Payer Perspectives on Patient Preference Information

Expert Profile

Section 1: Setting the Scene

1.1. When thinking about the pathology of non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH), what is important to remember?

Firstly, I think it is important to note that I am a gastroenterologist and hepatologist and for readers to understand that only a small proportion of us go purely down the hepatology pathway. This is usually in big teaching centres or, occasionally, in bigger district hospitals where you may have eight or ten gastroenterologists, meaning you can handle the additional specialization. The distinction is important to remember as our viewpoint and practices can be a bit different from academics, who focus on hepatology in a more academic context.

To return to your question, the first thing is to think about the pathology of fatty liver disease versus nonalcoholic steatohepatitis from a liver perspective, which is to say that simple fatty liver disease does not cause liver problems; NASH, meanwhile is a different kettle of fish altogether. NAFLD is, however, associated with diabetes, blood pressure, cardiovascular complications, mortality, et cetera, but we should not think about it as liver disease in that respect. What happens with nonalcoholic steatohepatitis, by contrast, is that, although there’s fat in the liver, an additional immune reaction occurs leading to irritation, inflammation, ballooning – a histological term that says you’ve got NASH. Patients with this immune reaction then develop progressive fibrosis and end-stage liver disease, liver cancer.

The thing about fatty liver disease, unlike a lot of other liver diseases, is that it’s going to be a really big healthcare issue and will place significant demands on healthcare institutions in the future.

The other question I think that we are looking into is whether or not this indication is just going to impact secondary care? The short answer there, from my perspective, is “no,” as I think it will also impact primary care, which is where treatment will likely be initiated.

1.2. What unmet needs are you seeing at the moment for the treatment of these indications?

As you will be aware, there are no approved therapeutics for NASH, which results in a huge unmet need.

It might be useful for me to run briefly through what happens when we suspect someone has NAFLD or NASH. The first thing is to make a diagnosis, before stratifying the patients. And the stratification relates directly to the patient’s fibrosis. The simple – or perhaps cruel – thing is that if you don’t have much fibrosis, we’ll send you back into a primary care setting. However, if you have significant fibrosis, then we will keep an eye on you. The reason for that is that we know things will progress and you may develop liver cancer, varices, and/or end-stage liver disease. Having said that, there is not a huge amount you can do for patients at the moment. Of course, we can survey patients for liver cancer, we can perhaps endoscope them to look for viruses and treat those pharmacologically or endoscopically, but it is watchful waiting.

1.3. Given there are no approved therapeutics, how do you support patients with these conditions?

What do we suggest? Well, it’s primarily diet and lifestyle related changes. The simple fact is that losing weight, eating less, and exercising more, is the only thing most patients are recommended. You may rightly ask, “How effective is that?” I think the answer to that questions is that it is fairly marginal, to say the least. As you know, the key thing about obesity, which even our Prime Minister [Boris Johnson] has realized, is that it has a significant impact on patients – everyone is trying all kinds of interventions to tackle obesity, which can even be simple things like riding your bike more often.

Weight loss is key, overall, however. We know that you lose 10% of the body weight, your degree of steatosis in your liver will decrease and liver function tests will improve. At the moment, this is the only way we have to assist patients in improving their levels of steatosis.Now, there are certain centers where diet and lifestyle are taken much more seriously than others. Certain centers will employ dieticians and have specific interventions to address obesity. In my view, though, that moves away from the fatty liver realm and into the weight-loss realm.

The other thing you have to consider – and which we have yet to mention – are the cardiovascular risk factors associated with fatty liver diseases. How should we tackle those given that we, undoubtedly, will see them in our patients? Should be prescribing statins, for example? If you do, then that brings us back into the world of primary care. In an ideal world, I would want to have a polyclinic with a GP, lipidologist, a cardiologist, a diabetologist, a hepatologist, a dietician, and perhaps even an exercise counselor, all working together to provide a holistic approach for the patient.

As it stands at the moment, if we want outcomes from liver disease to improve, then I think we’ve got to do better than just telling people what to do. I’m for sure, it doesn’t work, “Run around and eat less,” well, that’s nice, but it is a bit glib.

Section 2: Therapeutic Pipeline for NASH

2.1. How would you describe the therapeutic pipeline for NASH at the moment?

To be honest, I think it is still very early days. Which of the horses is going to win? Again, I think it is too early to say. I think we are going to see therapies in the pipeline with very different therapeutic targets. For example, there will be therapeutics that target fat, those that target fibrosis, and those that target inflammation. Consequently, the medication or more likely medications that will achieve approval in the future are likely going to target all three. The alternative, as I mentioned, is that you lose weight be that pharmacologically, surgically, or through willpower.

I expect we will eventually see a cocktail of drugs, a bit like for hepatitis C. You need two or three different drugs for hepatitis C because you have to hit the virus at different points. The same is true for the fatty liver pathway and NASH as I expect you will have to hit at least two, if not three of the points for NASH – fat, fibrosis and inflammation.

