Kaarina Kowalec's guest appearances

Kaarina Kowalec

Multiple Sclerosis Discovery: The Podcast of the MS Discovery Forum

Alan Alda

Tim Kennedy

Richard Cohen

David Baker

Jeffrey Cohen

Michael Levy

Alan Thompson

David Holtzman

Oscar Fernandez

Paul Matthews

Raj Kapoor

Adam Kaplin

Bruce Cree

Lilyana Amezcua

Daniel Hartung

OwlTail

[intro music] Host – Dan Keller Hello, and welcome to Episode Eighty-one of Multiple Sclerosis Discovery, the podcast of the MS Discovery Forum. I’m Dan Keller. The science of pharmacogenomics can help identify those genetic variants that are associated with a high or low risk for experiencing an adverse drug reaction or a beneficial therapeutic response. While at the ECTRIMS conference in Barcelona last fall, I spoke with Kaarina Kowalec, a postdoctoral fellow in the Pharmacoepidemiology in MS research group at the University of British Columbia in Vancouver, Canada. We discussed the potential for using pharmacogenomics to optimize the risk/benefit profile in a patient's favor, focusing first on the risk of liver injury with interferon-beta. Interviewer – Dan Keller How are you using pharmacogenomics to assess the risk for interferon-beta-induced liver injury? Interviewee – Kaarina Kowalec Yes, essentially we have two groups of patients. We have ones that have had the drug reaction and then the other ones that have been exposed to the same drug, but do not have the drug reaction. And so we take a saliva sample from all of them, and then we’re basically looking for genetic markers that would either increase or decrease the risk of having the drug reaction. And so by recruiting all these patients, we can use their saliva or their DNA to study whether or not they have some kind of genetic variant or genetic marker that would protect them from having the drug reaction. MSDF Are you doing genome-wide association studies or looking for specific markers? Dr. Kowalec Yes, we’re doing two-fold actually. So the first one is a candidate gene study. So this is looking at a more targeted approach to looking for genes that, based on previous literature, would be likely to be involved in the mechanism of predisposing to liver injury from interferon. So either this is related to interferon the way that it’s degraded in the body, the response towards interferon is regulated, or it can be related to the liver toxicity side. So there’s a lot of other studies that have been done looking at the genetic basis of liver toxicity from, say, flucloxacillin, amoxicillin clavulanates, a few other thrombin inhibitors, and some other cancer therapies. And so from that information we can look at those genes in our cohort. So that’s sort of the targeted approach. And then secondly, we’re doing more of a hypothesis-free type of approach, which is a general genome-wide association study. So this is where you look at every gene in the human genome, so over 20,000 genes. In each gene, you would look at, say, a few different markers within each gene. So we have a total of 1.7 million different markers that we’re looking at to see if they modify the risk of experiencing liver toxicity. MSDF Are you also doing the basic investigation, essentially heat maps, to see what genes are induced or suppressed when interferon is given? Dr. Kowalec No, so that would be, I guess, more microarray or gene expression. I think that would be sort of the next stage. If we could isolate one gene that would be involved, then we could I think then look at the expression of the gene, because, of course, that would be also important to see if interferon has any direct effect on turning on or turning off or reducing or increasing the level of a certain gene. But that would be probably for the next project, I think. MSDF Are you trying to develop a risk assessment model? Dr. Kowalec Yes, so essentially kind of like a test. So it would be once a new patient would come into clinic and, say, they were going to start one of the interferons, we could take their clinical and demographic information, like whether or not they were female, whether or not they were within a certain age group, whether or not they drinked, whether or not they took different concomitant medications; and then, as well, take a spit sample from them. And then, hopefully, within a few hours or a day or so we could tell them whether or not they would fit into a low risk or a high risk of having the drug reactions. So then the clinical decision by the neurologist or the nurses could then decide what medications they should go on. Of course, if they were in the low risk category, put them on that drug. And then if they were in the high risk, then maybe suggest something else, or still go on the medication and maybe just have more blood work done to monitor them a little more closely. MSDF Where does this stand? Developing a model is a long process. Has it started yet? Dr. Kowalec We’re in the discovery phase, so I’m going to be presenting the discovery phase where we’re initially trying to find the markers. And so we’ll finish this up within the next few months, and then the validation phase, which is basically where we would want to replicate these findings in an independent international cohort. So we have another cohort of patients that are from the US, as from Europe. That will probably take about a year or so. And then from there you could maybe implement it into the clinic, but likely the goal with looking at interferon-induced liver injury might be that we would use this information to study drug reaction with the newer medications. Because the new oral medications come into being used more, interferon might be used less, and so this just might provide some pilot work, I guess, for some of the newer oral medications. MSDF Will all this focus always on liver, or are there other toxicities that you would look at? Dr. Kowalec There’s definitely quite a few areas that I would want to look at. One, of course, is probably in the mind of most clinicians and patients as well would be PML or progressive multifocal leukoencephalopathy with natalizumab and then also with some of the newer medications as well. That would be probably the one, you know, stands out in most people’s mind that would be the likely area to study to see if we can reduce the incidence of that type of more severe drug reaction for sure. Some of the new medications definitely suppress the levels of white blood cells quite a bit, but that still kind of also ties in with PML. Mitoxantrone is not used quite as much, but it’s got a limited amount of use, because it’s associated with not only leukemia but also with inducing heart toxicity. That’s another area that would be frightening, obviously, for a lot of people. But I think those would be sort of how you could kind of round out what areas would be next likely drug reactions that would be needed to be