Dr. Kowdley reviews the different clinical needs of PBC and PSC and offer several available tools to predict their clinical course.
this morning we have for you treat dr chris cowardly who was nationally and internationally recognized expert in cola static disease PBC and PSC. And I've asked him to update those two topics for you today. Just to remind you, doctor called is the director of the libre Institute of Northwest in Seattle and also clinical professor of medicine to Floyd College of Medicine in Washington State University. And after Dr counties presentation this morning, we will then go directly to the debate into a panel. So chris take it away. Thank you paul. It's always an honor to participate in what I believe is the longest running hepatology cm course in the U. S. And also one of the best. Uh It's a pleasure to talk about primary biliary cholangitis and primary sclerosing cholangitis. You're my disclosures. Yeah. So PBC as many in the audience are well aware as a chronic progressive autoimmune disease which left inadequately treated may result in liver failure, need for liver transplantation and premature death. So we know that there's probably an underlying genetic predisposition in patients with PVC Uh that draws T cell mediated injury to the small bile ducts and deliver. These are generally 80 microns in size and that leads to portal inflammation and then bile acid or uh cold, static mediated liver injury. And persistent toxic exposure to build up of bile acids will then lead to progressive fibrosis, uh that may be associated with interface hepatitis and ultimately lead to cirrhosis. Now, some major changes in the diagnosis of PBC in the past few years, warrant mentioned, the diagnosis of PBC no longer requires a liver biopsy and as pointed out in the sld guidance and other publications, two out of three criteria are sufficient to mac make the diagnosis of PBC presence of Acholi static pattern of liver enzyme abnormalities, meaning a predominant elevation of alkaline phosphate tastes With or without elevation of Serum Billy Rubin and generally the ratio of alkaline phosphate taste to Amino. Transfer. Its elevation is at least 2-1 and sometimes more than that. The presence of an anti mitochondrial antibody, it sufficiently high tighter. In conjunction with an elevated Auckland foster tastes is sufficient to make the diagnosis cross sectional imaging using ultrasound is desirable to exclude any bile duct obstructive process. More recent data suggests that if you have the PBC specific A. N. A. Such as the sp 100 or the G. P. To 10 antibodies that would suffice as an alternative to am A positivity to make the noninvasive diagnosis of PBC. When these two biomarkers are absent, namely the anti mitochondrial antibody in the A. N. A. Then liver biopsy is required to show features of non separated destructive cholangitis and bile duct injury, and those are the cases in which liver biopsy is required. So a great deal of work in the past few years, from a variety of different cohort studies have established that alkaline phosphate tastes and billy Rubin are important markers of disease progression and identification of response to treatment. Now this is really important because the diagnosis of PBC and the PBC population that we face now is very different than in the era when the mayo PBC model or the mayo risk score was introduced because that was really determined based on predicting short to intermediate term survival free of transplantation, and was used as a guide to determine which patients should be worked up for liver transplant. But now, as we're diagnosing patients much earlier, we're looking at a much longer time horizon in predicting future risk of liver related adverse events and in that context, alkaline phosphates and billy Rubin have turned out to be very powerful biomarkers. Alkaline phosphate faces an early and ongoing indicator of PBC progression. And as I'll show you lowering alkaline phosphate taste is associated with longer transplant free survival or at least a lower alkaline phosphate cases associated with longer transplant free survival. Of course, billy Rubin is a marker of dr, pena and bile duct loss and therefore is an important predictor of survival in PBC and elevations in serum billy Rubin generally occur in later stages of the disease. So this landmark study by Wim Lammers that I had an opportunity to be a part of really established this concept that over a longer term horizon we can really start to use alkaline phosphates and billy Rubin as markers and predictors of risk as opposed to stage. And this is an important concept. Risk is the risk of future events stages where the patient is currently at now. And this slide shows that in fact, when you combine patients who have an elevated alkaline phosphate tous with those that have an elevated Billy Rubin, they have the worst transplant free survival over 15 years. Whereas those who have a normal serum Billy Rubin less than the upper limit of normal and an opulent foster taste less than twice the upper limit of normal have a substantially different transplant free survival over 15 horizon. And in