Introduction

Risankizumab (RZB) is a highly specific humanized monoclonal antibody that targets the p19 subunit of interleukin-23 and was designed to have low immunogenicity and high bioavailability, allowing for less-frequent dosing, although the clinical implications of these modifications have not been studied. The FORTIFY maintenance open label extension (OLE) is an ongoing phase 3 substudy evaluating the long-term efficacy and safety of RZB in pts with moderate to severe Crohn’s disease (CD). Here, we report interim efficacy and safety results from the FORTIFY OLE following up to 4 years (yrs) of RZB treatment.

Aims & Methods

The FORTIFY (NCT03105102) OLE enrolled pts who completed 52 weeks (wks) of RZB maintenance.^1,2 Pts received subcutaneous (SC) RZB 180mg every 8wks (Q8w) starting at wk56, except for pts who received rescue therapy prior to or during the OLE; these pts received SC RZB 360mg Q8w (see Table footnote for rescue therapy details). Pooled data (180mg+360mg) were analyzed through wk144 of the OLE (wk200 of cumulative RZB treatment) using as observed (AO) and modified nonresponder imputation (mNRI, pts were considered nonresponders for visits after premature discontinuation of RZB due to the primary reason of lack of efficacy or adverse event limited to Crohn’s disease only, as well as initiation of rescue, while other missing data were handled by multiple imputation [MI]) methods (‘All Patients [No Rescue or Prior to Rescue]’ group in Table). For pts who received rescue therapy, only their data obtained prior to receiving rescue were included in the aforementioned AO and mNRI analyses (‘All Patients [No Rescue]’ group in Table). Data from pts on the day of or after rescue were analyzed separately and reported AO starting at the initiation of rescue (defined as the last nonmissing value prior to or on initiation of rescue) and every 24 wks post-rescue (‘Rescue’ group in Table). Safety was evaluated in all pts receiving any RZB treatment in the OLE. Treatment-emergent adverse events (TEAEs) reported on/after the first dose in the OLE were summarized (cutoff date: 30DEC2024).

Results

A total of 1112 pts (excluding 36 pts who received RZB rescue at entry to OLE) received ≥1 dose of RZB 180mg or 360mg in the OLE. Efficacy rates (per mNRI analysis) were stable from OLE wk0 to wk144 for clinical remission per stool frequency/abdominal pain score (SF/APS, 64.5% to 75.8%) and per CD Activity Index (CDAI, 68.6% to 82.8%), endoscopic response (55.1% to 73.8%), and endoscopic remission (39.0% to 58.8%) (Table). Pts who received rescue therapy in the OLE demonstrated clinical and endoscopic improvements over time. The profiles of TEAEs and AEs of special interest were consistent with the known safety profile of RZB.^3,4
​

Conclusion

Durable clinical and endoscopic efficacy was observed in pts with moderate to severe CD who completed up to 4 yrs of RZB maintenance therapy in the FORTIFY OLE. Pts who received rescue therapy in the OLE also showed clinical and endoscopic improvements by wk144. No new safety risks for RZB were identified, supporting its long-term use in treating CD.

References

1. Ferrante M, et al. J Crohns Colitis. 2021;15(12):2001-2010.
2. Ferrante M, et al. Lancet. 2022; 399(10340):2031–46.
3. Papp KA, et al. J. Am. Acad. Dermatol. 2023; 89(6):1149–58.
4. Ferrante M, et al. J Crohns Colitis. 2024;18(Supplement_1):i168–70.