studied. MSDF Do these kinds of investigations require networks of collaborating centers or databases? Dr. Kowalec One center definitely can’t do it all. In order to get the number of cases that you need of the drug reaction, you probably get maybe 5 to 10 per center, and so you probably need somewhere in the range of 60 to 100. And so what we did was, because of the really strong network that we have in Canada of the Canadian MS Clinics, we use that, as well as we capitalized on another drug reaction surveillance network called the Canadian Pharmacogenomics Network for Drug Safety. Using those two different networks, we were able to recruit enough patients to form our discovery cohort. And then for the replication cohort, we used some of our connections in the US and then abroad. But definitely it’s a multicenter type of study, for sure. MSDF Can these sorts of models be used also for predicting who will respond best to a drug, not only worst? Some drugs are taken from the market, because you get adverse reactions, but they work for some people who don’t have adverse reactions, and that’s a loss. Dr. Kowalec Yes, it’s definitely unfortunate, and even in the case of natalizumab, where it was taken off market because of PML, there were obviously patients who were so passionate about having this drug available to them that they were able to get that decision reversed and just released on a more stringent, I guess, criteria. I’ve never heard of a drug being put back on the market because of pharmacogenetic findings or because someone was able to find a marker that would prevent people from having a drug reaction. I think that, for example, the FDA or Health Canada or any of the European agencies I don’t believe that they would feel comfortable enough with letting a drug back out there knowing that, even if they found some kind of genetic marker. Two drugs, ximelagatran (7:17) and one other cancer therapy, they were taken off the market because of liver toxicity concerns. And what’s interesting is that it was about a similar incidence as what interferon-beta-induced liver injury was. But, of course, with MS there wasn’t many medications, so that’s probably why interferon was probably allowed to stay on the market. But those drugs were taken off the market, and then they found some genetic markers, but they weren’t quite as strong, I guess, as they were hoping. And so it was not going to work as a predictive risk model or as a predictive genetic test, so they weren’t going to be allowed back on the market. But I think the ideal time to look at these types of genetic markers would be probably in some of the final stages of, say, clinical trial testing. And maybe pharmaceutical companies might be doing this, I’m not sure, but to look at these types of genetic markers in those stages would be really beneficial, because if you see them as they’re developing them, you could offer them as kind of like a companion diagnostic type of test, so whenever they would release the drug. Usually these drug reactions don’t actually occur until you’ve treated probably ten to fifteen thousand people, so that’s the other difficulty. So maybe another stage would be to just do sort of like an active surveillance to sort of recruit patients as they’re on the drug and just monitor all of them. But, of course, that takes a lot of money and takes a lot of time, so you need the funding for that type of study. MSDF This would be like a Phase 4 post-marketing study. Dr. Kowalec Yes, exactly. And they do that, right. They do a lot of active surveillance for drug reactions whenever a new drug comes onto market. But to actually develop some kind of predictive biomarker test at the same time, is not really done pretty readily, at least to my knowledge. So it would be great, because if you see how much money goes into developing every drug, you know, and if we want to keep it on the market, then maybe that’s what you have to do. MSDF People are developing in vitro liver assays. I guess that’s an early stage sort of thing before they go through a whole development process. Dr. Kowalec Yes, exactly. And that will definitely help as our technology certainly gets a lot better in the future, and we can study the liver much more readily, especially in people with MS. Just studying MS as a disease on its own is really difficult, and so studying the liver is very low down the list. And so we don’t even know really if MS affects the liver on its own, so that could be another entire study. MSDF Anything important to add? Dr. Kowalec You know, I really hope that we eventually get to a day where patients can take a drug that’s really effective. We’re definitely getting there. We’re definitely getting drugs that are more effective, but at the caveat that they definitely are more toxic. That’s definitely unfortunate, because the patients are scared, right? These side effects are fatal sometimes and are really very worrisome. And I can give one anecdotal experience that I had with a patient that experienced liver injury from interferon. And I’ve certainly had a lot of people that didn’t really believe that this drug reaction was all that important sometimes to study. And I met this one patient that experienced it, and she said, you know, I’m not really worried about this drug reaction itself. It’s just I don’t know what has happened to my liver. I know this one instance is over, but now for the rest of my life, I’m scared of every drink that I have or every time I want to take an acetaminophen pill for a headache or a fever or whatnot. If they don’t have to worry about one additional thing, you know, they’re already worried about how MS is going to affect their life. If we can maybe eliminate something like this, it’ll help some patients. MSDF Very good, thank you. Dr. Kowalec Thank you. [transition music] MSDF Thank you for listening to Episode Eighty-one of Multiple Sclerosis Discovery. This podcast was produced by the MS Discovery Forum, MSDF, the premier source of independent news and information on MS research. MSDF’s executive editor is Carol Cruzan Morton. Msdiscovery.org is part of the nonprofit Accelerated Cure Project for Multiple Sclerosis. Robert McBurney is our President and CEO, and Hollie Schmidt is Vice President of Scientific Operations. Msdiscovery.org aims to focus attention on what is known and not yet known about the causes of MS and related conditions, their pathological mechanisms, and potential ways to intervene. By communicating this information in a way that builds bridges among different disciplines, we hope to open new routes toward significant clinical advances. [outro music] We’re interested in your opinions. Please join the discussion on one of our online forums or send comments, criticisms, and suggestions to editor@msdiscovery.org. For Multiple Sclerosis Discovery, I'm Dan Keller.