fact, the differences are fairly prominent with a 29% transplant free survival versus a approximately 75% transplant free survival. So almost a four fold difference. And you have to keep in mind that if you see a PBC patient in the office, it may not be immediately apparent if a patient has a total billy Rubin of 1.3 or 1.2 which is above the upper limit of normal and has a lackland foster taste of 2 40 Compared to a patient who has a Billy Rubin of 1.0 and an outline foster taste of 2, 15 or 200. Those patients may look similar, but their long term risk is significantly different. Recent data from the Global PBC study group shows some interesting new observations. First, we used to think of alkaline phosphates and billy Rubin as dichotomous variables predicting outcome greater than 1.67 versus less than 1.67 Greater than two versus less than two. But these data show that in fact the relationship between outlined foster taste, elevation And likelihood of being free of liver transplantation or death is a linear function. So you can see here that when we evaluated almost 4600 patients with PBC who had undergone or so treatment for one year, you can see the alkaline phosphate taste comes down as you would expect with her. So deoxyribonucleic acid but then starts to gradually go up. And in fact, the likelihood of liver transplantation or death is linearly related to a alkaline phosphate taste threshold. And a similar relationship between billy Rubin and the risk of liver transplantation or death has also been observed after one year following her. So treatment being started and what this is telling us and what we impute from this is that our goal in treatment of PBC will evolve to not just getting patients to less than some threshold value, but really to try to get these values as low as possible and try and aim for what I would call a deep or complete biochemical remission. And intuitively there is no reason that this is any different than in patients with autoimmune hepatitis, where that's what we strive to achieve. We have also noted, based on data from the global PVC study group that in fact, the threshold value for Billy Rubin that predicts better long term outcomes is a cut off of 0.6 times upper limit of normal. As you can see when you compare 10 and 15 year outcomes in terms of risk of liver transplantation or mortality. In patients who achieved a billy Rubin less than 0.6 versus greater than 0.6, there is a 2.4 fold increase in these adverse events at 10 years and a two fold increase in these adverse events at 15 years. So Billy Rubin greater than .6 times upper limit of normal Associated with risk of liver transplantation or mortality, much higher than those who have a Billy Rubin less than .6 times upper limit of normal. And you wonder whether this will become another criteria that we will hope to accomplish as we get more effective and combination therapies. Now we presented last year at I. L. C. Virtual that another test that seems to be useful in adding further prognostic information is gamma GT. And the cut off level here appears to be 3.2. So as shown in the graph on the right patients who have a gamma GT greater than 3.2 times upper limit of normal and outlined phosphate is greater than 1.5 times upper limit of normal have a much lower survival probability Compared to those who have an alkaline foster taste less than 1.5 And less than 3.2 times you Ln. And in fact, gamma GT adds further granularity to showing differences in survival. In addition to our on top of alkaline phosphates. So it is also possible that down the road we will be routinely measuring gamma GT levels and aiming to try to bring those, if not to the normal range at least as low as possible. So let me move on and talk about treatment of primary biliary cholangitis. As you know, our Saudi oxalic acid was long the only approved therapy. It was approved in 1999 based on three cohorts showing a likelihood of being free of liver transplantation or death. Superior inner so versus non or so treated patients. Oh, Betty colic acid was approved in 2016 And the criteria for approval was based on the surrogate endpoint of alkaline phosphate tastes. And the primary endpoint in the poise study was a combination of achieving an alkaline phosphate taste less than 1.67 times upper limit of normal, With at least a 15% decline and maintaining a normal Billy Rubin. Long term follow up results of these of these data were published recently and there's also been a label update just last month for a better colic acid which I think the audience needs to know about. And then L. A. Fibrin or and sell delp are two different people are related compounds L. A. Fibrin or being people are alpha delta dual agonists and sell Adele par being a peep. Are delta agonists are currently in phase three trials. So the poise study designed was the following patients were randomized to either placebo with her. So uh oh Betty colic acid at five thai traded up to 10 mg uh over the period of six months and a better colic acid at 10 mg with her. So and all patients then after the completion of this double blind phase then were offered an opportunity