Introduction

Filgotinib (FIL) is a once-daily, oral, Janus kinase 1 preferential inhibitor approved for the treatment of ulcerative colitis (UC). FIL 200 mg (FIL200) was effective in inducing and maintaining clinical remission vs placebo (PBO) and well tolerated in patients with UC in the phase 2b/3 SELECTION trial (NCT02914522).¹

Aims & Methods

We assessed the efficacy and safety of continued FIL200 therapy in the ongoing SELECTION long-term extension (LTE) study (NCT02914535). In SELECTION, adults with moderately to severely active UC received induction (IND) FIL200, FIL 100 mg (FIL100) or PBO once daily for 11 weeks. Patients in clinical remission or with a Mayo Clinic Score (MCS) response at week 10 (responders) entered the 47-week Maintenance (MNT) Study. Patients who completed IND and MNT (completers), patients who were not responders at IND week 10 (non-responders), and patients with disease worsening during MNT were eligible to enter SELECTIONLTE and receive open-label FIL200. This interim analysis assessed the efficacy and safety of open-label FIL200 through LTE week 144 in completers and LTE week 192 in non-responders, respectively. Data are shown for up to a maximum of 3.9 years of treatment each (completers: 58 + 144 weeks; non-responders 10 + 192 weeks) as of the data cut-off (24 February 2022). Partial MCS (pMCS) was reported as observed without imputation and proportions of patients achieving pMCS remission (pMCS ≤1) and IBDQ remission (score ≥170) were reported as observed and using non-responder imputation (NRI). Adverse events (AEs) and AEs of interest were evaluated using exposure-adjusted incidence rates per 100 patient-years of exposure (PYE).

Results

This analysis included 148 completers and 372 non-responders (IND FIL100, n=212; IND FIL200, n=160). Proportions of patients achieving pMCS or IBDQ remission over time (as observed and NRI) are shown in the Table. Among completers, reductions in mean pMCS in SELECTION over weeks 0–10 were maintained up to LTE week 144. In non-responders, mean pMCS decreased from LTE baseline to LTE week 192. In completers, pMCS remission was achieved by 80.0% of patients at LTE week 144, as observed. In non-responders, pMCS remission was achieved by 59.2% of patients at LTE week 192, as observed. More than 70% of completers and non-responders achieved IBDQ remission (as observed) at LTE week 144/192 and proportions were maintained over time. Safety events among all patients treated with open-label FIL200 in the LTE study (total PYE=2055.5) revealed no new safety signals.

Table. Proportions of patients achieving pMCS or IBDQ remission in SELECTION and SELECTIONLTE (observed case and NRI)

Conclusion

FIL200 was effective in maintaining symptomatic remission and improvements in health-related quality of life for up to ~4 years. No new safety signals were observed over ~4 years of treatment, and incidence rates of safety events were similar to those seen in previous analyses.² Our data show that prolonged FIL treatment has a consistent and established safety profile and is efficacious for the long-term management of UC.