[intro music] Host – Dan Keller Hello, and welcome to Episode Eighty-one of Multiple Sclerosis Discovery, the podcast of the MS Discovery Forum. I’m Dan Keller. The science of pharmacogenomics can help identify those genetic variants that are associated with a high or low risk for experiencing an adverse drug reaction or a beneficial therapeutic response. While at the ECTRIMS conference in Barcelona last fall, I spoke with Kaarina Kowalec, a postdoctoral fellow in the Pharmacoepidemiology in MS research group at the University of British Columbia in Vancouver, Canada. We discussed the potential for using pharmacogenomics to optimize the risk/benefit profile in a patient's favor, focusing first on the risk of liver injury with interferon-beta. Interviewer – Dan Keller How are you using pharmacogenomics to assess the risk for interferon-beta-induced liver injury? Interviewee – Kaarina Kowalec Yes, essentially we have two groups of patients. We have ones that have had the drug reaction and then the other ones that have been exposed to the same drug, but do not have the drug reaction. And so we take a saliva sample from all of them, and then we’re basically looking for genetic markers that would either increase or decrease the risk of having the drug reaction. And so by recruiting all these patients, we can use their saliva or their DNA to study whether or not they have some kind of genetic variant or genetic marker that would protect them from having the drug reaction. MSDF Are you doing genome-wide association studies or looking for specific markers? Dr. Kowalec Yes, we’re doing two-fold actually. So the first one is a candidate gene study. So this is looking at a more targeted approach to looking for genes that, based on previous literature, would be likely to be involved in the mechanism of predisposing to liver injury from interferon. So either this is related to interferon the way that it’s degraded in the body, the response towards interferon is regulated, or it can be related to the liver toxicity side. So there’s a lot of other studies that have been done looking at the genetic basis of liver toxicity from, say, flucloxacillin, amoxicillin clavulanates, a few other thrombin inhibitors, and some other cancer therapies. And so from that information we can look at those genes in our cohort. So that’s sort of the targeted approach. And then secondly, we’re doing more of a hypothesis-free type of approach, which is a general genome-wide association study. So this is where you look at every gene in the human genome, so over 20,000 genes. In each gene, you would look at, say, a few different markers within each gene. So we have a total of 1.7 million different markers that we’re looking at to see if they modify the risk of experiencing liver toxicity. MSDF Are you also doing the basic investigation, essentially heat maps, to see what genes are induced or suppressed when interferon is given? Dr. Kowalec No, so that would be, I guess, more microarray or gene expression. I think that would be sort of the next stage. If we could isolate one gene that would be involved, then we could I think then look at the expression of the gene, because, of course, that would be also important to see if interferon has any direct effect on turning on or turning off or reducing or increasing the level of a certain gene. But that would be probably for the next project, I think. MSDF Are you trying to develop a risk assessment model? Dr. Kowalec Yes, so essentially kind of like a test. So it would be once a new patient would come into clinic and, say, they were going to start one of the interferons, we could take their clinical and demographic information, like whether or not they were female, whether or not they were within a certain age group, whether or not they drinked, whether or not they took different concomitant medications; and then, as well, take a spit sample from them. And then, hopefully, within a few hours or a day or so we could tell them whether or not they would fit into a low risk or a high risk of having the drug reactions. So then the clinical decision by the neurologist or the nurses could then decide what medications they should go on. Of course, if they were in the low risk category, put them on that drug. And then if they were in the high risk, then maybe suggest something else, or still go on the medication and maybe just have more blood work done to monitor them a little more closely. MSDF Where does this stand? Developing a model is a long process. Has it started yet? Dr. Kowalec We’re in the discovery phase, so I’m going to be presenting the discovery phase where we’re initially trying to find the markers. And so we’ll finish this up within the next few months, and then the validation phase, which is basically where we would want to replicate these findings in an independent international cohort. So we have another cohort of patients that are from the US, as from Europe. That will probably take about a year or so. And then from there you could maybe implement it into the clinic, but likely the goal with looking at interferon-induced liver injury might be that we would use this information to study drug reaction with the newer medications. Because the new oral medications come into being used more, interferon might be used less, and so this just might provide some pilot work, I guess, for some of the newer oral medications. MSDF Will all this focus always on liver, or are there other toxicities that you would look at? Dr. Kowalec There’s definitely quite a few areas that I would want to look at. One, of course, is probably in the mind of most clinicians and patients as well would be PML or progressive multifocal leukoencephalopathy with natalizumab and then also with some of the newer medications as well. That would be probably the one, you know, stands out in most people’s mind that would be the likely area to study to see if we can reduce the incidence of that type of more severe drug reaction for sure. Some of the new medications definitely suppress the levels of white blood cells quite a bit, but that still kind of also ties in with PML. Mitoxantrone is not used quite as much, but it’s got a limited amount of use, because it’s associated with not only leukemia but also with inducing heart toxicity. That’s another area that would be frightening, obviously, for a lot of people. But I think those would be sort of how you could kind of round out what areas would be next likely drug reactions that would be needed to be studied. MSDF Do these kinds of investigations require networks of collaborating centers or databases? Dr. Kowalec One center definitely can’t do it all. In order to get the number of cases that you need of the drug reaction, you probably get