Over 30 years since the disease was first described, we still await the first drug approval for the treatment of NASH. Considering the high and increasing prevalence, comorbidities associated with the disease, and lack of approved therapies, the NASH space presents a huge opportunity for drug developers.

NASH is the progressive form of Non-alcoholic Fatty Liver Disease (NAFLD) where excessive fat deposition causes inflammation and damage to the liver. It gradually leads to fibrosis then cirrhosis (one fourth of cases in the United States), risking liver failure and hepatocellular carcinoma in some cases. NASH is one of the leading causes of liver transplantation. Current management of the disease includes lifestyle changes (such as reducing weight, healthy diet, and regular exercise), off-label medications (includes anti-oxidant, anti-diabetic or lipid modifying agents) and continuous monitoring of the disease.

Lucrative pipeline for NASH

There are more than 20 candidates undergoing Phase II clinical trials for the treatment of NASH. The most promising emerging therapies expected to enter the NASH market in the near future are Genfit’s elafibranor and Intercept’s obeticholic acid (Ocaliva). Phase III trials for elafibranor and obeticholic acid are underway. Trial completion dates for both drugs are in 2021, but thanks to “Subpart H” approval, interim analyses will be used for earlier regulatory submissions. The most noteworthy element about elafibranor’s Phase III trial is the agreement on a new consensual definition of “NASH Resolution” by the FDA and KOLs. This development has put elafibranor in a stronger position because it needs to achieve only one primary endpoint (NASH resolution without worsening of fibrosis) in the Phase III RESOLVE-IT trial, which is very close to what it already demonstrated in its Phase IIb trial.

Obeticholic acid has to achieve both co-primary endpoints in the Phase III REGENERATE trial in order to apply for approval. Considering obeticholic acid’s Phase II trial failed to achieve similar primary and secondary endpoints in a Japanese population, Intercept is likely to be the more anxious of the two companies about gaining approval.

Most other pipeline candidates are in Phase II. Many large pharma companies such as Gilead Sciences, Novo Nordisk, and Bristol-Myers Squibb are developing drugs for NASH or its consequences, with Allergan the latest to enter the space. Allergan acquired Tobira Therapeutics Inc. and Akarna Therapeutics Ltd. in the second half of 2016. These acquisitions provide Allergan a readymade pipeline for the potentially lucrative NASH market.

Market roadblocks

The high prevalence and unmet need in NASH provides a multibillion-dollar opportunity; however, certain risk factors could potentially put the sales estimates of these drugs off track. Liver biopsy is the gold standard for diagnosis but is an invasive procedure that has contributed to low diagnosis rates for the early stages of the disease. Payers may be reluctant to cover highly priced agents considering the long duration of treatment, and that lifestyle modifications are the first steps in management of the disease. However, increasing awareness of NASH and the development of non-invasive diagnostic methods could act to further elevate the market potential of NASH.

DRG Perspective

Elafibranor and obeticholic acid are expected to launch around the same time. However, elafibranor is anticipated to be the future market leader based on its better safety and tolerability profile, compared to obeticholic acid, along with its potential cardio-metabolic benefits. Furthermore, the revised definition of NASH resolution has put elafibranor in the driver’s seat based on demonstrating significant effects on hepatocyte ballooning and inflammation in clinical trials. Elafibranor’s potentially cardio-protective profile will increase acceptance amongst physicians as well as payers, since cardiovascular diseases are the leading cause of deaths in NASH patients.

It will be interesting to see how the NASH market shapes up in the next couple of years while we observe how the early phase candidates perform and progress. Nevertheless, NASH presents an immense untapped opportunity for drug developers able to demonstrate positive treatment outcomes.

 

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