Disclosure

Marc Ferrante
Research grants from AbbVie, EG Pharma, Janssen, Pfizer, Takeda and Viatris. Consultancy fees from AbbVie, AgomAb Therapeutics, Boehringer Ingelheim, Celgene, Celltrion, Eli Lilly, Janssen-Cilag, MRM Health, Merck Sharp and Dohme, Pfizer, Takeda and ThermoFisher. Speakers’ fees from AbbVie, Biogen, Boehringer Ingelheim, Dr Falk Pharma, Ferring, Janssen-Cilag, Merck Sharp and Dohme, Pfizer, Takeda, Truvion Healthcare and Viatris
Remo Panaccione
Consulting fees from AbbVie, Abbott, Alimentiv, Amgen, Arena, AstraZeneca, Bristol Myers Squibb, Boehringer Ingelheim, Celgene, Celltrion, Cosmos Pharmaceuticals, Eisai, Elan, Ferring, Galapagos, Genentech, Gilead Sciences, GlaxoSmithKline, Janssen, Lilly, Merck, Mylan, Oppilan Pharma, Pandion Pharma, Pfizer, Progenity, Protagonist Therapeutics, Roche, Sandoz, Satisfai Health, Schering-Plough, Shire, Sublimity Therapeutics, Theravance, UCB, and Takeda; speaker fees from AbbVie, Arena, Celgene, Ferring, Gilead Sciences, Janssen, Lilly, Merck, Pfizer, Roche, Sandoz, Shire, and Takeda; and research/educational support from AbbVie, Ferring, Janssen, Pfizer, and Takeda. He has served on an advisory board for AbbVie, Amgen, Arena, Bristol Myers Squibb, Celgene, Celltrion, Ferring, Galapagos, Genentech, Gilead Sciences, GlaxoSmithKline, Janssen, Lilly, Merck, Mylan, Oppilan Pharma, Pandion Pharma, Pfizer, Sandoz, Shire, Sublimity Therapeutics, Takeda, and Theravance
Jean-Frederic Colombel
Research grants from AbbVie, Janssen Pharmaceuticals, and Takeda; payment for lectures from AbbVie, Allergan, Amgen, Ferring Pharmaceuticals, Shire, and Takeda; consulting fees from AbbVie, Amgen, Arena Pharmaceuticals, Boehringer Ingelheim, Bristol Myers Squibb, Celgene Corporation, Ferring Pharmaceuticals, Galmed Research, Genentech, GlaxoSmithKline, Imedex, Immunic, Iterative Scopes, Janssen Pharmaceuticals, Kaleido Biosciences, Lilly, Merck, Microbia, Novartis, PBM Capital, Pfizer, Protagonist Therapeutics, Sanofi, Takeda, TiGenix, and Vifor; and holds stock options in Intestinal Biotech Development.
Marla Dubinsky
Consulting fees from AbbVie, Arena, Bristol Myers Squibb, Celgene, Eli Lilly, Genentech, Gilead, Janssen, Pfizer, Prometheus Labs, and Takeda; and is founder and a shareholder of Trellus Health
Tadakazu Hisamatsu
Grant support from AbbVie, Daiichi-Sankyo, EA Pharma Co, Ltd. JIMRO, Mitsubishi Tanabe Pharma Corporation, Mochida Pharmaceutical Co., Ltd., Nippon Kayaku Co., Ltd., Pfizer Inc., Takeda Pharmaceutical Co., Ltd. Consulting fees from EA Pharma Co, Ltd., Janssen Research & Development, LLC., Gilead Sciences, Eli Lilly, Bristol Myers Squibb. Lecture fees from AbbVie, EA Pharma Co, Ltd, Mitsubishi Tanabe Pharma Corporation, Takeda Pharmaceutical Co., Ltd., Mochida Pharmaceutical Co., Ltd., Kissei Pharmaceutical Co, Ltd.
James O. Lindsay
Consultant and an advisory board participant for AbbVie, Atlantic Healthcare, Bristol Myers Squibb, Celgene, Celltrion, Eli Lilly, Ferring Pharmaceuticals, Galapagos, Gilead, GSK, Janssen, MSD, Napp, Pfizer, Shire, Takeda, and Vifor Pharma; has received speaker fees and sponsorship for academic meetings from AbbVie, Ferring Pharmaceuticals, Janssen, MSD, Napp, Norgine, Pfizer, Shire, Tillotts Pharma, and Takeda; and has received investigator-led research grants from AbbVie, Gilead, Pfizer, Shire and Takeda.
Geert D’Haens
Consultant for AbbVie, AgomAb, AstraZeneca, AM Pharma, AMT, Bristol Myers Squibb, Boehringer Ingelheim, Celltrion, Eli Lilly, Exeliom Biosciences, Exo Biologics, Galapagos, Index Pharmaceuticals,, GSK, Pfizer, Immunic, J&J, Origo, Polpharma, Procise Diagnostics, Prometheus Laboratories, Prometheus Biosciences, Progenity, Protagonist and Ventyx; and has received speakers bureau fees from AbbVie, Arena Pharmaceuticals, Galapagos, Gilead, Pfizer, Bristol Myers Squibb, and Takeda

Alexandra Song, Yi Yao, Yang Yang, Javier Zambrano, Fernando Aponte, and W. Rachel Duan are full-time employees of AbbVie and may own AbbVie stock or options.

