Nonalcoholic Steatohepatitis Drug Pipeline Overview

Nonalcoholic steatohepatitis (NASH) is characterized by fat in the liver with inflammation and damage. It can lead to cirrhosis, which reduces the capability of the liver to function normally, and it may eventually lead to end-stage liver disease and hepatocellular carcinoma in some patients.^1,2 It’s estimated that 2% to 5% of Americans have NASH.

Although there’s a lack of complete understanding of NASH’s cause, it’s believed to be connected to obesity, diabetes, and high cholesterol. As the rates of these conditions have increased in recent years, so has the prevalence of NASH.

Certain liver function tests and imaging techniques showing fat in the liver may indicate NASH, but the only way to determine a definitive diagnosis is through liver biopsy. New diagnostic tests that are less invasive are being developed. The availability of these tests could increase the diagnoses of NASH and prevent progression to cirrhosis, given that many patients, particularly those in earlier stages of the disease, don’t experience any symptoms.¹

The first line of defense against NASH is a healthy diet and regular exercise to keep obesity, diabetes, and high cholesterol under control. However, a substantial number of patients can’t or are unwilling to do this, and a pharmacological treatment may be beneficial for them.

Currently, there are no FDA-approved drug therapies for NASH. A large and growing patient population lacking available treatments creates a great opportunity for drug development. In fact, the global NASH market-spend is projected to be approximately $1.6 billion by 2020.³

A number of manufacturers are developing drugs to treat NASH, and approximately 95 drugs are in the pipeline worldwide at various stages of development. As with drug development for any disease state, many products in the early stages of testing are unlikely to ever receive FDA approval. If we limit the examination of the NASH pipeline to drugs that have advanced to phase 3 stages of trials in the United States, we are left with only 3 agents: obeticholic acid (OCA), elafibranor, and aramchol.⁴ Additionally, there are 7 NASH pipeline products with active phase 2 programs that have earned Fast Track designation from the FDA for NASH (Table⁴).

Table: Late-Stage NASH Pipeline⁴

Drug

Manufacturer

MOA

US Trial Phase

Notes*

Aramchol

Galmed

Stearoyl CoA desaturase-1 inhibitor

2B/3

FT; currently recruiting for phase 2/3 trial

Obeticholic acid

Intercept

Farnesoid X receptor agonist

3

Currently approved for primary biliary cholangitis; earned Breakthrough Designation for NASH with liver fibrosis

Cenicriviroc

Tobira, Dong-A

CCR2 and CCR5 chemokine antagonist

2

FT; phase 3 trials expected to begin in 2017

Elafibranor (GFT-505)

Genfit

PPAR alpha and delta agonist

3

FT; phase 3 trial underway in Europe

Emricasan

Conatus

Caspase inhibitor

2

FT; phase 2/3 trial expected to begin in early 2017

GR-MD-02

Galectin

Galectin-3 inhibitor

2

FT; phase 2 trial results expected in late 2017

GS-0976

Gilead

Acetyl CoA carboxylase inhibitor

2

FT; phase 2 trial results expected in mid-2017

Leucine + metformin + sildenafil

NuSirt

PDE-5 inhibitor, deacetylase sirtuin stimulator

2

FT; phase 2 trial results expected in 2^nd half of 2016

Tipelukast

MediciNova

Multiple

2

FT; phase 2 trial completion expected in September 2017

Volixibat (SHP-626)

Shire

Ileal sodium bile acid co-transporter inhibitor

2

FT; phase 2 trial completion expected in mid-2019

^{FT= Fast Track designation}

^{*Includes all NASH pipeline drugs that have active phase 3 trials in the United States and products with active phase 2 programs that have earned Fast Track designation from the FDA for NASH.}

OCA is a farnesoid X receptor agonist being developed by Intercept. It has earned Breakthrough Designation from the FDA for NASH in patients with liver fibrosis. It previously gained FDA approval for primary biliary cholangitis in May 2016 under the accelerated approval program and was branded Ocaliva. The pivotal trial to be used for its FDA submission for NASH is REGENERATE, a double-blind, placebo-controlled trial planned to include approximately 2500 patients who will receive 10 or 25 mg OCA or placebo. Primary endpoints of the REGENERATE trial are the proportion of patients given OCA who achieve liver fibrosis and NASH improvement compared with placebo. The trial is scheduled to complete in October 2021.

OCA’s phase 2 study in NASH demonstrated mixed results. Overall, the primary endpoint of a 2-point improvement in Nonalcoholic Fatty Liver Disease Activity Score without worsening of fibrosis wasn’t statistically significant for OCA versus placebo.⁴ However, the highest dose group evaluated in the study (40 mg) did meet the primary endpoint goal.⁵ It’s interesting to note REGENERATE is evaluating 10 and 25 mg doses, while only the 40-mg dose met the endpoint goal in the earlier phase study.

Aramchol is also being developed for NASH by Galmed and has earned Fast Track status from the FDA. It modifies the production and storage of fat and cholesterol by inhibiting stearoyl-CoA desaturase 1, as well as increasing cholesterol clearance from the intestines and liver.⁶ A phase IIb/III, multicenter, randomized, double-blind, parallel-assignment, placebo-controlled study called ARREST is ongoing with top-line trial data expected by early 2018.⁴

There doesn’t yet appear to be a clear winner in the NASH pipeline. OCA has progressed the furthest in trials and may have the inside track to become the first agent to gain FDA approval for NASH. However, somewhat mixed trial results may leave the door open for a competitor.

The NASH pipeline will be worth keeping an eye on due to the growing prevalence of the disease, lack of currently available treatments, and active developing treatment landscape.

References

1. National Institute of Diabetes and Digestive and Kidney Diseases. Nonalcoholic Steatohepatitis. NIH Publication No. 07-4921. November 2006.

2. Weinmann A, et al. Treatment and survival of non-alcoholic steatohepatitis associated hepatocellular carcinoma. BMC Cancer. 2015;15:210.

3. Allied Market Research. Global nonalcoholic steatohepatitis (NASH) market is expected to reach $1.6 billion by 2020. prnewswire.com/news-releases/global-non-alcoholic-steatohepatitis-nash-market-is-expected-to-reach-16-billion-by-2020---allied-market-research-270137171.html. Published August 6, 2014.

4. Thomson Reuters. Cortellis. Accessed August 30, 2016.

5. Intercept. Intercept Pharmaceuticals announces results of phase 2 trial of OCA in NASH in Japan. ir.interceptpharma.com/releasedetail.cfm?releaseid=938853. Published October 28, 2015.

6. Galmed. Research & Development. galmedpharma.com/rd/. Accessed September 12, 2016.