References

1. Feagan BG et al. Lancet 2021;397:2372–84.
2. Feagan BG et al. J Crohns Colitis 2022;16(Suppl1):i456–7.

Disclosure

BF reports grants and personal fees from AbbVie, Amgen, AstraZeneca, Bristol Myers Squibb, Janssen Biotech/Centocor, Johnson & Johnson/Janssen, Pfizer, Receptos and Takeda; personal fees from Ablynx, ActoGeniX, Akebia Therapeutics Inc., Allergan, Atlantic Pharma, Avaxia Biologics Inc., Avir Pharma, Baxter Healthcare Corporation, Biogen Idec, BiomX Israel, Boehringer Ingelheim, Boston Pharmaceuticals, Calypso Biotech, Celgene, Elan/Biogen, Eli Lilly, enGene, Exeliom Biosciences, Ferring Pharmaceuticals, Galapagos, Genentech/Roche, Gilead, Given Imaging, gIcare Pharma, GlaxoSmithKline, Gossamer Bio, Inception IBD Inc., Ironwood, Japan Tobacco Company, Kyowa Hakko Kirin Co., Ltd, Lexicon, Lycera Biotech, Merck, Mesoblast Pharma, Millennium, Nestlé, Novartis, Novo Nordisk, Par’Immune, Progenity, Prometheus Therapeutics and Diagnostics, Protagonist, Q32 Bio, Qu Biologics, Salix, Shire, Sienna Biologics, Sigmoid Pharma, Synergy Pharma, Teva Pharmaceuticals, TiGenix, Tillotts, UCB, Vertex, VHsquared, Vivelix Pharmaceuticals, Wyeth, Zealand and Zyngenia; and is the Senior Scientific Director of Alimentiv Inc. and a Professor of Medicine at Western University.
KM reports personal fees from AbbVie, Bristol Myers Squibb, Celltrion, EA pharma, Eli Lilly, Gilead, Janssen Pharmaceuticals, JIMRO, Kissei Pharmaceutical, Kyorin Pharmaceutical, Mitsubishi Tanabe Pharma, Mochida Pharmaceutical, Pfizer, Takeda and Zeria Pharmaceutical; and research grants from AbbVie, EA Pharma, JIMRO, Kissei Pharmaceutical, Kyorin Pharmaceutical, Mitsubishi Tanabe Pharma, Mochida Pharmaceutical, Nippon Kayaku and Takeda.
GR reports personal fees from AbbVie, AstraZeneca, Augurix, Bristol Myers Squibb, Boehringer Ingelheim, Calypso, Celgene, Dr. Falk Pharma, Ferring Pharmaceuticals, Fisher, Genentech, Gilead, Janssen Pharmaceuticals, MSD, Novartis, Pfizer, Phadia, Pierre Fabre, Roche, Takeda, Tillotts, UCB, Vifor, Vital Solutions and Zeller; and grants from AbbVie, Ardeypharm, Augurix, Calypso, Dr. Falk Pharma, Flamentera, MSD, Novartis, Pfizer, Roche, Takeda, Tillotts, UCB and Zeller.
LP-B reports personal fees from AbbVie, Allergan, Amgen, Arena Pharmaceuticals, Biogen, Bristol Myers Squibb, Celgene, Celltrion, Eli Lilly, Enthera, Ferring Pharmaceuticals, Fresenius Kabi, Galapagos, Genentech, Gilead, Gossamer Bio, InDex Pharmaceuticals, Inotrem, Janssen Pharmaceuticals, MSD, Mylan, Norgine, OSE Immunotherapeutics, Pandion Therapeutics, Pfizer, Roche, Samsung Bioepis, Sandoz, Takeda, Theravance Biopharma, Thermo Fisher Scientific, Tillotts, Viatris and Vifor; grants from AbbVie, Fresenius Kabi, MSD and Takeda; and stock options from CTMA.
MF, AO, AdH and CR and are employees and shareholders of Galapagos NV.
The SELECTION trial was sponsored by Gilead Sciences Inc (Foster City, CA, USA). The SELECTIONLTE trial was sponsored by Galapagos NV (Mechelen, Belgium), who funded these analyses.
Medical writing support for the development of this abstract was provided by Risha Bulusu, MBiochem, of PharmaGenesis London, London, UK, and was funded by Galapagos NV.

Introduction

Endoscopic ultrasound-guided portal pressure gradient (PPG) measurement (EUS-PPG) is a novel technique demonstrated to be safe and feasible. We aimed (i) to evaluate the utility of preoperative EUS-PPG assessment in patients with cirrhosis or suspected cirrhosis undergoing abdominal surgery, and (ii)to validate the technique against transjugular hepatic venous pressure gradient (HVPG) measurement.

Aims & Methods

This is a single-centre prospective study performed between May 2021 and August 2022. Patients with known chronic liver disease or clinical concern for liver disease planned for abdominal surgery were recruited. All patients underwent both EUS-PPG and transjugular HVPG measurement prior to surgery. EUS-PPG was performed using a linear echoendoscope and a 25G needle attached to a compact manometer. Surrogate markers assessing the severity of liver disease were also performed, including liver elastography, APRI and FIB-4 scores. Assessment of post-operative liver dysfunction and 90-day mortality undertaken were the primary endpoints.

Results

Nine patients (mean age 62; M: 4) with known Child A cirrhosis secondary to non-alcoholic fatty liver disease (NAFLD) (n=6) and deranged liver function test with suspected NAFLD (n=2) and suspected portal hypertension (unknown cause) (n=1) underwent EUS-PPG measurement. These patients were planned to undergo HCC liver resection (n=2), gastrectomy for cancer (n=2), hemicolectomy for cancer (n=2), gastric bypass (n=1), inguinal hernia repair (n=1) and duodenal lesion resection (n=1). EUS-PPG measurement was successful in 8 patients (88.9%) with an unsuccessful case secondary to inability to cannulate a very small hepatic vein (4mm) in a morbidly obesity patient (BMI>60kg/m2). The median pressure gradient was similar between the EUS-PPG measurements (median= 6.65mmHg; IQR: 1.2-15.3) and transjugular measurements (median= 6.5mmHg; IQR: 4.3-12), with a high correlation coefficient between the 2 techniques (R= 0.897; P=0.003). There were no complications from EUS-PPG or transjugular HVPG. EUS-PPG >5mmHg was significantly associated with liver elastography median scores (R=0.815, P=0.014) and FIB-4>3.25 (R= 0.7, P=0.048). Three patients had clinically significant portal hypertension based on EUS-PPG measurement. As a result, one patient was deemed not suitable for surgery. Two patients underwent pre-operative transjugular intrahepatic portosystemic shunt (TIPS) of which one patient underwent surgery, however another had decompensation within a month (hepatic encephalopathy) post TIPS and therefore surgery was cancelled. Despite TIPS, the patient who underwent surgery had mild liver decompensation post-operatively. The remaining five patients all had PPG<10mmHg and four have undergone surgery without any complications. There was no 90-day mortality. Seven patients preferred EUS-PPG over transjugular technique.