Funding
AbbVie funded this study and participated in the study design, research, analysis, data collection, interpretation of data, reviewing, and approval of the abstract. All authors had access to relevant data and participated in the drafting, review, and approval of this abstract. No honoraria or payments were made for authorship. AbbVie and authors thank all the trial investigators and the patients who participated in this clinical trial.
Medical writing support was provided by Stephanie Parsons, PhD, an employee of AbbVie.

Introduction

The cause of Crohn’s Disease (CD) remains unclear; however evidence suggests that dietary factors play a key role. With a rising incidence and no definitive cure, identifying modifiable risk factors is critical in preventing CD development. We aimed to study the association between fermentable dietary fibre intake and the future development of CD in an at-risk population.

Aims & Methods

Participants were recruited as part of the Crohn’s and Colitis Canada GEM study, a prospective cohort study of healthy first-degree relatives of patients with CD. At enrolment, a validated food frequency questionnaire was administered. Pectin, β-glucan, inulin, fructooligosaccharides (FOS), and arabinoxylan intake were quantified, and values energy-adjusted. Survival analysis was used to test the association between intake of fibre subtypes and risk of CD development. Generalized estimating equation tested the association between fibre intake and baseline impaired intestinal permeability (fractional urinary excretion of lactulose to mannitol ratio (LMR) >0.025); subclinical gut inflammation (faecal calprotectin (FCP) >250 μg/g); and faecal microbiome composition via 16s rRNA sequencing.

Results

76 of the 2,659 participants developed CD with a median follow-up of 8.9 years (IQR=5.7-12.3). Median age at recruitment was 17 years (IQR=12-25). 47% were male. Higher intake of inulin (HR = 0.78; 95% CI=0.61–0.99; p=0.04) and β-glucan (HR = 0.78; 95% CI=0.61–0.99; p=0.04) were associated with a reduced risk of CD development. No fibre subtype was associated with a higher risk of CD development. Lower intake of pectin, inulin, FOS and β-glucan was associated with impaired intestinal permeability (0.005<p<0.04). Lower inulin intake was associated with high FCP levels (p = 0.046). Higher pectin intake was associated with increased alpha diversity of faecal microbiome (p = 0.028). Higher inulin, FOS and pectin intake was associated with a shift in microbial taxa previously shown to be protective against CD onset in the GEM cohort; a reduction in Ruminococcus torques and an increase in NK4A214 group (phylum Firmicutes) presence (3.25×10⁻¹⁰<q<0.04).

Conclusion

This study demonstrates that dietary intake of fermentable fibre subtypes is associated with a reduced risk of CD development as well as with pleiotropic changes in CD risk biomarkers including microbiome, intestinal permeability, and subclinical inflammation. This suggests that the potential benefit of fermentable fibres on CD risk may involve changes in barrier function, and microbiome composition and function. Targeted interventions based on these findings could prove effective in preventing the onset of CD.

Introduction

Faecal microbiota transplantation (FMT) has shown promise as treatment in inducing remission in patients with ulcerative colitis (UC), however effectiveness varies (1). Optimizing FMT protocols involving anaerobic stool processing to improve bacterial viability, dual-route administration and donor selection may improve efficacy.

