Designing the Ideal NASH Therapy

What is the ideal therapy for patients with nonalcoholic steatohepatitis (NASH)? It should have several characteristics, and it may require combinations to target each patient’s specific pathology. Here’s my take on what we need and how emerging therapies are measuring up.

Oral vs Injectable?
First, we need a drug that is well tolerated. Ideally, this would be an oral drug that can be given once daily. Why do I say that? Because most patients with NASH are generally asymptomatic. They are typically diagnosed in their early to mid‑50s, when they have a lot of life ahead, and they generally do not feel bad. To expect these individuals to take a medicine to prevent future complications related to their liver disease—a disease that they aren’t necessarily feeling today (or in the next 5 years)—the medicine needs to have minimal to no adverse events. And because we know that this disease is characteristically and inexplicably linked to diabetes and obesity, 2 conditions that are chronic in nature, it stands to reason that therapy for NASH patients will also be chronic. So, we need to make it easy for them. That’s the goal we need to set.

What about injectable therapies? We have early data suggesting they can be very effective in resolving some of the histopathologic lesions seen in NASH, and for that reason, they do have a potential role. But we should be realistic about the feasibility of long-term use because they do have gastrointestinal tolerability issues and many patients are hesitant about injections. 

In my opinion, injectable therapies may make an ideal induction therapy for patients with NASH, particularly those with more advanced fibrosis who would benefit from rapid “defatting” of the liver and downstream positive impacts on inflammation, ballooning, and fibrosis. Then, patients could be transitioned to an oral, long‑term therapy to keep their disease either in remission or controlled.

Hepatic vs Extrahepatic Effects?
Next, we need a therapy that can resolve the histopathologic lesions of NASH that are linked to negative long‑term outcomes. For example, fibrosis portends a worse prognosis. At fibrosis levels of F2 and greater, we see impacts on both liver‑related morbidity and overall mortality.

In addition, we would ideally like a NASH drug that addresses the extrahepatic manifestations of fatty liver, such as body weight, glycemic control, and atherogenic lipids. This is important, because we know the number one killer of a patient with NASH is not liver disease, but cardiovascular disease. Hence, the drug that we use to treat NASH would ideally have downstream impacts on cardiovascular endpoints.

Putting these concepts together, our ideal NASH drug would work efficiently and effectively on both NASH and fibrosis—as well as atherogenic lipids, glycemic control, and weight—and would be highly tolerable and easy to take such that it can be given for the long haul.

Progress to Date
So, how are we doing toward developing this ideal therapy? We are making great strides. We have drugs in early‑phase trials that appear to be very effective on defatting the liver. We know that in liver disease, if we can remove the insult that drives the injury, the liver will begin to heal itself.

Paradoxically, this regeneration can also be a driver of liver disease. As part of the process, the liver lays down collagen that serves as a framework for new hepatocytes to regenerate and grow. When the insult is removed (eg, excess fat), that collagen is gradually reabsorbed. But if the insult for injury persists, collagen accumulates over time. When enough collagen accumulates, we call that cirrhosis, and that can have unintended negative consequences. So, it is important to target the drivers of fibrosis with drugs that are able to defat the liver very quickly. As a result, we see improvements in inflammation and ballooning that ultimately lead to improvement in fibrosis by downregulation of stellate cells. To this end, we are making good progress with the thyroid hormone receptor-beta agonists, as well as with fibroblast growth factor (FGF) analogues, including FGF21 and FGF19 analogues.

We are also seeing additional benefits from drugs in early‑phase trials that have impacts on de novo lipogenesis, which we know is the second leading cause of fat in the liver. Therapies including the acetyl‑CoA carboxylase inhibitors, fatty acid synthase inhibitors, and diacylglycerol acyltransferase inhibitors are capable of targeting this process. These agents are largely still in early development except for firsocostat, an acetyl‑CoA carboxylase inhibitor that is being evaluated in combination therapies with other drugs such as farnesoid X receptors and glucagon-like peptide-1 (GLP‑1) receptor agonists.

There are also drugs that appear to promote NASH resolution and fibrosis improvement. We have seen phase IIb data with the GLP‑1 receptor agonist semaglutide showing significant improvements in NASH resolution, although its impacts on fibrosis have yet to be fully elucidated. Lanifibranor, which is a pan–peroxisome proliferator-activated receptor agonist, has demonstrated positive effects on both NASH resolution and fibrosis improvement in a phase II trial.

Combination Therapies
There are many promising therapies in development for patients with NASH. Most are being developed as monotherapy, but I suspect that we will ultimately need targeted combination therapy to achieve favorable outcomes in the majority of patients with NASH and fibrosis. Harnessing different mechanisms of action may synergize in downregulating the pathways that drive NASH pathogenesis.

For example, for patients with more advanced fibrosis, it will be important to have a therapy that targets fibrosis as well as a therapy capable of modulating the metabolic factors. For patients with NASH and limited fibrosis, the priority would be to target the metabolic drivers of NASH to prevent the development of more advanced disease.

Your Thoughts?
What characteristics do you think are required of the ideal therapy for patients with NASH? Answer the polling question and join the conversation by posting in the discussion section.