Introduction

Etrasimod is an investigational, oral, once-daily, selective sphingosine 1‑phosphate (S1P)_1,4,5 receptor modulator in development for the treatment of moderately to severely active ulcerative colitis (UC).

Aims & Methods

The study design for phase 3 ELEVATE UC 52 (NCT03945188) and ELEVATE UC 12 (NCT03996369) trials has been described previously.¹ ELEVATE UC 52 comprised a 12‑week (wk) induction period followed by a 40‑wk maintenance period with a treat-through design. ELEVATE UC 12 comprised a 12‑wk induction period. Patients (pts) had a documented history of inadequate response/loss of response/intolerance to ≥ 1 treatment for UC. This subgroup analysis evaluated the efficacy and safety of etrasimod 2 mg once daily vs placebo (PBO) in adults with UC by prior exposure to advanced (biologic/Janus kinase inhibitor [bio/JAKi]) therapy. We present subgroup efficacy analyses of the primary and select secondary endpoints at Wk 12 and Wk 52 in ELEVATE UC 52 and Wk 12 in ELEVATE UC 12 in pts naïve to, or with prior exposure to, ≥ 1 bio/JAKi therapy. Additional symptomatic endpoints were analysed by study visit to Wk 12 (pooled ELEVATE UC 52 and ELEVATE UC 12).

Results

In ELEVATE UC 52 and ELEVATE UC 12, respectively, 274 and 222 pts with a baseline modified Mayo score 5–9 were treated with etrasimod, and 135 and 112 pts with PBO. Pts treated with etrasimod vs PBO, in both bio/JAKi‑naïve and -exposed subgroups, achieved statistically significant improvements in clinical remission, clinical response and endoscopic improvement at Wks 12 and 52 in ELEVATE UC 52 (Table). In ELEVATE UC 12, bio/JAKi-naïve pts achieved statistically significant improvements in all endpoints, while pts in both subgroups achieved statistically significant improvements in clinical response (Table). In bio/JAKi‑naïve and -exposed pts, respectively, pooled data showed the earliest significant improvements were during Wks 2 and 12 for symptomatic response and Wks 4 and 2 for symptomatic remission (Table).

Conclusion

In ELEVATE UC 52, both bio/JAKi-naïve and -exposed pts treated with etrasimod showed statistically significant improvements in induction and maintenance efficacy endpoints vs PBO. In ELEVATE UC 12, etrasimod demonstrated statistically significant improvements vs PBO in induction in bio/JAKi-naïve pts. For symptomatic response in the pooled analysis, a significant treatment difference occurred later for bio/JAKi-exposed than -naïve pts.