Aims & Methods

Our aim was to evaluate the effectiveness of an optimized FMT protocol using anaerobically prepared stool from pre-selected donors in a randomized controlled multi-centre trial using dual-route administration in patients with mild-to-moderately active UC. A total of 85 patients were randomized to either receive donor FMT (n = 44) or autologous FMT (n = 41) via four weekly FMTs comprising two dual-route administrations, nasoduodenal administration combined with enema, and two single enemas. The study was performed at the Amsterdam University Medical Centre and University Medical Centre Groningen from June 2020 till January 2025. Follow-up time is 12 months and ongoing. Donors were selected based on their microbiota profile, informed by our previous TURN trial (2, 3). The primary outcome was steroid-free clinical remission at week 8 defined as a total adapted Mayo score of ≤2, with a stool frequency subscore of ≤1, a rectal bleeding subscore of 0, and an endoscopic subscore of ≤1. Open-label extension was offered to patients in the autologous FMT group who did not reach clinical remission.

Results

Eighty-five patients were randomized (mean age 43.6 years, 48% female), with 76 (89%) patients completing all four treatments. In the modified intention-to-treat analysis, meaning all patients that received at least one FMT treatment (n = 82), primary endpoint was reached in 10 of 44 (23%) patients receiving donor FMT and in 2 of 38 (5%) patients receiving autologous FMT, (two-sided χ², p = 0.026). A further total of 26 patients received donor FMT in open-label extension of which 21 (81%) received all four treatments with 7/26 (27%) reaching the primary endpoint. Serious adverse events occurred in 6/44 (14%) in the donor FMT group vs 4/41 (10%) the autologous group. Two events were deemed related to the FMT treatment (pneumothorax after nasoduodenal placement and overnight hospitalization for abdominal pain one-day post FMT).

Conclusion

In this multi-centre randomized controlled trial, anaerobically processed, donor-selected, dual-route FMT demonstrated a higher likelihood of inducing clinical remission with donor FMT compared to autologous FMT at 8 weeks. The protocol proved feasible and generally safe. Larger trials are warranted to confirm efficacy and to optimize donor and patient selection strategies. ClinicalTrial.gov. Number: NCT05998213

References

1. Imdad A, Pandit NG, Zaman M, Minkoff NZ, Tanner-Smith EE, Gomez-Duarte OG, et al. Fecal transplantation for treatment of inflammatory bowel disease. Cochrane Database Syst Rev. 2023;4(4):Cd012774.
2. Fuentes S, Rossen NG, van der Spek MJ, Hartman JH, Huuskonen L, Korpela K, et al. Microbial shifts and signatures of long-term remission in ulcerative colitis after faecal microbiota transplantation. Isme j. 2017;11(8):1877-89.
3. Rossen NG, Fuentes S, van der Spek MJ, Tijssen JG, Hartman JH, Duflou A, et al. Findings From a Randomized Controlled Trial of Fecal Transplantation for Patients With Ulcerative Colitis. Gastroenterology. 2015;149(1):110-8.e4.

Disclosure

The authors report no COI with regard to this study

Introduction

Immune checkpoint inhibitors (ICIs) have marked a breakthrough in the management of a wide range of cancer types, leading to increased overall survival. However, this treatment is frequently associated with the onset of various immune-related adverse events (irAEs), including ICI-related diarrhea and colitis.¹ Current recommendations for patients with diarrhea or colitis grade 2 or higher (graded via CTCAE)² include the discontinuation of ICI and administration of immune suppressants (e.g. steroids or biologics), which may lead to worse outcomes in these patients.³ Therefore, alternative therapeutic strategies to manage irAEs are needed. The gut microbiota plays a pivotal role in the onset of gastrointestinal irAEs, but the role of its therapeutic modulation on these disorders is mostly unknown. ^4,5

Aims & Methods

Our aim was to evaluate the efficacy and safety of therapeutic microbiome modulation for gastrointestinal irAEs in cancer patients. We enrolled cancer patients affected by ICI-related diarrhea/colitis referred to our Microbiome Clinic from January 2023 to March 2025. After clinical evaluation, patients were stratified according to severity of diarrhea (graded via CTCAE)² and then received a microbiome-modulating therapy. Patients were followed-up for at least 8 week after the initiation of therapy. We collected data about patient demographics (age and gender), patient’s overall health status as assessed by the the Charlson Comorbidity Index (CCI)⁶, type of cancer, oncological therapy and its suspension, time in weeks from initiation of cancer therapy to onset of diarrhea, severity of diarrhea (graded via CTCAE)², time in weeks until resolution of diarrhea and resumption of oncological therapy

