Discussion
HBV or HCV infection, alcohol-related disease, HBV infection, cirrhosis, HCV infection, liver cirrhosis, NASH
HEPATIC IMPAIRMENT, DECOMPENSATED CIRRHOSIS, CHRONIC VIRAL HEPATITIS, LIVER, CIRRHOSIS, LIVER DISEASE, LIVER CIRRHOSIS, ALCOHOL-RELATED LIVER DISEASE, PORTAL HYPERTENSION, COMPLICATIONS
Currently, there are no approved therapies for patients with CSPH in compensated cirrhosis that directly target the increase in intrahepatic vascular resistance as pathophysiological mechanisms of portal hypertension. BI 685509, an sGC activator, has the potential to modulate portal pressure; these studies aim to assess the effects of BI 685509 on portal hypertension in patients with CSPH in cirrhosis due to various aetiologies of liver disease. Between both trials, patients with the four most common aetiologies of liver cirrhosis are included (alcohol-related liver disease, HBV infection, HCV infection and NASH). In a previous phase I MRD trial of BI 685509 in patients with mild and moderate hepatic impairment, no differences in PK parameters of BI 685509 were seen between patients with alcohol-related liver disease, chronic viral hepatitis (HBV or HCV infection) and NASH [HVPG is the current gold standard for assessing the severity of sinusoidal portal hypertension in patients with cirrhosis. The test–retest reliability of HVPG measurements has been shown to be high in the context of clinical studies, particularly those limited to patients with compensated cirrhosis, such as in the trials presented here [Liver and spleen stiffness measurements via transient elastography are emerging non-invasive tests for assessing portal hypertension [The treatment duration of 8 weeks in the 1366.0029 trial and the interim analysis at week 8 in the 1366.0021 trial will allow for the evaluation of short-term efficacy data from HVPG measurements and other non-invasive measures and for indirect comparisons between the two trials. The longer-term (24 weeks) assessment in the 1366.0021 trial will also investigate the potential for the adaptation to sGC activation on portal pressure with chronic treatment and the assessment of the maintenance of the response to therapy. HVPG can be considered to be an objective assessment with standardised procedures. Conducting central reads of the HVPG measurements, and using the same central reader for both trials, enhances confidence and increases the reliability of data. Furthermore, both trials will be conducted at the same study centres, improving the comparison of trial data from different aetiologies, and the global nature of the trials allows for a broad coverage of patients. The standardisation of transient elastography evaluations by using the same device across sites, standardised training of site personnel and, if possible, the use of the same operator for the assessments for a single patient will produce comparable results between the two trials.In the 1366.0021 trial, patients are required to abstain from significant alcohol misuse/abuse for at least 2 months prior to screening and abstain completely throughout the trial. For patients with an alcohol-related disease, this may be difficult and may present an increased risk of protocol deviation. To mitigate this, patient-reported information on abstinence from alcohol will be collected, and phosphatidylethanol, an alcohol-specific biomarker, will be measured during the treatment period. Furthermore, the maximum duration of treatment will be 24 weeks in the 1366.0021 trial, and hence no long-term data will be collected, and limited data will be obtained on whether sGC activation prevents other complications or decompensation. The 1366.0029 trial is not placebo-controlled and, with the exception of the NASH population, is not randomised. Although placebo data will be collected in the 1366.0021 trial, any comparisons with the other aetiologies will be indirect. Due to the modest patient numbers, these trials will not allow the collection of information on potential ethnic differences in treatment outcomes. However, based on the PK profile in phase I trials, no differences between major ethnicities are expected.The results of the presented trials will inform the clinical development of BI 685509 in pivotal phase III trials, which are intended to examine clinical endpoints.