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

Precedia/Cell therapy/Alofisel/Tox package

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

darvadstrocel · Allogeneic adipose MSC

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 Alofisel 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 cell therapies

FDA expects preclinical proof-of-concept and toxicology studies to identify active dose levels and support the choice of starting dose and escalation. The 2013 guidance gives no numeric formula or scaling rule for the starting dose.

“Selection of potential starting dose level, dose-escalation schedule, and dosing regimen for clinical trials.”

✓ VerifiedFDA 2013: Preclinical Assessment of Investigational Cellular and Gene Therapy…, p. 7Source ↗

This product's starting point

NOAEL / key findings: Perianal doses up to 2.5x10^6 cells/rat well tolerated; IV 10x10^6 cells caused fatal pulmonary embolism (EMA assessment report, p. 23)

Full method, every step sourced →

Longest repeat-dose systemic studies

Longest repeat-dose study and recovery

Athymic nude rat repeat-dose study (perianal) with 6-month post-dose observation; IV study similar

“Two repeat-dose toxicity studies were conducted with human eASC in male and female athymic nude rats (Crl:NIH-Foxn1rnu) via the perianal route, a study with a 3-month post-dose observation period and a study with a 6-month post-dose observation period.”

✓ VerifiedEMA assessment report, p. 23Source ↗

Pivotal GLP studies

GLP athymic rat: 2 doses 2 weeks apart, perianal (up to 12/24 wk post-dose) and IV (26 wk); 26-wk biodistribution

“Two repeat-dose toxicity studies were conducted with human eASC in male and female athymic nude rats (Crl:NIH-Foxn1rnu) via the perianal route”

✓ VerifiedEMA assessment report, p. 23Source ↗

DART package

Species: DART

Not conducted; biodistribution showed no migration to reproductive organs

“Reproductive and developmental toxicity studies have not been performed for Alofisel because preclinical biodistribution studies indicated no migration and integration of eASC into reproductive organs following administration of eASC via different routes.”