Peter Traber M.D. CEO, CMO, and President Galectin Therapeutics
Approved Pharmacologic Treatments for NAFLD, NASH, and Cirrhosis Are Desperately Needed
Nonalcoholic fatty liver disease (NAFLD) affects one out of four people in the world, making it the most prevalent of all liver diseases and a major public health problem.1,2 The disease is defined by abnormally increased fat deposition in liver cells, which can progress with the addition of inflammation and cell damage to nonalcoholic steatohepatitis (NASH), leading to progressive stages of fibrosis and, finally, cirrhosis. Early NASH is characterized by fat and inflammation associated with minimal amounts of fibrosis, and late NASH is associated with advanced fibrosis or cirrhosis. NAFLD is most closely associated with obesity and diabetes, although there are likely other genetic, nutritional, and environmental factors involved in the pathogenesis.
Although there are no approved pharmacologic treatments for NAFLD, NASH, or cirrhosis, there are over a dozen different companies researching possible treatments. However, the development of drug therapies for the NAFLD spectrum of disease is hampered by a number of challenges:
- the chronic nature of the disorder and ultimately low morbidity and mortality,
- the impact of weight loss on the disease,
- a complex and poorly defined pathophysiology,
- the lack of easily administered diagnostic testing, and
- the evolving status of regulatory endpoints.
NAFLD is generally asymptomatic until complications of cirrhosis arise, and only 5% of individuals with NAFLD develop cirrhosis, with 1–2% requiring liver transplant or dying of the disease.1 However, because of the enormous number of people with NAFLD, it is estimated that nearly 20 million people worldwide who currently have NAFLD will ultimately die of NASH cirrhosis.1
Morbidity and mortality from NAFLD typically only develops after many years. Patients with early NASH (stage 1 and 2 fibrosis) followed for up to 33 years had no increase in mortality in comparison to a reference population, whereas those with advanced fibrosis (stage 3 and 4 fibrosis) had increased mortality.3 This disparity provides challenges for drug development regarding the best point for intervention and the length of therapy required. Would it truly be useful to have a drug targeting early-stage NASH when such patients have no demonstrated increase in mortality and we have no way of predicting which patients will progress to the advanced stages?
Weight loss, either by lifestyle changes or bariatric surgery, is well known to improve and, in many cases, eliminate early NASH.4 Regulators and payers are very likely to evaluate new drug therapies in light of the effectiveness of weight loss, particularly in patients with minimal degrees of fibrosis.
The pathophysiology of NAFLD is entangled with the most basic nutritional and metabolic functions of energy utilization. Therefore, there are a wide variety of systems and cellular signaling pathways involved and many abnormal metabolic and protein expression profiles, as shown in a recent animal model of the disease that correlated with human findings.5 The choice of the most advantageous target is difficult to discern, and many different types of agents have worked in preclinical models.
The diagnosis of NASH and the degree of fibrosis are currently based on liver histology, which requires an invasive liver biopsy. Many serum biomarker and noninvasive tests, as well as composite scores of multiple tests, have been evaluated to diagnose NASH and to predict the degree of fibrosis, but none have yet supplanted liver biopsy as a standard. Only clinical trials that include multiple tests compared to liver biopsy will lead to new standard approaches to diagnosis and monitoring of therapy.
It is becoming widely acknowledged that patient outcomes are related to the degree of fibrosis, and ultimately the development of cirrhosis. Clinical trial endpoints must be tailored to the stage of disease, as they are clearly different for early NASH versus cirrhosis, as an example. As interactions between agencies, academia, and companies with clinical trials have increased, the regulatory landscape for acceptable surrogate and outcome endpoints are crystalizing, but until there are approved drugs there will be no one validated path to drug approval.6
Approaches to Treating NAFLD and NASH
Multiple drugs are currently in Phase II clinical trials for NASH, and two drugs are in Phase III. Although somewhat disparate mechanisms are being explored, the agents can be roughly grouped in four major categories—diabetic/lipid, bile acid/farnesoid X receptor (FXR) pathway, antiapoptotic, and anti-inflammatory/antifibrotic agents.
Because insulin resistance, and often overt diabetes, is a consistent feature of NASH, multiple antidiabetic drugs have been evaluated in NASH, mostly with early stages of fibrosis. They include:
- Elafibranor (Genfit), a peroxisome proliferator-activated receptor (PPAR) α/δ agonist drug, has shown positive Phase II results on reducing the NAFLD activity score (NAS) on biopsy and is currently in Phase III.
- Victoza® (liraglutide; Novo Nordisk), the marketed diabetes drug, a glucagon-like peptide–1 (GLP-1) agonist, has had success reversing NASH in a small trial.
- MSDC-0602 (Octeta Therapeutics), an agent that affects mitochondria and acts as an insulin sensitizer, is now in Phase II.
