Introduction

GLIMMER (NCT02966834) was a Phase 2b study of the ileal bile acid transport (IBAT) inhibitor, linerixibat, for treatment of cholestatic pruritus in primary biliary cholangitis (PBC). The study included 147 patients: the largest trial in this population to date. GLIMMER had few restrictions on concomitant medications with the exceptions of other IBAT inhibitors, bile acid sequestrants and obeticholic acid; stable doses of other treatments were permitted.

Aims & Methods

In this analysis we explore the pruritus treatment history of patients entering GLIMMER. Investigators recorded details of prior and concomitant use of itch medications on the electronic case report form. For categorisation of prior and/or concomitant itch medication: prior only included patients who had tried and stopped at ≥1 pruritus medication before first study treatment and were not using anything else during treatment with linerixibat/placebo; concomitant only included patients who had used ≥1 pruritus medication in the past, which they continued to use during treatment; prior and concomitant included patients who had tried and stopped ≥1 pruritus medication prior to the study and, continued to use ≥1 pruritus medication during treatment with linerixibat/placebo. This post hoc analysis included all treatments prescribed for itch; guideline treatments were defined as bile acid sequestrants, naloxone, naltrexone, nalmefene, nalfurafine, sertraline, rifampicin or gabapentin. Pruritus severity was defined using worst itch numeric rating scale (NRS).

Results

At baseline, 24% of patients had mild (NRS <4), 52% moderate (NRS ≥4–<7) and 25% severe (NRS ≥7–10) pruritus. Mean age at baseline was 55.8 years but varied by itch severity, with mild patients being older (60.1 years) than those with moderate and severe pruritus (56.8 and 49.6 years, respectively). Median duration of pruritus at baseline was 6.3 years and those with mild pruritus tended to have a longer history than those with moderate or severe itch. Overall, a large proportion of patients were never previously treated: 37% (n = 55) had no prior/concomitant itch medications. Similar proportions of patients, 24% (n = 36) and 26% (n = 38), had received only prior itch medications or received prior and concomitant treatment for pruritus, respectively; 12% (n = 18) of patients were using only concomitant itch medications. Only 25% of patients were treated with cholestyramine, despite it being the guideline-recommended first-line therapy. Treatment history differed by baseline itch severity: 43% of mild patients had no prior or concomitant treatment versus 28% of severe patients. However, differences were less marked for concomitant pruritus therapy use: 43%, 36% and 39% of mild, moderate and severe patients, respectively, continued concomitant itch medicines in GLIMMER. The majority of concomitant itch treatments were non-guideline recommended, with only 39% receiving guideline treatments.

Conclusion

Consistent with the literature, increased itch severity is associated with younger age. Many patients do not receive treatment despite lengthy history of pruritus, while prior use of cholestyramine is limited despite its position in treatment guidelines.
Funding: GSK (201000).
Encore statement: This abstract was originally presented at the American Association for the Study of Liver Diseases (AASLD) The Liver Meeting on November 7, 2022, this encore is presented on behalf of the original authors with their permission.

Disclosure

HTS, AC, MMM, AJW and AR are employees of, and hold shares in GSK. SD is an employee of GSK.

Introduction

The best risk-stratification strategy to predict liver-related outcomes (LROs) in the population remains unclear. The Chronic Liver Disease (CLivD) risk score was recently developed and validated to predict LROs in the population. It could thus identify the at-risk population that warrants liver fibrosis screening with non-invasive tests such as FIB-4. The ClivD score is based on age, sex, waist-hip ratio, alcohol use, smoking, diabetes, and gamma-glutamyltransferase measurement.

Aims & Methods

We investigated the combined/sequential use of the ClivD score and FIB-4 for stratifying the risk for LROs in the UK Biobank population.
From the UK Biobank data, we identified 362,330 individuals with no baseline liver disease and data available to calculate the CLivD score and FIB-4. LROs were ascertained through linkage with electronic healthcare registries for hospitalizations, cancers, and deaths related to compensated or decompensated liver cirrhosis or hepatocellular carcinoma. Discrimination performance was assessed by 10-year competing-risk area-under-the-curve (AUC) values and absolute cumulative risks by the cumulative incidence functions considering death without liver disease as a competing-risk event.

