Introduction

Seladelpar is a first-in-class delpar (selective PPAR-delta agonist) indicated for the treatment of primary biliary cholangitis in combination with ursodeoxycholic acid (UDCA) in patients (pts) with an inadequate response to UDCA or as monotherapy in pts unable to tolerate UDCA. RESPONSE was a Phase 3, randomised, placebo-controlled clinical trial of seladelpar in pts with inadequate response/intolerance to UDCA. Pts completing RESPONSE were eligible to roll over into ASSURE (NCT03301506), an ongoing, open-label, long-term, Phase 3 safety trial. Here, we describe data from month 18 (month 6 of ASSURE) in pts with or without prior use of fibrates or obeticholic acid (OCA) who rolled over from RESPONSE into ASSURE.

Aims & Methods

Pts received 10 mg seladelpar orally daily or placebo in RESPONSE; pts received open-label 10 mg seladelpar in ASSURE. Fibrates and OCA were prohibited during the study period and a 6-week washout was required prior to entry in RESPONSE. Data were described for pts in ASSURE with or without prior use of fibrates/OCA and based on whether they received seladelpar (continuous seladelpar pts) or placebo (crossover pts) in RESPONSE. Efficacy included the percentage of pts achieving a composite biochemical response (CBR; alkaline phosphatase [ALP] < 1.67 × upper limit of normal [ULN], ALP decrease ≥ 15%, and total bilirubin ≤ ULN). Safety assessments included adverse events (AEs) and laboratory parameters.

Results

Among pts who continued into ASSURE from RESPONSE (158), 16 continuous seladelpar and 11 crossover pts reported prior use of fibrates/OCA (total, n=27; 17%); 88 continuous seladelpar and 43 crossover pts reported no prior use of fibrates/OCA (total, n=131; 83%). At month 18, among continuous seladelpar pts, 9/15 (60%) pts with prior fibrate/OCA use achieved a CBR vs 54/87 (62%) pts without prior fibrate/OCA use. Among crossover pts, 7/11 (64%) pts with prior fibrate/OCA use vs 32/41 (78%) pts without prior fibrate/OCA use achieved a CBR at month 6 of ASSURE. From ASSURE initiation to month 6, incidence of AEs was similar across continuous seladelpar and crossover pts, regardless of prior OCA/fibrate use; no treatment-related serious AEs were reported.

Conclusion

In this interim analysis of continuous seladelpar and crossover pts from ASSURE, pts who reported prior use of fibrates/OCA achieved a similar sustained biochemical response with seladelpar compared with pts who reported no prior use. Seladelpar appeared safe and well tolerated in this subgroup.

Disclosure

AV reports receiving speaker fees from Intercept Pharmaceuticals and participation on an advisory board with Novartis. DP reports receiving consulting fees from Mediar Therapeutics. AEK reports receiving grants or contracts from Gilead Sciences, Inc., Intercept Pharmaceuticals and Roche; consulting fees from AbbVie; Advanz Pharma; Alentis Therapeutics; Alfasigma; Astellas; AstraZeneca; Attovia Therapeutics; Avior Bio; Bayer; Bristol Myers Squibb; Böhringer-Ingelheim; CymaBay Therapeutics; Escient Pharmaceuticals; Falk; Gilead Sciences, Inc.; GSK; Guidepoint; Intercept Pharmaceuticals; Ipsen; Merck Sharp & Dohme; Mirum Pharma; Novo Nordisk; Rectify Pharma; Roche; and Takeda; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from AbbVie; Advanz Pharma; AOP Orphan Pharmaceuticals; Bayer; Bristol Myers Squibb; CymaBay Therapeutics; Falk; Gilead Sciences, Inc.; GSK; Intercept Pharmaceuticals; Ipsen; Johnson & Johnson; Medscape; Merck Sharp & Dohme; Mirum Pharma; NewBridge Pharmaceuticals; Novartis; Roche; Vertex Pharmaceuticals; and Viofor; support for attending meetings and/or travel from Gilead Sciences, Inc.; participation on a data safety monitoring board with AbbVie; Advanz Pharma; Alentis Therapeutics; Alfasigma; AstraZeneca; Avior Bio; Bayer; Bristol Myers Squibb; CymaBay Therapeutics; Escient Pharmaceuticals; Falk; Gilead Sciences, Inc.; GSK; Guidepoint; Intercept Pharmaceuticals; Ipsen; Merck Sharp & Dohme; Mirum Pharma; Novo Nordisk; Roche; and Takeda; and a leadership or fiduciary role in other board, society, committee, or advocacy groups (paid or unpaid) with PBC Foundation, Swiss Association for the Study of the Liver (SASL), Swiss Gastroenterology Society (SGG), Swiss Hepa, and Swiss Transplant Society (STS). VC reports receiving speaker fees from AbbVie; Advanz Pharma; Echosens; Gilead Sciences, Inc.; Ipsen; and Roche; and participation on an advisory board with Advanz Pharma; Gilead Sciences, Inc.; Ipsen; and Roche. EGD reports receiving consulting fees from Ipsen; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from Ipsen; support for attending meetings and/or travel from Advanz Pharma; and participation on a data safety monitoring board or advisory board for GSK. CH, XQ, SP, WTB, and TRW are employees of Gilead Sciences, Inc., and may own stock in Gilead Sciences, Inc. SCG reports receiving grants or contracts from AbbVie, Arbutus Biopharma, CymaBay Therapeutics, GSK, Ipsen, and Mirum Pharma; and participation on a data safety monitoring board or advisory board with CymaBay Therapeutics, GSK, and Ipsen.