to enter a long term open label extension study Where O. ca was started at five mg for three months, after which patients had the option to up titrate based on tolerable itty and safety. And this analysis pulled the double blind placebo data to evaluate the efficacy for up to six years or 72 months. Uh and looked at different age groups such as male versus female age at entry and age at PBC diagnosis. And what did we learn from these long term data? First of all, there does not appear to be a significant difference in men versus women in terms of overall likelihood of response, there does not appear to be a very significant difference in terms of older versus younger patients at age of entry. Our older versus younger patients at age of diagnosis. Furthermore, we can see that those results were sustained for up to five years now due to the fact that there were a couple of dozen patients who died because of exposure to OC. A concern was raised about the possibility that uh oh, see a use should be uh with caution in patients with advanced liver disease and after a careful review of all of the real world data that were available and based on prognostic modeling just last month, uh in discussions or after discussions with the F. D. A. The update um for the Obama colic acid label was released. Um Now there are some key differences between how about a colic acid is licensed in the U. S. Versus in the EU and I want to spend a minute talking about that. So, first and foremost, for patients without cirrhosis, there is no change in how we use O. C. A. Started five mg daily titrate up to 10 at three months. And in the eu it's at six months. But I think it's up to the discretion of the physician for patients with compensated cirrhosis without clinically significant portal hypertension characterized by thrombosis, leukemia or other features of portal hypertension such as societies et cetera. The current recommendation is The same approach five mg once daily up to 10 With titillation at three months. And the EU label hasn't changed. However for patients with clinically significant portal hypertension or d compensated cirrhosis. O. C. A. Is now contra indicated for this population in the U. S. Interestingly in the eu this has not changed and uh the label remains the same. But of course the note that physicians prescribing O. C. A. For for those who have compensated cirrhosis with portal hypertension or d compensated cirrhosis in the you should monitor the patients carefully. So in summary patients with clinically significant portal hypertension or d. Compensated cirrhosis should not be treated with O. C. A. As of now. What about the other compounds that are currently in development? Elephant burner? Many of you are familiar was studied for non alcoholic Seattle hepatitis. Uh We presented some Phase two data showing that in fact when you compare 80 versus 1 20 versus placebo, elephant Brenner is effective in PBC. And in this phase to a study you can see that at 80 and 120 mg there's about a 48-41% reduction in alkaline phosphate tastes after only 12 weeks of treatment. Uh and this was highly significant compared to placebo. And then when you look at the composite endpoint, if you will the so called poise criteria, how many patients achieve that with L. A. Fibrin or in this Phase two study at 80 mg it was 67% of patients and at 120 mg it was 79% of patients. So although this is not a head to head comparison, a greater proportion of patients seemed to achieve this response compared to Osaka. And that is not surprising because as you know, the FX Ar agonists not only have a cold Reddick effect and improve bile duct mediated liver injury but also may induce alkaline phosphate tastes. Thus making the alkaline phosphate is not fall as much as they would with a fib a rate GT also significantly reduced and there was improvement in lipid markers, inflammatory markers and c four. What's particularly promising about both elephant Brenner and sell Dell par, as I'll mention in the next slide is that itching appears to improve with these agents as opposed to worsen. Using a visual analogue score, patients with baseline peratis um showed at 80 mg 24% and 49% at 120 mg improvement in Peru Itis. So this compound is now in a phase three trial worldwide. Similarly sala del par in a Phase two study showed that there was significant reduction in alkaline phosphate case um as well as in patients overall who met this composite endpoints 53 versus 69% at the 5 to 10 versus 10 mg dose and alkaline phosphate taste normalization was observed in one out of three patients in the 10 mg groups which sell Adele part and 93% of those with moderate to severe politis experienced improvement in niche with the visual analogue school or decrease of greater than 20 Now. Uh a Phase three trial with sala del par was in progress but was interrupted and in fact discontinued prematurely Because of some concerns. In a separate trial in Nash about liver histological changes associated with the medication that ultimately turned out to be not felt to be real. And uh and and and the study of sala Del part in PBC has been resumed but this study