Stem Cell Therapy for Complex Perianal Fistulas: Why the ADMIRE CD II Trial Missed Its Mark

Stem Cell Therapy for Complex Perianal Fistulas: Why the ADMIRE CD II Trial Missed Its Mark

Highlights

• The ADMIRE CD II Phase 3 trial did not meet its primary endpoint, showing no statistically significant difference in combined remission rates between darvadstrocel and placebo at 24 weeks.
• Remission was achieved in 48.8% of the darvadstrocel group compared to 46.3% in the placebo group, which received standard-of-care surgical closure.
• The high placebo response rate (46.3%) in this trial significantly exceeded rates seen in previous studies, potentially masking the therapeutic effect of the stem cell dispersion.
• Safety profiles remained consistent with previous findings, with no new safety signals or increased risk of treatment-emergent adverse events identified.

Introduction: The Burden of Complex Perianal Crohn’s Disease

Perianal fistulas represent one of the most debilitating and difficult-to-treat complications of Crohn’s disease (CD). Affecting up to 25% of patients over their lifetime, these complex tracts between the rectum and the perianal skin cause significant pain, discharge, and fecal incontinence, profoundly impacting quality of life. Current management strategies—including antibiotics, immunosuppressants, and anti-TNF therapies—often fail to achieve long-term closure. Even with advanced biologics, a substantial proportion of patients remain refractory, often facing repetitive, invasive surgical procedures such as seton placement, mucosal advancement flaps, or, in severe cases, permanent diversion stomas.

Darvadstrocel (formerly Cx601) emerged as a promising solution. As an allogeneic, expanded, adipose-derived stem cell (eASC) therapy, it was designed to modulate the local inflammatory environment and promote tissue healing. The initial ADMIRE CD trial in Europe and Israel provided the first high-level evidence of efficacy, leading to the product’s approval in several regions. However, to confirm these findings in a broader, more diverse population including North America, the ADMIRE CD II trial was initiated. The results of this confirmatory Phase 3 trial provide a critical, albeit sobering, look at the challenges of treating this condition.

Study Design: The ADMIRE CD II Framework

ADMIRE CD II (NCT03279081) was a double-blind, randomized, placebo-controlled Phase 3 trial conducted across multiple centers in Europe, Israel, and North America. The study enrolled 568 adults with CD and complex perianal fistulas characterized by no more than two internal and three external openings. All participants had previously shown an inadequate response to conventional therapies, including immunosuppressants or biologics.

Participants were randomized in a 1:1 ratio to receive either a single local administration of darvadstrocel (120 million stem cells) or a placebo (sterile buffered solution). A crucial aspect of the study design was that both groups underwent a standardized surgical preparation under general anesthesia. This included curettage of the fistula tracts and the surgical closure of the internal opening—a procedure that itself carries therapeutic potential.

The primary endpoint was defined as ‘combined remission’ at week 24. This required two components: clinical closure of all treated external openings (no drainage upon gentle finger pressure) and the absence of fluid collections larger than 2 cm on blinded central MRI. Key secondary endpoints included clinical remission (closure of external openings without MRI criteria) and the time to clinical remission.

The ADMIRE CD II Results: A Statistical Stalemate

The trial results, recently published in Gastroenterology, revealed that the primary endpoint was not met. At the 24-week mark, 138 out of 283 patients (48.8%) in the darvadstrocel group achieved combined remission. In the placebo group, 132 out of 285 patients (46.3%) achieved the same endpoint. The estimated treatment difference was a mere 2.4% (95% CI, -5.8 to 10.6; P = .571), failing to demonstrate superiority for the stem cell therapy.

Secondary outcomes mirrored the primary findings. Clinical remission at week 24 was achieved by 55.5% of the darvadstrocel group and 52.6% of the placebo group (P = .515). The median time to clinical remission also showed no significant difference between the two arms (P = .374). Despite the lack of efficacy differentiation, the study confirmed the safety of the product; treatment-emergent adverse events (TEAEs) occurred in 73.0% of the darvadstrocel group and 73.4% of the placebo group, with most being mild or related to the underlying disease.

Expert Commentary: Interpreting the High Placebo Response

The most striking feature of ADMIRE CD II is the exceptionally high response rate in the placebo arm. In the original ADMIRE CD trial, the placebo-group remission rate was approximately 34%. In this second trial, nearly half of the placebo group healed. This “placebo” group, however, was not untreated; they received vigorous curettage and surgical closure of the internal opening. The success of this standardized surgical intervention may have created a “ceiling effect,” making it statistically difficult to show an incremental benefit from the addition of stem cells.

Clinicians and researchers are now debating several factors that may have influenced these results:

1. Surgical Excellence vs. Cellular Efficacy

The rigorous standardization of the surgical preparation (curettage and closure) across all sites may have elevated the standard of care to a level where the additional biological effect of stem cells was marginalized. In real-world practice, surgical closure of internal openings without cellular therapy often has lower success rates, suggesting that the trial’s focus on surgical quality control was highly effective.

2. Population Heterogeneity

The inclusion of North American sites introduced a different patient demographic and potentially different practice patterns compared to the original European-centric study. Variability in baseline disease activity or prior biologic exposure might have played a role, though subgroup analyses are needed to clarify this.

3. The Complexity of Fistula Biology

The underlying biology of Crohn’s fistulas is notoriously heterogeneous. While mesenchymal stem cells are potent immunomodulators, their efficacy may depend on a specific inflammatory milieu that was not uniformly present across all 568 participants. Identifying biomarkers that predict a favorable response to cell therapy remains a high-priority research gap.

Conclusion: The Future of Cell Therapy in IBD

The failure of ADMIRE CD II to meet its primary endpoint is a significant setback for the clinical adoption of darvadstrocel in North America. However, the trial provides invaluable data. It underscores the vital importance of surgical preparation in fistula management and highlights the difficulties of demonstrating the efficacy of advanced biologics when the control arm performs exceptionally well.

For patients, the results are a reminder that while stem cell therapy is safe, it is not yet a “silver bullet” for every case of complex perianal disease. Moving forward, the focus must shift toward identifying which specific phenotypes of Crohn’s patients are most likely to benefit from cellular intervention and whether combining stem cells with other advanced therapies might yield better results than monotherapy.

Funding and ClinicalTrials.gov

The ADMIRE CD II trial was funded by Takeda Pharmaceuticals. The study is registered at ClinicalTrials.gov under the identifier NCT03279081 (referenced in some reports as NCT002209456).

References

1. Colombel JF, Garcia Olmo D, Chen ST, et al. Darvadstrocel in Patients With Crohn’s Disease With Complex Perianal Fistulas: The ADMIRE CD II Phase 3 Randomized Trial. Gastroenterology. 2026. PMID: 41790076.
2. Panés J, García-Olmo D, Van Assche G, et al. Expanded allogeneic adipose-derived mesenchymal stem cells (Cx601) for complex perianal fistulas in Crohn’s disease (ADMIRE-CD): a phase 3, randomised, double-blind controlled trial. Lancet. 2016;388(10051):1281-1290.
3. Gecse KB, Bemelman W, Khanna R, et al. Toward standardised management of inflammatory bowel disease-related rectovaginal fistulas: an ECCO novelty. J Crohns Colitis. 2015;9(2):176-181.