, Volume 32, Issue 6, pp 627–634 | Cite as

Darvadstrocel: A Review in Treatment-Refractory Complex Perianal Fistulas in Crohn’s Disease

  • Lesley J. ScottEmail author
Adis Drug Evaluation


Darvadstrocel (Alofisel®) consists of a suspension of expanded human allogeneic adipose-derived mesenchymal stem cells (eASCs). It is the first mesenchymal stem cell (MSC) advanced therapy approved in the EU for the treatment of complex perianal fistulas in adult patients with non-active/mildly active luminal Crohn’s disease, when fistulas have shown an inadequate response to ≥ 1 conventional or biologic therapy. In the pivotal phase 3 ADMIRE-CD trial in this difficult-to-treat patient population, after standard-of-care fistula conditioning, add-on therapy with a single dose of darvadstrocel (120 million eASC) administered into the tissue surrounding complex perianal fistulas was significantly more effective than placebo (saline), with the darvadstrocel group having a higher combined remission rate (i.e. clinically-assessed fistula closure plus MRI-assessed absence of abscesses) at 24 weeks in intent-to-treat (ITT primary analysis), modified ITT and per-protocol analyses. Clinical remission was maintained in > 50% of patients at 52 weeks’ follow-up. Given the very limited treatment options available for this difficult-to-treat rare condition, darvadstrocel is a promising, novel, minimally invasive therapy that represents an important advance in the therapeutic options for complex perianal fistulas in adult patients with non-active/mildly active luminal Crohn’s disease when fistulas have shown an inadequate response to ≥ 1 conventional or biologic therapy.



During the peer review process, the manufacturer of darvadstrocel was also offered an opportunity to review this article. Changes resulting from comments received were made on the basis of scientific and editorial merit.

Compliance with Ethical Standards


The preparation of this review was not supported by any external funding.

Conflicts of interest

Lesley Scott is a salaried employee of Adis/Springer, is responsible for the article content and declares no relevant conflicts of interest.


