Transcription
Enzyme tests, are they normal? What does your fiber scan look like? What are the results of that liver biopsy?
So, the end point is really the measurable thing at the end of the study that's going to help us determine if this is an effective medication. There's always going to be secondary endpoints that are safety related. How many adverse events did patients have? Um, those types of things. But efficacy is really going to be dependent on the disease in question and it's really going to be tailored to something measurable that we can say changed from the start of the study to whatever time point. You know, some studies um might have a clinical endpoint at six months and then a second endpoint a year later or 18 months later. It's going to be the same thing, the same endpoint, but we're going to look at how that changed from baseline.
Um, so yeah, regarding endpoints, it is um in autoimmune hepatitis, it is something that because there has not been a drug that's been approved for autoimmune hepatitis, the endpoints that are accepted by the Food and Drug Administration are really still being worked out. And this is one of the really interesting uh or difficult parts is because as clinicians, we know what we're looking for. We're looking to help someone live a long, healthy life and the disease fades to the background. Like that's our goal. Um, and how do we achieve that? We want labs to feel good and we want your labs to be normal. But in a clinical trial, we need to, the endpoint needs to be a little bit more than that. We need to show that indeed the, that the inflammation has decreased uh a sufficient amount and that often requires a liver biopsy um as part of the endpoint for a clinical trial for autoimmune hepatitis. That is great.
So Ethan, Aparna, I hate to put you on the spot, but there's another online question. And Ethan, maybe you could take a stab at it because you talked about exposures, COVID vaccine and/or COVID and onset of AIH.
>> This is in your wheel, this is in your wheelhouse unless Kim wants to answer it. [snorts]
>> So um, Aparna actually put this in, in her slide, which was really good, was that the trigger could be a lot of things. There's, there's that genetic predisposition that you have to developing an an an autoimmune disease and then there's some trigger. And could that trigger be a vaccine? Could be an infection? Um, could it be an environmental exposure? All those are possible. And I think where the COVID vaccine gets a lot of press is because so many people got it in a short amount of time. We don't hear nearly as much about uh the hepatitis B vaccine doing this because we, people get that spread throughout their lives. But we, you know, this was an unprecedented thing that happened with the pandemic was that we have these vaccines that everyone is getting and everyone is getting multiple of them. And so I think that just like we, I showed you about this drug-induced autoimmune like hepatitis, the incidence uh is is low, but there I, I, I'm not going to tell you that the COVID vaccine didn't trigger autoimmune hepatitis in someone and there may be people in this room that that was the case, but it's not unique to, I would say a vaccine, any particular vaccine or infection.
>> I completely agree. So the, there are case series, there's small series that have been published that have linked, and this might be something that was looked up, that have been linked to COVID vaccine, COVID-19 vaccinations and triggering autoimmune hepatitis. So it's theoretically feasible, but the, of the series that have been published, of the millions of people that were vaccinated, it's very difficult to establish that there was true causality. So the evidence for it is incredibly weak. All of our societal guidelines still recommend that all of our patients with autoimmune hepatitis, because they're immunosuppressed, still receive the COVID-19 vaccination. So um, it is not something that is definitively linked at all to autoimmune hepatitis. But that being said, it is possible in a particular patient or in a particular person that it did trigger the development of autoimmune hepatitis.
>> So let me add gasoline to that fire. So we did a study at IU. We looked at liver test abnormalities after COVID vaccine and we found a point prevalence that was extremely low. We then looked at flu vaccine the three years before COVID came and it was double that of COVID. So I think there's, you know, this idea that there are, we are living, breathing organisms, we, we take in environmental antigens, whether it's vaccine, drugs, just living in a city, this may interact and may be important as an environmental contribution to your disease. So I think it's, those are really good points. Are there other questions here in person?
>> Talking about the triggers? What is the average delay between a trigger and it presenting in your levels?
>> I don't think there's a clear answer to that. I think that in general, when we ask our history of for our patients and we're trying to identify a trigger, I will normally say, you know, within [snorts] the past three to six months of these laboratory test abnormalities, was there an exposure? Was there new medications? All the triggers that Dr. Weber sort of mentioned, but I don't think it's entirely um, it's not so specific. You know, there's very different timelines depending on the medication, depending on the person. Usually something temporal though.
>> Can I just add on top of this? Outside of that, I want to contest the the thioguanine metabolite piece. So in that same study that we've looked at, one thing that was striking to me was patients that were at threshold despite normal limits, if you follow them longer, they were less likely to lose remission. So let me ask the audience, how many people routinely get thiopurine metabolites, the the thing that Dr. Weineberg talked about for azathioprine monitoring? Really just a a few or TGN? Okay, if you're a patient of mine, you should be raising your hand. But um, Okay. So, so this is a question of targeting again. I tend to target if patients are tolerating azathioprine. I don't know. Aparna, where do you land on thioguanine metabolites?