References

1. Sandborn WJ et al. Lancet 2023; 401: 1159–1171

Disclosure

SV: research: AbbVie, MSD, Pfizer, Galapagos, Takeda; consultancy/advisory: AbbVie, AbolerIS, Alimentiv, Arena, AstraZeneca, Avaxia, BMS, Boehringer Ingelheim, Celgene, CVasThera, Dr. Falk, Eli Lilly, Ferring, Galapagos, Genentech/Roche, Gilead, Hospira, Imidomics, Janssen, J&J, MateriaPrima, MiroBio, Morphic, MrMHealth, MSD, Mundipharma, Pfizer, Prodigest, Progenity, Prometheus, Robarts Clinical Trials, Second Genome, Shire, Surrozen, Takeda, Theravance, Tillotts, Zealand; speaker: AbbVie, Dr. Falk, Ferring, Hospira, MSD, Takeda, Tillotts.
BES: research: Arena, Janssen. Speaker: BMS, Janssen, Lilly, Pfizer, Takeda. consultancy/advisory: AbbVie, Alimentiv, Amgen, Arena, AstraZeneca, Boehringer-Ingelheim, BMS, Celltrion, Fresenius Kabi, Genentech, GSK, Janssen, Lilly, Merck, Pfizer, Prometheus, Sun, Takeda, Teva. Stock: Ventyx. Non-financial: Janssen, Lilly, Pfizer, Takeda.
LPB: research: Takeda, Fresenius Kabi, Celltrion; consultancy: AbbVie, Alimentiv, Alma Bio, Amgen, AppliedMolecular Transport, Arena, Biogen, BMS, Celltrion, CONNECT Biopharm, Cytoki, Enthera, Ferring, Fresenius Kabi, Galapagos, Genentech, Gilead, Gossamer, GSK, HAC, IAG Image Analysis, Index, Inotrem, Janssen, Eli Lilly, Medac, Mopac, Morphic, MSD, Norgine, Novartis, OM, ONO, OSE, Pandion, Par'Immune, Pfizer, Prometheus, Protagonist, Roche, Sandoz, Takeda, Theravance, Thermo Fisher, TiGenix, Tillotts, Viatris, Vifor, Ysopia, Abivax; speaker: Galapagos, AbbVie, Janssen, Genentech, Ferring, Tillotts, Celltrion, Takeda, Pfizer, Sandoz, Biogen, MSD, Amgen, Vifor, Arena, Eli Lilly, Gilead, Viatris, Medac, Sanofi; stock: CTMA.
GD’H: advisor: AbbVie, AstraZeneca, Alimentiv, BMS, Boehringer Ingelheim, Celltrion, Cosmo, Eli Lilly, Galapagos, GSK, J&J, Takeda, Pfizer, Polpharma, Prometheus, Tillotts, Ventyx; speaker: AbbVie, Boehringer Ingelheim, Celltrion, J&J, Takeda, Pfizer, Tillotts.
JP: personal: AbbVie, Arena, Athos, Atomwise, Boehringer Ingelheim, Celgene, Celltrion, Ferring, Galapagos, Genentech/Roche, GSK, Immunic, Janssen, Mirum, Morphic, Nestlé, Origo, Pandion, Pfizer, Progenity, Revolo, Takeda, Theravance, Wassermann; grants: AbbVie, Pfizer.
AJY: consultancy: Pfizer, Arena, Takeda, BMS; speaker: BMS.
DW: research grants: AbbVie, Arena, BMS, Janssen, Pfizer, Takeda, Ventyx; speaker: AbbVie, BMS, Janssen, Pfizer, Takeda; consultant: AbbVie, Arena, BMS, Janssen, Pfizer, Takeda.
TR: speaker: Takeda, Janssen, Pfizer, BMS, AbbVie, Lilly; Data Adjudication: Ferring/Rebiotix; Advisory boards: AbbVie, Ardelyx, Arena, Boehringer Ingelheim, BMS/Celgene, Ferring, Genentech/Roche, Gilead, Intercept, Iterative Scopes (shareholder), Janssen, Lilly, Pfizer, Prometheus, Sanofi, Takeda, Nestle/Seres
SS: speaker: AbbVie, Arena, Biogen, BMS, Celgene, Celltrion, Dr. Falk, Fresenius, Janssen, MSD, Pfizer, Takeda; consultancy/advisory: AbbVie, Arena, Biogen, BMS, Celgene, Celltrion, Dr. Falk, Fresenius, Gilead, IMAB, Janssen, MSD, Mylan, Pfizer, Protagonist, Provention, Takeda, Theravance.
KS, CJR: employees & shareholders of Pfizer.
MVC: grants: Pfizer, Janssen, Novartis, BMS; consultancy: AbbVie, Arena, BMS, Medtronic, Pfizer, Prometheus, Eli Lilly, Janssen, Takeda; speaker: AbbVie, Janssen, Medtronic, Pfizer, BMS, Takeda.
FB: research: AbbVie, Amgen, Janssen, Takeda; speaker: AbbVie, Arena, Celltrion, Ferring, Galapagos, Janssen, MSD, Pfizer, Takeda; consultancy: AbbVie, Amgen, Arena, Celgene, Celltrion, Ferring, Fresenius Kabi, Janssen, MSD, Pfizer, Sandoz.
MCD: research: Janssen; consultancy: AbbVie, Arena, BMS, Celgene, Eli Lilly, Galapagos, Genentech, Gilead, Janssen, Pfizer, Prometheus, Takeda, Trellus Health, UCB; stock: Trellus; directorship/ownership interests: Trellus.
MG: employee & shareholder of Pfizer AG.
SD: consultancy/advisory: AbbVie, Allergan, Amgen, AstraZeneca, Biogen, Boehringer Ingelheim, Celgene, Celltrion, Ferring, Gilead, Hospira, Janssen, J&J, MSD, Mundipharma, Pfizer, Roche, Sandoz, Takeda, TiGenix, UCB, Vifor; speaker: AbbVie, Amgen, Ferring, Gilead, Janssen, Mylan, Pfizer, Takeda; directorship/ownership interests: Gastroenterology and Endoscopy.
BGF: consultant/advisory board: AbbVie, AbolerIS, AgomAB, AllianThera, Amgen, AnaptysBio, AppliedMolecular Transport, Arena, Avoro Capital, Atomwise, BIOJAMP, Biora, Boehringer Ingelheim, Boxer, Celsius, Celgene/BMS, Connect, Cytoki, Disc Medicine, Duality, EcoR1, Eli Lilly, Equillium, Ermium, First Wave, FirstWord, Galapagos, Galen Atlantica, Genentech/Roche, Gilead, Gossamer, GSK, Hinge, HotSpot, InDex, Imhotex, Immunic, JAK, Janssen, Japan Tobacco, Kaleido, Landos, Leadiant, L.E.K., Lenczner Slaght, LifeSci, Lument AB, Millennium, MiroBio, Morgan Lewis, Morphic, Mylan, OM, Origo, Orphagen, Pandion, Pendopharm, Pfizer, Prometheus, Diagnostics, Play to Know AG, Progenity, Protagonist, PTM, Q32, Rebiotix, REDX, Roche, Sandoz, Sanofi, Seres, Silverback, Surrozen, Takeda, Teva, Thelium, TiGenix, Tillotts, Ventyx, VHSquared, Viatris, Ysios, YSOPIA, Zealand; speaker: AbbVie, Janssen, Takeda; Alimentiv Senior Scientific Director (central reading services; not a company employee, no equity); shareholder: Gossamer

