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P436 Darvadstrocel treatment outcomes in Crohn’s disease patients with complex perianal fistulas: the role of TNFi co-treatment in ADMIRE CD

J. Panés*1, D. García-Olmo2, D. Lindner3, I. Tagarro García4, C. Agboton3

1Hospital Clínic de Barcelona, Gastroenterology Department, Barcelona, Spain, 2‘Fundación Jiménez Díaz’ University Hospital, Autonomous University of Madrid, Department of Surgery, Madrid, Spain, 3Takeda Pharmaceuticals International AG, Zurich, Switzerland, 4Takeda Spain, Madrid, Spain

Background

Darvadstrocel (DVS) is an expanded, allogeneic, adipose-derived, mesenchymal stem cell therapy indicated in the treatment of complex perianal fistulas (CPAF) in patients with Crohn’s disease (CD).1,2 In ADMIRE CD (NCT01541579), a pivotal Phase 3, double-blind, randomised study, more patients who received DVS in addition to standard of care achieved combined remission at Weeks 24 and 52 compared with standard of care with placebo (PBO).1,2 This post-hoc analysis assessed the role of co-treatment with tumour necrosis factor inhibitors (TNFi) on the outcomes for DVS therapy in treatment-refractory patients with CPAF in CD.

Methods

In ADMIRE CD patients were randomised to receive DVS or PBO. Allowed co-treatments were TNFi or immunomodulators (IMM). Randomisation was stratified by co-treatment received at baseline. This analysis was performed on the modified intent-to-treat population (mITT) (received study treatment and had at least one post-baseline efficacy assessment). Two subgroups were examined: TNFi co-treatment (with or without IMM); and no co-treatment. The outcomes examined were combined remission (clinical assessment of closure of all treated external openings draining at baseline, and the absence of collections >2 cm confirmed by MRI) and clinical remission (closure of all treated external openings that were draining at baseline despite gentle finger compression) at Weeks 24 and 52.

Results

In both subgroups at Weeks 24 and 52, the proportion of patients achieving combined and clinical remission in the DVS arm was greater than with PBO. TNFi with DVS achieved and sustained greater clinical remission compared with TNFi with PBO at Week 24 (58.7% vs. 50.0%) and Week 52 (61.9% vs. 43.5%). In the TNFi subgroup, the number of treatment-emergent adverse events related to study treatment was greater in the PBO arm than in the DVS arm, the most frequent being anal abscess.

Table 1. Combined and clinical remission at Week 24 by TNFi co-treatment (mITT population). *LOCF rules applied. **No TNFi or IMM co-treatment at baseline. ***Patients co-treated with IMM only.

Combined remission,* 24 weeksClinical remission,* 24 weeks
Co-treatmentDVS n, % (95% CI)PBO n, % (95% CI)Treatment difference (p.p.) (95% CI)DVS n, % (95% CI)PBO n, % (95% CI)Treatment difference (p.p.) (95% CI)
TNFi (with or without IMM) n = 12535, 55.6 (43.3 to 67.8)26, 41.9 (29.7 to 54.2)13.6 (–3.7 to 31.0)37, 58.7 (46.6 to 70.9)31, 50.0 (37.6 to 62.4)8.7 (–8.7 to 26.1)
No co-treatment** n = 4313, 54.2 (34.2 to 74.1)4, 21.1 (2.7 to 39.4)33.1 (6.0 to 60.2)14, 58.3 (38.6 to 78.1)5, 26.3 (6.5 to 46.1)32.0 (4.1 to 60.0)
Full mITT population*** n = 20453, 51.5 (41.8 to 61.1)36, 35.6 (26.3 to 45.0)15.8 (2.4 to 29.2)57, 55.3 (45.7 to 64.9)43, 42.6 (32.9 to 52.2)12.8 (–0.8 to 26.4)
Confidence interval [CI]Percentage points (p.p.)

Table 2. Combined and clinical remission at Week 52 by TNFi co-treatment (mITT population). *LOCF rules applied. **No TNFi or IMM co-treatment at baseline.***Patients co-treated with IMM only.

Combined remission,* 52 weeksClinical remission,* 52 weeks
Co-treatmentDVS n, % (95% CI)PBO n, % (95% CI)Treatment difference (p.p.) (95% CI)DVS n, % (95% CI)PBO n, % (95% CI)Treatment difference (p.p.) (95% CI)
TNFi (with or without IMM) n = 12538, 60.3 (48.2 to 72.4)25, 40.3 (28.1 to 52.5)20.0 (2.8 to 37.2)39, 61.9 (49.9 to 73.9)27, 43.5 (31.2 to 55.9)18.4 (1.1 to 35.6)
No co-treatment** n = 4314, 58.3 (38.6 to 78.1)6, 31.6 (10.7 to 52.5)26.8 (–2.0 to 55.5)16, 66.7 (47.8 to 85.5)7, 36.8 (15.2 to 58.5)29.8 (1.1 to 58.6)
Full mITT population*** n = 20458, 56.3 (46.7 to 65.9)39, 38.6 (29.1 to 48.1)17.7 (4.2 to 31.2)61, 59.2 (49.7 to 68.7)42, 41.6 (32.0 to 51.2)17.6 (4.1 to 31.1)
Confidence interval [CI]Percentage points (p.p.)

Conclusion

In patients not receiving TNFi co-treatment, at Week 52 DVS compared with PBO had a benefit of similar magnitude compared with patients receiving concomitant TNFi. At Week 52, only the DVS groups achieved >60% clinical remission regardless of TNFi use. In summary, with or without TNFi, DVS consistently provided greater benefit than PBO alone. Further studies with larger cohorts are needed to confirm these post-hoc observations.

References

1. Panés J, García-Olmo D, Van Assche G 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;388:1281–90.

2. 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;154:1334–1342.e4