Darvadstrocel

Darvadstrocel contains expanded adipose stem cells (eASC), which exhibit immunomodulatory and anti-inflammatory effects at inflammation sites. Anal fistulas typically present as fissures penetrating the intestinal lumen and perianal skin surface, and are characterised by local inflammation that is exacerbated by bacterial infections and faecal contamination. In the inflamed area, there is infiltration of activated lymphocytes and local release of inflammatory cytokines.

Inflammatory cytokines, in particular IFN-γ released by activated immune cells (i.e. lymphocytes), activate eASC. Once activated, eASC impair proliferation of activated lymphocytes and reduce the release of pro-inflammatory cytokines. This immunoregulatory activity reduces inflammation, which may allow the tissues around the fistula tract to heal.

Pharmacodynamic effect

In the ADMIRE-CD study, 63/103 of the eASC-treated patient population were analysed for the presence of donor-specific antibodies (DSA) at baseline and Week 12. At Week 12, 23/63 (36%) showed anti-donor antibody production. Of patients with DSA at Week 12, 7/23 (30%) had cleared DSA by Week 52. Lack of de novo DSA generation was observed between Week 12 and Week 52. No association between DSA results and safety or efficacy up to Week 52 was seen in the subset tested.

The product is intended for local injection.

The nature and intended clinical use of darvadstrocel are such that conventional studies of pharmacokinetics (absorption, distribution, metabolism and elimination) are not applicable.

Biodistribution studies in preclinical models were conducted with the objective of evaluating the persistence of eASC at the site of injection and their potential migration into other tissues or organ systems. After perianal and intrarectal injection of human eASC in athymic rats, cells were present in the rectum and jejunum at the site of injection for at least 14 days and were undetectable after 3 months. eASC were not present in any of the tissues analysed after 3 months or 6 months.

Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology and repeated dose toxicity.

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

The effect of ex vivo expansion on the genetic stability of cells has been assessed in vitro without any indication of carcinogenic potential.