Introduction

The risk of postoperative recurrence (POR) within 1 year after ileocecal resection (ICR) for Crohn’s disease (CD) remains high. Currently, there is no consensus on how to optimally reduce the risk of endoscopic (e)POR, clinical (c)POR or surgical (s)POR.

Aims & Methods

The PORCSE study aims to evaluate the impact of two strategies: early medical prophylaxis (proactive strategy) versus treatment driven by findings at elective endoscopy 6-12 months after ICR (reactive strategy).
A retrospective, observational, multicentric, superiority study was performed including CD patients undergoing first ICR between 2008-2019. Patients were assigned to cohort 1 if prophylactic biological or immunomodulator therapy was administered early after ICR, or to cohort 2 if no postoperative prophylaxis was started and medical treatment was driven by endoscopic findings 6-12 months after ICR. The primary endpoint was the rate of ePOR evaluated at ileocolonoscopy 6-12 months post ICR and was defined as Rutgeerts score >i1. Secondary endpoints were colonic disease activity at first endoscopy, severe ePOR (Rutgeerts i3-i4), cPOR (symptoms leading to restart of therapy), sPOR (repeated surgery or endoscopic balloon dilatation) and differences between participating centres.
Statistical analyses were performed with SPSS v28. Propensity score matching was used for regression analyses.

Results

In total 346 patients were included from 26 centres in 9 European countries. Of these, 47.4% received prophylactic postoperative treatment before postoperative endoscopy (cohort 1) and 52.6% did not (cohort 2). Strategy selection differed significantly between countries (P=0.024). The proactive strategy was preferred in Spain and Portugal whereas the reactive strategy in Belgium, France and Ireland. Although not statistically significant (P=0.143), the same trend was noticed in postoperative metronidazole use.
Patients in cohort 1 had more refractory disease with more upper GI disease, more bio-experienced patients, more penetrating disease phenotype and longer disease duration prior to surgery. Furthermore, metronidazole was more frequently started postoperatively in the proactive cohort (31.7%vs14.3%, P<0.001).
Bivariate logistic regression analyses showed significantly higher odds for ePOR in the reactive treatment group (OR 1.809, 95%CI 1.03-3.18, P=0.039). Furthermore, univariate analyses showed higher rates of colonic disease activity in the reactive group at elective endoscopy 6-12 months after surgery. No significant difference in severe ePOR was found at first endoscopy (OR 1.285, 95%CI 0.60-2.74, P=0.517). After first endoscopy until end of follow-up, patients in the reactive group had significantly higher odds of clinical POR (OR 3.047, 95%CI 1.53-6.08, P=0.002). Surgical recurrence rates were numerically higher in the reactive group (OR 2.586, 95%CI 0.995-6.72, P=0.051) and Cox proportional hazards regression analysis showed a trend towards protective effect of the proactive approach (HR 2.497, 95%CI 0.97-6,40, P=0.057).

