Initiating Resmetirom for Patients with MASH: Recommendations on Patient Selection, Treatment Response, and Patient Monitoring
In this video, Naim Alkhouri MD, FAASLD, moderates a roundtable discussion with Amreen M. Dinani, MD, FRCPC, and Mazen Noureddin, MD, MHSc, on the practical clinical applications associated with starting and monitoring resmetirom in patients with metabolic dysfunction-associated steatohepatitis and moderate advanced fibrosis. The experts weigh in on a recent study that tackles this subject, they explain how they assess patient response to resmetirom, and more.
Additional Resources:
Noureddin M, Charlton MR, Harrison SA, et al. Expert Panel Recommendations: Practical Clinical Applications for Initiating and Monitoring Resmetirom in Patients with MASH/NASH and Moderate to noncirrhotic Advanced Fibrosis. Clin Gastroenterol Hepatol. Published online July 20, 2024. doi:10.1016/j.cgh.2024.07.003
TRANSCRIPTION:
Naim Alkhouri MD, FAASLD: Hello, everyone. Thank you for joining us. I’m Dr Naim Alkhouri, the chief medical officer and director of the Steatotic Liver Program at Arizona Liver Health in Phoenix, Arizona. I am joined today by Dr Amreen Dinani, who is Associate Professor of Medicine at Duke University and one of the leaders of this steatotic liver program and Professor Mazen Noureddin, Professor of Medicine at Houston Methodist Hospital and founder and director of the Houston Research Institute.
Our topic for today is to discuss a recent paper with the title “Expert Panel Recommendations: Practical Clinical Applications for Initiating and Monitoring Resmetirom in Patients with MASH/NASH and Moderate to Noncirrhotic Advanced Fibrosis.” This was published in Clinical Gastroenterology and Hepatology on July 15th of this year. So, we were all happy this year to see the first FDA approval of a MASH medication, resmetirom. This was approved for patients with MASH and stage 2 and 3 fibrosis. So, significant fibrosis without cirrhosis. This approval was based on the MAESTRO/NASH clinical trial.
This was a randomized placebo-controlled clinical trial that included 966 patients randomized to resmetirom 80 milligrams, 100 milligrams versus placebo. Treated for 52 weeks, they had a biopsy at baseline, showing NASH or MASH with F2, F3 fibrosis, including a small group of patients with F1 also, and then at 52 weeks, they had a repeat liver biopsy to assess for efficacy. We are encouraged to see that there was response on NASH or MASH resolution around 30% with the 20% delta from placebo.
And there was also a regression of fibrosis by stage 1 and about 25% within 11% delta from placebo. The medicine was well tolerated. The main side effects were mild nausea and mild diarrhea.
So, based on this trial, the FDA approved the medication. However, this created issues because the trial was based on histologic improvement. You needed the liver biopsy at the beginning to be included in the trial and the liver biopsy at the end to assess for response. We all know that in our clinical practice, we try to avoid doing too many biopsies. So, this is what led to this publication to guide clinicians on how to select patients and monitoring them.
So with this background, I’m going to ask Dr Dinani, what is your approach in your clinic in terms of using a non-invasive test, what we call NITs, to select patients that need pharmacologic treatment who may benefit from clinical trials?
Amreen Dinani MD, FRCPC: Great, thanks. So, I mean, the most common referral for MASLD would be someone who's been referred for elevated liver tests, and usually this is in the presence of hepatic steatosis. So as a first test getting a Fib4, I think, is the first step, and this is a good test, a simple test, to rule out advanced fibrosis.
And then, in my clinic specifically, we have access to multiple different non-invasive tests, but I think the next secondary assessment should be either using a fiber scan or vibration-controlled transient elastography or an ELF (enhanced liver fibrosis). And I say one or the other because, you know, some clinicians may not have access to fiber scan. So just know that there is another secondary test that you could use.
