ABSTRACT
Background: An association between shorter disease duration and improved clinical efficacy has been shown in post hoc analyses of clinical trial data with biological therapies in Crohn's disease (CD). The efficacy and safety of risankizumab (RZB) as induction and maintenance therapy have been recently reported. Here, the efficacy of RZB stratified by baseline CD duration is reported. Methods: In ADVANCE (NCT03105128) and MOTIVATE (NCT03104413), patients with moderately to severely active CD received intravenous (IV) RZB induction therapy or placebo (PBO) for 12 weeks. Patients with clinical response to RZB IV induction were re-randomised in a 52-week maintenance study (FORTIFY, NCT03105102) to receive subcutaneous (SC) RZB or PBO (ie, withdrawal). For this post-hoc analysis, patient subgroups were stratified by years of CD duration at baseline (< 2, 2-5, > 5-10, and > 10 years). Induction analyses focused on patients who received RZB 600 mg IV or PBO for 12 weeks. As all patients who entered maintenance responded to RZB IV induction, maintenance analyses were limited to those patients who responded to induction and then received RZB 360 mg SC for 52 weeks. Clinical and endoscopic outcomes were evaluated using nonresponder imputation incorporating multiple imputation to handle missing data due to impact of the COVID-19 pandemic. Safety was assessed throughout the studies. Results: The induction and maintenance analyses included 527 patients who received RZB 600 mg IV and 141 patients who received RZB 360 mg SC, respectively. At the end of induction (week 12), patients with CD duration of < 2 years achieved higher rates of endoscopic outcomes with IV RZB induction vs patients with longer durations of disease (Figure 1), and regardless of baseline CD duration, greater proportions of RZB-treated patients achieved clinical remission (defined by stool frequency and abdominal pain), endoscopic response, endoscopic remission, and ulcer-free endoscopy vs PBO (P ≤ .05). Clinical remission rates at week 12 were numerically higher in patients with CD duration of < 5 years vs > 5 years (Figure 1). Similar results for improved clinical and endoscopic outcomes associated with shorter disease duration were observed at week 52 with RZB 360 mg SC maintenance treatment (Figure 2). RZB was well tolerated with lower rates of serious adverse events and serious infections vs PBO in induction, across CD duration subgroups. Conclusion: RZB induction and maintenance therapy was effective and well tolerated with a safety profile generally similar across CD duration subgroups. Achievement of clinical and endoscopic endpoints were higher in patients with shorter duration of CD, suggesting that earlier introduction of RZB therapy may lead to improved outcomes.
ABSTRACT
Background: Treatment of perianal fistulizing Crohn's disease (PFCD) is a major unmet need. Filgotinib (FIL) is a once-daily, oral, preferential Janus kinase 1 inhibitor in development for the treatment of inflammatory bowel diseases. The efficacy and safety of FIL for the treatment of PFCD was evaluated in the phase 2, double-blind, randomized, placebo (PBO)-controlled DIVERGENCE 2 study (NCT03077412). Methods: Patients (18-75 years old) with PFCD (documented diagnosis of CD for at least 3 months and 1-3 external openings [EOs] with drainage [spontaneous or on compression] for ≥ 4 weeks before screening) previously treated with antibiotics, immunomodulators and/or tumour necrosis factor inhibitors (TNFi) were randomized (2:2:1) to receive FIL 200 mg, FIL 100 mg or PBO once daily for up to 24 weeks. Active luminal CD was permitted providing that the Crohn's Disease Activity Index score was ≤ 300 at screening. The primary endpoint was combined fistula response (reduction of ≥ 1 from baseline in the number of draining EOs determined by investigator assessment and no fluid collections > 1 cm on centrally read pelvic magnetic resonance imaging [MRI]) at Week 24. Combined fistula remission (closure of all draining EOs present at baseline and no fluid