- Aramchol (Galmed Pharmaceuticals) and GS-0976 (Gilead Sciences), a promising acetyl-coenzyme A carboxylase inhibitor, are drugs in Phase II that inhibit lipid metabolism.
Bile Acid/FXR Pathway Agents
Bile acids and other agents that activate FXR are attractive because they affect multiple pathways that may be involved in NASH pathogenesis. Among these are:
- Ocaliva® (Intercept Pharmaceutics), the modified bile acid obeticholic acid recently approved for use in primary biliary cholangitis, has shown activity in NASH Phase II studies, and is currently in Phase II.
- GS-9674 (Gilead Sciences) and LJN-452 (Novartis) are other non-bile acid FXR agonists in development.
- BMS-986036 (Bristol-Myers-Squibb), a PEGylated fibroblast growth factor (FGF) 21, and NGM282 (Merck), a form of FGF19, are biological agents that are downstream of the FXR pathway and currently under investigation.
- Volixibat (Shire), an apical sodium-dependent bile acid transport inhibitor (ASBTi) in the bile acid metabolism group, is the subject of a recently initiated NASH Phase II study.
Apoptosis (programmed cell death) of hepatocytes and stellate cells has been implicated in the pathogenesis of NASH. Drugs in this category include:
- Emricasan (Conatus Pharmaceuticals), a pan-caspase inhibitor, has been shown to reduce serum markers of apoptosis and signs of inflammation in NASH and is in Phase II clinical trials for NASH, including cirrhosis.
- GS-4997 (Gilead Sciences) is an apoptosis signal-regulating kinase-1 (ASK-1) inhibitor in Phase II clinical trials that has effects on multiple pathways, including insulin resistance, lipid metabolism, and fibrogenesis.
Inflammation of the liver leads to fibrogenesis, so agents that affect inflammation primarily and/or directly affect fibrosis (production or degradation) are anticipated to be effective drugs in NASH. Among these are:
- Cenicriviroc (Tobira Therapeutics), a CCR2/CCR5 receptor antagonist, has shown promise in interim Phase II data.
- Tipelukast (MediciNova), a multiple target antagonist of inflammation, is in Phase II trials.
- GR-MD-02 (Galectin Therapeutics), a galectin 3 inhibitor, has both anti-inflammatory and antifibrotic activity in preclinical studies and is in Phase II clinical trials with the primary target indication of NASH cirrhosis.
- Simtuzumab (Gilead Sciences), a monoclonal antibody, is primarily an antifibrotic agent focused on collagen degradation by virtue of inhibiting the enzyme LOXL2 and is in Phase II clinical trials in NASH with advanced fibrosis and NASH cirrhosis.
In addition to these programs, there are multiple agents that are poised to enter Phase II that address a number of additional mechanisms. These include:
- CP-94598 (Pfizer), a cannabinoid-1 receptor antagonist.
- A Rho-associated kinase 2 (ROCK2) kinase inhibitor (Kadmon).
- Thyroid hormone beta agonists (MGL-3196; Madrigal Pharmaceuticals) and VK2809 (Viking Therapeutics).
- SSAO/VAP-1 (Boehringer Ingelheim), an adhesion protein inhibitor.
- DUR-928 (Durect), a nuclear hormone modifier.
The search for NASH therapies represents an exciting area of research that is addressing a very large, unmet medical need. The results of multiple clinical trials over the next few years will clarify potential therapies and target pathways. Overall, NAFLD represents an enormous societal problem with its roots in obesity, and there is a great need for increased awareness, noninvasive diagnostic methods, and preventative approaches.
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2. Younossi ZM, Koenig AB, Abdelatif D, Fazel Y, Henry L, Wymer M. Global epidemiology of nonalcoholic fatty liver disease—meta-analytic assessment of prevalence, incidence, and outcomes. Hepatology 2016;64:73–84.
3. Ekstedt M, Hagstrom H, Nasr P, Fredrikson M, Stal P, Kechagias S, Hultcrantz R. Fibrosis stage is the strongest predictor for disease-specific mortality in NAFLD after up to 33 years of follow-up. Hepatology 2015;61:1547–1554.
4. Vilar-Gomez E, Martinez-Perez Y, Calzadilla-Bertot L, Torres-Gonzalez A, Gra-Oramas B, Gonzalez-Fabian L, Friedman SL, Diago M, Romero-Gomez M. Weight loss through lifestyle modification significantly reduces features of nonalcoholic steatohepatitis. Gastroenterology 2015;149:367–378.
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6. Sanyal AJ, Friedman SL, McCullough AJ, Dimick-Santos L. Challenges and opportunities in drug and biomarker development for nonalcoholic steatohepatitis: findings and recommendations from an American Association for the Study of Liver Diseases-U.S. Food and Drug Administration Joint Workshop. Hepatology 2015;61:1392–1405.
Peter Traber, M.D. ([email protected]), is chief executive officer, chief medical officer and president of Galectin Therapeutics.