Part 2 – Non-Alcoholic Fatty Liver Disease and Non-Alcoholic Steatohepatitis
In our previous post, we looked at glucagon-like peptide receptor agonists (GLP-1RAs) and how their initial development for type 2 diabetes (T2D) is expanding to the treatment of obesity, based on the significant weight loss that many individuals experience with the use of these drugs. As newer GLP-1 drugs, with even greater efficacy & tolerability and less frequent dosing requirements gain approval and use as obesity treatments, some experts believe they could command a $100 billion market within the next 10 years. But the market for GLP-1RAs may be larger yet, as drug developers explore their potential utility to address another unmet medical need: the treatment of non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH).
NAFLD is a condition commonly associated with obesity, in which excess fat builds up in the liver. People with NAFLD have a higher risk of high blood pressure and cardiovascular disease (the leading cause of death in this population), as well as metabolic syndrome leading to T2D. Experts estimate that up to 75% of overweight individuals and 90% of those with severe obesity have NAFLD. NASH is a more severe form of NAFLD, where inflammation of the liver can lead to serious organ damage and fibrosis. Such damage can become permanent, progressing to cirrhosis, and potentially leading to liver cancer and/or the need for liver transplant. Experts estimate that about 1.5%- 6.5% of those affected with NAFLD have NASH. There are currently no approved drug treatments for NASH or NAFLD, although the latter can be managed through weight loss (exceeding 10% of baseline weight) and exercise, which have been shown to reverse liver inflammation and fibrosis.
Growing evidence from published observational studies, controlled clinical trials, and meta-analyses has shown an association between GLP-1RA use in patients with T2D and reductions in liver fat content and liver enzyme elevation. As a result, a growing number of drug developers are studying GLP-1RAs as a potential treatment for NAFLD and NASH.
For example, Lilly’s GLP-1RA dulaglutide (Trulicity) has shown an ability to reduce plasma levels of alanine transaminase (ALT), a marker of liver damage, in a pattern consistent with liver fat reduction. Similarly, Lilly’s tirzepatide (Mounjaro) was shown in an MRI substudy of the Phase 3 SURPASS 3 trial to improve liver fat content and abdominal adipose tissue, with over twice as many treated participants experiencing a greater than 30% reduction in liver fat content compared to those receiving insulin degludec. In a Novo Nordisk Phase 2 trial of semaglutide (Wegovy), a 0.4 mg dose achieved its primary endpoint with a significantly higher percentage of treated patients seeing NASH resolution versus placebo, but it missed a secondary endpoint of fibrosis improvement. Novo now has a Phase 2 trial of semaglutide in NASH ongoing at the same 2.4 mg dose that the FDA approved for obesity, with interim data due in 2024. Novo is also investigating another new GLP-1 agent, CagriSema, a combination of the amylin analogue cagrilintide and semaglutide, in both obesity and NASH, and has an ongoing Phase 2 study in the latter condition.
Relative newcomers to the GLP-1 field are also exploring their own agents in NASH. For example, AstraZeneca is studying its GLP-1/glucagon agonist cotadutide in non-cirrhotic NASH with fibrosis and expects to announce data from its Phase 2/3 Proxymo-Advance trial in 2023. Altimmune saw initial success in September 2022 in a Phase 1 trial with its dual GLP-1/glucagon agonist pemvidutide, which hit its primary endpoint of reducing liver fat in all doses studied. Results with the 1.8 mg dose were particularly good, with 94% of trial participants receiving that dose achieving at least a 30% reduction in liver fat, while trial participants on each of the doses studied experiencing reductions in serum ALT. The company is now awaiting results of a 24-week extension study, as well as interim data from its Phase 2 Momentum study in obesity.
Like obesity, NASH has been a particularly difficult indication for successful drug development, with plenty of failures even for GLP-1 drugs. Pfizer ended NASH investigations with its oral GLP-1RA, danuglipron, in mid-2022 for unspecified reasons while continuing to study that agent in obesity. Pfizer also ended development in NASH for several non-GLP-1RA drug candidates in recent years, as did Bristol Myers Squibb. We will take a further look at NASH drug development outside the field of GLP-1RAs in a future post.