was stopped and the data here is with three months of treatment. But you can see that in this phase three trial after three months of treatment, The poise criteria, if you will, the composite score was achieved in almost 80% of patients in the 10 mg group, which is very promising and similarly to the face to study a significant improvement in the itching using a NRS core which is in some ways more specific and more granular in evaluating itch and an N. R. S Greater than four is generally consistent with moderate to even severe peratis. So improvement and poor itis and significant improvement in alkaline phosphate is this study was presented at easel last year and it really provides some real world data suggesting what changes in outcomes might actually be associated with using a fib rate. Now in this case they use business vibrate which is not available in the U. S. But it's a pan people are agonists And they have a Japanese cohort of almost 10,000 patients who have been followed. And what the study showed is in the 8000 patients that were analyzed Better vibrate add on therapy with her. So showed dramatic improvements in hazard ratio for liver related death or liver transplant are all caused death or liver transplant with hazard ratios of .21 and .23 respectively. So almost an 80% reduction in liver related death and all cause mortality. And you can see here liver transplant free survival significantly different in the er So and does it vibrate group compared to her so alone compared to those who are untreated. Now of course this is a population based cohort historical registry with its usual caveats and limitations. But these data are really quite impressive and suggests that we can really change the natural history of this disease with combination therapies in addition to her. So, so in summary with PBC, it's a slowly progressive disease. We have 1st and 2nd line therapies and additional therapies are currently under understudy most patients do not achieve a complete biochemical response, fatigue and peratis remain determinants of quality of life. And we need additional therapies. Let me switch gears and talk about primary sclerosing cholangitis in some ways similar but in some ways a much more difficult and challenging disease to study PSC has a long natural history. Um But the median survival free of transplant is about 15 to 20 years, which may sound like a long time, but not so much when you realize that some patients are 15 to 20 years old. At the time of diagnosis, PSC has been classified into small duct and large duck varieties. Uh Large duck, meaning the changes on the, on the bile ducts are visible on colon geography. Small duct where they're angiograms are normal, but the biopsy shows abnormalities. Um There are many genetic and autoimmune associations with PSC, suggesting that there is a genetic footprint if you will, that starts the disease. But clearly a combination of environmental insults may be required to precipitate the clinical manifestations. There is a strong association with IBD. 5% of patients with PPS with IBD will develop PSC. And if you look at uh different studies among the population of patients with inflammatory bowel disease who have had adequate biopsies. Um and patients with PSC who have been carefully characterized, 50 to 80% of patients with PSC will have IBD. And this may influence clinical events. There is this growing recognition that there is an overlap between G four autoimmune cholangitis apathy and PSC. And it is always important, I think, to measure I G four levels to see if that is taken founder in the diagnosis as I will point out in a minute Histological features, maybe non specific and the biopsy, although it is used as the primary endpoint in several trials, uh is limited by sampling and biological variability, only 20% of the time. Will you see the path a demonic tombstone sign of the fiber ability of cholangitis And 20% of the time biopsies and PSC are normal. So uh this is a challenge. So we clearly need surrogates to predict clinical events to optimize clinical follow up, identify patients at higher risk and design endpoint selection in clinical trials. So we know that small duck versus large duck PSC has different prognosis. This may be that this is a time bias and small duck patients have been diagnosed for shorter period of time. We know that the combination of I. G. Four cholangitis on top of PSC can accelerate disease progress or disease progression. And this slide shows very interestingly from mayo that if you look at patients with PSC who have a normal I. G. Four level compared to those who have an elevated IgG four level, Their likelihood of being free of liver transplantation is much better compared to those with an elevated level. And some of the more confusing but very interesting data in PSC. And long term survival. And prognosis has to do with alkaline phosphate taste levels. And these data from Scandinavia showed that patients with persistently uh normal or Elevated alkaline phosphate taste levels less than 1.5 times the upper limit of normal had significant greater likelihood of survival compared to those who