Emerging therapies for NASH - the future is now

KEYWORDS:

• NAFLD
• NASH
• therapy
• drug development
• obeticholic acid
• elafibranor

1. Introduction

Non-alcoholic fatty liver disease (NAFLD) represents an increasingly recognized disease entity with rising prevalence about 25% in the general population [1]. Given a substantial liver-related and cardiovascular mortality in affected individuals NAFLD causes an enormous socioeconomic impact in industrialized countries worldwide [2]. Surprisingly under these conditions, there are currently no drugs approved to treat patients with NAFLD. This situation reflects the fact that the ‘epidemic’ of obesity and related organ diseases has been neglected over long time not only by physicians but consequently also by the pharmaceutical industry. Surveys in Western countries like Germany just recently highlighted that an increasing amount of attention is paid to the fact that patients with metabolic syndrome and often type 2 diabetes are at a considerable risk for liver-related complications and mortality [3]. Current guidelines in Western countries recommend a multistep screening algorithm based on initial ultrasound and risk prediction tools like the NAFLD fibrosis score (http://nafldscore.com) followed by transient elastography stratification for the indication for liver biopsy. With increased awareness and implementation of screening algorithms in primary care more and more patients with Non-alcoholic steatohepatitis (NASH)-related fibrosis will be diagnosed in the near future. Epidemiological studies document an increased mortality with advanced fibrosis clearly highlighting the need for effective treatment options in these patients [4].

Different systems of histologic scoring/reporting are established. These include the NIDDK NASH CRN system which utilizes the NAFLD Activity Score (NAS) as a sum score consisting of the categories steatosis, lobular inflammation and ballooning as an activity score with fibrosis stage as a separate score [5]. A pattern of disease is reported with regard to the prognostically relevant zonation of NASH (zone 1 versus zone 3). It is important to note that the general pathological diagnosis ‘NAFL’ versus ‘NASH’ is based on the defined microscopic criteria (presence of steatosis, ballooning, inflammation) while the terms ‘borderline NASH’ and ‘definite NASH’ are solely based on the sum of the NAS. In contrast, diagnosis of ‘NASH’ in the European SAF/FLIP algorithm is entirely numeric, not pattern based and solely scores four features including steatosis >0, activity (ballooning >1 and lobular inflammation >1) >2 together with fibrosis [6].

In general, the principal therapeutic goal for NAFLD patients is the reduction of metabolic risk factors and the treatment of the metabolic syndrome as the underlying cause. The most effective treatment consists of weight reduction and lifestyle modification with an increase in physical activity, which has been confirmed to be able to improve histological results in NAFLD patients. However, these interventions are often difficult to realize in every-day practice. A medical therapy with long-term effectiveness that would beneficially affect the course of fibrosis does currently not exist. Over the past decade, different drugs licensed for diabetes therapy have been investigated in randomized, placebo controlled studies in NAFLD. Metformin has not been found to have any effect of significance on histology but it may have a positive effect in terms of the incidence of HCC. Pioglitazone improved the steatosis as well as the inflammation in several studies but no anti-fibrotic effect could be proven to date, data on the long-term effects and safety are lacking and a peripheral weight gain is observed as a typical adverse effect[7,8].

Given the epidemic increase of NAFLD as a serious threat without licensed medical treatment, regulatory agencies such as the FDA and the European Medicines Agency (EMA) have defined an unmet medical need and implemented several initiatives to expedite the development of drugs for NASH treatment. These emerging treatment options under clinical development will be reviewed in the following.

2. Review of emerging therapies

In recent years, new drugs acting on various pathophysiological processes in NASH have entered clinical development. These drugs combine beneficial metabolic effects on one hand and anti-inflammatory as well as antifibrotic effects on the other hand to treat NASH. These substances include agonists of nuclear receptors such as FXR agonists or PPAR agonists as well as analogs of enterohepatic hormones such as GLP-1 and other specific antifibrotic agents.

