Introduction

Inflammatory bowel diseases (IBD), encompassing ulcerative colitis (UC) and Crohn’s disease (CD), are associated with increased risk of primary sclerosing cholangitis (PSC). However, population-level data for optimal screening strategies in incident IBD are lacking.

Aims & Methods

We aimed to determine the occurrence and predictors of PSC in patients with newly diagnosed IBD. Since May 1^st, 2021, all adult and pediatric patients with incident IBD within a catchment area encompassing 20% of Denmark were enrolled in the prospective population-based Copenhagen IBD Inception Cohort.¹ All adult patients were invited for MRCP and blood tests (albumin, alanine aminotransferase (ALT), alkaline phosphatase (ALP), bilirubin, and INR) at IBD diagnosis. PSC-like lesions on MRCPs were evaluated by two experienced radiologists. Multivariate Cox proportional hazard analyses adjusting for age, gender, smoking, and disease phenotype were performed (adjusted HR, aHR, 95% confidence interval).

Results

Between May 2021 and May 2023, 527 patients (UC: 326; CD: 201) were included, with 242 (74.2%) and 147 (73.1%) undergoing MRCP, respectively, within a median of 2.4 months (interquartile range (IQR) 1.3-4.9) of IBD diagnosis. No clinical differences were observed between patients who underwent MRCP and those who did not.
PSC-like lesions on MRCP were detected in 33 patients (8.5%), including 17 (7.0%) and 16 (10.9%) with UC and CD, respectively. Of those, 19 patients (4.9%), including 11 (4.5%) with UC and 8 (5.4%) with CD, had definite PSC. No difference was observed in the occurrence of PSC (p=0.37) or PSC-like lesions (p=0.08) in UC vs. CD, nor according to the phenotype of CD; however, PSC lesions in both intra- and extrahepatic bile ducts were more common in UC than in CD (46.2% vs. 6.3%, p=0.02). In addition, a larger proportion with PSC had extensive UC (62.5% vs. 27.1%, p=0.04) or were males (87.5% vs. 44.9%, p=0.03) compared to those without PSC.
Abnormal hepatobiliary biochemistry was found in 34 (14.0%) and 39 (26.5%, p<0.01) patients with UC and CD, respectively, with a higher prevalence observed in patients with definite PSC (9/19 (47.4%)) or PSC-like lesions (8/14 (57.1%)) compared to those with normal MRCP (56/356 (15.7%), p<0.01). Receiver operating characteristic analysis identified ALT≥25 U/L and ALP≥117 U/L to predict PSC best (accuracy and sensitivity: 0.65, specificity: 0.63, positive predictive value (PV): 0.96, and negative PV: 0.09).
During a follow-up of 2.1 years (IQR 1.6-2.6), PSC and PSC-like lesions were both independently associated with increased risk of intestinal resections (aHR 5.69, 1.13-28.54), biologics (aHR 2.00, 1.04-3.86), hospitalization (aHR 2.70, 1.02-7.12), and systemic steroids (aHR 2.45, 1.02-5.89) in CD but not in UC. Abnormal hepatobiliary biochemistry was associated with hospitalization (aHR 2.11, 1.12-4.00) and flare-up of CD (aHR 1.13, 1.02-1.96) as well as biologics in UC (aHR 2.49, 1.15-5.38). None of the PSC cases died, developed cancers, varices, or required liver transplantation within the follow-up period.

Conclusion

In this prospective population-based cohort, we found a considerable proportion (8.5%) to have undetected PSC or PSC-like lesions, despite normal hepatobiliary biochemistry in half of these cases. Notably, both definite PSC, PSC-like lesions, and abnormal hepatobiliary biochemistry had a negative impact on IBD prognosis. The results underscore the importance of systematic screening to mitigate the risk of overlooking PSC, thereby improving the management and outcomes of IBD.

