Gecse, Krisztina Barbara

Abstract Background Darvadstrocel (DVS), a suspension of expanded allogeneic adipose-derived mesenchymal stem cells, is approved for the treatment of complex Crohn’s perianal fistulas (CPF). INSPIRE (EUPAS24267) is a European observational post-approval study evaluating real-world effectiveness and safety of DVS in patients with complex CPF for up to 36 months. Here we report preliminary clinical and safety outcomes from INSPIRE. Methods Patients with complex CPF who had received DVS according to local standard practice were eligible to enrol. Clinical response (closure of ≥50% of external openings [EOs]) and clinical remission (closure of all EOs) of DVS-treated fistulas that were draining at baseline, were evaluated in the all-treated (AT; received ≥1 dose of DVS with an evaluation for fistula response after 6 months) and per-protocol (PP; received DVS as per label-approved guidelines) cohorts. Treatment-emergent adverse events (TEAEs), serious TEAEs and AEs of special interest were reported for the safety cohort (all patients treated with DVS). Results As of April 2023, 652 patients had enrolled (Table 1). Complete data to evaluate 12-month clinical response and remission were available for 134 (AT cohort) and 124 (PP cohort) patients, of whom 79.9% (AT, n = 107) and 79.8% (PP, n = 99) had a clinical response and 76.1% (AT, n = 102) and 76.6% (PP, n = 95) had clinical remission (Figure 1). From baseline to Month 12, there was a decrease in the mean (standard deviation [SD]) Perianal Disease Activity Index score (–3.5 [3.3]; n/N = 96/302 and –3.7 [3.2]; n/N = 89/249) and a decrease in the mean (SD) Harvey–Bradshaw Index for Crohn’s disease activity (-0.3 [2.8]; n/N = 102/302 and -0.4 [2.9]; n/N = 95/249) in the AT and PP cohorts, respectively. Complete safety data were available for 619 patients (median [min–max] follow-up 480 [6–1595]) days. Overall, 26% (n = 162) had ≥1 TEAE and 10% (n = 63) ≥1 serious TEAE. The most frequent TEAEs were anal abscess (6.9%), COVID-19 (1.9%) and proctalgia (1.1%). No deaths were reported. One breast cancer lymph node metastasis and one ovarian epithelial cancer were reported; both events were confounded by immunosuppressant treatment and were not considered related to DVS treatment. Conclusion These preliminary data are consistent with the pivotal ADMIRE-CD study and demonstrate a single dose of DVS in patients with complex CPF is associated with positive clinical outcomes in up to 80% of patients, and a favourable safety profile, both of which are maintained after 12 months. The inherent limitations of registry-based studies mean these data should be interpreted with caution. However, the ongoing INSPIRE study will provide longer follow-up data to confirm these observations with respect to any study limitations.

Abstract Background Tofacitinib is an oral, small molecule Janus kinase inhibitor for the treatment of ulcerative colitis (UC). Patients with inflammatory bowel disease are susceptible to Clostridium difficile infection (CDI). Here, we evaluate CDI in the tofacitinib UC clinical program. Methods Events from 4 randomized, placebo-controlled studies (phase [P] 2 or P3 induction [NCT00787202; NCT01465763; NCT01458951], P3 maintenance [NCT01458574]) and an open-label, long-term extension (OLE) study (NCT01470612), were analyzed as 3 cohorts: Induction (P2/P3 induction), Maintenance (P3 maintenance), and Overall (patients receiving tofacitinib 5 or 10 mg twice daily [BID] in P2, P3, and OLE studies; including final data from the OLE study, as of August 24, 2020). Proportions and incidence rates (unique patients with events per 100 patient-years of exposure) of CDI were evaluated. Results The overall cohort comprised 1157 patients who received ≥1 dose of tofacitinib 5 or 10 mg BID, with a total of 2814.4 patient-years of tofacitinib exposure and up to 7.8 years of treatment. A total of 82.6% of patients received predominantly tofacitinib 10 mg BID. In the induction, maintenance, and overall cohorts, 3 (2 tofacitinib treated, 1 placebo treated), 3 (all placebo treated), and 9 patients had CDI, respectively; the overall cohort incidence rate was 0.31 (95% confidence interval, 0.14-0.59). CDI were all mild–moderate in severity and resolved with treatment in 8 patients. Six of 9 patients continued tofacitinib treatment without interruption. Two patients had events reported as serious due to hospitalization. Two patients were receiving corticosteroids when the CDI occurred. Conclusion CDIs among patients with UC receiving tofacitinib were infrequent, cases were mild–moderate in severity, and most resolved with treatment.

Abstract Background Darvadstrocel (DVS) is a suspension of expanded allogeneic adipose-derived mesenchymal (stromal) stem cells approved for the treatment of complex Crohn’s perianal fistulas (complex CPF). The INSPIRE (EUPAS24267) registry is a European observational, post-approval study designed to evaluate the real-world effectiveness and safety of DVS in patients with complex CPF for up to 36 months after DVS administration. Here we report clinical and safety outcomes from the first interim analysis at 6 months post treatment. Methods Patients with complex CPF treated with DVS according to local standard practice were eligible to enrol. Primary outcomes were clinical response (defined as closure despite gentle finger compression of ≥50% of external openings treated with DVS that were draining at baseline) and clinical remission (defined as closure despite gentle finger compression of all external openings treated with DVS that were draining at baseline). Outcomes were evaluated in the All Treated (AT) and Treated Per Protocol (PP) cohorts (Table 1) 6 months post treatment in patients who had received a single administration of DVS. The number and nature of adverse events (AEs), serious AEs (SAEs) are reported for the AT cohort. Results As of September 2021, 230 patients had enrolled, 225 met the inclusion criteria and 205 had complete treatment data and comprised the AT cohort, of these, 176 were treated per protocol. A total of 138 (AT) and 120 (PP) patients were 6 months post treatment, 66% (92/138) and 58% (69/120) had a 6-month visit, of which, 85% (78/92) and 100% (69/69) had evaluable data at Month 6, respectively. Baseline demographics and clinical and fistula characteristics are shown in Tables 1 and 2. In the AT and PP cohorts, respectively, 73% (57/78) and 74% (51/69) of patients had a clinical response, and 65% (51/78) and 65% (45/69) had clinical remission. Changes in Crohn’s disease (CD) activity (assessed with the Harvey–Bradshaw Index) post treatment were minimal, and most patients had no change in CD activity from baseline. In the AT cohort, 20% (41/205) of patients had ≥1 AE and 9.3% (19/205) had ≥1 SAE. There were no reports of ectopic tissue formation and no deaths. Conclusion This is the first real-world, multi-centre study reporting the effectiveness and safety data after DVS treatment for complex CPF. These interim analysis data are consistent with the pivotal ADMIRE-CD study in terms of effectiveness and safety. The ongoing status of the registry and small number of evaluable patients mean these data should be interpreted with caution, pending future analyses in larger numbers of patients with longer follow-up times.