collections > 1 cm) at Week 24 was a key secondary endpoint. The study was not powered for statistical comparisons and was prematurely terminated owing to low recruitment rates during the COVID-19 pandemic. Results: Baseline characteristics were broadly similar across the treatment groups (Table 1). Overall, 91.2% of patients had complex perianal fistulae and TNFi treatment had previously failed in 64.9% of patients. A lower proportion of patients randomized to receive FIL 200 mg discontinued the study compared with those who received PBO (Table 2). The proportion of patients who achieved a combined fistula response at Week 24 was numerically higher in the FIL 200 mg group (47.1%;90% confidence interval [CI]: 26.0-68.9) than in the PBO group (25.0%;90% CI: 7.2-52.7) (Figure 1), with similar results observed for combined fistula remission (FIL 200 mg [47.1%;CI: 26.0-68.9] versus PBO [16.7%;CI: 3.0-43.8]) (Figure 2). Treatment-emergent severe adverse events were highest in the FIL 200 mg group (Table 2). Adverse event rates were otherwise similar across treatment groups. Conclusion: In this phase 2 study, numerically higher fistula response and remission rates were observed after 24 weeks of treatment with FIL 200 mg versus PBO in patients with active PFCD and a history of multiple medical treatment failures. FIL was well tolerated overall. Further studies of FIL for the treatment of PFCD are warranted.
ABSTRACT
Introduction: A subcutaneous (SC) infliximab (IFX), CT-P13 SC, has received regulatory approval from the European Medicines Agency for indications including inflammatory bowel disease.1 In response to the coronavirus disease 2019 (COVID-19) pandemic, clinical guidance has recommended considering switching from intravenous (IV) treatment to SC alternatives to minimise hospital visits.2 Aims & Methods: In this analysis, data from the pivotal randomised controlled trial (NCT02883452) of CT-P13 SC in patients with active Crohn's disease (CD) and ulcerative colitis (UC) were analysed to investigate the clinical impact of switching from IV to SC IFX.3 Patients in the CT-P13 IV arm of the pivotal trial received CT-P13 5 mg/kg IV every 8 weeks from Week (W) 6 until W22. At W30, patients switched to receive CT-P13 SC every 2 weeks up to W54 (dose 120 mg or 240 mg for patients <80 kg or ≥80 kg, respectively).3 This post hoc analysis compared per-patient pairwise data at W30 (pre-switch) and W54 (post-switch) from the CT-P13 IV arm for the following outcomes: trough serum concentration (Ctrough;5 μg/mL was considered to be the target exposure level), clinical response (for CD patients, ≥100-point decrease in Crohn's Disease Activity Index score;for UC patients, ≥2-point decrease in partial Mayo score with accompanying ≥1-point decrease in rectal bleeding subscore or an absolute rectal bleeding subscore of 0 or 1) and immunogenicity (anti-drug antibody [ADA] and neutralising antibody [NAb] positivity;as measured by a drug tolerant assay;ADA negative was regarded as NAb negative). For pairwise comparisons, patients with missing data at either W30 or W54 were excluded from the analysis. Statistical comparisons used Fisher's exact test. The differences are reported in a descriptive manner. Results: Overall, 65 patients (25 CD;40 UC) were included in the CT-P13 IV arm. The proportion of patients with a Ctrough level exceeding target exposure was significantly higher post-switch (36/41, 87.8%) than pre-switch (8/41, 19.5%;p<0.00001) (Table). Clinical response rates were comparable at both pre- and post-switch timepoints (40/49 [81.6%] vs 44/49 [89.8%], respectively;p=0.3873). Positive ADA and NAb rates at pre-switch and post-switch were also comparable, in which some changes were regarded from patients with marginal value (Table). Conclusion: Switching from IV to SC IFX did not detrimentally affect the clinical outcomes of patients with active CD or UC. Further, switching from IV to SC IFX might confer more favourable pharmacokinetic outcomes, although larger comparative studies are warranted. (Table Presented).