Non-alcoholic steatohepatitis on the rise around the world

Increasing rates of obesity around the world – termed an epidemic by the World Health Organization¹– are driving another significant health challenge: the rise of non-alcoholic steatohepatitis (NASH).

NASH is a type of fatty liver disease, which may occur in people who drink little to no alcohol. It is characterized by the buildup of fat in the liver, inflammation, and damage to liver cells (hepatocytes) which can lead to fibrosis and even cirrhosis, an irreversible condition, similar to that caused by alcohol abuse. The most common cause of chronic liver disease in the Western world, NASH often precedes the development of type 2 diabetes.²

It also requires much costly care. A diagnosis of NASH is associated with a very high lifetime economic burden, estimated at $223 billion for the total patient population in 2017.³

Believed to affect between 3 and 12 percent of adults in the United States, NASH is difficult to diagnose due to lack of specific symptoms. Some tests may suggest a diagnosis of NASH, but a biopsy may be required to verify the diagnosis.

No drugs to treat NASH have yet been approved for use in the United States; treatment has mostly consisted of lifestyle adjustments – diet modification and weight loss or controlling conditions associated with NASH such as diabetes and hyperlipidemia – and does not mitigate the fibrosis component of the disease.

Pharmaceutical manufacturers are in a race to develop what has been called the “Holy Grail,” an agent that reduces inflammation and mitigates fibrosis in patients with NASH.⁴

“An ideal drug for NASH would be a drug that targets fat deposition, has anti-inflammatory and antifibrotic properties, and reduces cardiovascular risk, which is the most frequent cause of mortality in NASH,” according to experts.⁵

The NASH drug pipeline

The pipeline is robust. CVS Health Pipeline Services is monitoring 30 drugs in development for the treatment of NASH, including several targeting use in in adults with stage 2 or 3 liver fibrosis that have received Breakthrough Therapy designation from the US Food and Drug Administration (FDA):

• Ozempic (semaglutide, Novo Nordisk). The manufacturer is in development seeking a supplemental indication for its blockbuster GLP-1, which has been used to treat diabetes since 2017.⁶ FDA approval may occur early in 2024.
• Resmetirom (Madrigal). This thyroid hormone receptor agonist is a new molecular entity currently in phase III development. FDA approval may occur early in 2024.
• Lanifibranor (Inventiva). Also a new molecular entity, this drug is a peroxisome proliferator-activator receptor (PPAR) pan agonist. It is in phase III development; FDA approval is unlikely before late 2026.

Other drugs in the pipeline include Lipaglyn (Zydus), a PPAR gamma agonist/alpha agonist in Phase II trials for the treatment of NASH with fibrosis that may be approved in 2025.

Across the class, these drugs have varied mechanisms of action – as many as 29, according to some sources.⁷ Identifying appropriate targets for drug therapy is part of the challenge of developing drugs to treat NASH.⁸ Drug trials are challenged to develop clinical endpoints, due to the lack of specific symptoms of NASH.⁹

With a potential global market of $13 billion annually by 2030, it is likely that this high level of pipeline activity will continue.