Non-alcoholic fatty liver disease, or NAFLD, is a disorder resulting from accumulation of fat in the liver of people who do not consume alcohol.
NAFLD is a less serious condition, although non-alcoholic steatohepatitis, or NASH — a subset of NAFLD — is life-threatening, given its potential to cause liver scarring and cirrhosis.
NAFLD affects about 80-100 million people in the U.S. alone — roughly 25 percent of the total population.
NASH affects about 30 million people in the U.S., or about 12 percent of the adults, according to National Institutes of Health estimates.
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No Approved Drug
Notwithstanding the prevalence of the disorder, there is no FDA-approved therapy for NAFLD or NASH. Treatment options are available for improving the insulin resistance often found in NAFLD and NASH patients.
Diagnosis of the disorder requires biopsy of the liver, which physicians do not want to do without a clear need. NASH is a silent killer that often does not manifest itself loudly enough for it to be diagnosed before it becomes lethal. Additionally, a lack of knowledge of the pathways that cause NAFLD is also a deterrent.
Potential Market Opportunity
NASH offers a $20 billion to $35 billion opportunity for companies developing drugs that target the condition, according to Biopharmadrive, which cited analyst estimates. The NASH biomarker market is estimated to reach $2.05 billion by 2025, according to Grand View Research estimates.
A biomarker is a biologic feature used to measure the presence or progress of a disease or the effects of treatment.
The NAFLD-NASH Pipeline
About 50 investigational drugs are in the pipeline that are being evaluated as treatment options for NAFLD/NASH, Biopharmadrive said. Of this, only four are in late-stage trials, while the mid-stage and early-stage pipeline is crowded out, with 14 and 30 candidates, respectively.
Could Gilead Win Development Race?
Gilead Sciences, Inc. GILD has Selonsertib, a Phase 3 candidate it's testing for NASH fibrosis. It is an apoptosis signal-regulating kinase 1, or ASK1, inhibitor.
The results from two separate late-stage studies, STELLAR 3 and STELLAR 4, are due in the first half of this year.
Apart from this Phase 3 asset, Gilead recently entered a collaborative agreement with Scholar Rock Holding Corp SRRK, which gives it potential access to a mid-stage fibrosis candidate. The deal provides Gilead with options to license worldwide rights to product candidates from the latter's TGFbeta programs, which have the potential to treat fibrotic diseases.
Gilead also entered into a licensing and collaboration agreement with South Korea's Yuhan Corp. to co-develop therapeutics for treating advanced fibrosis due to NASH.
Gilead is evaluating a NASH combo comprised of Selonsertib, FXR agonist GS-9674 and ACC inhibitor GS-0976 in a midstage trial dubbed ATLAS. The results from this trial are also due in 2019.
Intercept Pharma Running Neck-And-Neck With Gilead
Intercept Pharmaceuticals Inc ICPT, a biotech specializing in therapies for non-viral liver diseases, is due to release top-line data from the interim analysis of a Phase 3 trial dubbed REGENERATE in the first quarter of 2019.
The trial is evaluating obeticholic acid, or Ocaliva, in non-cirrhotic NASH patients with advanced liver fibrosis.
The company said it expects to complete enrollment of its late-stage REVERSE trial evaluating Ocaliva in NASH patients with compensated cirrhosis in 2019.
Raymond James' Steve Seedhouse assigned a 90-percent probability of at least one approvable endpoint of the study being met. Seedhouse also sees the possibility of Gilead making an offer for Intercept, given its quest to buy a commercially ready NASH asset.
Allergan
Allergan plc AGN's NASH asset Cenicriviroc is being evaluated in a Phase 3 study dubbed AURORA. This study is conducted in two parts, with the first evaluating the surrogate endpoint of improvement in fibrosis of at least one stage and no worsening of steatohepatitis at month 12. The second part will randomize the subjects from part one and additional subjects to evaluate long-term clinical outcomes composed of histopathologic progression to cirrhosis, liver-related clinical outcomes and all-cause mortality.
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Genfit
French biotech Genfit SA GNFTF's lead product candidate Elafibranor, or GFT505, is being evaluated in a Phase 3 study dubbed RESOLVE-IT.
In December, the company said the Data Safety Monitoring Board issued a positive recommendation for the continuation of the trial. The company said it has completed recruitment of the cohort needed for an interim analysis. Top-line results from the study are due by the end of 2019.
Others Waiting In The Wings
Madrigal Pharmaceuticals Inc MDGL and Viking Therapeutics Inc VKTX are among the others that have midstage assets for NASH.
Madrigal's MGL-3196 is a first-in-class, oral, once-daily, liver-directed, thyroid hormone receptor β-selective agonist. The company expects to begin a Phase 3 trial this year, having successfully completed a Phase 2 trial in 2018.
Viking's VK2809 is being evaluated to treat patients with NAFLD and elevated low-density lipoprotein cholesterol. The candidate met the primary and secondary endpoints of a Phase 2 study and is likely to be advanced into a Phase 3 trial in 2019.
A micrograph of non-alcoholic fatty liver disease. Photo by Nephron/Wikimedia.
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