Obeticholic acid (OCA) as agonist of the bile acid receptor farnesoid X receptor (FXR) has passed two successful phase II studies in NASH [9,10]. In the larger phase II study (FLINT), 283 patients with histology-proven NASH were treated over 72 weeks with OCA (25 mg) or placebo [10]. OCA treatment induced a significant improvement of all histological hallmarks of NASH (but not diagnosis resolution), fibrosis grade and the NAFLD Activity Score (NAS) together with a reduction in serum transaminases and a weight loss. However, in both studies OCA treatment was associated with increased serum LDL cholesterol and a mostly mild pruritus was noticed in OCA-treated NASH patients (FLINT). OCA was the first drug ever that achieved a significant fibrosis improvement as predefined end point after 72 weeks of treatment. This fact led to the assignment of a breakthrough status by the FDA. An ongoing phase III study examines the long-term effects of OCA treatment in patients with NASH fibrosis on both histology and overall mortality (REGENERATE Trial). In the meantime, OCA has been approved by FDA and EMA for the second-line treatment of primary biliary cholangitis (PBC). LJN452, another potent oral FXR agonist which is structurally not related to bile acids is currently in phase II development for NASH patients (FLIGHT-FXR).

Pegylated FGF21 (BMS-986036) represents another substance derived from the FGF family and is an attractive approach for NASH treatment. FGF21 plays a central role in glucose- and lipid metabolism and in a phase I study in healthy obese subjects this compound demonstrated a beneficial effect on body weight, insulin resistance, serum triglycerides, and LDL-cholesterol [11]. A recent phase II study in type 2 diabetic patients showed a significant improvement in insulin sensitivity (composite insulin sensitivity index) and serum lipid profiles [12]. A phase II study in NASH patients is ongoing.

Glucagon-like peptide-1 (GLP-1) belongs to a family of enterohepatic hormones with favorable metabolic effects particularly on glucose metabolism. GLP-1 analogs represent a clinically established class of drugs in current diabetes and obesity therapy. Liraglutide (NN2211) is a long-acting glucagon-like peptide-1 analog, which stimulates insulin secretion like endogenous GLP-1. In the phase II LEAN trial beneficial effects of a 48 week liraglutide treatment were observed on liver histology with a significant improvement of NASH (diagnosis resolution defined as a disappearance of hepatocyte ballooning) without worsening of fibrosis. However, this was mainly based on a histological improvement in steatosis and ballooning without improvement in inflammation or NAS [13].

The activation of the peroxisome proliferator-activated receptor through PPAR agonists induces beneficial effects in glucose as well as lipid metabolism. PPAR agonists have been used for long time for the treatment of the metabolic syndrome to lower serum triglyceride and glucose levels. Furthermore, PPAR agonists exert an established anti-inflammatory effect. Elafibranor (GFT505), a dual PPAR α/δ agonist with fast track status by the FDA, has been studied in phase IIb in NASH patients (GOLDEN trial) [14]. 276 patients with biopsy-proven NASH without cirrhosis were treated with elafibranor 80 mg, 120 mg or placebo for 52 weeks. No significant difference was observed between the elafibranor groups and placebo for the protocol-defined end point improvement of NASH (diagnosis resolution defined as the absence of at least 1 of the 3 components of NASH) without worsening of fibrosis. However, in a post hoc analysis based on a currently recommended more stringent definition of NASH reversal (disappearance of ballooning together with either disappearance of lobular inflammation or mild lobular inflammation only), significantly more patients in the 120 mg elafibranor group reached the primary end point compared to placebo (most prominent in patients with NAS ≥4). Despite the relatively short treatment duration, a significant reduction in fibrosis stage could be observed in the elafibranor 120-mg group in those patients with clinical overall response. As a characteristic feature of elafibranor, a beneficial effect on the cardiometabolic risk profile has been confirmed. Elafibranor was well tolerated and did not cause weight gain. An ongoing phase III study (RESOLVE-IT) now investigates the effects of elafibranor 120-mg treatment for 72 weeks on the reversal of NASH without worsening of fibrosis and a composite end point of overall mortality, cirrhosis, and liver-related complications after four years. As another candidate IVA337, a pan-PPAR agonist which activates three different receptor isoforms α, δ, and γ, has shown a beneficial safety profile in clinical phase I. In preclinical studies of IVA337, both antifibrotic and beneficial metabolic effects have been documented. In a phase II study 15 type 2 diabetic patients were treated with different oral dosages and a significant serum transaminase reduction was observed besides improved serum triglycerides and insulin resistance (HOMA) [15]. A phase II study for IVA337 in NASH is currently conducted.