And then it just really depends on what that score comes up with. But in general, what I try to do is I try get more than one, at least two non -invasive tests, usually fiber scan and an ELF test to try further, better risk stratify that patient for fibrosis stage. So, for instance, a fib four of 1.3 and higher, that's someone who is sitting with an indeterminate fibrosis range. Those patients should then go on to get a fiber scan or an ELF. So if you come up with a fiber scan score with a liver stiffness measurement, that's, let's, for instance, say, 9 kilopascals, that person probably needs another test to either confirm that stage of fibrosis. And similarly, if you had an ELF test that was, for instance, 9.7, which just sits below that limit that we use of 9.8, they would probably need another test. So, I use those in combination.
The other test that I commonly use is an MRI elastography in combination with MRI-PDFF, and I use this for a couple of reasons. One of the first reasons I use this for if there's some discordance between my non-invasive tests.
So now I have a couple of non-invasive tests, for instance, the fiber scan and the ELF test that are discordant. I need a test that will help me truly determine, you know, does this person have a significant fibrosis or not? So I'll use an MRI elastography. As we know that this is probably the best non-invasive imaging -based technology that we have to determine accurately for advanced fibrosis.
And then the reasons for using my MRI PDFF is, and we may go into this later on, is because you can use this in a very informed way to, one, determine disease, but also it’s a tool to use as you monitor patients on treatment, and especially with the rollout of more medications as they get approved, this can be a tool that can be used to assess treatment response or failure to treatment because we have good data to support changes in MRI with histological outcomes and liver-related outcomes as well. There's also a whole bunch of other fancy tests that we could use, but these are some very basic tests that we could all probably use and have access to in our clinical practice.
Dr Alkhouri: I agree with everything you said, except maybe the FIB-4 piece initially. I feel like this is more to enrich in the primary care population diabetes clinic. For me, I use just kind of like a clinical pretest probability. So if I’m seeing a diabetic patient who had diabetes for 10, 15 years and had elevated liver enzymes, I don't rely on the FIB-4 because we've seen, unfortunately, in the context of clinical trials and in our hepatology practices, that many patients that have fibrodic MASH or at-risk MASH with F-2 -F-3 have F-4 less than 1.3, especially in diabetics. So, I just do this kind of like pre-test probability in my head as I walk into the clinic to talk to the patient, and we do at least a fiber scan or VCTE. I mean, liver stiffness can be measured with other machines, but this is one thing that I just do on everyone, and then the ELF is helpful. Of course, MRE is a great test.
Dr Noureddin, let me ask you about the paper itself. Can you provide us with the recommendations on which patients are the ideal candidates for resmetiron based on the expert panel paper and, you know, how were the cut points generated? Because they're slightly different than what we've seen and some of the guidelines that we utilize.
Mazen Noureddin, MD, MHSc: Well, Naim, first of all, thank you for having me, and thank you for highlighting this paper that you were part of it and many other experts. They were part of it. Of course, we don't have all the experts on it. And there was a group of us that jumped in and they, after the many questions, you, Amreen, and I got from the community asking us, “Hey, how can we start? And how can we monitor?” And the starting was easier piece, right? Because we have a lot of data. But the monitoring is a little bit, it was a little bit more difficult because we're lacking data and assessing treatment response because this is the first drug we have treatment response with, right? And also, the trial itself doesn't have all the treatment response data as yet. So that is coming. Stay tuned. We're doing a lot of analysis, and I think the AASLD meeting and the EASL meeting will show a lot of that.
So going back to the paper, and as I’m Amreen said, we looked at everything. And importantly, as we said, it's a consensus paper. It takes in consideration what is available, what is convenient. And I got some unhappy people's like, oh, my test is the best, and this is the best, and this is the best. Again, like, we're trying to help the patients and treat the patients. So, to be specific, and not treat everyone at the same time, we get the patients that they need treatment, we relied on the MAESTRO/NASH data, meaning we looked at the population there, and I remind everyone, there was a pre-screening of transient elastography of 8.5 before patients got PDFF and then liver biopsy.
But what ended up on the FDA label, in particular, that was our first thing that we relied on, what is in the label? Then, we looked at the New England Journal of Medicine paper, and there was a slight difference between what's in the FDA label and the NEJM. The difference is in the FDA label, there was only the analysis of F2s, F3s, and in the MAESTRO NASH, New England Journal paper, there was also the F1s, if you want to say that.
