The nonalcoholic steatohepatitis (NASH) drug development graveyard: established hurdles and planning for future success

Abstract

Introduction: Numerous pharmacological compounds that target the different molecular targets involved in the pathobiology of nonalcoholic steatohepatitis (NASH) are currently in clinical testing. So far, there are no regulatory approvals. Areas covered: This paper sheds light on the molecular pathways involved in NASH and the drugs targeting these pathways. We have identified 10 compounds whose clinical development program has been halted. Moreover, we explore early phase clinical trials and dissect the reasons for termination of development. Expert opinion: The main goal of NASH pharmacotherapy is to halt or reverse hepatic fibrosis or to achieve the resolution of steatohepatitis. There is an intense competition to develop compounds with disease-modulating properties with a focus on anti-metabolic, anti-inflammatory or anti-fibrotic properties. Numerous study programs, even in late-phase trials, have been halted because of lack of efficacy, safety concerns or drug-drug interactions. This underscores the urgent need to provide robust preclinical data and an extensive clinical trial program that builds on reliable data generated in earlier stages of clinical development before moving into late stage development.

Genetic predisposition similarities between NASH and ASH: Identification of new therapeutic targets

“…Unfortunately, classical biomarkers cannot accurately stratify the risk of progressive liver disease, and there are no approved drugs to treat FLD. Indeed, the first drugs reaching late stage development for NASH either failed or were burdened by an unfavorable side effects profile [21]. Innovative approaches for biomarkers discovery and therapeutic target identification are therefore urgently needed.…”

Perspectives on Precision Medicine Approaches to NAFLD Diagnosis and Management

“…Decades of intensive research have indeed led to an improved understanding of disease epidemiology and pathogenesis [9,[23][24][25] but this has not yet translated into success in identifying effective drug treatments. In fact, a significant portion of investigational drugs have failed in showing efficacy even in late phase randomized controlled trials (RCTs) [26,27]. While myriads of explanations may, in principle, account for this therapeutic failure, it should constantly be kept in mind that the pathogenesis of disease is multilayered and extraordinarily composite [28,29], which may explain the variability, in the individual patient, of NAFLD clinical course and outcomes, from a benign to a progressive and deadly disease, and from hepatic to extrahepatic manifestations and complications.…”

Differences between current clinical guidelines for screening, diagnosis and management of nonalcoholic fatty liver disease and real-world practice: a targeted literature review

“…Despite substantial investment in clinical development, pharmacological treatment has yet been approved for advanced disease, despite the existence of evidence that interventions can reduce steatosis and dysmetabolism. The absence of clear, evidence-based recommendations for pharmacotherapy of NAFLD is partly due to the practical challenges of designing and implementing trials of new drugs in NAFLD impeding progress [49] and partly due to the timing of data availability versus guideline development [47].…”

“…Both classes of antidiabetic appear to have better benefit-risk profiles than pioglitazone, which features in NAFLD guidelines from EASL [26], NICE [31] and the AASLD [16,27]. Other, novel agents with mechanisms of action that target metabolic, inflammatory, or fibrotic processes have also been studied, some in late-phase trials, but development has stalled due to benefit-risk profiles perceived as inadequately favorable [49,50]. For patients with multiple cardiovascular risk factors, statins have been viewed favorably due to their proven safety profile and their strong efficacy for the reduction of the cardiovascular risk, but not for benefits in NAFLD per se [34].…”