maybe 5 to 10 per center, and so you probably need somewhere in the range of 60 to 100. And so what we did was, because of the really strong network that we have in Canada of the Canadian MS Clinics, we use that, as well as we capitalized on another drug reaction surveillance network called the Canadian Pharmacogenomics Network for Drug Safety. Using those two different networks, we were able to recruit enough patients to form our discovery cohort. And then for the replication cohort, we used some of our connections in the US and then abroad. But definitely it’s a multicenter type of study, for sure. MSDF Can these sorts of models be used also for predicting who will respond best to a drug, not only worst? Some drugs are taken from the market, because you get adverse reactions, but they work for some people who don’t have adverse reactions, and that’s a loss. Dr. Kowalec Yes, it’s definitely unfortunate, and even in the case of natalizumab, where it was taken off market because of PML, there were obviously patients who were so passionate about having this drug available to them that they were able to get that decision reversed and just released on a more stringent, I guess, criteria. I’ve never heard of a drug being put back on the market because of pharmacogenetic findings or because someone was able to find a marker that would prevent people from having a drug reaction. I think that, for example, the FDA or Health Canada or any of the European agencies I don’t believe that they would feel comfortable enough with letting a drug back out there knowing that, even if they found some kind of genetic marker. Two drugs, ximelagatran (7:17) and one other cancer therapy, they were taken off the market because of liver toxicity concerns. And what’s interesting is that it was about a similar incidence as what interferon-beta-induced liver injury was. But, of course, with MS there wasn’t many medications, so that’s probably why interferon was probably allowed to stay on the market. But those drugs were taken off the market, and then they found some genetic markers, but they weren’t quite as strong, I guess, as they were hoping. And so it was not going to work as a predictive risk model or as a predictive genetic test, so they weren’t going to be allowed back on the market. But I think the ideal time to look at these types of genetic markers would be probably in some of the final stages of, say, clinical trial testing. And maybe pharmaceutical companies might be doing this, I’m not sure, but to look at these types of genetic markers in those stages would be really beneficial, because if you see them as they’re developing them, you could offer them as kind of like a companion diagnostic type of test, so whenever they would release the drug. Usually these drug reactions don’t actually occur until you’ve treated probably ten to fifteen thousand people, so that’s the other difficulty. So maybe another stage would be to just do sort of like an active surveillance to sort of recruit patients as they’re on the drug and just monitor all of them. But, of course, that takes a lot of money and takes a lot of time, so you need the funding for that type of study. MSDF This would be like a Phase 4 post-marketing study. Dr. Kowalec Yes, exactly. And they do that, right. They do a lot of active surveillance for drug reactions whenever a new drug comes onto market. But to actually develop some kind of predictive biomarker test at the same time, is not really done pretty readily, at least to my knowledge. So it would be great, because if you see how much money goes into developing every drug, you know, and if we want to keep it on the market, then maybe that’s what you have to do. MSDF People are developing in vitro liver assays. I guess that’s an early stage sort of thing before they go through a whole development process. Dr. Kowalec Yes, exactly. And that will definitely help as our technology certainly gets a lot better in the future, and we can study the liver much more readily, especially in people with MS. Just studying MS as a disease on its own is really difficult, and so studying the liver is very low down the list. And so we don’t even know really if MS affects the liver on its own, so that could be another entire study. MSDF Anything important to add? Dr. Kowalec You know, I really hope that we eventually get to a day where patients can take a drug that’s really effective. We’re definitely getting there. We’re definitely getting drugs that are more effective, but at the caveat that they definitely are more toxic. That’s definitely unfortunate, because the patients are scared, right? These side effects are fatal sometimes and are really very worrisome. And I can give one anecdotal experience that I had with a patient that experienced liver injury from interferon. And I’ve certainly had a lot of people that didn’t really believe that this drug reaction was all that important sometimes to study. And I met this one patient that experienced it, and she said, you know, I’m not really worried about this drug reaction itself. It’s just I don’t know what has happened to my liver. I know this one instance is over, but now for the rest of my life, I’m scared of every drink that I have or every time I want to take an acetaminophen pill for a headache or a fever or whatnot. If they don’t have to worry about one additional thing, you know, they’re already worried about how MS is going to affect their life. If we can maybe eliminate something like this, it’ll help some patients. MSDF Very good, thank you. Dr. Kowalec Thank you. [transition music] MSDF Thank you for listening to Episode Eighty-one of Multiple Sclerosis Discovery. This podcast was produced by the MS Discovery Forum, MSDF, the premier source of independent news and information on MS research. MSDF’s executive editor is Carol Cruzan Morton. <a href="http://Msdiscovery.org" rel="nofollow" target="_blank">Msdiscovery.org</a> is part of the nonprofit Accelerated Cure Project for Multiple Sclerosis. Robert McBurney is our President and CEO, and Hollie Schmidt is Vice President of Scientific Operations. <a href="http://Msdiscovery.org" rel="nofollow" target="_blank">Msdiscovery.org</a> aims to focus attention on what is known and not yet known about the causes of MS and related conditions, their pathological mechanisms, and potential ways to intervene. By communicating this information in a way that builds bridges among different disciplines, we hope to open new routes toward significant clinical advances. [outro music] We’re interested in your opinions. Please join the discussion on one of our online forums or send comments, criticisms, and suggestions to editor@msdiscovery.org. For Multiple Sclerosis Discovery, I'm Dan Keller.

