Prioritization of Therapeutic Targets and Trial Design in Cirrhotic Portal Hypertension

Abstract

Portal hypertension (PH) is the main driver of cirrhosis decompensation, the main determinant of death in patients with cirrhosis. PH results initially from increased intrahepatic vascular resistance. Subsequently, increased inflow from splanchnic vasodilation and increased cardiac output lead to a further increase in portal pressure (PP). Reducing PP in cirrhosis results in better outcomes. Removing the cause of cirrhosis might improve PP. However, this is a slow process and patients may continue to be at risk of decompensation. Additionally, for some chronic liver diseases, such as nonalcoholic fatty liver disease (NAFLD), etiological treatments are not yet available. Therefore, there is a need to develop better therapies specifically aimed at reducing PP. For over 35 years, the mainstay of such therapy has been the use of nonselective beta‐blockers (NSBBs) that act by reducing portal venous inflow. Recently, many drugs (mainly targeting intrahepatic mechanisms) have shown promise in preclinical and early clinical studies and may act alone or synergistically with NSBBs in reducing PP in cirrhosis. The objective of this position paper is to propose a novel framework for the design of clinical trials (phase 1, 2, and 3) in patients with cirrhosis and PH and to prioritize targets and pharmacological therapies in this setting. We have focused the discussion on patients with compensated cirrhosis. The paper summarizes discussions held at The American Association for the Study of Liver Diseases (AASLD) Industry Colloquium in January 2018, with the participation of clinical and translational investigators, regulatory professionals, and industry partners.

Changes in Hepatic Venous Pressure Gradient Predict Hepatic Decompensation in Patients Who Achieved Sustained Virologic Response to Interferon‐Free Therapy

“…(13) On the one hand, it cannot be ruled out that treatments targeting intrahepatic resistance (e.g., statins) have beneficial effects despite achieving less pronounced but consistent reductions in HVPG. (20) Especially in patients undergoing etiological therapy, even small changes may denote a trend in the "right" direction (i.e., disease regression). However, on the other hand, the required HVPG reduction could also be higher, (39) because of the absence of the nonhemodynamic effects of NSBB.…”

“…(18,19) HVPG is currently not accepted as a surrogate endpoint for the accelerated approval of medical therapies for PH by regulatory authorities, because there is limited evidence supporting its use as a surrogate endpoint for other treatments than NSBB. (20) This is particularly problematic in patients with cACLD, in whom the incidence of hepatic decompensation is comparatively low, resulting in tremendously larger trials and longer study periods, if clinical endpoints (e.g., hepatic decompensation) are assessed. Because resources are limited, only a minority of the emerging treatment approaches are tested in phase 3 clinical trials assessing direct endpoints, which greatly inhibits scientific progress in the field of PH.…”

“…However, conventional NSBB have completely different modes of action, as compared with etiological therapies or other treatments that primarily act by decreasing intrahepatic resistance . HVPG is currently not accepted as a surrogate endpoint for the accelerated approval of medical therapies for PH by regulatory authorities, because there is limited evidence supporting its use as a surrogate endpoint for other treatments than NSBB . This is particularly problematic in patients with cACLD, in whom the incidence of hepatic decompensation is comparatively low, resulting in tremendously larger trials and longer study periods, if clinical endpoints (e.g., hepatic decompensation) are assessed.…”

Medikamentöse Langzeittherapien zur Prognoseverbesserung bei Leberzirrhose und zur Vermeidung von Komplikationen der portalen Hypertension

“…In den letzten Jahren sind verschiedene medikamentöse Therapien zur Vermeidung von Komplikationen der portalen Hypertension vorgeschlagen worden, wodurch Lebensqualität und Prognose dieser Patienten verbessert werden sollten [7,8]. Die meisten eingesetzten Substanzen zielten dabei auf die Absenkung des portalen Drucks und die Vermeidung damit assoziierter Komplikationen der Leberzirrhose sowie auf eine Hemmung der bakteriellen Translokation als Folge der erhöhten Durchlässigkeit der Darmwand bei portaler Hypertension [9,10].…”

A Prognostic Strategy Based on Stage of Cirrhosis and HVPG to Improve Risk Stratification After Variceal Bleeding

“…Patients with ascites and/or HE on top of bleeding have a high mortality risk, which has led to the recommendation that the main goal of therapy in such cases be survival. (2,28,29) Current recommended therapy for the prevention of variceal rebleeding is the combination of NSBBs plus endoscopic band ligation (EBL), (2) both for patients with or without ascites/ HE. This study explores in a large cohort of patients receiving the recommended treatment for prevention of variceal rebleeding whether considering the presence/ absence of ascites and/or HE and adding the finding of a baseline HVPG below or over 16 mm Hg to the traditional criteria of hemodynamic response may improve risk stratification and simplify the use of HVPG-based therapeutic decisions.…”