Results

Mean age was 56.6 years (SD 8.1), 48% were men, mean BMI 27.2 kg/m2 (SD 4.6), 5% had diabetes, mean alcohol intake was 16.7 g/week (SD 16.6), and 10% were current smokers.
During a median follow-up of 12.6 years (IQR 12.0-13.4), there were 1285 incident LROs. Both the CLivD score and FIB-4 were significantly associated with LROs (P<0.001). The 10-year AUC-value of the CLivD score was 0.80 (95% CI 0.80-0.80) and of FIB-4, 0.75 (95% CI 0.75-0.75) for the prediction of LROs. The predictive performance of FIB-4 improved as a function of increasing CLivD scores: 10-year AUC values of FIB-4 were 0.61 in the minimal-risk CLivD subgroup as compared to 0.81 in the high-risk CLivD subgroup (Table). This effect modification of CLivD for FIB-4’s discrimination performance was also evident for absolute risks. Namely, within the minimal-risk CLivD subgroup, 10-year cumulative incidences of LROs ranged from 0.05% to 0.3% between low and high FIB-4 strata (Table). In contrast, within the high-risk CLivD subgroup, 10-year cumulative incidences of LROs ranged from 1.7% to 21.6% between low and high FIB-4 strata.

Conclusion

Defining the at-risk population by the CLivD score markedly improves the predictive performance of FIB-4. Thus, sequential use of the CLivD score and FIB-4 emerges as a simple way to stratify the population regarding the risk for LRO.

Introduction

Bowel urgency is increasingly recognized as a common and impactful symptom in patients with Ulcerative Colitis (UC)¹. However, there are limited data exploring the relationship of bowel urgency with work productivity. We examined the relative association of bowel urgency clinically meaningful improvement (CMI) and bowel urgency remission with Work Productivity and Activity Impairment (WPAI) scores in the presence of rectal bleeding (RB) remission and stool frequency (SF) remission as potential confounding variables using data from LUCENT-1 (NCT03518086) and LUCENT-2 (NCT03524092) phase 3 trials.

Aims & Methods

Bowel urgency severity was assessed using the Urgency Numeric Rating Scale (UNRS; 0=no urgency to 10=worst possible urgency). Bowel urgency CMI is a ≥3-point decrease and bowel urgency remission is a UNRS score of 0 or 1². WPAI scores (absenteeism, presenteeism, and work productivity loss in employed patients, and activity impairment in all patients) were measured using a 6-item questionnaire; higher scores indicate greater impairment and less productivity. Mediation analyses were performed to separately examine the relative association between the direct effect of bowel urgency CMI and bowel urgency remission (predictor) and WPAI scores while adjusting for the potential confounding effects of RB remission and SF remission (mediator). Analyses were treatment agnostic and combined patients from mirikizumab and placebo groups from LUCENT-1 (N=1162) and LUCENT-2 (N=544) trials.

Results

At week (W)12 and W52, the direct effect of bowel urgency remission accounted for 43%–49% and 27%–57% of the improvement in all WPAI domain scores except absenteeism, respectively. The association values greater than 100% at W12 and W52 (153% and 148%, respectively) reflect the critical importance of SF remission in the improvement of absenteeism score. Bowel urgency CMI resulted in the largest proportion of improvement in WPAI domain scores (except absenteeism) at W12 (71%–74%) and W52 (66%–78%). Bowel urgency CMI accounted for 68% and 239% of the improvement in absenteeism scores at W12 and W52, respectively. At W52, 750% of the effect was mediated by RB remission.

Conclusion

Improvement in work productivity and regular activities were primarily ascribed to bowel urgency remission or bowel urgency CMI relative to RB remission and SF remission in patients with moderately-to-severely active UC. These findings suggest that bowel urgency is a critical and independent symptom that considerably impacts patients’ productivity.

References

1. Dubinsky MC, et al. Crohn's & Colitis 360. Volume 4, Issue 3, July 2022;7(4):3.
2. Dubinsky MC, et al. J Patient Rep Outcomes. 2022;6(1):114.