As another principal mode of action, two primarily anti-inflammatory and antifibrotic substances are in the clinical development program. Cenicriviroc is a dual inhibitor of the chemokine receptors CCR2 and CCR5 with fast track status by the FDA. In a recent placebo controlled, randomized phase II study in NASH patients with liver fibrosis (F1-F3) cenicriviroc (150 mg) has been tested for a treatment duration of 12–24 months (CENTAUR trial). After 12 months of treatment, significantly more patients in the cenicriviroc reached the defined primary end point with improvement in fibrosis without worsening of NASH whereas NASH reversal (complete resolution) was not different [16]. The ASK1 inhibitor (apoptosis signal-regulating kinase 1, selonsertib) represents another substance with beneficial effects on inflammation, apoptosis, and fibrosis. Recent phase II study data in NASH patients documented a significant reduction of fibrosis without worsening of NASH (no difference in NAS reduction by >2 or diagnosis resolution) with a considerably short treatment duration of only 24 weeks selonsertib compared to placebo [17]. The side effect profile was favorable. In contrast, the combination with simtuzumab (GS-6624), a humanized monoclonal lysyl oxidase-like (LOXL)-2 antibody, which also targets fibrogenesis by inhibition of collagen cross-linking in pathological stroma, brought no additional benefit.

3. Expert opinion and recommendations

These different novel therapeutic approaches in NAFLD patients are very promising for the future. And the future is almost here! Groundbreaking new achievement is a significant reduction of hepatic fibrosis within a considerably short duration of treatment. Reversal of fibrosis or even cirrhosis not necessarily means regeneration back to normal architecture. Whether this will translate into a reduction of liver-related events and overall mortality is still open. Complementary modes of action suggest the potential of synergistic effects and render many of these new substances attractive partners for combination. Several substances with beneficial effects on cardiometabolic risk factors are particularly attractive to treat the population of NAFLD patients with almost universal metabolic syndrome and cardiovascular disorders.

The most difficult question to answer is what will be the target population of future NAFLD treatment. Should we treat everybody with a fatty liver? Treating an early stage of simple steatosis, whose benignity is still challenged, appears attractive to prevent a future progress toward NASH, especially at the light that prevention is better than using drugs. However, universal treatment of NAFLD (including bland steatosis) affecting one-fourth of the population will be difficult to achieve. A more practicable strategy could be to treat individuals with significant fibrosis which are identified by the currently recommended screening algorithms. Identification of meaningful biomarkers to predict disease progression, liver-related events, and overall mortality are urgently needed and will hopefully speed up drug development. Despite the encouraging results of recently published and ongoing clinical studies, it is important to point out that none of these substances is licensed to date. It will still take some time to have access to the results of phase III studies and to have these potential drugs available in clinical practice.

4. The following recommendations can be made

• Prevention strategies against the further ‘spread’ of the metabolic epidemic will be the most important measure. Health education must start in school age and extend into early adulthood.

• Patients at risk should be identified by established screening algorithms. Novel biomarkers for disease progression will further improve non-invasive risk assessment in the patients.

• The most effective treatment consists of weight reduction and lifestyle modification. NAFLD patients should first be encouraged to exercise as the most reliable and least expensive approach recommended by current guidelines.

• Diabetic NAFLD patients should be preferentially treated with drugs licensed for diabetes treatment and proven benefit on the liver disease such as pioglitazone, liraglutide and metformin.

• Non-diabetic NAFLD patients with detectable fibrosis should be included into ongoing clinical trials which are widely available due to the large number of patients in endpoint-directed studies.

• Patients without signs of fibrosis progression may benefit from the approval of new NASH drugs expected in the near future.

Declaration of interest

A Geier served as an advisor for Novartis, Intercept, Gilead, Abbvie, BMS, Alexion and as a speaker for Novartis, Intercept, Gilead, Abbvie, BMS, Falk and Alexion. Study medication from Burgerstein. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Additional information

Funding

This paper was not funded.