References

1. Attauabi M, Madsen GR, Bendtsen F, et al. Influence of Genetics, Immunity and the Microbiome on the Prognosis of Inflammatory Bowel Disease (IBD Prognosis Study): the protocol for a Copenhagen IBD Inception Cohort Study. BMJ Open. 2022;12(6):e055779. doi:10.1136/bmjopen-2021-055779

Disclosure

Mohamed Attauabi: None
Gorm Roager Madsen: Personal fees from Tillotts
Jakob M Møller: None
Yousef Jesper Wirenfeldt Nielsen: None
Annette Bøjer Jensen: None
Frank Krieger Jensen: None
Hartwig Roman Siebner: has received honoraria as speaker from Sanofi Genzyme, Denmark and Novartis, Denmark, as consultant from Sanofi Genzyme, Denmark, Lophora, Denmark, and Lundbeck AS, Denmark, and as editor-in-chief (Neuroimage Clinical) and senior editor (NeuroImage) from Elsevier Publishers, Amsterdam, The Netherlands. He has received royalties as book editor from Springer Publishers, Stuttgart, Germany and from Gyldendal Publishers, Copenhagen, Denmark.
Eva Fallentin: None
Flemming Bendtsen: Tillotts, Ferring
Jakob Benedict Seidelin: has received research grants from Takeda, Janssen, the Danish Research Council, and the Capital Region Denmark, and is national coordinator of studies from AbbVie, Arena Pharmaceuticals, Ely Lilly, and Boehringer Ingelheim.
Johan Burisch: reports grants and personal fees from AbbVie, grants and personal fees from Janssen-Cilag, personal fees from Celgene, grants and personal fees from MSD, personal fees from Pfizer, grants and personal fees from Takeda, grants and personal fees from Tillots Pharma, personal fees from Samsung Bioepis, grants and personal fees from Bristol Myers Squibb, grants from Novo Nordisk, personal fees from Pharmacosmos, personal fees from Ferring, personal fees from Galapagos, outside the submitted work.

Introduction

Metabolic dysfunction-associated steatohepatitis (MASH) is often associated with metabolic disorders such as obesity, metabolic syndrome, and/or diabetes. FGF21 analogs are promising therapies for MASH due to their direct anti-fibrotic effects as well as additional hepatic and extrahepatic benefits. Pegozafermin (PGZ), an FGF21 analog, was evaluated for safety and efficacy in a Phase 2b trial (ENLIVEN) with either weekly (QW) or every two-week (Q2W) dosing versus matching placebo in MASH patients with biopsy-proven F2/F3 fibrosis. Primary histology endpoints and non-invasive tests (NITs) were assessed at week 24, followed by additional NIT evaluation at the end of a 24-week blinded extension for a total of 48 weeks.

Aims & Methods

Patients were randomized to PGZ 15mg QW, 30mg QW, or 44mg Q2W or placebo for 24 weeks (histology-based primary endpoints). During the 24-week extension, most patients continued their assigned treatment with the exception of a subset of placebo patients who were re-randomized to receive PGZ 30mg QW. The full analysis set includes F2/F3 patients with NAFLD activity score (NAS) ≥4 at baseline (n=192).

Results

At 24-weeks, PGZ 30mg QW or 44mg Q2W led to statistically significant and clinical meaningful improvement in both primary histological endpoints (one stage of fibrosis improvement without worsening of MASH and MASH resolution without worsening of fibrosis) compared to placebo. Non-invasive testing at weeks 24 and 48 demonstrated that PGZ treatment was associated with robust and sustained reductions in liver fat content (MRI-PDFF), biomarkers of fibrosis (VCTE, ELF, PRO-C3) and liver injury (ALT, AST). PGZ also improved metabolic parameters such as lipids and HbA1c at both 24 and 48 weeks. PGZ was generally safe and well tolerated with the most common treatment emergent adverse events (TEAEs) being mild/moderate nausea and diarrhea. No deaths occurred; six early terminations for TEAEs including one drug-related serious AE occurred.