Disclosure

Bruce Sands: Consulting: Amgen, Arena Pharmaceuticals, Artugen Therapeutics, AstraZeneca, Bacainn Therapeutics, Boehringer-Ingelheim, Boston Pharmaceuticals, Calibr, Celltrion Healthcare, ClostraBio, Entera, Evommune, Galapagos, Genentech, Gilead Sciences, GlaxoSmithKline, Gossamer Bio, Index Pharmaceuticals, Inotrem, Innovation Therapeutics, Ironwood Pharmaceuticals, Kaleido, Kallyope, Lilly, Miro Bio, Morphic Therapeutics, MRM Health, Progenity, Prometheus Biosciences, Protagonist Therapeutics, Q32 Bio, Surrozen, Teva, TLL Pharmaceutical, USWM Enterprises, VielaBio; consulting, speaking, research funding: Bristol Myers Squibb; consulting, speaking, grant/research support: Janssen; consulting, speaking: Abivax, Pfizer, Takeda
Brian Feagan: Consulting: AbbVie, AbolerIS, AgomAB Therapeutics, Allianthera, Amgen, AnaptysBio, Applied Molecular Transport Inc., Arena Pharma, Avir, Azora Therapeutics, BioJamp, Biora Therapeutics, Boehringer-Ingelheim, Boston Pharma, Boxer, Celgene/BMS, Connect BioPharma, Cytoki, Disc Medicine, Duality, EcoR1, Everest Clinical Research Corp., Lilly, Equillium, Ermium, Ferring, First Wave, Galapagos, Galen Atlantica, Genentech/Roche, Gilead, Glenmark, Gossamer Pharma, GSK, Hoffmann-LaRoche, Hot Spot Therapeutics, Index Pharma, Imhotex, ImmunExt, Immunic Therapeutics, Intact Therapeutics, JAKAcademy, Janssen, Japan Tobacco Inc., Kaleido Biosciences, Landos Biopharma, Leadiant, L.E.K. Consulting, LifeSci Capital, Lument AB, Millennium, MiroBio, Morphic Therapeutics, Mylan, OM Pharma, Origo BioPharma, Orphagen, Otsuka, Pandion Therapeutics, Pfizer, Prometheus Therapeutics and Diagnostics, Play to Know AG, Progenity, Protagonist, PTM Therapeutics, Q32 Bio, Rebiotix, RedHill, Biopharma, REDX, Roche, Sandoz, Sanofi, Seres Therapeutics, Silverback Therapeutics, Surrozen Inc., Takeda, Teva, Thelium, Theravance, Tigenix, Tillotts, UCB Pharma, VHSquared Ltd., Viatris, Ysios, Ysopia, Zealand Pharma; speakers bureau: AbbVie, Janssen, Takeda. Scientific advisory board member: AbbVie, Amgen, Boehringer-Ingelheim, Celgene/BMS Genentech/Roche, Janssen, Novartis, Origo BioPharma, Pfizer, Prometheus, Takeda,Tillotts Pharma, Teva, Progenity, Index, Ecor1Capital, Morphic, GSK; stock shareholder: Gossamer Pharma.
Employment: Western University, Alimentiv Inc.
Stefan Schreiber: Consulting and personal fees: AbbVie, Arena, BMS, Biogen, Celltrion, Celgene, Falk, Ferring, Fresenius, Galapagos/Gilead, HIKMA, IMAB, Janssen, Lilly, MSD, Mylan, Pfizer, Protagonist, Provention Bio, Takeda, and Theravance.
Vipul Jairath: Consulting/advisory board fees: AbbVie, Alimentiv Inc., Arena pharmaceuticals, Asahi Kasei Pharma, Asieris, Astra Zeneca, BMS, Celltrion, Lilly, Ferring, Flagship Pioneering, Fresenius Kabi, Galapagos, GlaxoSmithKline, Genentech, Gilead, Janssen, Merck, Metacrine, Mylan, Pandion, Pendopharm, Pfizer, Protagonist, Prometheus, Reistone Biopharma, Roche, Sandoz, Second Genome, Sorriso pharmaceuticals, Takeda, Teva, Topivert, Ventyx, Vividion. Speaker’s fees: Abbvie, Ferring, BMS, Galapagos, Janssen Pfizer Shire, Takeda, Fresenius Kabi.
Alessandro Armuzzi: Consulting/advisory board fees: AbbVie, Allergan, Amgen, Arena, Biogen, Boehringer-Ingelheim, BMS, Celgene, Celltrion, Lilly, Ferring, Galapagos, Gilead, Janssen, MSD, Mylan, Pfizer, Protagonist Therapeutics, Roche, Samsung Bioepis, Sandoz, Takeda.
Speaker’s fees: AbbVie, Amgen, Arena, Biogen, BMS, Lilly, Ferring, Galapagos, Gilead, Janssen, MSD, Novartis, Pfizer, Roche, Samsung Bioepis, Sandoz, Takeda, Tigenix.
Research grants: MSD, Takeda, Pfizer, Biogen.
Theresa Hunter Gibble: Employment and stockholder: Eli Lilly and Company
Anthony Keohane: Employment and stockholder: Eli Lilly and Company
William J Eastman: Employment and stockholder: Eli Lilly and Company
Kristina A Traxler: Employment and stockholder: Eli Lilly and Company