Fibrosis reversal would be particularly good because we know that this means patients are less likely to progress to liver cancer. In other words, an anti-fibrotic Is very important, especially for patients with advanced fibrosis as you want to drive back the cancer risk as much as possible.

2.2. Are there any particular pipeline agents you are excited by?

I think all of the drugs are still really, really early in their development, and are not anywhere near arriving onto the market. Over the years, I have seen a lot of drugs come close – they had great potential but never make it onto the market. I expect this will be the case for a few of the current pipeline agents as well.

2.3. Why is it so difficult to get a drug approved for this indication?

Yeah, it’s funny, isn’t it? Over the past 8-10 years, a few drugs have received a lot of attention for their potential in treating this indication. The first group was pioglitazone and liraglutide, both antidiabetic drugs. Vitamin E has also been heavily investigated, although this can lead to some cardiovascular complications. Finally, statins have been looked at because of their anti-fibrotic benefits. There are a few drugs out there that could have an impact, but none of them are game changers.

This issue is that for drugs like statins their beneficial potential for NASH patients was only noticed as a coincidence, rather than being a primary drug under trial to confirm whether or not they work specifically for NASH. Having said that, things like statins are cheap as chips now, so we could use theoretically them. It is certainly interesting why they haven’t been used more date. It might be because all the KOLs have their research funded by pharma companies for the new drugs, but not for generic statins – who knows?

Looking forward, I suppose it will be interesting to see whether there is a push towards looking into whether repurposing drugs could be effective for NASH as we know that it can be highly effective for other indications.

2.4. Obeticholic acid has been touted as one of the potential front-runner candidates to be the first approved therapeutic for NASH. What are your thoughts on the potential of obeticholic acid here?

We already have access to obeticholic acid for a condition called primary biliary cholangitis (‘PBC’), and we have seen good data in that field. I have seen the data in the fatty liver field, and I have to say that it is not fantastic – it’s not game-changing. I haven’t seen any data to suggest it is like the hep C drugs or hep B drugs, which are real game changers. I certainly agree that obeticholic acid works in a few patients more than a placebo, but not much more than that, to be honest. I think we would probably use it in those with advanced disease. Although currently, I can only see it being used as a stopgap.

Moreover, certainly for PBC when it first came out, the price of obeticholic acid was pretty eye-watering, to say the least. It’d be interesting what the price would be because if you’re going to treat 20-30% of the whole population of Britain, that’s going to be eye wateringly expensive.

2.5 What impact do you think the approval of obeticholic acid would have on the competitive pipeline for NASH?

Even if it does achieve approval for NASH, I still think that other agents in the pipeline will play a significant role in the future because there will not be a one-drug solution, nor will obeticholic acid be a game-changer in and of itself. Other manufacturers, therefore, will probably think, “Well, the manufacturer of obeticholic acid has a lead on us, but so what?” This is because there is a huge patient population that needs treatment. If the price of obeticholic acid is particularly high as it was for PBC – around GBP 20,000-30,000/annum – then there will be plenty of opportunities for other companies to undercut them with competing agents with the same therapeutic targets, or with those that exhibit reasonable efficacy but with other targets altogether.

2.6 In an ideal world, what would you like to see come to market for the treatment of NASH?

In an ideal world, I suppose the first I would want is a tablet over an injection. I know there are discussions about injections, but patients always prefer a tablet. Secondly, the therapeutic has to act on both inflammation and fibrosis. If you said I could only have one, then I’d probably go for inflammation because we know that fibrosis can, in some cases, regress.

To expand on that second point, briefly: as you may know, fibrosis is considered in stages. When you get to F3 or F4, cirrhosis has occurred – F3 is near enough cirrhosis to be considered in the same bucket here. Sometimes these stages overlap, and you can’t be exactly certain whether you’ve got F3 or F4. Even with a biopsy, which calls the gold standard, there’s a bit of grayness about it. All that being said, any therapeutic that could assist with fibrosis reduction, would be great. Moreover, fibrosis reduction can back a fair way, although whether it normalizes is slightly difficult to say. The important thing is that you do not develop cirrhosis and if you do have it, the important thing is to ensure it remains compensated cirrhosis and that it does not become decompensated. The jury is still somewhat out on cirrhosis regression. However, if you don’t yet have cirrhosis, then certainly there’s very good evidence that fibrosis can regress. We have already seen that in, for example, hep B and hep C.

2.7 Finally, what is important to be thinking about when considering the future pipeline for this indication?

I would emphasise that NASH is going to be a very common, prevalent condition. To summarize, I think it will be important to think about whether the agent is anti-inflammatory versus anti-fibrotic or a combination of both. Will it be a polypill for example?

I would also stress the importance of remembering comorbidities, which is key. We, as hepatologists, are usually only interested in the liver, but actually, it is blood pressure, cardiac comorbidities, or diabetes that kills the patients or shortens their life, rather than the cirrhosis, liver cancer, or decompensation. If you can control these comorbidities and reduce, for example, a patient’s risk of stroke, heart attack, or cholesterol levels, then that can also have a positive impact on NASH. Ultimately, I don’t think you can treat NASH in isolation and any manufacturer will have to keep that in mind.