Conclusion

PPG measurement by EUS approach is highly feasible, safe and correlates very closely with the gold-standard transjugular approach. EUS-guided PPG is uniformly preferable to transjugular approach. PPG measurement was able to guide decision making and a low PPG predicts a lack of post-operative complication. Findings of clinically significant portal hypertension on PPG measurement allowed for change in management prior to surgery suggesting the utility of EUS-guided PPG measurement in patients with suspected liver disease who require abdominal surgery.

Introduction

Fecal microbiota transplantation (FMT) is the most effective therapy in the treatment of recurrent Clostridioides difficile infection (rCDI), and can be offered in fresh, frozen or lyophilized formulation with similar efficacy. Microbial engraftment is thought to be one of the mechanisms mediating its efficacy. However, the importance of microbes has been questioned by two small preliminary clinical studies that showed sterile fecal filtrate could prevent C. difficile recurrence.

Aims & Methods

Aims: 1) determine if lyophilized sterile fecal filtrate (LSFF) is non-inferior to lyophilized FMT (LFMT) in efficacy; 2) evaluate changes in patient reported health related quality of life (HRQOL); 3) understand patient preferences for different attributes of FMT.
Methods: This double-blind, non-inferiority (margin= 10%) study in 4 academic centers in Canada randomized rCDI patients with > 3 CDI episodes to either LSFF or LFMT (1:1) between 2019 and 2023. Each treatment consisted of 15 oral capsules. Primary outcome was proportion of participants without CDI recurrence at 8 week. Secondary outcomes included 1) proportion of participants without CDI recurrence at week 24 weeks, 2) serious adverse events (mortality, hospitalization and infections related to treatments), and 3) minor adverse events (nausea, vomiting, abdominal pain and fever). Exploratory outcomes included changes in HRQOL and relative importance of different attributes of FMT.

Results

137 participants were randomized (mean [SD] age, 61.2 [18.6] years; 89 women [65.4%]; mean CDI episodes 3.8) to LFMT group (66 participants) and LSFF (71 participants) group. In per-protocol analysis, prevention of rCDI 8 weeks after assigned treatment was achieved in 63.8% of participants in LSFF group and 86.9% in LFMT group (difference, -23.1%), resulting in trial termination. Serious adverse events were infrequent: 4 hospitalizations deemed not related and 1 hospitalization possibly related, and 1 death from COVID deemed not related to assigned treatment. Minor adverse events were self-limited and infrequent: nausea (6), vomiting (2), abdominal discomfort (15) and fever (2). Following treatment, participants had significant increases in EQ-5D-5L (n=99) VAS (median change: 10; p <0.001) and index value (median change: 0.04; p<0.001), and Cdiff32 (n=94) physical domain (median change: 16.07; p <0.001), mental domain (median change: 29.46; p<0.001), and social relationships domain (median change: 7.37; p<0.001). Work impairment decreased (n=21; median change: -10%; p<0.001) and activity impairment decreased (n=101; median change: -20%; p<0.001). Participants (n=103) indicated the 3 most important attributes of FMT were: treatment effectiveness, unknown risks of treatment and known risks of treatment.
Table 1. Participant baseline characteristics

Conclusion

Among adults with rCDI, LSFF was inferior to LFMT by oral capsules in preventing recurrent infection over 8 weeks. The result emphasizes the importance of microbes in mediating FMT efficacy. Preserving microbial viability in future development of microbial therapeutics is paramount.

Disclosure

none

Introduction

Mirikizumab (miri), an anti-IL-23p19 antibody, has shown efficacy in patients with moderately-to-severely active Crohn’s disease (CD) to Week (W)52. We explored the potential relationship between early histologic and endoscopic responses on long term clinical outcomes after 2 years of miri treatment in a double-blind, placebo (PBO)-controlled Phase 2 trial (NCT02891226) in patients with CD.

