NASH Treatment in 2022: Review of Current and Future Therapies for Non-Alcoholic Steatohepatitis

Prof. Stephen Harrison (USA) reviews current and future therapies for Non-Alcoholic Steatohepatitis (NASH). After a focus on the pathogenesis of NASH and the different pathways on how underlying steatohepatitis is developed, he presents his expert perspective on how patient outcomes can be improved.
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INTRODUCTION ABOUT PROFESSOR Steven Harrison

Hello, I’m Steven Harrison, a visiting professor of hepatology at the Radcliffe Department of Medicine, University of Oxford, the medical director of Pinnacle Clinical Research and the president of summit clinical research.

It is my distinct privilege and honour today to talk to you about NASH treatment in 2022.

OVERVIEW OF NASH Treatment in 2022 Current and Future Therapies for Non-Alcoholic Steatohepatitis

Here’s the overview of my lecture. I will cover multiple areas:

Table of Contents

  • NASH: Potential Therapeutic Targets
  • Targeting
  • Agents in Phase 2 Development-Route of Administration
  • Agents in Phase 3 Development
  • NASH Development Landscape
    • Nash Resolution
  • Both NASH Resolution AND Fibrosis Improvement
  • NASH Cirrhosis Studies
  • The Future of NASH Therapeutics Ongoing Phase 3 Trials
  • Lessons Learned from these failures
  • Agents may have different profiles of histopathologic effects (fibrosis, NASH resolution) vs Extrahepatic Effects
  • First NASH Drugs in Development
  • Combination Therapy
  • Ideal Combination

NASH: Potential Therapeutic Targets

To understand where we are with NASH therapy, we must take a brief tour through the pathogenesis of this disease and understand that there are multiple different pathways, by which patients develop underlying steatohepatitis. 

NASH: Potential Therapeutic Targets

There are three main ways that disease presents in these patients:

Number one is insulin resistance:All of these patients are insulin resistant and/or have diabetes. What happens with insulin resistance is adipocytes become dysfunctional, and they release free fatty acids that are very toxic to the liver ? They’re taken up in the portal vein and delivered to the liver where the liver has a couple of options. Those toxic-free fatty acids can be esterified to triglyceride and stored as fat. They can be burned in through beta-oxidation within the mitochondria. Or they can be repackaged and shipped out of the liver in the form of very low-density lipoprotein.

Additionally, in patients with underlying non-alcoholic fatty liver disease and nonalcoholic steatohepatitis, there’s a disproportionate amount of upregulated de novo lipogenesis, and this provides another opportunity for target therapeutics. 

So, in addition, as livers become full of toxic free fatty acids, mitochondrial dysfunction begins to take place. Endoplasmic reticulum stress increased in the unfolded protein response, which ensues and drives pro-inflammatory mediators accentuated by the development of reactive oxygen species as well.

This leads to apoptosis and subsequent activation of padic stellate cells. There’s also an overlay of dysfunctional regulation with the immune cell pathways and that can also contribute. In addition, the microbiome may be playing a role here as well, and genetic influences such as hsd17 beta 13 and P and pla3 may also be contributing to the underlying pathogenesis of the disease.

Now all of these provide opportunities for drug targets – many you see listed here, and I’ve broken them down into metabolic anti-inflammatory in anti-fibrotic. The majority of therapies being developed today for NASH target metabolic processes, as you see Illustrated via ethics, are agonism fgf-19 fgf 21 PPAR agonist, thyroid hormone receptor beta agonist glp-1 receptor agonist fasten inhibitors and acetyl-coa carboxylase inhibitors. This is where we see the majority of work being done today. And where we’ll focus our energy.

However, it does not mean that there are no other pathways on the right targeting anti-inflammatory therapeutics and direct anti-fibrotic therapeutics. There are those being developed too. Just not quite as many, and ultimately, we are likely going to use combination therapy where we’ll target multiple of these different pathways in our treatment of underlying NASH. So just to drill down on what I mentioned a little bit further. There are really five different buckets. We could put drug therapies in targets related to insulin resistance into our lipid metabolism targets related to lipotoxicity and oxidative stress. Targets related to inflammation and immune Cell Activation and then targeting stellate cells directly or targeting cells that are undergoing apoptosis or necrosis. I’ve highlighted in the next slide all of the treatments currently in development with a special highlight in red for those that are currently in Phase 3. And as you can see the majority again are in the first two buckets, with some development being done on fibrosis and a few with immune cell activation and targets related to cell death. It’s also important to note that some of these drugs have pleiotropic effects and may occur in multiple different buckets. Now, I’d like to take this opportunity to explore the drugs in phase two. Now we can break this down into phase 2 a on the left in phase 2B on the right the phase two a trials are generally shorter duration. And in addition, they’re non-invasive, meaning they don’t do histopathology and you see a myriad of drugs currently in development on the right even more

drugs have made it into phase to be here. It requires paired liver biopsies, generally a biopsy to get in and a biopsy to get out. Also, generally, these trials are larger in scope. and longer in duration now. In the box shaded green, I’ve highlighted the drugs that are currently ongoing in phase 2B. Using the arrow. These are drugs that have either completed enrollment or have read out the results. So as you can see, there is a tremendous amount of activity underway right now in this field, and 2022 promises to report out numerous of these drugs and we’re hopeful that they will have positive results, and we can also break the phase two treatments down into those that are oral agents and those that are injectable or infusions. 