 Multiple Sclerosis Discovery -- Episode 81 with Dr. Kaarina Kowalec

Full transcript: [intro music] Host – Dan Keller Hello, and welcome to Episode Eighty of Multiple Sclerosis Discovery, the podcast of the MS Discovery Forum. I’m Dan Keller. Interferon beta is a well-known and long used treatment for relapsing-remitting MS, but it's not without potential problems for some patients. While at the ECTRIMS conference in Barcelona last fall, I spoke with Kaarina Kowalec, a post-doctoral fellow in the Division of Neurology at the University of British Columbia in Vancouver, Canada. We discussed interferon beta and other drugs and their potential for liver toxicity. Interviewer – Dan Keller In terms of liver toxicity of interferon beta, what's the problem? Interviewee – Kaarina Kowalec I would say that about 1 in 50 patients that are exposed to this drug will experience a side effect known as drug-induced liver injury, or liver toxicity, essentially; it's an abnormality in their blood work. Most times it'll just go back down to normal and everything is fine, but in the rare occurrence sometimes it can lead to more severe outcomes such as needing a liver transplant, sometimes even liver failure, and sometimes even death. That's definitely a very rare scenario, but it certainly is an issue, and it's definitely a worry for some patients and definitely for clinicians, as well. MSDF Also, it's not only interferon, a lot of drugs have liver effects. Is that right, new drugs especially? Dr. Kowalec It's the number one reason that drugs are taken off the market, and it's usually one of the top concerns for any new drug that's entering into the market. Obviously, the liver has many different functions, but one being that it detoxify foreign components like drugs like interferon, like alcohol, food, many different things. So it definitely plays a major role, that's why it's usually effected so much.   MSDF What are some of the factors that affect both efficacy and toxicity of drugs in general? Dr. Kowalec You know, if you see it kind of a pie chart, the genetic component can be pretty variable. So from person to person, it could be anywhere from a few percent to up to 50 to 60%. But the rest of that pie, I guess, is made up of variation in how much of an enzyme we make that needs to detoxify the drug, as well as our age, our BMI—how much we weigh—how tall we are, whether or not we're male or female. There's a variety of different demographic-type factors that come into play, as well. It's definitely very difficult to predict who will have a safe and effective response to a drug. MSDF Does polypharmacy play a role, especially you had mentioned enzymes; things that induce or suppress enzymes? Dr. Kowalec Yeah, definitely. So in the case of an interferon, there's some evidence to suggest that interferon might suppress some of the cytochrome, or drug-metabolizing enzymes. And in that case if they were taking any additional medications, such as like Tylenol (acetaminophen) or ibuprofen, that could create an issue because interferon is inhibiting the enzymes that are necessary to detoxify the acetaminophen, then obviously the body might have trouble with just acetaminophen on its own. MSDF All interferon betas, do they vary in their effects? Dr. Kowalec Yes. The versions that people with MS get as a drug therapy, there is a few different variations. So I guess half of them are made in a Chinese hamster ovary cell line, and then the other half are made in an E. coli cell line. So there are differences in the immunogenicity of those two forms, so the ones that are made in the animal cell lines are more similar to the version that we would all make endogenously, whereas the versions that are made in the E. coli cell lines are different, they're slightly more immunogenic. They're just more foreign than what we would normally make. MSDF Is it a difference in amino acid sequence, or glycosylation, or both? Dr. Kowalec Yeah, exactly. So the amino acid sequence is slightly different for the E. coli cell line versions, as well as the E. coli version is not glycosylated. So, again, that's why it's a little bit different than the human version. MSDF Do you know some of the mechanisms by which interferon betas cause liver injury? Dr. Kowalec So how it causes liver injury exactly is certainly unknown, and that's definitely an area of which I'm trying to figure out. There's two sort of competing theories, I guess. One is that interferon, because we make it endogenously, but this version is obviously still different than the version we make, it might be that obviously in MS they have an aberrant immune system; they could be recognizing the interferon as being a foreign agent and its attacking it, and then some of the cytokines that are released might be targeting the liver. So that's one theory. The other theory is that once interferon is incorporated into the cell, it might have some sort of direct effect on the mitochondria, and so it might be that it's reducing the energy metabolism of the cell and causing harm into the liver. But which of those two, we're not sure yet. MSDF Do you know risk factors for liver injury, and as they are picked up by aminotransferase elevations? Dr. Kowalec Yes. And some of the risk factors that we know for interferon-induced liver injury are related to gender, age. Sometimes it's polypharmacy, so whether or not they're taking acetaminophen or ibuprofen. One study will come out that'll say that there is an effect, one study comes out there's no effect, so it's still a little bit unclear. With gender, we know that for males they are more likely to have some of the more minor transient elevations in the aminotransferases, whereas females are more likely to be at risk for the more severe symptomatic hepatitis, or liver injury, I guess. MSDF And is it equally prevalent, or there's different gender prevalences? Dr. Kowalec I would say that overall when we looked at all the genders together, it was about the same, about 1 in 50, or 2% or so. I would say that if you're looking at just severe injury, the effect that's more symptomatic, something that a patient would actually notice, it's likely that females are more susceptible. MSDF What about duration of treatment, does that have an effect; early, late, how long? Dr. Kowalec Yeah, typically it's quite quick that they would experience this. So the median time is about the first 3 months is the greatest risk period—I guess probably 3 to 6 months – but it certainly can still occur later on, say even 2 to 5 years, or even 7 years later on, so that's why it's still really necessary to remain diligent on testing their liver aminotransferase levels even later on, even like I said, 5 to 7 years after being on treatment. The effect doesn't seem to go away, for some people anyways. MSDF I suppose