Nonalcholic steatohepatitis (NASH) is a hard to diagnose liver disease, characterized by steatosis, chronic inflammation, and progressive fibrosis that may lead to cirrhosis, liver failure. NASH is also a significant risk factor for the development of hepatocellular carcinoma. 

The worldwide prevalence of NASH is expected to increase by 63% between 2015 and 2030. NASH is also likely to be the leading reason for liver transplants.1,2 

The lack of appropriate treatments leads to an array of unmet needs in the NASH space. Currently, there are no approved therapies for NASH, and first-line treatment includes lifestyle modifications followed by off-label treatment options such as pioglitazone, vitamin E, and pentoxifylline.

NASH: A Lucrative Market with Opportunities for Years to Come

A rapidly growing patient population combined with the lack of a ground-breaking clinical approach means that NASH will likely be a lucrative market with opportunities for years to come. Companies are focusing on variant patient populations, with drugs having a variety of different mechanisms of action. A snapshot of the various mechanisms utilized by prospective companies is given below:

1. Drugs targeting hepatic fat accumulation

• Farnesoid X receptor agonists - (e.g., Obeticholic acid)
• Peroxisome proliferator-activator receptors (PPAR) agonists - (e.g. Elafibranor) 
• ACC (Acetyl-CoA carboxylase) inhibitor - (e.g. Firsocostat)
• Fibroblast growth factor-21 analogs (e.g., Pegbelfermin)

2. Drugs targeting oxidative stress, inflammation, and apoptosis

• Apoptosis signaling kinase 1 (ASK1) inhibitor (e.g., Selonsertib)

3. Drugs focussed on hepatic fibrosis

• CCR2 and CCR5 (Cysteine-cysteine motif chemokine receptor-2/5) receptor antagonist (e.g., Cenicriviroc)
• Galectin 3 antagonist (e.g., Belapectin)

4. Drugs targeting intestinal microbiomes and metabolic endotoxemia

The Race to Market the First Drug

Researchers around the world have been increasingly investigating the most advanced or unique strategies in the race to develop the first-ever treatment for NASH. Various investigational drugs are at different stages of clinical development. Amongst the competing various investigational drugs, some have managed to reach phase III trials and can certainly be addressed as the frontrunners in this race. The list of promising contenders includes Obeticholic Acid (Intercept), Elafibranor (Genfit), Cenicriviroc (Allergan), and Resmetirom (Madrigal Pharmaceuticals). 

1. Intercept’s Ocalavia 

A farnesoid X receptor (FXR) agonist, obeticholic acid, is currently being evaluated in the phase 3 REGENERATE trial. Intermediate results of phase 3 showed mixed outcomes in fibrosis (F2 F3), which were far below the expected projections done based on phase 2b. 

As per the 18-month interim analysis of the REGENERATE trial, obeticholic acid can improve fibrosis in patients with pre-cirrhotic NASH. However, the second endpoint, the NASH resolution endpoint, was not met. Further, the proportion of patients who achieved an improvement in fibrosis (defined as an improvement of one or more stages, with no worsening of NASH) was only modest. Tolerability was also a concern, with reports of adverse events such as a rise in LDL cholesterol and pruritus, which may decrease patient compliance.

2. Genfit’s Elafibranor

Genfit’s Elafibranor is regarded as Ocalavia’s main competitor. Elafibranor is a dual-PPAR alpha/delta agonist and has demonstrated reversal of NASH without worsening of fibrosis in a post-hoc analysis of phase 2 trial data. Elafibranor also demonstrated good safety and tolerance profile. The drug is currently being evaluated in a pivotal Phase III trial RESOLVE-IT, with preliminary data expected in the second half of this year. The safety profile of Elafibranor was further confirmed when the Data Safety Monitoring Board (DSMB) issued a positive recommendation for the continuation of the Phase III trial.

Genfit is also reported to explore the use of elafibranor in pediatric NASH.

3. Allergan’s Cenicriviroc 

Allergan’s drug candidate for NASH is Cenicriviroc, an immune modulator that induced liver regression in the Phase 2b NASH trial. Cenicriviroc is a CCR2/5 receptor antagonist. CCR2/5 receptors are intricately involved in the inflammatory and fibrogenic pathways in NASH; thus by blocking CCR2/5 receptor, Cenicriviroc possess a dual-targeting mechanism for NASH.

Cenicriviroc is currently being evaluated in the phase III AURORA trials. The top-line phase 3 interim data readout on the 52-week study of cenicriviroc in patients with biopsied NASH fibrosis is expected by the fourth quarter of 2020.

4. Madrigal Pharmaceutical’s Resmetirom 

Madrigal Pharmaceutical’s Resmetirom is a thyroid hormone receptor-beta selective agonist. In the Phase 2 study, Resmetirom demonstrated a statistically significant and meaningful reduction of hepatic fat at 12 weeks, which was sustained over 36 weeks. Based on the positive Phase 2 clinical study results, in March 2019, Madrigal initiated MAESTRO-NASH, a phase 3 study of resmetirom in patients with NASH and fibrosis to resolve NASH and reduce progression to cirrhosis and/or hepatic decompensation.

5. Gilead’s Selonsertib

Gilead has multiple novel investigational compounds focussed on treating advanced fibrosis due to NASH. Investigational compounds in development include the ASK1 inhibitor selonsertib, the selective, non-steroidal FXR agonist, cilofexor, and the ACC inhibitor, firsocostat.  

Gilead’s selonsertib is an ASK1 inhibitor. ASK1 is involved in inflammation, cell death, and fibrosis in settings of increased oxidative stress, which is associated with the pathogenesis of NASH. By blocking ASK1, selonsertib has shown a reduction in liver fibrosis associated with NASH. Unfortunately, Gilead’s selonsertib’s launch has been pushed back due to the drug’s failure to meet its 48-week endpoint of at least one stage improvement in liver fibrosis in the Phase III STELLAR-trial. 