Treatments, tests and findings 

I want to focus on the right injections and infusions. So if you are injected if you are treating a patient with a hormone, there is no oral therapy for that. It has to be injected and that’s what we see with fgf19 and fgf21.There’s only one fgf 19 analog that’s in GMS Al deferment and that is currently in a phase 2B trial with well compensated cirrhosis.There are multiple drugs multiple companies studying fgf21 agonist. In fact many are well underway with enrollment and it is anticipated that CARO will read out their 24-week paired liver biopsy study later this year.

When looking at the GOP one receptor Agonist, I not only put GOP one’s alone. But also those in combination with either GOPs such as chairsepotide or glucagon agonists such as cadutide or pim budotide and then a triple agonist. There’s also a dgat2 inhibitor. This is using antisense technology and digat to work with lipogenesis to block De Novo lipogenesis and then finally galectin three. This is the only drug in development right now that looks at prevention of progression of disease every one of these agents listed here and that I will talk about. Currently our targeting improvement of underlying histopathology or improvement in non-invasive technology galectin 3 inhibitors is an infusion given every two weeks. It is an adaptive phase 2b3 study right now.The idea being patients are enrolled with well-compensated cirrhosis who have no evidence of esophageal varices. And the goal of treatment is to prevent the progression of various two varieties. Now, let’s look at the drugs in phase three, there are currently five. 

We’ll spend the rest of our time talking about the four that are currently in development. There’s an FXR agonist, a beta colic acid, and PPAR agonist lanifibranor. A thyroid hormone receptor beta agonist resmedarone and a GOP-1 receptor agonist semaglutide. So first, let’s look at drugs that have shown evidence of benefiting the patient from a fibrosis perspective. So here I’ve listed the drugs across the top efruxiferman lanifibrinor aldeferment resmatterome, salida del par, aram-call some agletide and okaliba and then the dosing duration above that and these bar graphs are looking at the proportion of subjects with at least one stage improvement in fibrosis, and no worse thing of the natural activity score. Let’s first look at those drugs that are in phase two and they’re highlighted in green.So a flux of ferment. Was dosed for 16 weeks and we see 62% Improvement in fibrosis with the high dose group and 48% when you take all comers compared to placebo with zero now. It’s interesting to note. The way this study was designed is that patients only underwent liver biopsy if they had Improvement in the non-invasive test, particularly MRI PDF.So not many people in placebo achieve that, in fact only two underwent biopsy. So the numbers are relatively small but it does show the potential impact of this class of drug on fibrosis.Now there is an fgf-19 analog and we see a 20 percentage point treatment effect delta with one milligram versus placebo when treated for 24 weeks when we focus on solidale part. It’s a p part delta agonist. It’s an oral therapy study that was for 36 weeks and we see at the high dose group a 37% response on fibrosis with placebo at 20%. Now this was not statistically significant, but it was a post-talk analysis and it was not powered for that endpoint when looking at compounds that are now in phase three development. I’ll show you results from their phase 2 trial and here we have lanifibrinor 48% with the 1.2 gram dose or the 1200 milligram dose compared to 29% for placebo resmedarone 29% versus 24% and I must say parenthetically with lanifibrinor that fibrosis treatment effect delta was significant with ResMed ROM.. They’re targeting predominantly NASH resolution in their phase 3 aram call 29.5% for high-dose versus 17.5 for placebo semaglutide a bit all over the map. But you see a 32 to 49 percent treatment response rate with drugs versus 33% for Placebo. 