while you're taking it you're getting older, and also you probably have different medications coming in and out. Dr. Kowalec Yeah, and it's not even just the other pharmaceutical therapies that you're taking, it could also be your diet, how much you exercise. There's a lot of things that can affect the liver aminotransferases, unfortunately, so sometimes it can be difficult to determine whether or not it's actually interferon beta that's the causative agent. MSDF What should patients be looking for? Dr. Kowalec You know, I think just staying up with a healthy lifestyle; not drinking excessively, eating the right foods, making sure that whatever therapies that you are taking are compatible with interferon. Your neurologist or your clinician will advise you on those areas anyways, and also keeping an open dialog with your neurologist in that you know exactly what the risks are with taking any medication. And most times your clinician will be able to tell you everything that'll be possible side effects, so just keeping an open dialog with the clinicians, I think, is great. MSDF Are there symptoms which might raise concern? Dr. Kowalec You know, I mean sort of the typical things that we think of with liver issues, like jaundice, abdominal pain—they're really like, I mean, abdominal pain that can be a symptom from many different things, right? Malaise, same thing. Really I would say jaundice is probably one of the things that would stick out in my mind to most people as having an issue with your liver, right? By the time you notice symptoms, it certainly is in the more severe end, so usually you have something else that would precede that, like the abnormal blood work. So most people don't get to that stage, which is good. MSDF Is there something physicians should be doing or looking out for? Dr. Kowalec No, I would say they're doing a really great job with just monitoring the blood work. They know that once typically patients get to 5 times the upper limit of normal for ALT, or the liver aminotransferase, that's when it's recommended that they stop the drug. So normally because they are tested quite often for the blood work abnormalities, the clinicians are really going to go about monitoring by lowering the dose of the drug or just stopping them, and then slowly titrating them back on again. They still have many options if they experience the side effects, so they're doing a great job with monitoring. MSDF Is this becoming less of a problem with new drugs, vis-à-vis, interferon beta itself? Dr. Kowalec I believe almost all of the new oral medications have all had some case reports of having liver injury associated with them, which is unfortunate. But, again, like I said, most drugs will use the liver in order to be detoxified, it's not, I guess, surprising that this is happening. So I think that we definitely need to study the theory. And that's sort of why we're studying interferon beta, because there's so many people that have taken it, there's enough people that we can study, whereas the new medications, they haven't reached sort of that level yet; they don't have 20 years of data yet. So that's why interferon beta really represents a really great way to study this type of side effect, because now hopefully maybe some of these findings we can apply to the new medications that are going to be more relevant in the future. MSDF Have you been able to see whether a history of interferon beta affects susceptibility to liver injury with any of the newer drugs? Dr. Kowalec I've seen a few patients that have had liver toxicity from interferon, and then gone on to take, say, glatiramer, and they have had that same reaction, or Copaxone. Individual clinic, they've seen it, but they just haven't had many publications on that, so it's sort of unclear, I guess, right now. I guess I should still say in the wider literature in other liver toxicity from, say, like antibiotics, there are some common mechanisms. It seems like that some people, that if they have it to one drug, they have it to multiple drugs. So there could be some underlying, I guess, common mechanisms between all of them. MSDF It would be hard to separate out whether it's a function of the patient being susceptible liver to liver injury from almost anything, versus having a history specifically of beta-interferon. Dr. Kowalec Yeah, we don't know the long-term effects of interferon beta, we don't know really what happens to them in the long run. We can only really follow the ones that have had the really severe outcomes, like liver transplant, for example. But people that experience the more minor elevations, or even the level that we study, most often we see that the liver enzymes go back down to normal. But, you know, we're only looking at this for maybe 5 to 7 years, and then after that we don't know what happens. And then, of course, then once they get older, you would expect that things might go downhill and they might have more issues. MSDF Have we missed anything important? Dr. Kowalec This is an area that with respect to toxicity with the MS medications, it's definitely an area that is not as well studied, because, of course, the overall goal is to have an effective treatment. If we have an effective and safe treatment, that's the end goal, but that's not always what happens, because we can't sort of have everything that we really need. And so I think studying these areas is definitely really important, because although patients want their disability to be prevented, they're willing to take a lot of risk. And they shouldn't have to, they should be able to have an effective treatment that is safe, as well. So I think by studying these adverse drug reactions more often, I think we'll hopefully get to that end goal eventually. MSDF Very good, thank you. [transition music] Thank you for listening to Episode Eighty of Multiple Sclerosis Discovery. This podcast was produced by the MS Discovery Forum, MSDF, the premier source of independent news and information on MS research. MSDF’s executive editor is Carol Cruzan Morton. Msdiscovery.org is part of the nonprofit Accelerated Cure Project for Multiple Sclerosis. Robert McBurney is our President and CEO, and Hollie Schmidt is Vice President of Scientific Operations. Msdiscovery.org aims to focus attention on what is known and not yet known about the causes of MS and related conditions, their pathological mechanisms, and potential ways to intervene. By communicating this information in a way that builds bridges among different disciplines, we hope to open new routes toward significant clinical advances. [outro music] We’re interested in your opinions. Please join the discussion on one of our online forums or send comments, criticisms, and suggestions to editor@msdiscovery.org. For Multiple Sclerosis Discovery, I'm Dan Keller.