So, the drug label is more specific. So that was the number one evidence that we relied on by the NEJM paper. And then when we had gaps, we relied on data such as NIMBLE (Non-Invasive Biomarkers of Metabolic Liver Disease) data from Nature Medicine, a recent publication.
And basically, what we tried to target was the population with F2 and F3, equivalent to those on biopsy, which translate into significant advanced fibrosis without cirrhosis or moderate and advanced fibrosis without cirrhosis or at-risk match without cirrhosis. So, we wanted to be specific with that population in general and avoid the cirrhotics. And what that translated on based on the baseline characteristics is transient elastography between 10 to 20. Now, some of the people that they really want to treat is like what happens between 8.5 and 10, I’m like you can't consider them if you can confirm the F2 and F3, especially on a couple of NITs or even biopsy. So that population and transient elastography between 10 and 20, we felt those are the sweet spot.
But let me just take you one step before I jump into this. You must confirm the patient has MASLD. We must confirm that the patient has nothing else going on, especially two big things. I say alcoholic liver disease, alcohol-related liver disease, so we don't start treating those. They're still drinking and they're not, you deem them as non-responders. And the other big category is the autoimmune hepatitis because we don't want to miss those. And if you feel that they you're not 100% sure, just go for biopsy. Of course, viral hepatitis and all this, but the two big things is alcohol-related liver disease and autoimmune hepatitis. And we defer to the AASLD guidelines.
Then we went into this category, and we gave it the toolbox, transient elastography between 10 and 20, and especially when you get to closer to 20 make sure they don't have cirrhosis or hypertension and we put one of the indicators lately at less than 140, which was exclusion criteria. We used ELF between 9.2 and 10.3-ish, and then also a model historiography between 3.3 and 5, and we used the other AASLD guidelines scores. So I'll stop here for a second and get your reaction on this NITs and then after that, I'll go to monitoring, which is a little bit more complex, as I mentioned, unless if you want me to go to the monitoring. But there's a toolbox. There's really nice figures there. Transient elastography between 10 and 20. Magnetic resonance elastography 3.3 and 5, and they're off between 9.2 and all the way to 11.3, but you have to be careful toward the end with else.
Dr Alkhouri: You know, I was part of the paper, so I totally agree with you, but I would like to hear from Dr Dinani. What's your impression when you saw the paper?
Dr Dinani: No, you know, I thought it was very thoughtful, and it really comes from a practical standpoint. You can tell that the thought process behind it is really based on what we will see in the clinical world, right? I think the biggest thing that I also, I caution on because, you know, I treat patients with resmetirom, and I use non-invasive tests on a regular basis to re-stratify my patients.
When, if there is a doubt, I think to reiterate Mazen's point is if you are suspicious that they have early cirrhosis or cirrhosis and they are scoring higher on your non-invasive tests, you should confirm that because we don't have any data on that patient population. And that's what I have done. You know, the patients who have two solid tests, liver stiffness measurement test and that health tests, which are consistent with what we are describing as moderate to advance fibrosis.
I think that's a pretty good way to be confident that you have that right patient population. And like you mentioned, right, you've already kind of done all the stuff in your head. You know, it's the right patient population. They have the risk factors. They have, you know, a couple of metabolic diseases. You know, you've ruled out all these other etiologies and then you have two confident tests that tell you that they're moderate to advanced fibrosis. I think you can go with that in terms of being certain that they have that diagnosis. So, I like the ranges. The ranges are important because everybody won't fit with just one number.
But I want to just highlight especially from, you know, seeing a lot of these patients that each patient's different. So, if there's any suspicion that you're not meeting that category, do something else, right? Do an additional test if needed and make sure that person doesn't have autoimmune hepatitis and do not have cirrhosis. But yeah, I like the cutoffs. Those are cutoffs that I use consistently. So, it was great. It was great to see somebody else say it in published material. So just really reinforces. It's reinforced what I've been, as I say, winging in my clinic.
Dr Noureddin: And I support what you do, Amreen. And I’m just going to say, like my personal experience, like Naim, I think the FIB-4s belong to primary care for screening and it improved screening and I hope it will improve it more once this PCP listen because oftentimes, we're still like, you know, why we need to do it? It's a lot of work and all this until they get the cirrhotic here and there that they have been following their clinic and they just did not know. Now, when a patient comes to me, I do transient elastography and when the numbers are high, I confirm it with MRI-PDFF and a model photography.