>> Yeah. So, I, in my practice, I do something similar to what Dr. Weineberg mentioned, where I'm only really checking it if someone's labs are abnormal. And that's to check for both reasons. One is if the labs are abnormal, it could be because one of the metabolites of azathioprine could be in a toxic range and could be driving those liver test abnormalities. And then the other reason being that if the therapeutic metabolite is still at a lower level, then I have room to increase it potentially. But I, in in my patients that are on longstanding doses of azathioprine with normal liver tests, I'm not monitoring um their thiopurine levels and I'm not adjusting my azathioprine dose if their liver tests are normal.
>> So you just mentioned hepatotoxicity with a drug that we're using in patients with liver inflammation.
>> Yeah. Isn't that crazy?
>> So you're talking about 6-MP, which is one of the byproducts. Can I ask you how do, how do you guys implement their practice? And in fact, do you ever use allopurinol to shunt back to thioguanine? And maybe you can explain what that means to the
>> Uh, yes. So I, the beautiful graph that Dr. Weinberg showed showed that azathioprine or 6-MP is broken down into two different products that are measured on blood tests. The one product is 6-TGN. The other one is 6-MM. 6-TGN was the one that we know is actively controlling the immune system and is quieting it down. The 6-MM one is the one that can cause uh hepatotoxicity, can cause damage to the liver. Um, if the 6-MM levels are high and the 6-TGN levels are low, then you can alter the way that the azathioprine is broken down by using allopurinol as a xanthine oxidase inhibitor. And yes, I, I have done that for some of my patients. Or I'll give up on azathioprine and I'll move to Cell. [laughter]
>> Ethan, what do you do? Use
>> Uh, I tend, so when I, I would, but I tend if, if someone is has a TPMT that's low, I tend just to use mycophenolate instead and not even worry about it. Um, it pretty much, and that, that's been my practice in the last few years is that if you're a, that that was one of the details I, I didn't get into in my talk was that we check the enzyme, you're everyone has different enzyme activity for how they can break down azathioprine and about 10% of the population is what are have have a harder time metabolizing, more at risk of having some of these toxicities. And so rather than do a lot of juggling to manage that, I tend to just say, let's do Cellcept because or mycophenolate, just because it, it's easier. Um, now if, if I did that and then they, there was an intolerance to mycophenolate, then I would, then I would do the whatever needed to be done using to try to help with that before moving on to some of the other medications. But I think um, Dr. and I have very similar practices to our azathioprine sort of monitoring.
>> Steal that for just a second. I'm gonna bring it back to me, which my kids will say I'm very good at doing. Um, listening to this conversation, you've heard different ways of treating similar presentations, right? And so when um drug developers are designing clinical trials, they're going to be on the phone with these guys. There's always a scientific advisory board. They're always soliciting the feedback from the experts about how are you treating these patients so that they get the best and and most experienced people talking about how are they treating this really diverse population that presents entirely differently in every single person. So the drug developers are engaging in these conversations. They're understanding the disease a little bit better so that when we do make strict guidelines about what the study is going to look like, make sure that they're selecting the right endpoints, that they have buy-in from the thought leaders and the people that are really leading the forefront on treating the these diseases. So this conversation was phenomenal, but it also probably sparked a lot of questions. How do we design a clinical trial that's going to cover all of these different situations? And the drug developers are always going to go to the experts, understand how they're treating, what they would want to do, um, and see if they can come to some consensus so that they do reduce the bias throughout the course of the study. Sorry, [laughter]
>> I had a question. So it was more back with the trigger thing, like is there a direct correlation to the amount of liver damage you have to the length of time that you've had AIH or can it be like a trigger, it's aggressive and you can have stage three fibrosis in six months?
>> It, it is highly variable. It can be like what you said, it can be, you can get rapid fibrosis or someone could have sort of smoldering autoimmune hepatitis for years that went undiagnosed. Um, I, I've seen both of them many times.
>> Yeah. Kim, can I ask a question? As an organization?
>> Sure.
>> As a nonprofit, as a patient-led organization, how should we be working with industry and CROs to to best get the word out for clinical trial and potential involvement?
>> Yeah, that's a great question, Greg. [laughter] I think again, you know, Craig put a lot on you all at at the onset of the retreat, right, to say talk to your providers. I think ask questions. Are there clinical trials coming? Do you know of any nearby? You know, maybe your physician isn't participating actively in one, but you're not far from Stanford or you're not far from IU. I think having the conversation about clinical trials and what what might be available to you as a patient is going to prompt um more questions, more concern, more education about the disease state. Um, Dr. Gle mentioned earlier, you know, as a drug was coming out, then all of a sudden there was this campaign to educate the physicians, but the first step in that is is really coming from the patient. Um, having us present at these types of events so you know that clinical trials are an option. Um, and really having those conversations with healthcare providers.