  1. 1.
    Panés J, Rimola J. Perianal fistulizing Crohn’s disease: pathogenesis, diagnosis and therapy. Nat Rev Gastroenterol Hepatol. 2017;14(11):652–64.CrossRefPubMedGoogle Scholar
  2. 2.
    Schwartz DA, Ghazi LJ, Reguiero M, et al. Guidelines for the multidisciplinary management of Crohn’s perianal fistulas: summary statement. Inflamm Bowel Dis. 2015;21(4):723–30.CrossRefPubMedGoogle Scholar
  3. 3.
    Gecse KB, Bemelman W, Kamm MA, et al. A global consensus on the classification, diagnosis and multidisciplinary treatment of perianal fistulising Crohn’s disease. Gut. 2014;63(9):1381–92.CrossRefPubMedGoogle Scholar
  4. 4.
    Garcia-Olmo D, Schwartz DA. Cumulative evidence that mesenchymal stem cells promote healing of perianal fistulas of patients with Crohn’s disease: going from bench to bedside. Gastroenterology. 2015;149(4):853–7.CrossRefPubMedGoogle Scholar
  5. 5.
    Lightner AL, Faubion WA. Mesenchymal stem cell injections for the treatment of perianal Crohn’s disease: what we have accomplished and what we still need to do. J Crohns Colitis. 2017;11(10):1267–76.CrossRefPubMedGoogle Scholar
  6. 6.
    Garcia-Bosch O, Ricart E, Panés J. Review article: stem cell therapies for inflammatory bowel disease - efficacy and safety. Aliment Pharmacol Ther. 2010;32:939–52.CrossRefPubMedGoogle Scholar
  7. 7.
    European Medicines Agency. Orphan Maintenance Assessment Report. Alofisel (expanded human allogeneic mesenchymal adult stem cells extracted from adipose tissue): treatment of anal fistula 2018. Accessed 11 Sep 2018.
  8. 8.
    American Gastroenterological Association Clinical Practice Committee. American Gastroenterological Association medical position statement: perianal Crohn’s disease. Gastroenterology. 2003;125:1503–7.CrossRefGoogle Scholar
  9. 9.
    Bermejo F, Guerra I, Algaba A, et al. Pharmacological approach to the management of Crohn’s disease patients with perianal disease. Drugs. 2018;78(1):1–18.CrossRefPubMedGoogle Scholar
  10. 10.
    Molendijk I, Duijvestein M, van der Meulen-de Jong AE, et al. Immunomodulatory effects of mesenchymal stromal cells in Crohn’s diease. J Allergy. 2012. Scholar
  11. 11.
    Panés J, Ordás I, Ricat E. Stem cell treatments for Crohn’s disease. Expert Rev Clin Immunol. 2010;24(4):597–605.CrossRefGoogle Scholar
  12. 12.
    Nauta AJ, Fibbe WE. Immunomodulatory properties of mesenchymal stromal cells. Blood. 2007;110(10):3499–506.CrossRefPubMedGoogle Scholar
  13. 13.
    TiGenix S. A. U. Alofisel (Darvadstrocel): summary of product characteristics. 2018. Accessed 10 Sep 2018.
  14. 14.
    de la Portilla F, Alba F, García-Olmo D, et al. Expanded allogeneic adipose-derived stem cells (eASCs) for the treatment of complex perianal fistula in Crohn’s disease: results from a multicenter phase I/IIa clinical trial. Int J Colorectal Dis. 2013;28(3):313–23.CrossRefPubMedGoogle Scholar
  15. 15.
    EMA Committee for Advanced Therapies. Guidelines on quality, non-clinical and clinical aspects of medicinal products containing genetically modified cells (EMA/CHMP/410869/2006). 2012. Accessed 18 Sep 2018.
  16. 16.
    EMA Committee for Advanced Therapies. Reflection paper on stem cell-based medicinal products. 2011. Accessed 18 Sep 2018.
  17. 17.
    Panés J, Garcia-Olmo D, Van Assche G, et al. Expanded allogeneic adipose-derived mesenchymal stem cells (Cx601) for complex perianal fistulas in Crohn’s disease: a phase 3 randomised, double-blind controlled trial. Lancet. 2016;388(10051):1281–90.CrossRefPubMedGoogle Scholar
  18. 18.
    Panés J, Salas A. Mechanisms underlying the beneficial effects of stem cell therapies for inflammatory bowel disease. Gut. 2009;58(7):898–900.CrossRefPubMedGoogle Scholar
  19. 19.
    Data on file, TiGenix S.A.U, 2018.Google Scholar
  20. 20.
    Panés J, García-Olmo D, Van Assche G, et al. Long-term efficacy and safety of stem cell therapy (Cx601) for complex perianal fistulas in patients with Crohn’s disease. Gastroenterology. 2018;154(5):1334.e4–13342.e4.CrossRefGoogle Scholar
  21. 21.
    Panés J, García-Olmo D, Parfionovas A, et al. Patient-reported outcomes in pain and discharge correlate with objective assessments of perianal fistula remission in Crohn’s disease (CD) [abstract no. P594]. J Crohn’s Colitis. 2018;12(Suppl. 1):S408–9.CrossRefGoogle Scholar
  22. 22.
    García-Olmo D, Panés J, Brayshaw N, et al. Cx601, a novel stem cell therapy for complex perianal fistulas in Crohn’s disease has rapid onset of clinical remission and low relapse rate by week 52 [abstract no. P691]. J Crohn’s Colitis. 2018;12(Suppl 1):S460–1.CrossRefGoogle Scholar
  23. 23.
    Adegbola SO, Pisani A, Sahnan K, et al. Medical and surgical management of perianal Crohn’s disease. Ann Gastroenterol. 2018;31(2):129–39.PubMedPubMedCentralGoogle Scholar
  24. 24.
    Schwartz DA, Ghazi LJ, Reguiero M. Guidelines for medical treatment of Crohn’s perianal fistulas: critical evaluation of therapeutic trials. Inflamm Bowel Dis. 2015;21(4):737–52.CrossRefPubMedGoogle Scholar
  25. 25.
    Gionchetti P, Dignass A, Danese S, et al. 3rd European evidence-based consensus on the diagnosis and management of Crohn’s disease 2016. J Crohn’s Colitis. Part 2: surgical management and special situations. 2017;11(2):135–49.CrossRefGoogle Scholar
  26. 26.
    Georgiev-Hristov T, Guadalajara H, Herreros MD, et al. A step-by-step surgical protocol for the treatment of perinanal fistula with adipose-derived mesenchymal stem cells. J Gastrointest Surg. 2018. Scholar
  27. 27.
    Molendijk I, Van der Meulen-de Jong AE, Verspaget HW, et al. Standardization of mesenchymal stromal cell therapy for periananl fistulizing Crohn’s disease. Eur J Gastroenterol Hepatol. 2018;30(10):1148–54.CrossRefPubMedGoogle Scholar
  28. 28.
    Jani M, Dixon WG, Chinoy H. Drug safety and immunogenicity of tumour necrosis factor inhibitors: the story so far. Rheumatology. 2018. Scholar
  29. 29.
    McConachie SM, Wilhelm SM, Bhargava A, et al. Biologic-induced infections in inflammatory bowel disease: the TNF-α antagonists. Ann Pharmacother. 2018;52(6):571–9.CrossRefPubMedGoogle Scholar
  30. 30.
    Lightner AL, Wang Z, Zubair AC, et al. A systematic review and meta-analysis of mesenchymal stem cell injections for the treatment of perianal Crohn’s disease: progress made and future directions. Dis Colon Rectum. 2018;61(5):629–40.CrossRefPubMedGoogle Scholar
  31. 31.
    Ciccocioppo R, Klersy C, Leffler D, et al. Safety and efficacy of local injections of mesenchymal stem cells in perianal fistula in Crohn’s disease: a systematic review and meta-analysis of the clinical trials and observational cohort studies [abstract no. Mo1653]. Gastroenterology. 2018;154(6 Suppl 1):784–5.CrossRefGoogle Scholar

Copyright information

© Springer Nature Switzerland AG 2018

Authors and Affiliations

  1. 1.SpringerAucklandNew Zealand

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