Introduction

Currently, about 25-30% of the world population is affected by non-alcoholic fatty liver disease (NAFLD); over time, about 20% tends to develop a certain degree of inflammation in the liver tissue, defying the non-alcoholic steatohepatitis (NASH). Moreover, approximately 20% of NASH patients evolve into a high-grade liver fibrosis condition that leads to severe liver impairment (cirrhosis) (1, 2, 3).
The serial use of non-invasive fibrosis tests can refine prognosis in patients with non-alcoholic fatty liver disease (NAFLD) and evaluate the progression or improvement of liver fibrosis.

Aims & Methods

We evaluated predictors of improvement or worsening of liver stiffness measurements (LSM) in well characterized cohorts of patients with NAFLD from London (UK) and Milan (Italy).
We included two consecutive cohorts of 405 patients with at least two outpatient visits between 2014 and 2022. The minimum time interval between baseline and follow-up LSM was >6 months. LSM worsening was defined as an increase of >20% kPa if the baseline LSM was ≥5 kPa, or a follow-up LSM >6 kPa if the baseline LSM was <5 kPa. An LSM improvement was defined as an LSM decrease of >20% kPa (if the baseline LSM was >6 kPa).
A significant change in weight was defined as a >5% reduction or increase at follow-up, while a significant change in glycated hemoglobin (HbA1c) was defined as a >10% reduction or increase.
The variation between the true and expected FIB-4 index (based on the patient’s age at the follow-up visit, but using the blood tests performed at the first visit) was calculated. A significant improvement or worsening in FIB-4 was defined as a >20% variation between the actual and “expected” FIB-4.

Results

Of the 405 patients, 282 (70%) were males; mean age was 54±11 years. The median time from the first visits was 20.3 (13.9 – 28.7) months.
128 and 54 patients had an LSM >8 kPa and LSM>12 KPa at follow-up, respectively.
77 patients (19.3%) had an LSM improvement, while 67 (16.8%) had an LSM worsening; 256 patients (63.9%) maintained a stable value.
In patients with an LSM improvement, 22 had an improvement, 12 had worsening, while 37 had stable FIB-4.
In patients with an LSM worsening, 10 had an improvement, 20 had worsening, while 33 had a stable FIB-4.
In multiple logistic regression analysis, LSM worsening was independently associated with an increase in ALT and in HbA1c levels (OR 1.02 and 1.03 respectively), but also with a reduction in total cholesterol and AST levels (OR 0.98 for both). LSM improvement was independently associated with weight and ALT reduction (OR 0.93 and 0.98 respectively), but also with an increased AST level (OR 1.02).

Conclusion

More than 35% of patients with NAFLD have significant changes in their LSM measurements over a period of 20 months, with worsening or improvement at similar rates. Improvement in weight is independently associated with significant improvement in LSM measurements. On the converse, worsening in metabolic comorbidities, particularly glycemic control, could be associated with significant worsening in LSM, further supporting a multidisciplinary model of care.

References

1. Younossi Z, et al. Global burden of NAFLD and NASH: trends, predictions, risk factors and prevention. Nat Rev Gastroenterol Hepatol 2018;15(1):11-20.
2. Sheka AC, et al. Nonalcoholic Steatohepatitis: A Review. JAMA 2020;323(12):1175-1183.
3. Liu J, et al. Estimating global prevalence, incidence, and outcomes of non-alcoholic fatty liver disease from 2000 to 2021: systematic review and meta-analysis. Chin Med J (Engl). 2022 Jul 20;135(14):1682-1691.