Conclusion

At 24 weeks, treatment with PGZ in MASH patients with F2/F3 fibrosis led to significant fibrosis regression and MASH resolution, which was corroborated by improvement across a variety of non-invasive tests including liver fat, inflammation, fibrosis, and metabolic markers. Benefits on NITs were sustained over the full 48-weeks of the study, with favorable safety and tolerability. PGZ is the first therapy to achieve fibrosis regression and MASH resolution with a Q2W dosing regimen. Phase 3 studies in noncirrhotic (ENLIGHTEN-Fibrosis) and cirrhotic (ENLIGHTEN-cirrhosis) patients are currently underway to confirm these results.

Disclosure

Jörn Schattenberg: Consultant: Akero, Alentis Therapeutics, Astra Zeneca, 89Bio, Boehringer Ingelheim, GSK, Ipsen, Inventiva Pharma, Madrigal, MSD, Northsea Therapeutics, Novartis, Novo Nordisk, Pfizer, Roche, Sanofi, Siemens Healthineers; Speaker: Gilead Sciences, Advanz, Echosens, MedPublico GmbH; Grants: Boehringer Ingelheim, Siemens Healthcare GmbH; Stock Options: AGED diagnostics, Hepta Bio
Arun J Sanyal: Consulting: Genefit, Gilead, Malinckrodt, Pfizer, Salix, Boehringer Ingelheim, Novartis, Bristol Meyers Squibb, Merck, Hemoshear, Lilly, Novo Nordisk, Terns, Albireo, Jannsen, Poxel, 89bio, Siemens, AstraZeneca, NGM Bio, Amgen, Regeneron, Genentech, Alnylam, Roche, Madrigal, Inventiva, Covance, Prosciento, HistoIndex, PathAI; Grants: Gilead, Malinckrodt, Boehringer Ingelheim, Novartis, Bristol Meyers Squibb, Merck, Lilly, Novo Nordisk, Fractyl, Madrigal, Inventiva; Stock holder: Exhalenz, GenFit, Hemoshear, Durect, Indalo, NorthSea, Tiziana, Rivus
Naim Alkhouri: Research funding: 89Bio, AbbVie/Allergan, Akero, Better Therapeutics, Boehringer Ingelheim, Bristol-Myers Squibb, Corcept, DSM, Galectin, Genentech, Genfit, Gilead, Hepagene, Healio, Intercept, Inventiva, Ionis, Madrigal, Merck, NGM, Noom, NorthSea, Novo Nordisk, Perspectum, Pfizer, Poxel, Viking, and Zydus; Speaker bureau: AbbVie/Allergan, Alexion, Echosens, Eisai, Exelixis, Gilead, Intercept, Perspectum, Salix, and Theratechnologies; Consultant: 89Bio, AbbVie/Allergan, Echosens, Fibronostics, Gilead, Intercept, Madrigal, Novo Nordisk, Perspectum, Pfizer, and Zydus.
Rohit Loomba: Consultant: Aardvark Therapeutics, Altimmune, Anylam/Regeneron, Amgen, Arrowhead Pharmaceuticals, AstraZeneca, Boston Pharmaceuticals, Bristol-Meyers Squibb, CohBar, Eli Lilly, Galmed, Gilead, Glympse Bio, Hightide, Inipharma, Intercept, Inventiva, Ionis, Janssen Inc., Madrigal, Metacrine, Inc., NGM Biopharmaceuticals, Novartis, Novo Nordisk, Merck, Pfizer, Sagimet, Theratechnologies, 89bio, Terns Pharmaceuticals and Viking Therapeutics; Grants: Arrowhead Pharmacetuicals, AstraZeneca, Boegringer-Ingelheim, Bristol-Meyers Squibb, Eli Lilly, Galectin Therapeutics, Galmeed Pharmaceuticals, Gilead, Hanmi, Intercept, Inventiva, Ionis, Janssen, Madrigal Pharmaceuticals, Merck, NGM Biopharmaceuticals, Novo Nordisk, Pfizer, Sonic Incytes and Terns Pharmaceuticals; Stockholder: Co-founder LipoNexus, Inc
Mildred D Gottwald, Shibao Feng, Germaine D Agollah, Cynthia L Hartsfield, Hank Mansbach, Maya Margalit: 89bio employee and stock holder