This was not statistically significant and with Ocala 23% versus 12, the treatment effect of 11 percent was significant and that was in the Phase 3 trial. So everything I showed you up until o’clivo was data from phase two of the Okaliva study was the regenerate trial. That’s the large phase three trial that led to the initial filing for the new drug application, unfortunately because the therapeutic index was deemed to not be adequate because of some adverse events linked to This drug the FDA did not approve the drug. However on July 7th the company announced they are pursuing a refiling of this drug based on additional data. They were able to obtain additional safety data as well. So more to come as they begin the filing process. Now, let’s look at NASH resolution again using the same color coding for those drugs from phase 2. We see a Crux of ferment having a 54 to 48 percent response compared to Placebo of 50% But remember only two patients in placebo underwent to biopsy so some of these numbers might be conflated a bit and I just think we need more data before we understand exactly how effective this particular drug which is an ftf-21 Agonist is on resolution of NASH. Additionally treatment was only for 16 weeks so additional asterisk there for that particular patient that did respond was that the patient lost 25 pounds or 11% weight reduction during the period so it makes sense that there would be NASH resolution Alda Furman 24% versus 9% sell a Del part 26% versus 8% when looking at those drugs now. In phase 3, we see that there was a response with lanifibranor 49% high dose versus 22% that was significant with ResMed ROM 25 versus 15% which was significant a ram calls on whole but it did show a 16.7% with high dose versus 5% and some agletide 59% with the 0.3 milligram dose daily injection versus 17% for placebo.You see a treatment effect of 12% with high dose versus eight percent. That was not statistically.significant now maybe a higher bar absolutely a higher bar is hitting both Nash resolution and fibrosis Improvement and we see data in phase two here with the fruxa ferment out of ferment in cells. So first with the Flux Of ferment 28% versus 0% again higher bar here what you’ll see consistently with this histopathologic endpoint is that it’s harder for placebo to achieve success and many people look at that as potentially an attractive target then because you’re stabilizing placebo response rate. Yes, it’s harder for drugs to hit that as well. But it’s potentially easier to see the ground truth. How well is your drug is really working now without a furman 22 versus zero and then we’ll C19.6 with high dose versus 8.3 with placebo and a nice dose response relationship is seen it’s also important.Into highlight the stabilization of placebo response rate now for phase 3 lanifibranor. We see 3525 and 9 so a nice dose response relationship again Placebo single digits with some agletide 37% versus 15 a little bit higher Placebo response rate there may be something we haven’t seen with others when looking at this combination, but there was a higher response with some magma tide as well. Now, what about cirrhosis, where are we at? In drug development for cirrhosis. Well, we have five ongoing phase two or phase three trials. I have them all listed here. You have a beta-cholic acid, which is an FXR agonist Bellapectin, which is that galectin three inhibitor. I already mentioned it is an infusion given every two weeks. That’s a unique adaptive phase 2b3 study looking at the prevention of development of varices. 

So let’s briefly touch on where, when and what we anticipate these phase three trials reading out. As I mentioned already a ramcall is on hold resmedarone is anticipating a readout not Q3 shifted to the right there, but in Q4 of this year with long-term outcomes anticipated sometime between Q2 and Q3 of 2024 a beta colic acid. I mentioned on July 7th this year a press release came out that they are refiling based on new data and additional safety endpoints additional safety data in many many more patients, but that study is also pushing forward to an outcome that is anticipated in Q3 at 2025. So the refiling is based on the surrogate endpoint or conditional approvable endpoint of a liver biopsy at 18 months, but they still have the trial ongoing to look for overall outcomes. So magnetite is still enrolling with anticipated surrogate endpoint readout in Q3 of 2024 for some agletide and Q2 2024 for lanifibranor. Now, what are some lessons learned along the way in drug development? Well, there are many trials that have ended in failure, but it doesn’t mean we didn’t learn from them many of the drugs you see listed here. What I would like to say is we need to begin to look at these drugs not only for their histopathologic effect, but further extra hepatic effect as well and their tolerability profile. When we think of drugs, we think of therapeutic index. Therapeutic index is how effective the drug is versus how well it’s tolerated.Now I broke this slide into two parts non-serotic on the left and serotic on the right and I’ve color-coded the drugs read for mild Adverse Events and blue for mild to moderate adverse events. The ideal drug in my opinion would be a drug that’s in the upper right hand corner of this graph.For both non-serotic and serotic. Let’s start first with non-serotic NASH. We see very good results on extra hepatic effects of drugs with somagnotide a GOP one receptor agonist and afraxoferman an fgf-21 agonist. These drugs have shown beneficial effects.

Not only in the liver but also on glycemic control atherogenic lipids and weight loss for somagatide.and for effects of ferment weight is neutral to slightly down with potential impacts also on blood pressure now histopathologically, we see their ranked kind of in the middle because the data sets are small for a flux of furman and we don’t fully yet know the potential impact on histology, but with semaglutide there was no benefit seen in the large phase to be trial on fibrosis, but a very nice improvement of NASH. Lanifibranor gets maybe slightly better not on histology, but not quite as good on extra hepatic effects. It does have impacts on glycemic control and atherogenic lipids, but it also is linked to potential weight gain when looking at the right with the Flux Of Furman that is the drug that we have maybe some data on and I think it’s important to note with cirrhosis. We’re very limited in liver biopsy data certainly with Bella pectin. There is no histologic effect scene in phase two and it is being studied to look at prevention of progression to varices. There is no extra hepatic benefit that we know of would be affected alternatively with the flux of firm and I’ve already listed the extra paddock benefits where we’re limited is just on the overall ponderance of evidence on histology in a well compensated population of serotic patients. There’s only been a handful of patient stud.Need although in that study a third of them had resolution of cirrhosis. So finally, we’re at the Wright brothers stage of drug development. We’re just getting to the point where we’re taking off and able to have some response where we want to go is the F-35 precision medicine strike fighter approach where we’re honing in on therapeutics for patients that are targeted to their metabolic profile and to their genetic profile and it’s also important that we’re likely to use combination therapy to get to this point. 