Table 1: Demographics and POR

Conclusion

The retrospective PORCSE study provides evidence to support a proactive approach over a reactive approach in terms of prevention of not only endoscopic but also clinical and surgical postoperative recurrence after first ileocecal resection for Crohn’s disease.

Disclosure

Authors have nothing to disclose related to this project

Introduction

Tumor necrosis factor–like cytokine 1A (TL1A) is a mediator of inflammation and fibrosis in CD. Tulisokibart, an anti-TL1A monoclonal antibody, demonstrated robust efficacy without adverse safety signals during the 12-week induction period in adults with moderately to severely active CD in the multicenter, open-label, phase 2a APOLLO-CD study.¹ We report long-term efficacy and safety data for tulisokibart from the APOLLO-CD open-label extension (OLE).

Aims & Methods

Responders to tulisokibart induction at 12-weeks (defined as a decrease from baseline in CD activity index [CDAI] of ≥100 points or CDAI <150 at week 12) were given the opportunity to enter the OLE study, whereas 12-week non-responders discontinued the study. At week 14, responders were randomized to receive intravenous tulisokibart 100 mg or 250 mg every 4 weeks until week 170. Reported here are the endoscopic, clinical, and biomarker endpoints through week 50 in the intention-to-treat population. Safety was evaluated in all patients who received ≥1 dose of tulisokibart. Descriptive statistics were used to summarize observed data.

Results

53 of 55 patients completed the 12-week induction period, 37 were considered induction responders and were randomized to receive tulisokibart 100 mg (n=19) or 250 mg (n=18). A greater proportion of patients who were biologic-naive entered the OLE in the tulisokibart 250 mg vs 100 mg group (44% vs 21%). Improvements in clinical, endoscopic, and biomarker outcomes observed were generally maintained through week 50 in both dose groups. At week 50, a greater proportion of patients achieved clinical and endoscopic outcomes with tulisokibart 250 mg vs 100 mg (Table). In addition, normalization of high-sensitivity C-reactive protein (hsCRP) favored the 250 mg dose vs the 100 mg dose. During the 12-week induction period, 78% of patients reported AEs. At week 50, AEs were reported in 83% and 84% of patients receiving tulisokibart 250 mg and 100 mg, respectively, and were mostly mild-to-moderate in severity. Serious AEs occurred in 6% of patients receiving tulisokibart 250 mg and 11% of patients receiving tulisokibart 100 mg. The most frequently occurring AEs of special interest (>10% of patients in either dose group) were urinary tract infection (11% vs 16%), COVID-19 (11% vs 11%), upper respiratory tract infection (6% vs 16%), bronchitis (11% vs 0%), clostridium difficile infection (11% vs 0%), and influenza (0% vs 11%).

Conclusion

At week 50, maintenance of treatment efficacy was generally observed in 12-week induction responders. A trend for higher maintenance efficacy with tulisokibart 250 mg vs 100 mg maintenance treatment was observed at week 50. Tulisokibart was well tolerated with no safety signals identified through 50 weeks of treatment. Larger trials are needed to confirm these findings.

