated review, p. 120Source ↗

Carcinogenicity timing

2-year mouse and 2-year rat studies completed and reviewed in the NDA

“Based on the FDA statistical analysis of the 2-year mouse and rat carcinogenicity studies, atogepant was not carcinogenic.”

✓ VerifiedFDA integrated review, p. 120Source ↗

Summary across all 211 small molecules →

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

Before first-in-human

Longest repeat-dose systemic studies

DART package

Carcinogenicity

Email me this as a cited memo

Same question, other small molecules