Darvadstrocel

Identification

Summary

Darvadstrocel is a mesenchymal stem cell advanced therapy used to treat complex perianal fistulas in adults with non-active or mildly active luminal Crohn’s disease after an inadequate response to at least one standard treatments.

Generic Name

Darvadstrocel

DrugBank Accession Number

DB16581

Background

Darvadstrocel is a suspension of expanded human allogeneic adipose-derived mesenchymal stem cells extracted from the subdermal adipose tissue of healthy donors via liposuction.¹ Darvadstrocel was first approved by the European Commission on March 23, 2018, under the brand name Alofisel. It is indicated for the treatment of complex perianal fistulas in adult patients with non-active or mildly active luminal Crohn’s disease when fistulas have shown an inadequate response to at least one conventional or biologic therapy.⁵ It is the first mesenchymal stem cell therapy approved in Europe for this therapeutic indication. Perianal fistula is a common manifestation of Crohn’s disease and is often difficult to manage, as it may be associated with complex presentations and symptoms. Darvadstrocel exhibits immunomodulatory and anti-inflammatory effects: it aims to reduce local inflammation and enhance tissue repair in perianal fistulas.¹

Type

Biotech

Groups

Approved, Experimental

Biologic Classification

Cell transplant therapies
Other cell transplant therapies

Synonyms

Darvadstrocel

External IDs

CX-601
CX601

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Pharmacology

Indication

Darvadstrocel is indicated for the treatment of complex perianal fistulas in adult patients with non-active or mildly active luminal Crohn’s disease, when fistulas have shown an inadequate response to at least one conventional or biologic therapy. Darvadstrocel should be used only after conditioning of the fistulas.⁵

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Associated Conditions

Indication Type	Indication	Combined Product Details	Approval Level	Age Group	Patient Characteristics	Dose Form
Treatment of	Complex perianal fistula		••••••••••••	•••••	•••••• •••••••••••• •••••••• •• ••••• ••• ••••• •••••••	•••••••••

Contraindications & Blackbox Warnings

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Pharmacodynamics

Darvadstrocel mediates immunomodulatory and anti-inflammatory effects to allow the tissues around the fistula tract to heal. It works by promoting the secretion of anti-inflammatory molecules and sending paracrine signals to maintain local anti-inflammatory environment.² In clinical trials, administration of darvadstrocel into the tissue surrounding complex perianal fistulas was associated with an increased remission rate than placebo at 24 weeks: this effect was maintained at more than 50% of patients at 52 weeks.¹

Mechanism of action

Perianal fistula is a common manifestation of Crohn’s disease.¹ It typically presents as fissures penetrating the intestinal lumen and perianal skin surface and is accompanied by local inflammation, which bacterial infections and fecal contamination can exacerbate.⁵ At the site of inflammation, there is increased infiltration of lymphocytes, increased release of inflammatory cytokines (e.g., interleukin (IL)-6, TNF-α, IL12), and upregulated matrix metalloproteinase (MMP) enzymes.^1,5

The pathogenesis of perianal fistulas is unclear; however, there is evidence of epithelial-to-mesenchymal transition (EMT) involvement,³ among other proposed mechanisms like altered immune response due to genetic predisposition ¹ and overexpression of matrix remodelling enzymes.² EMT is a biologic process by which the epithelial characteristics of a cell are reprogrammed to adopt mesenchymal phenotype. Cells with a mesenchymal phenotype have increased invasion and metastasis potential. EMT is characterized by increased expression of MMPs, MMP-induced degradation of the extracellular matrix, and the loss of cell polarity and invasive ability.⁴ Although EMT is a normal physiological response to restore intestinal barrier after epithelial damage, immunomediators such as TGF-β and IL-13 can aberrantly upregulate EMT so that it becomes a detrimental process.²

Darvadstrocel contains expanded human allogeneic adipose-derived mesenchymal stem cells. Its main mode of therapeutic action comes from its immunomodulatory and anti-inflammatory effects, rather than an ability to stimulate tissue regeneration.² Upon direct injection into the site of tissue injury, inflammatory cytokines released by activated immune cells - such as IFN-γ - activate darvadstrocel, or expanded adipose stem cells.⁵ Darvadstrocel suppresses T cell activation and proliferation; dendritic cell differentiation, maturation, and function; B-cell differentiation; and natural killer cell (NKC) proliferation. By reducing pro-inflammatory cytokine secretion by dendritic cells and NKCs, darvadstrocel induces a more anti-inflammatory microenvironment. Darvadstrocel also enhances the production of IL-10 and transforming growth factor-β, which are cytokines that promote T_reg differentiation and inhibit Th1 cell differentiation.^1,2

Absorption