References

1. Feagan BG, et al. J Crohns Colitis. 2023;17(Supplement_1):i162-i164.

Disclosure

CAS is a consultant/advisory board for AbbVie, BMS, Boomerang, Buhlmann, Janssen, Lilly, Napo Pharmaceuticals, Pfizer, Prometheus Biosciences, Prometheus Labs, Roivant, Takeda, Trellus Health; speaker for CME activities for AbbVie, Janssen, Pfizer, Takeda; grant support from AbbVie, Janssen, Pfizer, Takeda.
RWL reports advisory board membership for AbbVie, Aspen, BMS, Celgene, Celltrion, Chiesi, Ferring, Glutagen, Hospira, Janssen, Lilly, MSD, Novartis, Pfizer, Prometheus Biosciences, Takeda; research grant recipient: Celltrion, Shire, Janssen, Takeda, Gastroenterological Society of Australia, NHMRC, Gutsy Group, Pfizer, Joanna Tiddy grant, McKusker Charitable Foundation.
JKA, BD, and MY are employees of Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA.
BES reports consulting fees from AbbVie, Adiso Therapeutics, Agomab, Alimentiv, Amgen, AnaptysBio, Arena Pharmaceuticals, Artugen Therapeutics, Astra Zeneca, Biolojic Design, Biora Therapeutics, Boehringer Ingelheim, Boston Pharmaceuticals, Calibr, Celgene, Celltrion, ClostraBio, Equillium, Enthera, Envied Biosciences, Evommune, Ferring, Fresenius Kabi, Fiat, Galapagos, Genentech (Roche), Gilead Sciences, GlaxoSmithKline, Gossamer Bio, Imhotex, Index Pharmaceuticals, Innovation Pharmaceuticals, Inotrem, Kaleido, Kallyope, Merck & Co., Inc., Rahway, NJ, USA, Microba, Mobius Care, Morphic Therapeutics, MRM Health, Nexus Therapeutics, Nimbus Discovery, Odyssey Therapeutics, Progenity, Prometheus Biosciences, Prometheus Laboratories, Protagonist Therapeutics, Q32 Bio, Rasayana Therapeutics, Recludix Therapeutics, Reistone Biopharma, Sanofi, Spyre Therapeutics, Sun Pharma, Surrozen, Target RWE,Teva, TLL Pharmaceutical, Tr1X, Union Therapeutics, Ventyx Biosciences; consulting and speaking fees from Abivax; consulting and speaking fees and other support from Lilly; research grants, consulting and speaking fees and other support from Bristol Myers Squibb, Janssen, Pfizer, Takeda; research grants and consulting fees from Theravance Biopharma; and stock/stock options from Ventyx Biopharma.
SD has received consultancy fees from AbbVie, Alimentiv, Allergan, Amgen, Applied Molecular Transport, AstraZeneca, Athos Therapeutics, Biogen, Boehringer Ingelheim, Bristol Myers Squibb, Celgene, Celltrion Healthcare, Dr. Falk Pharma, Eli Lilly and Company, Enthera, Ferring, Gilead, Hospira, Inotrem, Janssen, Johnson & Johnson, Morphic, MSD, Mundipharma, Mylan, Pfizer, Roche, Sandoz, Sublimity Therapeutics, Takeda, Teladoc Health, TiGenix, UCB Inc., Vial, and Vifor and lecture fees from AbbVie, Amgen, Ferring, Gilead, Janssen, Mylan, Pfizer, and Takeda.
BGF is a consultant for AbbVie, AbolerIS, AgomAB Therapeutics, Allianthera, Amgen, AnaptysBio, Applied Molecular Transport Inc., Arena Pharma, Atomwise, Avoro Capital Advisors, BioJamp, Biora Therapeutics, Boehringer Ingelheim, Boxer, Bristol Myers Squibb/Celgene, Celsius Therapeutics, Connect BioPharma, Cytoki, Disc Medicine, Duality, EcoR1 Capital, Equillium, Ermium, First Wave, First Word Group, Galapagos, Galen Atlantica, Genentech/Roche, Gilead, GlaxoSmithKline, Gossamer Pharma, Hinge Bio, Hot Spot Therapeutics, Imhotex, Immunic Therapeutics, InDex Pharmaceuticals, JAKAcademy, Janssen, Japan Tobacco Inc., Kaleido Biosciences, Landos Biopharma, Leadiant, L.E.K. Consulting, Lenczner Slaght, LifeSci Capital, Lilly, Lument AB, Millennium, MiroBio, Morgan Lewis, Morphic Therapeutics, Mylan, OM Pharma, Origo BioPharma, Orphagen, Pandion Therapeutics, Pendopharm, Pfizer, Play to Know AG, Prometheus Therapeutics and Diagnostics, Progenity, Protagonist, PTM Therapeutics, Q32 Bio, Rebiotix, REDX, Roche, Sandoz, Sanofi, Seres Therapeutics, Silverback Therapeutics, Surrozen Inc., Takeda, Teva, Thelium, Tigenix, Tillotts, Ventyx Biosciences, VHSquared Ltd., Viatris, Ysios, Ysopia, and Zealand Pharma; on the Speakers’ Bureau for AbbVie, Janssen, and Takeda; and on advisory boards for AbbVie, Amgen, AMT, AnaptysBio, Axio Research, Boehringer Ingelheim, Bristol Myers Squibb/Celgene, EcoR1 Capital, Genentech/Roche, GlaxoSmithKline, InDex Pharmaceuticals, Janssen, Lilly, MiroBio, Morphic, Origo BioPharma, Pfizer, Progenity, Prometheus, REDX Pharma, Sanofi, Takeda, Teva, and Tillotts Pharma.