Aims & Methods

Patients were randomized 2:1:1:2 to 4 treatment arms: miri 1000mg, 600mg, 200mg, and PBO administered intravenously (IV) at W0, W4, and W8. Patients who received miri and achieved ≥1 point improvement at W12 in Simple Endoscopic Score for Crohn’s disease score were re-randomized to either continue their induction IV dose or receive miri 300mg subcutaneously (SC) every 4 weeks up to W52. Subjects reported to experience clinical benefit received 300mg SC from W52 to W104. Biopsies were obtained during endoscopy at W0, W12 and W52 from the edges of any ulcers or from the most inflamed mucosa in the terminal ileum and 4 colonic segments and were scored by blinded central readers. Endpoints were defined post-hoc and prior to analyses (see Table 1). Among patients receiving miri with active histological disease at baseline, we determined the relationship between histologic and/or endoscopic response or remission at W12 and W52 and with clinical remission based on the Crohn’s Disease Activity Index (CDAI), patient-reported outcomes (PRO), and hospitalization rates at W104. Non-responder imputation for CDAI or PRO at W104 was used for patients who have observed histologic and endoscopic outcome value at W52 or W12. Hospitalizations were summarized by observed value. P-values for categorical values were determined with Fisher’s exact test.

Results

At W104, 56.9% patients (N=137) achieved CDAI remission compared to 41.5% of 176 patients at W52. We observed no association between early (W12) histologic, endoscopic, or combined (histo-endo) response and clinical remission (CDAI & PRO) at 2 years. After 2 years, the percentage of patients achieving remission based on CDAI varied according to their response at W52 by histology (60%), endoscopy (25.9%), both histo-endo (56.3%), or neither (10.5%, p=0.006; Table 1). Similarly, the proportion of patients who achieved 2-year clinical remission (by CDAI) varied according to W52 remission by histology (72.7%), endoscopy (40%), both histo-endo (40%) or neither (19.5%, p=0.007). Hospitalization rates during this period were low and varied according to W52 response by histology (16.7%), endoscopy (0%), both (0%) or neither (3.9%, p=0.021).

Table 1. Week 104 clinical remission and hospitalization rates by histologic and endoscopic response at Week 12 and Week 52, and by histologic and endoscopic remission at Week 52

Conclusion

In CD patients treated with miri for 2 years, long term clinical remission (CDAI, PRO) was significantly correlated with histologic response alone as well as combined histologic-endoscopic response at Week 52, but not at Week 12. The small sample size was likely a limitation. This data will be further studied in Phase 3 trials.

Disclosure

VJ reports consulting/advisory board fees from AbbVie, Alimentiv Inc (formerly Robarts Clinical Trials), Arena pharmaceuticals, Asahi Kasei Pharma, Asieris, Bristol Myers Squibb, Celltrion, Eli Lilly, Ferring, Flagship Pioneering, Fresenius Kabi, Galapagos, GlaxoSmithKline, Genentech, Gilead, Janssen, Merck, Mylan, Pandion, Pendopharm, Pfizer, Protagonist, Reistone Biopharma, Roche, Sandoz, Second Genome, Takeda, Teva, Topivert, Vividion; speaker’s fees from, Abbvie, Ferring, Galapagos, Janssen, Pfizer, Shire, Takeda, Fresenius Kabi. 
WR reports lecture fees from AbbVie, Actelion, Alpha Wasserman, AstraZeneca, Cellerix, Cosmo Pharmaceuticals, Ferring, Genentech, Grunenthal, Johnson & Johnson, Millennium, Merck, NovoNordisk, Nycomed, Pfizer, Pharmacosmos, Schering-Plough, Salix, Takeda, UCB Pharma, and Vifor; consultant fees from AbbVie, Actelion, Alpha Wasserman, AstraZeneca, Cellerix, Cosmo Pharmaceuticals, Ferring, Genentech, Grunenthal, Johnson & Johnson, Millennium, Merck, NovoNordisk, Nycomed, Pfizer, Pharmacosmos, Schering-Plough, Salix, Takeda, UCB Pharma, and Vifor; and serves as an advisory board member for AbbVie, Actelion, Alpha Wasserman, AstraZeneca, Cellerix, Cosmo Pharmaceuticals, Ferring, Genentech, Grunenthal, Johnson & Johnson, Millennium, Merck, NovoNordisk, Nycomed, Pfizer, Pharmacosmos, Schering-Plough, Salix, Takeda, UCB Pharma, and Vifor.
GDH reports that his institution has received fees for his clinical trial activities with Centocor J&J.
NH has served as an advisory board member or consultant for Eli Lilly and Company, Abbvie Inc., Bristol Meyer Squibb, Inc., and PathAI, Inc.
RP reports consulting fees from Seres Therapeutics, Eli Lilly, Protagonist, Genentech, and Robarts Clinical Trials.
MP, ZL, RH, HC are employees and minor shareholders of Eli Lilly and company. 
FM served as speaker for Abbvie, Arena, Biogen, Bristol-Myers Squibb, Falk, Ferring, Hospira, Janssen, Laboratórios Vitoria, Pfizer, Lilly, Merck Sharp & Dohme, Sandoz, Takeda, UCB, Vifor.