Results

We enrolled 42 patients in the study period (8 males, 34 females, mean age 58,3 years-old, mean CCI-index 5.8). All patients were treated with ICI (Pembrolizumab: n=25 , Dostarlimab: n=4, Nivolumab: n=4; Atezolizumab: n=3; Novulumab and Ipilumab: n=2, Cemiplimab: n=2; Mogamulizumab: n=1; Pertuzumab: n=1). Ten patients experienced G1 diarrhea (23,8%), 16 (38,1) G2, 15 (35,7%) G3 and one G4 (2,4%). As indicated by current European Guidelines³, 30 patients (71,4%) had to interrupt ICI due to diarrhea. Multi-strain probiotics were administered to 27 (64.3% ) patients, rifaximin to 22 (52,4%). Overall, 21 patients (50%) needed therapy with systemic steroids. Seven patients who experienced ICI-related colitis refractory to steroids and biologics were successfully treated with FMT. Twenty-eight patients (66.7% ) had a resolution of the diarrhea (G0) and 11 patients (26.2%) had diarrhea G1 at a mean time of 8 weeks. Upon resolution of diarrhea, nine of the 30 patients who had interrupted ICI (30%) were able to resume the treatment. None of the patients experienced any adverse event related to gut microbiota modulation as defined by CTCAE².

Conclusion

Therapeutic modulation of gut microbiota appears to be a promising safe and effective approach for treating ICI-related diarrhea and colitis. However, these preliminary findings need confirmation through more consolidated and well-designed studies.

References

1. Dougan M, Wang Y, Rubio-Tapia A, Lim JK. AGA Clinical Practice Update on Diagnosis and Management of Immune Checkpoint Inhibitor Colitis and Hepatitis: Expert Review. Gastroenterology. 2021;160(4):1384-1393. doi:10.1053/j.gastro.2020.08.063
2. Freites-Martinez A, Santana N, Arias-Santiago S, Viera A. Using the Common Terminology Criteria for Adverse Events (CTCAE - Version 5.0) to Evaluate the Severity of Adverse Events of Anticancer Therapies. Actas Dermosifiliogr. 2021;112(1):90-92. doi:10.1016/j.ad.2019.05.009
3. Haanen J, Obeid M, Spain L, et al. Management of toxicities from immunotherapy: ESMO Clinical Practice Guideline for diagnosis, treatment and follow-up. Ann Oncol. 2022;33(12):1217-1238. doi:10.1016/j.annonc.2022.10.001
4. Wang Y, Wiesnoski DH, Helmink BA, et al. Fecal microbiota transplantation for refractory immune checkpoint inhibitor-associated colitis. Nat Med. 2018;24(12):1804-1808. doi:10.1038/s41591-018-0238-9
5. Wang T, Zheng N, Luo Q, et al. Probiotics Lactobacillus reuteri Abrogates Immune Checkpoint Blockade-Associated Colitis by Inhibiting Group 3 Innate Lymphoid Cells. Front Immunol. 2019;10. doi:10.3389/fimmu.2019.01235
6. Charlson ME, Pompei P, Ales KL, MacKenzie CR. A new method of classifying prognostic comorbidity in longitudinal studies: Development and validation. J Chronic Dis. 1987;40(5):373-383. doi:10.1016/0021-9681(87)90171-8

Disclosure

G.I. has received personal fees for acting as speaker for Biocodex, Danone, Sofar, Malesci, Metagenics and Tillotts Pharma, and for acting as consultant and/or advisor for Ferring Therapeutics, Giuliani, Malesci and Tillotts Pharma. A.G. reports personal fees for consultancy from Eisai Srl, 3PSolutions, Real Time Meeting, Fondazione Istituto Danone, SinergieSrl, Board MRGE and Sanofi SpA personal fees for acting as a speaker for Takeda SpA, AbbVie and Sandoz SpA and personal fees for acting on advisory boards for VSL3 and Eisai. G.C. has received personal fees for acting as advisor for Ferring Therapeutics. All other authors have no conflicts of interest to disclose.