NASH, the chronic, but silent disease is a leading cause of liver-related morbidity and mortality worldwide, also poised to be the leading cause of liver transplants by 2020. Despite this, there are currently no FDA-approved treatment therapies for NASH. Therefore, serious concerns have been generated to develop effective treatment strategies for NASH throughout the medical community.

NASH represents the most severe form of NAFLD (non-alcoholic fatty liver disease) and involves inflammation and cell injury with or without fibrosis which may further progress to cirrhosis and ultimately hepatocellular carcinoma. As far as pathophysiology goes, data shows that a plethora of events with simultaneous origins from the liver, adipose tissue, and the gastrointestinal tract are responsible.

While, insulin resistance, the main consequence of obesity and metabolic syndrome, leads to fat build-up in the liver, the real culprit is oxidative stress which causes peroxidation of the hepatocyte lipid membrane and ultimately leads to progressive disease or NASH. Variance amongst the proinflammatory and anti-inflammatory adipokines and adipocytes induced cytokines are other additional mechanisms held responsible.

Need of the hour? Innovative therapies

With a multitude of pathways responsible for the development of the disease, effective treatment strategies, that can manage the complex pathophysiologic processes of NASH is the need of the hour. Lack of approved treatments and a large patient pool is driving research and innovation in the biopharmaceutical industry towards this highly unmet medical need.

Moreover, due to its classification as a medical condition of an unmet therapeutic need, FDA has conferred an accelerated approval pathway to medications showing promising benefits in NASH. As an advantage to the increasing understanding of the various molecular pathways responsible for the progression of NASH, a number of novel therapeutic agents are being evaluated to effectively combat this dreaded disease.

Non-availability of an approved pharmacotherapy has led ‘big pharma’ and other companies to treat NASH as a unique economic opportunity with analysts estimating the size of the global market for NASH treatments to be $35 to $40 billion by 2025.

Frontrunners- who will win the race for NASH therapy?

Various investigational drugs work on the diverse mechanism of action and all are at different stages of clinical development. Amongst the competitors, few have managed to enter phase III clinical trials and can certainly be addressed as the frontrunners in this race.

Harnessing the power of combination therapies

Given the complex and multifactorial nature of NASH, combination therapy seems to be a logical strategy which can be employed by prospective NASH focussed companies.

• Novartis is expecting to combine its FXR agonist, tropifexor (LJN452) with Allergan’s cenicriviroc. Novartis is also planning to test a combination of tropifexor with emricasan- an irreversible caspase inhibitor.
• Gilead Sciences is also focussing on combination therapy to treat NASH fibrosis. Encouraging results were obtained in a proof-of-concept study combining selonsertib (formerly GS-4997) plus GS-0976 (ACC inhibitor) or GS-9674 (FXR agonist).
• The regimens containing GS-0976 (combined with selonsertib or as monotherapy) produced the greatest changes in liver fat content. Patients receiving the combination also experienced the greatest reduction in a protein called lumican, a marker of fibrogenesis (formation of scar tissue).

Future prospects

With a therapeutic pipeline boosting of numerous investigational drugs in various phases of development, the highly untapped NASH market is certainly on its way to a promising therapy option.

Owing to the chronic nature of the disease, the main goal of any NASH therapy should be to justify its cost/effectiveness model in the long run. Drugs targeting a later stage of fibrosis and cirrhosis, where the risk of cancer development/liver failure is highest, would likely gain more acceptances from the payers.

As a liver biopsy is the current gold standard for disease diagnosis, another aspect to be considered is the development of better screening methods for patient identification and treatment efficacy. Specific biomarkers may improve diagnosis and can also help to monitor the stage of the disease.

With potential drugs in phase 3 studies, there is hope that the next few years will definitely roll out a suitable therapy option in clinical practice. However, cost-effectiveness and patient-centred benefits will certainly play a pivotal role in the whole process.