I’m big on MRI-PDFF and a MR-elastography. I've done a lot of research on it. I’m a big believer in it. But in the that paper, we give options because it's, we totally understand it's not widely available. In my opinion, and for the MAESTRO NASH paper, it was one of the most accurate biomarkers. And MR-elastography is actually very accurate in fibrosis assessment.
I think it's better than transient elastography. That's my opinion, and that's the little literature we have out there in terms of the comparison. So to answer your question, I’m in terms of treatment response, and this is the tricky part. The best predictive treatment response in that paper was MRI-PDFF for both national resolution fibrosis improvement. The transient elastography aggregate data was good. CAP (controlled attenuation parameter) was not bad for both natural resolution fibrosis improvement. ALT (alanine transaminase) was okay. So, we say what happened in that clinical trials, when PDFF predicted response, it was very good. But some patients that responded on histology, you still did not see that respond on the CAP, transient elastography, and sometimes ALT.
So we say before you deem patients as non-responders on ALT and transient elastography, make sure they actually, they're really not responders because they could be still responding. And here, that's why I use the PDFF because it shows me that nice response. The other day, and I'll give you this that my personal thing. I had a patient that we forgot to do PDFF on him. When we started, we relied on transient elastography, baseline, as well as ALT. But that patient had a biopsy.
I said if I, before I deem him, non-responders, I probably get a biopsy at the end of the year. And this is a patient that did not have a problem having the biopsy. But again, biopsy is not needed. I think you have to be cautious with interpretation. Again, people's like, this test is better, this test is better. Look at the entire picture, look at platelet count, look at ALT, AST, look at stiffness and CAP. And we have been doing this for years. So, let's add the clinical flavor that we're doing every day in our clinic as hepatologists.
Dr Alkhouri: I think, you know for us, as you said, Dr Noureddin, that you have to look at the aggregates of the data and you have to have maybe multiple liver enzymes checked. I mean, in my practice, I do them every 3 months initially in the first year.
And then I like to do my baseline VCTE (vibration-controlled transient elastography), do it at 6 months and do it at 12 months also, and then look at, you know, the entire response data and then decide. But in my mind, Yes, VCTE has limitations, ALT has limitations, but if someone's ALT is decreasing, if someone's CAP score, which indicates the amount of steatosis on VCTE, is decreasing, liver stiffness, even if it stays the same after 1 year, in my mind, this is someone who's responding, and it may take a little bit longer for transient elastography to improve. We know fibrosis is a little bit harder. But I think, you know, this is what we do with other chronic liver diseases, right? Whether it's autoimmune hepatitis, we follow the enzymes in liver stiffness. And PBC, we follow the alkaline phosphatase, bilirubin, and liver stiffness. So, I think it's going to be similar. Of course, if you have access to PDFF and MRE, I think these are two good tests to also follow up with. Dr. Dinani, what's your impression about the efficacy data from MAESTRO/NASH? How big of a step forward is this medication, resmetiron.
Dr Dinani: You know, I've been asked that question before. And, you know, honestly, you know, this is an exciting time for MASH because this is the first liver-directed treatment that has been approved for MASH with moderate-to-advanced fibrosis. And most importantly, it has the data supportive of improvement in steatohepatitis without worsening of fibrosis, but also has shown us that there's fibrosis improvement without worsening at steatohepatitis at the end of this study, which was 52 weeks. So, the first liver-directed therapy to be able to show improvement in both the inflammatory features, but also this, you know, the fibrotic feature. So, this is a big deal.
We've had multiple agents that have come to this point, but really haven't been able to show these outcomes, especially the fibrotic outcomes, which we know are very closely related to MALO and other liver and overall mortality outcomes. The other part that I think, you know, I always get told, well, you know, delta is only 20% for steatohepatitis and the delta is only 10% for fibrosis improvement is that good enough?
