Advanced Drug Therapies for NASH and Fatty Liver Disease

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• Obeticholic Acid FXR Agonist
• Resmetirom Thyroid Hormone Agonist
• Semaglutide GLP-1 Agonist
• Repurposed Drugs for NASH
• Safety and Tolerability Considerations
• Future of NASH Therapy
• Full Transcript

Obeticholic Acid FXR Agonist

Obeticholic acid is a leading NASH drug candidate that activates the Farnesoid X nuclear receptor. Dr. Scott Friedman, MD, explains this small molecule was the most advanced in phase three clinical trials. The drug demonstrated a significant benefit by doubling the likelihood of fibrosis regression from 11% to 23% in treated patients.

Despite its efficacy, Dr. Scott Friedman, MD, notes the FDA raised safety concerns that delayed its approval. The manufacturer, Intercept Pharmaceuticals, is working to address these concerns. If successful, Obeticholic acid could become the first FDA-approved medication specifically for NASH treatment.

Resmetirom Thyroid Hormone Agonist

Resmetirom represents another promising phase three candidate for NASH therapy. Dr. Scott Friedman, MD, describes this drug as a thyroid hormone beta receptor agonist. Unlike other NASH medications, Resmetirom appears exceptionally well-tolerated and safe in clinical trials.

Dr. Scott Friedman, MD, emphasizes this drug's dual benefit for NASH patients. Resmetirom not only treats liver disease but also improves cardiovascular risk factors by lowering lipids. This is particularly important since cardiovascular disease remains the leading cause of death in NASH patients before cirrhosis develops.

Semaglutide GLP-1 Agonist

Semaglutide, a glucagon-like peptide-1 agonist, has generated significant excitement in NASH treatment. Dr. Scott Friedman, MD, explains this diabetes medication shows promise for fatty liver disease. Novo Nordisk's drug is currently undergoing phase three clinical trials for NASH indication.

According to Dr. Friedman, Semaglutide may offer similar dual benefits as Resmetirom. The medication could simultaneously treat diabetes and improve liver fat content. Data from large-scale trials are anticipated to provide clearer efficacy evidence for this approach.

Repurposed Drugs for NASH

Many existing medications are being studied for repurposing in NASH therapy. Dr. Scott Friedman, MD, mentions several drug classes under investigation. These include statins, metformin, non-steroidal anti-inflammatory agents, ACE inhibitors, and even some cancer drugs like erlotinib.

Dr. Friedman provides important context about these repurposed drugs. While statins are recommended for NASH patients with hyperlipidemia, they don't directly treat the liver disease. Most repurposed medications have shown limited efficacy in phase two NASH trials despite their safety profiles.

Safety and Tolerability Considerations

Safety and tolerability are paramount considerations for NASH drug development. Dr. Scott Friedman, MD, emphasizes that NASH patients typically have no liver-related symptoms. This means treatments must be exceptionally well-tolerated for lifelong administration, similar to hypertension medications.

Dr. Scott Friedman, MD, discusses practical administration concerns for NASH therapies. Drugs requiring daily injections present significant challenges for long-term patient compliance. The ideal NASH treatment would be easy to administer with minimal side effects, ensuring patient adherence over decades of therapy.

Future of NASH Therapy

The future of NASH treatment involves targeting multiple pathways in disease pathogenesis. Dr. Scott Friedman, MD, notes dozens of drug candidates are in various development stages. These medications target everything from gut health to liver inflammation and fibrosis progression.

Dr. Anton Titov, MD, and Dr. Friedman discuss the comprehensive approach needed for NASH management. Successful treatment will likely involve combination therapies addressing both liver disease and associated metabolic conditions. The ongoing clinical trials will determine which drug candidates offer the best balance of efficacy, safety, and practicality for long-term use.

Full Transcript

Dr. Anton Titov, MD: What are the leading candidates for the treatment of NASH and non-alcoholic fatty liver disease? How do they work? Can you give a general overview, perhaps because there are a lot of clinical trials going on?

Dr. Scott Friedman, MD: There are literally probably now for NASH. As you may know, drugs are tested in a sequential way as dictated by the FDA. There is phase one for safety, phase two for efficacy in small groups of patients, phase three for efficacy and safety in large groups, hundreds or thousands of patients.

One of the ways to prioritize or stratify the prospects for drug therapy of NASH is by looking at the drugs that are most advanced in terms of their phase of testing. The one that was and has been ahead of the pack was a drug known as Obeticholic acid. It is a small molecule that activates a cellular receptor known as Farnesoid X nuclear receptor.

The company that generated or made a test, Farnesoid X nuclear receptor ligand, Intercept, had a phase three trial that I think at least a couple of years ago showed some benefit. It increased the likelihood of fibrosis regression, doubled the likelihood of fibrosis regression, from about 11% to 23%. In those who were treated with the drug, that probably should have been enough to gain approval.