Introduction

Irritable bowel syndrome (IBS), the most prevalent gastrointestinal disorder globally, has a significant impact on the quality of life of 10 - 15% of the population, with a higher prevalence among women than men. Despite the identification of certain contributing factors, the pathophysiology of IBS remains largely unknown.

Aims & Methods

We firstly performed Genome-wide association study (GWAS) on the IBS cohort from the All of Us Research Program and adjusted for sex, age, and top 10 principal components. We conducted GWAS meta-analyses of IBS and its subtypes in 80,737 IBS cases and 1,019,143 asymptomatic control subjects from five independent cohorts (All of Us Research Program, UK Biobank, Bellygenes, Genetic Epidemiology Research on Aging, FinnGen). IBS risk loci were functionally annotated to identify candidate genes. Systematic variant-level analysis, including variants annotation, functional genomics and expression quantitative trait loci, prioritized potential causal variants. Gene-level analyses, including transcriptome-wide association study, colocalization analysis and Mendelian randomization, nominated the potential causal genes.

Results

We identified two independent IBS susceptibility loci at genome-wide significance (P < 5 × 10⁻⁸) in All of Us Research Program cohort totaling 14,897 cases and 245,388 controls. GWAS-meta analysis identified 12 novel independent (P < 5×10^-8) signals and 5 unreported loci (rs143348218, rs3748618, rs6432674, rs9536395, rs976714). Subtype-specific (P < 5×10^-8) findings based on subtype-specific GWAS meta-datasets included 3 loci for subtype IBS-C (3 novel independent loci) , 44 loci for IBS-M (2 novel independent loci). By integrating evidence from layers of different analyses, we prioritized the most plausible causal genes for IBS including CADM2, PCLO, PHF2 and SHISA6. Notably, PCLO (associated with bipolar disorder and major depressive disorder) and SHISA6 (overexpression in Platelet and T-lymphocyte) have been previously unreported in association with IBS.

Conclusion

Our study not only showed the power of the last large-scale GWAS in deciphering the genetic aetiology of IBS, but also uncovered 5 new genetic risk variants, potential unreported causal variants, genes and therapeutic targets for IBS.

References

1 Chey WD, Kurlander J, Eswaran S. Irritable bowel syndrome: a clinical review. JAMA. 2015;313:949–58. doi: 10.1001/jama.2015.0954
2 Soubieres A, Wilson P, Poullis A, et al. Burden of irritable bowel syndrome in an increasingly cost-aware National Health Service. Frontline Gastroenterology. 2015;6:246–51. doi: 10.1136/flgastro-2014-100542
3 Eijsbouts C, Zheng T, Kennedy NA, et al. Genome-wide analysis of 53,400 people with irritable bowel syndrome highlights shared genetic pathways with mood and anxiety disorders. Nat Genet. 2021;53:1543–52. doi: 10.1038/s41588-021-00950-8
4 Bonfiglio F, Zheng T, Garcia-Etxebarria K, et al. Female-Specific Association Between Variants on Chromosome 9 and Self-Reported Diagnosis of Irritable Bowel Syndrome. Gastroenterology. 2018;155:168–79. doi: 10.1053/j.gastro.2018.03.064
5 DeBoever C, Tanigawa Y, Aguirre M, et al. Assessing Digital Phenotyping to Enhance Genetic Studies of Human Diseases. Am J Hum Genet. 2020;106:611–22. doi: 10.1016/j.ajhg.2020.03.007
6 Venner E, Muzny D, Smith JD, et al. Whole-genome sequencing as an investigational device for return of hereditary disease risk and pharmacogenomic results as part of the All of Us Research Program. Genome Med. 2022;14:34. doi: 10.1186/s13073-022-01031-z
7 Weeks EM, Ulirsch JC, Cheng NY, et al. Leveraging polygenic enrichments of gene features to predict genes underlying complex traits and diseases. Nat Genet. 2023;55:1267–76. doi: 10.1038/s41588-023-01443-6

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.