The other drugs, Cilofexor, and Firsocostat are being studied in the Phase 2 ATLAS trial as single agents and combinations in advanced fibrosis (F3 and F4) due to NASH.

6. Galectin Therapeutic’s Belapectin 

Belapectin (also known as GR-MD-02) is a complex carbohydrate drug that targets galectin-3, a critical protein in the pathogenesis of fatty liver disease and fibrosis. Galectin-3 plays a major role in diseases that involve the scarring of organs, including fibrotic disorders of the liver, lung, kidney, heart, and vascular system. The drug binds to galectin-3 proteins and disrupts its function. Belapectin is the first drug in a large, randomized clinical trial to demonstrate a clinically meaningful improvement in portal hypertension or liver biopsy in patients with NASH cirrhosis without varices. Galectin therapeutics is undertaking a Phase 3 clinical trial in this patient population.

7. Galmed Pharmaceutical’s Aramchol

Galmed Pharmaceutical’s Aramchol is a novel fatty acid bile acid conjugate, inducing beneficial modulation of intra-hepatic lipid metabolism. In the phase 2b trial of Aramchol, notable effects on NASH resolution and fibrosis improvement along with a good safety profile were observed. 

Aramchol is currently being evaluated in a phase 3/4 clinical study, the ARMOR study. The ARMOR study is designed based on the phase 2b results and FDA guidance and is powered to meet the two alternative key histology-based endpoints: 

• NASH resolution and no worsening of liver fibrosis
• Fibrosis improvement without NASH worsening. 

Meeting one of these endpoints is expected to suffice for the study success of the first part. 

Key Challenges in Developing Drugs for NASH

The challenges in defining endpoints in NASH clinical trials

Defining a clear and meaningful endpoint in NASH is a difficult; this is because in NASH, most patients are asymptomatic, and it’s challenging to set symptom and/or functional-based outcomes. Apart from this, the heterogeneous nature of NASH is influenced by the environment, genetic susceptibility, and several modifiable risk factors, which restricts the ability to designate a definite endpoint.

The gold standard for diagnosis is an invasive and expensive liver biopsy 

The gold standard for diagnosis is an invasive and expensive liver biopsy, which further complicates its diagnosis. A major chunk of the patients remains undiagnosed and, ultimately, untreated.

A history of late-stage failures 

The NASH space has a history of late-stage failures. While the prospects for some drugs look bright at the moment, it’s difficult to assess how far the drug candidates would be successful until they receive regulatory approval for NASH and begin accessing real-world evidence.

FDA Issues Draft Guidance on NASH Drug Development

The FDA has issued a draft guidance on developing NASH drugs to treat patients with liver fibrosis. The guidance provides recommendations for preclinical and clinical development as well as trial design and endpoint selection. The key recommendations from the guidance are as follows:3

• For Phase 3 studies, sponsors should enroll patients with a histological diagnosis of NASH with liver fibrosis made within six months of enrollment. The patients’ weight should be stable for three months prior to enrollment.
• Phase 3 studies for NASH should be double-blind and placebo-controlled with the goal of slowing, halting, or reversing disease progression and improving clinical outcomes.
• Because of the slow progression of NASH and the time required to conduct a trial that would evaluate clinical endpoints such as progression to cirrhosis or survival, the FDA recommends liver histological improvements as endpoints reasonably likely to predict clinical benefit to support accelerated approval.
• As liver biopsy is currently the only reliable method for diagnosing the disease, FDA encourages sponsors to develop and validate biomarkers for diagnosing and grading NASH and liver fibrosis.

The Way Forward – High-Risk, But Massive Payout 

Due to the challenges and the risks associated with drug development, pharmaceutical companies and api pharma companies may be hesitant to take on these drugs in their pipelines; however, if successful, the payout could be high for the first drugs to take on the market.

With promising drugs in phase 3 trials, there is hope that a game-changing clinical approach is on the verge of being approved and entering this highly untapped market. NASH trial failures should be viewed as learning opportunities by competing companies to understand, analyze, and adapt. 

As NASH is a chronic disease, the main objective of any NASH therapy should be to justify its cost/effectiveness model in the long run. Drugs targeting the later stage of fibrosis and cirrhosis, where the risk of cancer development/liver failure is highest are the need of the hour.

Following a personalized medicine approach and adapting treatments to specific patient groups could help achieve better clinical results. Given the complex and multifactorial nature of NASH, harnessing the power of combination therapy also seems to be a logical strategy that can be employed by prospective NASH focussed companies. 

References：

Estes C, Razavi H, Loomba R, Younossi Z, Sanyal AJ. Modeling the epidemic of nonalcoholic fatty liver disease demonstrates an exponential increase in burden of disease. Hepatology. 2018;67(1):123–133.

Canbay A, Sowa JP, Syn WK, Treckmann J. NASH Cirrhosis - the New Burden in Liver Transplantation: How Should It Be Managed?. Visc Med. 2016;32(4):234–238. doi:10.1159/000446379

https://www.fda.gov/regulatory-information/search-fda-guidance-documents/noncirrhotic-nonalcoholic-steatohepatitis-liver-fibrosis-developing-drugs-treatment

About the Author:

Neeta Ratanghayra is a freelance medical writer, who creates quality medical content for Pharma and healthcare industries. A Master’s degree in Pharmacy and a strong passion for writing made her venture into the world of medical writing. She believes that effective content forms the media through which innovations and developments in pharma/healthcare can be communicated to the world."

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