And I’m going to say that's good enough for now. You know, we are seeing fibrosis, which takes years to lay down. We are seeing a signal at 52 weeks, which is a year, right? So, you know, my take is this is exciting. This is a step forward. We have now, we have, I think, a pretty solid agent that can improve underlying liver disease and fibrosis. You know, in terms of a safety profile, pretty well-tolerated. You know, there's some GI-related side effects.
And if you look at even the dataset, you know, a lot of these side effects can improve over time, but also sending up your patient for that expectation that these are common. The nausea and the diarrhea are common and how can we manage those effects. I think the other big thing with this medication is there aren't some big, huge contraindications in terms of drug-drug interactions. We must be careful not to use it with cyclosporine and gemfibrozil to name, you know, a couple. But otherwise, pretty safe with a lot of other medications that a lot of our patients who have metabolic diseases have. I think we have strong enough evidence because a lot of our patients are on statins. So we have some guidance in that sense as well.
And, you know, we have cardiologists that we can work with, especially people who require high-dose statins. So I think the work around the molecule is sound and supportive. Yeah, do we need more information in people who have concomitant diseases? Of course we do. Do we need to learn a little bit more as we do it? Of course we do. But I think for now, this is a great exciting time for our patients.
Dr Alkhouri: Thank you. I agree with everything you said. I think the bar was set too high, you know, to achieve NASH resolution on a biopsy. You need to lose all ballooned hepatocytes, which is not an easy feast to achieve and then fibrosis regression is such a high bar.
And also, I'd like to highlight that this is what we call intent-to-treat analysis. So, if a patient didn't get the second biopsy, they're counted as a non-responder, although we don't know exactly what happened. So this is important to understand.
So just to conclude, I want to ask you guys, I mean, now we have the medication is approved. We have the paper to guide us how to use it without a biopsy. So how is your real-world experience with the NITs and the medicine so far? And we'll end at this. Dr Noureddin?
Dr Noureddin: It has been, we're getting the first cycle, actually. I think this is the 3 months. Yeah. The approval and all this. And now like we're seeing the first cycle we started like the week 12 we started seeing the liver enzymes trending down I’m not doing a fiber scan at three months I’m going to do it at the 3, 6 months. I just had a patient the day before yesterday and she told me that her right upper quadrant discomfort that she had for years has started getting better I mean I’m not going to say you know that's it but it makes sense right defatting the liver the volume shrinking and she has not lost weight so I started seeing that i started hearing questions from my colleagues uh that the chicken liver enzymes at four weeks that they some has gone up uh not that much though and those are usually the pieces on status so I just say be patients and uh don't panic we have seen that and the patients that they were in statin. So yeah, we're fortunate to have this first FDA drug approved. We have options for patients. And I look forward to see this 6-month reward data and the 1-year data.
Dr Alkhouri: Dr Dinani?
Dr Dinani: Yeah, similar experience. You know, probably circling around, you of the 3-month mark, you know, so far pretty well tolerated. The one piece that I share is I have a patient who actually did have quite a bit of diarrhea, and she was at the 100 milligram dose.
So, I actually, appropriately, I think, dose-adjusted her to 80 milligrams to see if that would improve her symptoms. We just helped manage some of her symptoms as well with anti-diarrheal agents and she seems to be doing well at the 80-milligram dose and her 3-month liver enzymes are trending downwards despite a dose reduction in her. so yeah so far so good. We really haven't had many issues, and similar to Dr Noureddin, we're going to do a 6-month do fiberscan. We've just brought patients in, like, a quick check at 3 months. How are you doing? Is everything going okay? Let's get some liver tests. But so far, so good.
Dr Alkhouri: Yeah, this is so refreshing to hear that now we have a medicine, and the patients are responding. It's well-tolerated. I've had a similar experience with the patient improving right upper quadrant pain. I’m a little bit impatient, so I did a fiber scan the other day on a patient at the three-month mark and I saw significant reduction in the cap score and, you know, mild reduction in the liver stiffness, definite improvement in liver enzymes.
We are living in very exciting times for our patients with MASLD and MASH. I want to thank my two panelists and colleagues, Dr. Noureddin, Dr. Dinani. And thank you for joining us.
Dr Dinani: Thank you for having us.