did not achieve this result. And this is one reason that some of us uh including myself, believe that it's reasonable to include a trial of her so early in diagnosis at the appropriate dose to see if we can achieve this if it doesn't happen spontaneously. And when you look at survival times, in those who have reduced levels of alkaline phosphate is compared to those who don't or so has no effect. When you look at non responders versus responders, um there is a significant difference and it appears to be independent of whether patients were treated with or so or not. So if you can add or so and get the patient to a biochemical response, maybe you can improve outcomes. There are several prognostic models that are being developed for PSC. I'm not going to go through all of them, but I'll highlight a couple, namely the Amsterdam Oxford model, the presto model and the revised mayo model, which appears to be just as good as any other model, alkaline phosphate tastes unfortunately does not appear to have the same degree of predictive value in PSC as in PBC, these are data from the symptoms a map trial and you can see that although baseline serum alkaline phosphate taste was associated with progression to cirrhosis and PSC related clinical events with a fairly small level of statistical significance changes from baseline. We're not prognostic. So liver biopsies where we're sort of stuck. And if you look at the shock or Naganuma, which is the other staging system, there does appear to be a predictive value for more advanced histology compared to milder stages of histology. In predicting PSC related clinical events, there's a lot of excitement in serum fibrosis markers in particular. Elf. And if you look at the Elf au Rock for sensitivity specificity and negative predictive value, it's quite good but you could argue that it's not that much better than Fib for uh in terms of the Eu rock but does appear to have a better negative predictive value. But FB four has a pretty acceptable positive predictive value and high specificity. So this is a very active area of discussion and research and conversations between regulators, academicians and drug developers as to how these fibrosis markers should be deployed. What about fiber scan? Well, there is a pretty good data from the FICA study, which is a large european consortium showing that in fact, if you look at patients classified based on less than 9.59 point 6 to 14.3 or greater than 14.4 that segregates transplant free survival Pretty well with patients who have less than 9.5 having excellent transplant free survival at five years. So the predictive performance of liver stiffness assessed by this AU ROC curve is 0.87 for predicting survival in the last couple of minutes. Let me talk about therapy of PSC. Uh you can see that there's a lot of different possible targets uh possibly targeting obliterate, obliterated fibrosis of the bile ducts blocking gut derived lPS blocking FX are in the gut as well as FX. Are not blocking but activating effects are in the gut, in the terminal ilium as well as in the liver peep ours. And our ers have also been studied and there's a lot of interest possibly via FX are or independently vancomycin is generating a tremendous amount of enthusiasm in terms of alteration of microbiota that might lead to end a toxin or LPS transition to deliver in a different manner. Biologics have been looked at, especially those that are used for IBD but have not shown any clear benefit. Scenic River Rock has been studied in a small pilot study and was not conclusive. Santuzza mob was studied as an anti fiber optic and didn't work. And nor are so which causes an intra Paddick collate shunt and essentially Working by a similar mechanism as or so is currently in a Phase three trial in Europe. So in order so, uh showed improvement in Cali stasis with a significant reduction in alkaline phosphate is about a 26% decrease at the highest dose was safe and well tolerated. Also showed a reduction in G. T. And a Phase three trial using a liver biopsy over 96 weeks is currently underway in europe. The Aesop trial which I had the opportunity to present with a better colic acid, looked at two doses 1.5 thai traded 23 and five thai traded to 10. And you can see that there is a significantly higher reduction in Auckland phosphates in the 5 to 10 group, lower in the 1.5 to 3 groups. But over time this benefit seems to be attenuated in the higher dose group, mainly because Peratis is a significant dose related adverse event. And in the high dose group over 90% of patients in with PSC developed Peratis. And so at this point there is not much clarity about whether there's a role for O. C. A. In PSC. So in summary it's important to risk stratify PSC patients. We have available tools to predict clinical course and additional tools are being developed, liver biopsy, unfortunately, or fortunately remains currently, the tool for evaluating outcomes in Phase three trials and a combination of imaging and functional tests may be needed down the road, treatment options are limited, but several Phase three trials are currently underway. Thank you for your attention.