Full transcript: [intro music] Host – Dan Keller Hello, and welcome to Episode Eighty of Multiple Sclerosis Discovery, the podcast of the MS Discovery Forum. I’m Dan Keller. Interferon beta is a well-known and long used treatment for relapsing-remitting MS, but it's not without potential problems for some patients. While at the ECTRIMS conference in Barcelona last fall, I spoke with Kaarina Kowalec, a post-doctoral fellow in the Division of Neurology at the University of British Columbia in Vancouver, Canada. We discussed interferon beta and other drugs and their potential for liver toxicity. Interviewer – Dan Keller In terms of liver toxicity of interferon beta, what's the problem? Interviewee – Kaarina Kowalec I would say that about 1 in 50 patients that are exposed to this drug will experience a side effect known as drug-induced liver injury, or liver toxicity, essentially; it's an abnormality in their blood work. Most times it'll just go back down to normal and everything is fine, but in the rare occurrence sometimes it can lead to more severe outcomes such as needing a liver transplant, sometimes even liver failure, and sometimes even death. That's definitely a very rare scenario, but it certainly is an issue, and it's definitely a worry for some patients and definitely for clinicians, as well. MSDF Also, it's not only interferon, a lot of drugs have liver effects. Is that right, new drugs especially? Dr. Kowalec It's the number one reason that drugs are taken off the market, and it's usually one of the top concerns for any new drug that's entering into the market. Obviously, the liver has many different functions, but one being that it detoxify foreign components like drugs like interferon, like alcohol, food, many different things. So it definitely plays a major role, that's why it's usually effected so much. MSDF What are some of the factors that affect both efficacy and toxicity of drugs in general? Dr. Kowalec You know, if you see it kind of a pie chart, the genetic component can be pretty variable. So from person to person, it could be anywhere from a few percent to up to 50 to 60%. But the rest of that pie, I guess, is made up of variation in how much of an enzyme we make that needs to detoxify the drug, as well as our age, our BMI—how much we weigh—how tall we are, whether or not we're male or female. There's a variety of different demographic-type factors that come into play, as well. It's definitely very difficult to predict who will have a safe and effective response to a drug. MSDF Does polypharmacy play a role, especially you had mentioned enzymes; things that induce or suppress enzymes? Dr. Kowalec Yeah, definitely. So in the case of an interferon, there's some evidence to suggest that interferon might suppress some of the cytochrome, or drug-metabolizing enzymes. And in that case if they were taking any additional medications, such as like Tylenol (acetaminophen) or ibuprofen, that could create an issue because interferon is inhibiting the enzymes that are necessary to detoxify the acetaminophen, then obviously the body might have trouble with just acetaminophen on its own. MSDF All interferon betas, do they vary in their effects? Dr. Kowalec Yes. The versions that people with MS get as a drug therapy, there is a few different variations. So I guess half of them are made in a Chinese hamster ovary cell line, and then the other half are made in an E. coli cell line. So there are differences in the immunogenicity of those two forms, so the ones that are made in the animal cell lines are more similar to the version that we would all make endogenously, whereas the versions that are made in the E. coli cell lines are different, they're slightly more immunogenic. They're just more foreign than what we would normally make. MSDF Is it a difference in amino acid sequence, or glycosylation, or both? Dr. Kowalec Yeah, exactly. So the amino acid sequence is slightly different for the E. coli cell line versions, as well as the E. coli version is not glycosylated. So, again, that's why it's a little bit different than the human version. MSDF Do you know some of the mechanisms by which interferon betas cause liver injury? Dr. Kowalec So how it causes liver injury exactly is certainly unknown, and that's definitely an area of which I'm trying to figure out. There's two sort of competing theories, I guess. One is that interferon, because we make it endogenously, but this version is obviously still different than the version we make, it might be that obviously in MS they have an aberrant immune system; they could be recognizing the interferon as being a foreign agent and its attacking it, and then some of the cytokines that are released might be targeting the liver. So that's one theory. The other theory is that once interferon is incorporated into the cell, it might have some sort of direct effect on the mitochondria, and so it might be that it's reducing the energy metabolism of the cell and causing harm into the liver. But which of those two, we're not sure yet. MSDF Do you know risk factors for liver injury, and as they are picked up by aminotransferase elevations? Dr. Kowalec Yes. And some of the risk factors that we know for interferon-induced liver injury are related to gender, age. Sometimes it's polypharmacy, so whether or not they're taking acetaminophen or ibuprofen. One study will come out that'll say that there is an effect, one study comes out there's no effect, so it's still a little bit unclear. With gender, we know that for males they are more likely to have some of the more minor transient elevations in the aminotransferases, whereas females are more likely to be at risk for the more severe symptomatic hepatitis, or liver injury, I guess. MSDF And is it equally prevalent, or there's different gender prevalences? Dr. Kowalec I would say that overall when we looked at all the genders together, it was about the same, about 1 in 50, or 2% or so. I would say that if you're looking at just severe injury, the effect that's more symptomatic, something that a patient would actually notice, it's likely that females are more susceptible. MSDF What about duration of treatment, does that have an effect; early, late, how long? Dr. Kowalec Yeah, typically it's quite quick that they would experience this. So the median time is about the first 3 months is the greatest risk period—I guess probably 3 to 6 months – but it certainly can still occur later on, say even 2 to 5 years, or even 7 years later on, so that's why it's still really necessary to remain diligent on testing their liver aminotransferase levels even later on, even like I said, 5 to 7 years after being on treatment. The effect doesn't seem to go away, for some people anyways. MSDF I suppose while you're taking it you're getting older, and also you probably have different medications coming in and out. Dr. Kowalec Yeah, and it's not even just the