Lessons on Drug Development: A Literature Review of Challenges Faced in Nonalcoholic Fatty Liver Disease (NAFLD) Clinical Trials

Abstract

NAFLD is the most common chronic liver disease worldwide, occurring in both obese and lean patients. It can lead to life-threatening liver diseases and nonhepatic complications, such as cirrhosis and cardiovascular diseases, that burden public health and the health care system. Current care is weight loss through diet and exercise, which is a challenging goal to achieve. However, there are no FDA-approved pharmacotherapies for NAFLD. This review thoroughly examines the clinical trial findings from 22 drugs (Phase 2 and above) and evaluates the future direction that trials should take for further drug development. These trialed drugs can broadly be categorized into five groups—hypoglycemic, lipid-lowering, bile-pathway, anti-inflammatory, and others, which include nutraceuticals. The multitude of challenges faced in these yet-to-be-approved NAFLD drug trials provided insight into a few areas of improvement worth considering. These include drug repurposing, combinations, noninvasive outcomes, standardization, adverse event alleviation, and the need for precision medicine with more extensive consideration of NAFLD heterogenicity in drug trials. Understandably, every evolution of the drug development landscape lies with its own set of challenges. However, this paper believes in the importance of always learning from lessons of the past, with each potential improvement pushing clinical trials an additional step forward toward discovering appropriate drugs for effective NAFLD management.

Molecular Mechanisms of Fucoxanthin in Alleviating Lipid Deposition in Metabolic Associated Fatty Liver Disease

“…32 The failures in drug development for MAFLD can be attributed to several factors, including the complex and multifaceted nature of the disease itself, making it challenging to pinpoint a single target for effective therapy. 33 Additionally, the lack of definitive biomarkers for disease progression and end points in clinical trials has posed significant hurdles in assessing the efficacy of potential treatments accurately. Moreover, the intricate pharmacotherapies specifically targeting MAFLD.…”

“…Several drug candidates aiming to treat MAFLD and its advanced stage, nonalcoholic steatohepatitis (NASH), have undergone clinical trials with varied success rates . The failures in drug development for MAFLD can be attributed to several factors, including the complex and multifaceted nature of the disease itself, making it challenging to pinpoint a single target for effective therapy . Additionally, the lack of definitive biomarkers for disease progression and end points in clinical trials has posed significant hurdles in assessing the efficacy of potential treatments accurately.…”

Steatotic Liver Disease: Pathophysiology and Emerging Pharmacotherapies

“…Based on the available evidence, MRI-PDFF, MRI-based corrected T1, and parameters as measured by transient elastography (FibroScan, Echosens, Paris, France), namely controlled attenuation parameter (CAP), are most frequently pursued as primary and/or secondary endpoints in randomized clinical trials (RCTs), usually to determine the degree of hepatic fibrosis. Furthermore, Nterminal type III collagen propeptide, enhanced liver fibrosis, and cytokeratin 18 seem to be the most promising biomarkers to assess physiological changes (Siddiqui et al, 2019;Hydes et al, 2021;Andersson et al, 2022;Jincheng Wang et al, 2022) in response to interventional treatment in a phase 2a trial design and may serve as primary and/or secondary endpoints (Ampuero and Romero-Gomez, 2020;Chen et al, 2023)…”

Immunotherapy for NAFLD and NAFLD-related hepatocellular carcinoma

“…It involves a spectrum of diseases, including hepatic steatosis and non-alcoholic steatohepatitis (NASH) (2). NAFLD may lead to lifethreatening hepatic diseases, such as liver cirrhosis and hepatocellular carcinoma (HCC), and extrahepatic diseases, such as cardiovascular disease and dementia (3)(4)(5)(6). Along with advances in retrospective operational definitions, such as fatty liver index and Korea National Health and Nutrition Examination Survey-NAFLD score, and non-invasive diagnostic approaches for NAFLD, prevention, management, and treatment of NAFLD are being actively investigated (7)(8)(9).…”