Introduction

Complex perianal fistulas represent one of the most challenging manifestations of Crohn’s disease. Combined surgical and medical therapy with biologic drugs represents today the first-line treatment option, but its efficacy does not exceed 60% in terms of healing. Recently, new therapeutic approaches, such as autologous microfragmented adipose tissue (M-Fat) injection, have shown promising results. Indeed, a recent non-profit prospective pilot study on 15 patients has demonstrated that the local injection of M-Fat is a safe and promising “rescue therapy” for patients with multiresistant complex fistulizing Crohn’s disease (PCD), with a 66.7% rate of combined remission in such difficult patients. It has to be highlighted that the M-Fat injection is minimally invasive, with less risk of sphincteric damage and can be carried out in day-surgery setting.

Aims & Methods

The primary aim of this multicentre double-blind randomized controlled trial (ATTIC) is to evaluate the efficacy of the infiltration of M-Fat in the healing of perianal complex fistulas not-responding to treatment with biologics. Consecutive patients referring to the 6 investigation Centers for surgical treatment of persistent complex fistulizing PCD refractory to biosurgical approach were assessed for eligibility. After baseline pelvic magnetic resonance imaging, those included were submitted to surgical drainage with “cone-like” fistulectomy, and then randomized to receive a 15 to 20 cc local injection, at the internal orifice level and along fistula tracts, of M-Fat obtained by a lipoaspiration and processed with an enzyme-free technology (treatment group), or a suture placement and injection of 15 cc of saline solution at the internal orifice (control group). Clinical follow-up were conducted at 2, 4, 8, 12, and 24 weeks; at 24 weeks after surgery, pelvic magnetic resonance was obtained. Success was defined as “combined remission”, combination of clinical (absence of drainage upon gentle finger compression) and radiological healing (absence of residual collections > 3 mm). Clinical remission was defined as clinical healing of all external openings not confirmed at radiological assessment.

Results

An overall 92 patients were screened, and 66 (33 per group) completed the 24-week follow-up. A statistically significant difference in favour of the treatment group in terms of combined remission emerged at the primary endpoint at 24-week follow-up (control group, 18.18%; treatment group: 57.58%; p = 0.0020). No significant differences in clinical outcome measures were encountered at any of the other follow-up points. No significant differences emerged between the groups in terms of recurrence rate, complication rate, and number of adverse events. Clinical remission was 63.64% in the treatment group compared to 51.52% in the control group with no statistically significant difference (p > 0.05).

Conclusion

This multicentre double-blind randomized controlled trial demonstrates that the intraoperative injection of M-Fat, associated with surgical complete drainage of perianal sepsis, is safe, effective, and reproducible in healing complex multirefractory perianal Crohn's disease, while improving the quality of life and significantly reducing the risk of definitive oostomy.