Effects and implications of combination therapy 

When we think of combination therapy, we need to think of the risk tolerance, the safety and where the patients are in their liver disease progression. For instance if patients have very mild fibrosis, but have evidence of a lot of fat and inflammation, a drug that is focused predominantly on improving metabolic profiles might be the backbone target with an overlay of some fibrosis improvement with a second agent. Alternatively if a patient has cirrhosis or advanced liver disease, we want to halt disease progression as quickly as we can and so we want to target a drug that might have more anti-fibrotic effect and marry it with a drug that potentially has some metabolic benefits as well because we want to get their disease arrested or improve it but also hit the drivers of fibrosis blocking new formation of scar. 

So what is the ideal combination therapy? Well, in my opinion, it’s a drug that’s oral, well tolerated and safe and essentially is able to combine therapies in a single pill. We want them to be synergistic, improving histology and improving extra hepatic metabolic profiles with the long-term goal of improving outcomes. Not only major adverse liver outcomes, but major adverse cardiac events as well. What would that be? Well, I illustrate this slide which comes from a good friend of mine Mike Charlton where he showed this Jamaican 4×100 meter relay world record team that you see Illustrated here. They set the world record in 2011 in Seoul and a couple things to note. All of these individuals were world-class sprinters on their own, right they got along well with each other they had complementary strengths and similar endurance. And from the same home ideally combination therapy for NASH will hit four of these five world-class on their own, right they are harmonized and synergistic with each other but they have complementary strengths and they’re meant for the Long Haul in other words. We don’t develop a situation where the drug no longer works in the patient over time because of anti-drug antibodies or some other reason that they have endurance. So combination therapies that are currently underway are listed here and I would just say that there are more and more of these coming forward and this is what I’m very excited about for the future when we think of combination therapies. We need to think of different buckets.Those that target overnutrition or endocrinopathies those that focus on ER stress lipotoxicity or mitochondrial dysfunction those that target inflammation cholesterol toxicity or are multifunctional and those that target fibrosis and ideally we would pick drugs from each of these different buckets, or at least two different drugs from different buckets, just as an example. I’ve put in green hearts those that I think might be good combinations. So some agletide on the left lanifibranor in the middle and maybe even a beta colic acid on the right because it does have some fibrosis Improvement qualities that I think would go well with say something like resmedram, which is a thyroid hormone receptor beta agonists that is shown beneficial effects on steatosis Improvement and Nash resolution, but less affects to date anyway on fibrosis. So putting that oral drug with the oral drug of beta colic acid, potentially. We would synergize Nash resolution fibrosis Improvement. We would get additional benefits on pathogenic lipid Improvement and we would potentially be able to mitigate some of the Adverse Events of the beta acrylic acid by in theory using a lower dose of that drug. When combined with risk matter room, finally future therapeutic considerations, I think as we move toward Precision medicine Several things that we could do to target that one is CAR-T therapy and I illustrate this by the mouse model on the right. So we historically think of CAR-T therapy in cancer. What about using it in an advanced sirotic population or fibrotic population? This is a very elegant study published in nature in 2020 of an animal model with significant fibrosis where CAR-T therapy was utilized targeting senescent stellate cells and by blocking these fibrosis producing cells, you can see that there was resolution of scar over time. In addition to that, there was also Improvement in the liver chemistry test. We’re a long way to go before we can use this in humans, but it illustrates the principle that specific targeted precision medicine getting after a specific cell type might be advantageous and potentially used in combination therapy.

Finally therapeutic oligonucleotides provide another mechanism by which we could target therapies. I mentioned one already and I want to highlight it again today. The d-gat2 antisense oligonucleotide is already in Phase to be therapy. It’s an injectable. There’s also another one targeting fibrosis, not nash specifically and that’s heat shock protein 47.We can also Target the microbiome as we begin to learn more and more about the microbiome and its influences in the setting of Nash.genetic polymorphisms can also be evaluated and targeted specifically those in development Now hst17 Beta 13 loss of sense mutation and then PNPla3 With that I would like to conclude my presentation and thank you for your attention.

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Prof. Stephen Harrison

Prof. Stephen Harrison

With over 20 years in the industry, Dr. Harrison has formed a multitude of global and local relationships with like-minded physicians and experts to raise awareness of liver disease and find a treatment for the patients that need it most.

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