But the FDA raised some concerns about the safety of some patients. And so the company is in the midst of trying to address safety concerns and convince the FDA that the drug is not only effective, but it's safe. If they can do that successfully, and I don't know if they will, then they may be the first drug for NASH to be approved.

The other drug that's in phase three trials that looks very well tolerated and certainly so far is very safe is a drug known as resmetirom. It is a small molecule that also activates a kind of a nuclear receptor in responsive cells. But in this case, the receptor is the thyroid hormone beta receptor. And so this is a thyroid hormone beta-agonist. And that's in phase three studies.

Now resmetirom looks very safe. In contrast to the FXR agonists from an Intercept and other drugs, resmetirom also improves cardiovascular risk factors. In particular, resmetirom seems to lower the lipids that give rise to a risk of heart disease.

It's worth digressing for a minute and reminding ourselves that the most likely cause of death in a patient with NASH until they develop liver cirrhosis, the most likely cause is cardiovascular disease. I mentioned this as part of a systemic disease, known as the metabolic syndrome.

And so drugs that not only improve the liver but could reduce the risk of cardiovascular events, like perhaps resmetirom, have a sort of a double benefit for treating or killing two birds with one stone if you will, in treating both cardiovascular and liver complications. Resmetirom is still in phase three trials. We hope to learn more about its efficacy in a large number of patients by the end of 2022.

Most recently, there's been a lot of excitement about a class of diabetes drugs that are glucagon-like peptide one agonist. The most widely known drug is semaglutide. It is made by Novo Nordisk. There have been some clinical trials that suggest that it's very effective not only at treating diabetes but may improve fat in the liver as well.

Semaglutide is undergoing phase three clinical trials. Similar to Resmetirom, Semaglutide may offer the benefit of both treating diabetes as well as the liver disease. But data are still anticipated.

Beyond that, there are dozens of other drugs for NASH. They are mostly in phase two trials, a few in phase three. They are too numerous to mention. We can say that NASH drug candidates are targeting every element of the NASH pathogenesis. It begins with the gut going right through to the liver and the inflammation and liver scarring as well.

There is lot of medications are off-patent. There is a strategy to repurpose drugs for NASH, non-alcoholic steatohepatitis, or for fatty liver disease treatment, and therefore also to reduce the risk of hepatocellular carcinoma liver cancer.

So I'll just mention a few 'repurposed' drugs studied for NASH therapy. So there are statins, Metformin, non-steroidal anti-inflammatory agents, such as celecoxib, aspirin, perhaps. There is rapamycin, sirolimus, ACE inhibitors against high blood pressure, such as perindopril and ramipril. Erlotinib was also mentioned. These are all already oncology-related drugs.

There are also some compounds such as curcumin, such as vitamin D, and also coffee. So as I mentioned, the concept of using drugs or repurposing existing drugs is a very sound one. And there is certain evidence not only from my lab but from other sites that some of these drugs may have benefits.

Now, I have to say of those that you mentioned, most of them have been tested in NASH and are not terribly effective. Metformin, ACE inhibitors, statins, and pretty much everything on your list has been tried admittedly in smaller phase two trials. But certainly, there was no signal that would suggest that this is really going to be the answer to NASH.

Now, patients with NASH should probably be on statins because most of them have hyperlipidemia. And we know that those drugs are universally pretty safe, and they are as safe in NASH patients as they are in patients without NASH. So it is true that many patients with NASH, in fact, perhaps most patients with NASH will end up on a statin.

But we should have no illusions that statin is not going to cure or improve their NASH. So additional therapies, in addition to treating their cardiovascular risk with a statin, may be necessary.

Erlotinib is effectively receptor blocker chemotherapy. As I understand it, Erlotinib is not that well tolerated. Now, it's tolerable enough for a patient with cancer where the risk is profound and immediate. But we have to remember that if we're going to be treating NASH, most patients are going to have no symptoms from their liver.

So it's a little bit like treating hypertension. We know that treating hypertension saves lives reduces the risk of stroke and heart attack. But patients with hypertension generally have no symptoms.

So it took many years to get to the point where we have anti-hypertension drugs that were well tolerated and that had no symptoms. So that we could effectively treat hypertension across the population. And so it's similar insofar as NASH is a chronic disease as well.

And when we think about therapies, we need to assume that these are going to be lifelong therapies, just like we treat hyperlipidemia lifelong with statins. And we treat hypertension with antihypertensives. All of which is a way of saying that the drug for NASH needs to be well tolerated and easy to administer.

So, for example, there have been some drugs and clinical trials that require the patient to be injected every day. Now, that's great to prove whether a NASH drug is effective. But think about convincing a patient to inject a drug every day. It's not insulin, which of course, you have no choice.

But the concept of trying to develop a drug for NASH that might require daily injections for years or decades is a pretty tough sell.