Effective treatments for patients with primary biliary cholangitis are limited. Seladelpar, a peroxisome proliferator-activated receptor delta agonist, has potential benefits.
In this phase 3, ...12-month, double-blind, placebo-controlled trial, we randomly assigned (in a 2:1 ratio) patients who had had an inadequate response to or who had a history of unacceptable side effects with ursodeoxycholic acid to receive oral seladelpar at a dose of 10 mg daily or placebo. The primary end point was a biochemical response, which was defined as an alkaline phosphatase level less than 1.67 times the upper limit of the normal range, with a decrease of 15% or more from baseline, and a normal total bilirubin level at month 12. Key secondary end points were normalization of the alkaline phosphatase level at month 12 and a change in the score on the pruritus numerical rating scale (range, 0 no itch to 10 worst itch imaginable) from baseline to month 6 among patients with a baseline score of at least 4 (indicating moderate-to-severe pruritus).
Of the 193 patients who underwent randomization and treatment, 93.8% received ursodeoxycholic acid as standard-of-care background therapy. A greater percentage of the patients in the seladelpar group than in the placebo group had a biochemical response (61.7% vs. 20.0%; difference, 41.7 percentage points; 95% confidence interval CI, 27.7 to 53.4, P<0.001). Normalization of the alkaline phosphatase level also occurred in a greater percentage of patients who received seladelpar than of those who received placebo (25.0% vs. 0%; difference, 25.0 percentage points; 95% CI, 18.3 to 33.2, P<0.001). Seladelpar resulted in a greater reduction in the score on the pruritus numerical rating scale than placebo (least-squares mean change from baseline, -3.2 vs. -1.7; least-squares mean difference, -1.5; 95% CI, -2.5 to -0.5, P = 0.005). Adverse events were reported in 86.7% of the patients in the seladelpar group and in 84.6% in the placebo group, and serious adverse events in 7.0% and 6.2%, respectively.
In this trial involving patients with primary biliary cholangitis, the percentage of patients who had a biochemical response and alkaline phosphatase normalization was significantly greater with seladelpar than with placebo. Seladelpar also significantly reduced pruritus among patients who had moderate-to-severe pruritus at baseline. The incidence and severity of adverse events were similar in the two groups. (Funded by CymaBay Therapeutics; RESPONSE ClinicalTrials.gov number, NCT04620733; EudraCT number, 2020-004348-27.).
The significance of portal tract histological changes in non-alcoholic fatty liver disease (NAFLD) remains unclear. In 2019, CymaBay Therapeutics halted clinical trials of seladelpar (a PPARδ ...agonist) because initial end-of-treatment liver biopsies of patients with non-alcoholic steatohepatitis (NASH) showed concerning features of portal inflammation with plasma cells, interface hepatitis and focal bile duct abnormalities. Adjudication concluded that these findings were present in the initial, as well as the subsequent biopsies. Thus, this study's aim was to determine the prevalence and clinical significance of portal inflammation, portal plasma cells, interface hepatitis and features of bile duct damage in liver biopsies of adult patients with NAFLD. The pathology database was searched for cases of NAFLD, including steatosis alone and NASH, from January 2016 to October 2020. Liver biopsies were selected from age and sex matched adult patients with diagnoses of steatosis alone (n=10), NASH fibrosis stage 1 (n=10), stage 2 (n=10), stage 3 (n=10), and stage 4 (n=10). There were 24 males and 26 females with a mean age of 48 years (range 20–79). Exclusion criteria included age <18 years, daily alcohol intake >14 drinks per week, elevation of alkaline phosphatase level, comorbid chronic liver disease, or liver biopsy performed as part of a clinical trial for NASH. Control liver biopsies were selected from age and sex matched persons without significant steatosis and normal liver biochemical tests (n=10). Histological parameters were evaluated in 10 portal tracts or 10 septal areas in each liver biopsy. Portal inflammation and interface hepatitis were graded on a scale of 0–4. Portal plasma cells and bile duct damage were scored from 0–3. Ductular proliferation was assessed by CK7 immunostain and graded from 0–4. NASH biopsies with advanced fibrosis (stage 3 and 4) showed portal inflammatory infiltrates (score 2–3) with readily identifiable plasma cells (score 2), and mild to moderate interface hepatitis (score 2–3). All cases and controls showed focal, mild cholangiocyte changes, characterised by cytoplasmic vacuolation, segmental loss of nuclei, nuclear disarray and apoptosis. NASH patients with advanced fibrosis had frequent and diffuse cholangiocyte changes, along with focal lymphocytic cholangitis and moderate to marked ductular reaction (score 3–4). Histopathological features of advanced NASH frequently include increased portal inflammation with plasma cells, interface hepatitis, cholangiocyte injury and prominent ductular reaction.
National organizations recommend screening for hepatitis B virus (HBV) before chemotherapy but differ regarding which patients should be screened. We aimed to determine contemporary screening rates ...at a cancer center and the possible influence on these rates of publication of national recommendations.
We conducted a retrospective cohort study of HBV screening in cancer patients registered during the period from January 2004 through April 2011. Screening was defined as HBsAg and anti-HBc tests ordered around the time of initial chemotherapy. We compared screening rates for 3 periods: January 1, 2004, through December 18, 2008 (Food and Drug Administration and American Association for the Study of Liver Diseases 2007 recommendations); December 19, 2008, through September 30, 2010 (Centers for Disease Control and Prevention, National Comprehensive Cancer Network, American Association for the Study of Liver Diseases 2009, Institute of Medicine, and American Society of Clinical Oncology recommendations); and October 1, 2010, through April 30, 2011. Logistic regression models were used to identify predictors of screening.
Of 141,877 new patients, 18,688 received chemotherapy, and 3020 (16.2%) were screened. HBV screening rates increased over the 3 time periods (14.8%, 18.2%, 19.9%; P <0.0001), but <19% of patients with HBV risk factors were screened. Among patients with hematologic malignancies, over 66% were screened, and odds of screening nearly doubled after publication of the recommendations (P <0.0001). Less than 4% of patients with solid tumors were screened, although odds of screening increased 70% after publication of the recommendations (P =0.003). Other predictors of screening included younger age, planned rituximab therapy, and known risk factors for HBV infection.
Most patients with solid tumors or HBV risk factors remained unscreened, although screening rates increased after publication of national recommendations. Efforts are needed to increase awareness of the importance of HBV screening before chemotherapy to identify patients who should start antiviral prophylaxis.
Hepatitis B virus reactivation (HBVr) during and after immunosuppressive/immunomodulatory (IS/IM) therapy is associated with significant morbidity and mortality, including hepatic decompensation and ...acute liver failure. The risk of HBVr with IS/IM has been heterogeneous and often unpredictable. As a result, patients with active or previous HBV infection are often excluded from clinical drug trials of such agents. Thorough screening for HBV infection, antiviral prophylaxis, and careful monitoring for HBVr have proven to be effective in reducing the rate of HBVr and improving its outcome in the context of IS/IM. Therefore, safe enrollment and management of certain HBV-marker–positive patients in clinical trials is possible. There is a great, unmet need for consistent, evidence-based recommendations for best practices pertaining to enrollment, monitoring, and management of HBVr in clinical trial participants receiving IS/IM. The aim of these consensus guidelines is to provide a step-by-step blueprint to safely enroll, monitor and manage the patient with inactive chronic or resolved HBV in IS/IM clinical trials from the time of screening through to the end of post-treatment follow up.
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