other pharmaceutical therapies that you're taking, it could also be your diet, how much you exercise. There's a lot of things that can affect the liver aminotransferases, unfortunately, so sometimes it can be difficult to determine whether or not it's actually interferon beta that's the causative agent. MSDF What should patients be looking for? Dr. Kowalec You know, I think just staying up with a healthy lifestyle; not drinking excessively, eating the right foods, making sure that whatever therapies that you are taking are compatible with interferon. Your neurologist or your clinician will advise you on those areas anyways, and also keeping an open dialog with your neurologist in that you know exactly what the risks are with taking any medication. And most times your clinician will be able to tell you everything that'll be possible side effects, so just keeping an open dialog with the clinicians, I think, is great. MSDF Are there symptoms which might raise concern? Dr. Kowalec You know, I mean sort of the typical things that we think of with liver issues, like jaundice, abdominal pain—they're really like, I mean, abdominal pain that can be a symptom from many different things, right? Malaise, same thing. Really I would say jaundice is probably one of the things that would stick out in my mind to most people as having an issue with your liver, right? By the time you notice symptoms, it certainly is in the more severe end, so usually you have something else that would precede that, like the abnormal blood work. So most people don't get to that stage, which is good. MSDF Is there something physicians should be doing or looking out for? Dr. Kowalec No, I would say they're doing a really great job with just monitoring the blood work. They know that once typically patients get to 5 times the upper limit of normal for ALT, or the liver aminotransferase, that's when it's recommended that they stop the drug. So normally because they are tested quite often for the blood work abnormalities, the clinicians are really going to go about monitoring by lowering the dose of the drug or just stopping them, and then slowly titrating them back on again. They still have many options if they experience the side effects, so they're doing a great job with monitoring. MSDF Is this becoming less of a problem with new drugs, vis-à-vis, interferon beta itself? Dr. Kowalec I believe almost all of the new oral medications have all had some case reports of having liver injury associated with them, which is unfortunate. But, again, like I said, most drugs will use the liver in order to be detoxified, it's not, I guess, surprising that this is happening. So I think that we definitely need to study the theory. And that's sort of why we're studying interferon beta, because there's so many people that have taken it, there's enough people that we can study, whereas the new medications, they haven't reached sort of that level yet; they don't have 20 years of data yet. So that's why interferon beta really represents a really great way to study this type of side effect, because now hopefully maybe some of these findings we can apply to the new medications that are going to be more relevant in the future. MSDF Have you been able to see whether a history of interferon beta affects susceptibility to liver injury with any of the newer drugs? Dr. Kowalec I've seen a few patients that have had liver toxicity from interferon, and then gone on to take, say, glatiramer, and they have had that same reaction, or Copaxone. Individual clinic, they've seen it, but they just haven't had many publications on that, so it's sort of unclear, I guess, right now. I guess I should still say in the wider literature in other liver toxicity from, say, like antibiotics, there are some common mechanisms. It seems like that some people, that if they have it to one drug, they have it to multiple drugs. So there could be some underlying, I guess, common mechanisms between all of them. MSDF It would be hard to separate out whether it's a function of the patient being susceptible liver to liver injury from almost anything, versus having a history specifically of beta-interferon. Dr. Kowalec Yeah, we don't know the long-term effects of interferon beta, we don't know really what happens to them in the long run. We can only really follow the ones that have had the really severe outcomes, like liver transplant, for example. But people that experience the more minor elevations, or even the level that we study, most often we see that the liver enzymes go back down to normal. But, you know, we're only looking at this for maybe 5 to 7 years, and then after that we don't know what happens. And then, of course, then once they get older, you would expect that things might go downhill and they might have more issues. MSDF Have we missed anything important? Dr. Kowalec This is an area that with respect to toxicity with the MS medications, it's definitely an area that is not as well studied, because, of course, the overall goal is to have an effective treatment. If we have an effective and safe treatment, that's the end goal, but that's not always what happens, because we can't sort of have everything that we really need. And so I think studying these areas is definitely really important, because although patients want their disability to be prevented, they're willing to take a lot of risk. And they shouldn't have to, they should be able to have an effective treatment that is safe, as well. So I think by studying these adverse drug reactions more often, I think we'll hopefully get to that end goal eventually. MSDF Very good, thank you. [transition music] Thank you for listening to Episode Eighty of Multiple Sclerosis Discovery. This podcast was produced by the MS Discovery Forum, MSDF, the premier source of independent news and information on MS research. MSDF’s executive editor is Carol Cruzan Morton. <a href="http://Msdiscovery.org" rel="nofollow" target="_blank">Msdiscovery.org</a> is part of the nonprofit Accelerated Cure Project for Multiple Sclerosis. Robert McBurney is our President and CEO, and Hollie Schmidt is Vice President of Scientific Operations. <a href="http://Msdiscovery.org" rel="nofollow" target="_blank">Msdiscovery.org</a> aims to focus attention on what is known and not yet known about the causes of MS and related conditions, their pathological mechanisms, and potential ways to intervene. By communicating this information in a way that builds bridges among different disciplines, we hope to open new routes toward significant clinical advances. [outro music] We’re interested in your opinions. Please join the discussion on one of our online forums or send comments, criticisms, and suggestions to <a href="mailto:editor@msdiscovery.org">editor@msdiscovery.org</a>. For Multiple Sclerosis Discovery, I'm Dan Keller.

 Multiple Sclerosis Discovery -- Episode 80 with Dr. Kaarina Kowalec