Alan Bonder, MD, on Updates in Autoimmune Liver Disease

Dr Bonder reviews presentations from the European Association for Liver Diseases meeting providing updates on treatments for autoimmune liver diseases.

Alan Bonder, MD, is medical director of liver transplantation at Beth Israel Deaconess Medical Center and assistant professor of medicine at Harvard University Medical School in Boston, Massachusetts.

TRANSCRIPT

Welcome, everyone. I am Dr. Alan Bonder. I am the editor for the Hepatology section for the Gastroenterology Learning Network. And today I'm pleased to give you kind of the updates from EASL, which took place in Amsterdam in May of this year. So I want to start with, this was a very heavy autoimmune liver meeting, and I want to really share that there were some really good updates about specifically about PSC. So I'm going to start talking about the two clinical trials that were presented in oral presentations about PSC that had really a lot of clinical relevance.

The first one was the 96-week data on norucholic acid. This is a really, really well-done and well-designed study where basically patients who were aged between 18 and 75 who had a diagnosis established of large duct PSC or cholangiography and also had a liver biopsy within 2 months prior to entering the study were able to either receive norucholic acid, 1500 milligrams every day, randomized in a 2 to 1 versus placebo for 192 weeks, there are 144 weeks follow -up and finally up to 72 weeks over the open-label trial. Kind of the exclusion criteria were other concomitant liver disease, another autoimmune liver disease, and then when the patient had cirrhosis with a Child-Pugh more than 9 a total bilirubin of more than 4 were excluded from the study. The 2 main endpoints, the primary endpoint was a partial normalization of the elevations follows, a less than 1.5 from the upper limit of normal. And also, which is one of the first kind of stages of fibrosis endpoints, no worsening of disease stage as it says by the Ludwig staging, which basically it takes us as this is the first design study for PSC that's including stage of fibrosis. And then secondary endpoints, which is partially normalization of the elevations and no worsening of the disease stage, as that's by another staging of their liver biopsy.

So what we saw, we saw 96 patients in the placebo group. We saw 205 patients in the treated group. There are really no significant differences. I want to just basically point out the most important ones—the liver stiffness were pretty similar, the ALP scores was also very similar, and the stages of fibrosis, I would say most of the patients had between stage 1, 2, and 3, with basically less than 6% of the total patients included in the study had cirrhosis. Again, it's just also very important to stage that patients in stage 3 were like basically a third of the patients in the placebo group and a little bit more than 40 % in the treatment group.

So, when we look at the primary endpoints, when we look at the partial normalization of the elevations of less than 1.5 of the upper limit of normal and no worsening of the Ludwig disease when you look at the intention to treat patients. In the norucholic acid, the 1500 milligrams q-day, there was a significant difference, 15% versus the placebo of 0.2%. We see that concomitant use of ursodial was present in the significant amount of patients. And when you look at the stages of disease, we are seeing for the first time in any PSC trial that's being recorded, no changes in the stage of fibrosis, meaning there was own change in stages 0, 1 to 2, and even 3s. Although basically, we have a lot of patients that were stage 3s, but we are seeing that even at low stages of fibrosis, there were no movement in our stage of fibrosis, which basically takes us, this is the first time we are seeing results in the PSC population, looking at stage of fibrosis of a primary endpoint.

When we look at other really kind of endpoints, we look at changes in liver enzymes, we saw an improvement in norucholic acid when we compared them from the elevations, the GGT, and the ALT. So, I would say in conclusion of this study, this is the first randomized control trial in PSC with positive data. We know that there is, we don't have a really good set of endpoints, but now we've finally seen both liver chemistries and stages of fibrosis. And finally, just comment on the safety profile. It was an unremarkable safety profile when we compare norucholic acid to placebo. So this is exciting. I think this is the first trial that we have some positive results in PSC and hopefully this will take it to the next really round.

The other trial that I want to mention in the PSC world is called the Elmwood study. The Elmwood study was a phase 2 randomized control trial of elafibranor for PSC. In this study, patients who were eligible to study had large duct PSC and elevations of more than 1.5 of the upper limit of normal. There were stable background use of UDCA and also patients had IBD or stable IBD. Same exclusion criteria, decompensation from cirrhosis, ALT-AST more than 5 upper limit of normal, a platelet count of less than 100,000 in an eGFR of less than 60. The primary endpoint of this study was safety and tolerability of elafibranor with 80 and 120 milligrams compared to the placebo and the secondary endpoints were changing from baseline in the biochemistries and also changed from baseline into noninvasive markers of fibrosis.

Now the study looked like a randomization. There was 12 weeks of medication, both placebo, elafibranor, and elafibranor, and then everyone entered the open label study at week 12 to a week 108. When you look at baseline characteristics, the 3 groups— placebo, the elafibranor 80, and 120 were pretty similar. Again, pointing out that the liver stiffness were as well as liver function, and also there were some kind of patient reported outcomes that were also very similar.

So the result of the Elmwood study was very interesting, and again, also positive, with a grain of salt, this is only a 12 -week study. We saw a difference in the alkaline phosphatase, if we look at compared to placebo versus 80 and 120, we saw changes from baseline more than 120 milligrams, which were significantly compared to the placebo group. And also, the liver stiffness or elastography was also compared. And again, this is only a 12-week study, but we saw in those patients who were treated with 120 milligrams of elafibranor had a stabilization or only an increase of 0.4 of kilopascals at 12 weeks. And finally, changes in their itching at baseline also were more significant in the elafibranor, both at 80 and 120 compared to the placebo.

So finally the safety profile was pretty similar and not really significant AEs. So I would say in conclusion this was the first study showing that elafibranor was well tolerated over 12 weeks with over 95% of the patients going on to take part in the long-term extension. Significant improvement in elevations and stabilization of fibrosis, although we are just looking at 12 weeks of therapy. And we are seeing patient-related outcomes, data showed in patients with PSC that show a marked itch improvement. But again, this is, again, just a 12 -week data and not one of the primary endpoints.

So again with these 2 studies, we are really happy to say that we are making some progress in the PSC world and also we have different objectives and outcomes that we can use to hopefully get medications approved for this disease.