Understanding Treatment Options for Phenylketonuria Webcast January 2011 Marie LeFrancois, Dt.P. John Mitchell, M.D. Anna Maiorino Please remember that the views expressed on Patient Power do not necessarily reflect the opinions of our sponsors, our partners, or Patient Power. Our discussions are not a substitute for seeking medical advice or care from your own doctor. Please have this discussion with your own doctor in order to receive the care that is most appropriate for you. Hello! Today we would like to present to you a program where the topic will be trying to understand PKU. In fact, we often call it PKU in English, but in French, the abbreviation is PCU, for the name phénylcétonurie. We will also be speaking about the new treatments that are now available, and about emerging treatments. So, in order to give you some insight into all of this today, I will be your humble servant. My name is Marie Le François, and I am a nutritionist at the Montréal Children s Hospital. With me is Dr. John Mitchell, who works with me on a medical genetics team, where we treat patients who were born with various metabolic conditions, including PKU and others. Dr. Mitchell is also involved in research studies related to PKU. So that will give you an idea of the subjects that we are going to will cover today. We will begin by presenting an introduction to PKU. So, why do your doctor and your nutritionist always say that you must maintain low levels, and there are certain levels that they ask you about all the time? After that, will tell you about the new medications and treatments that are available to help you to keep them below the required levels. Also, what you should expect from what you will see in the literature. So without further ado, I think I would like to present Anna, one of our adult patients here at the Montréal Children s Hospital, because we also treat people who come back to us after being treated here as children. Anna has been trying to follow a diet that is low in phenylalanine since she was 8 years old. She came to us a while ago and told us that she wanted to get pregnant. And you know that when a woman with phenylketonuria wants to get pregnant, it can harm the fetus if the levels are not controlled. So Anna came to see us again, and we were happy to work with her again and establish acceptable levels for her during her pregnancy. Also, I have to tell you that Anna was surprised at all of the changes that had occurred, and she gave birth to a beautiful and healthy baby girl nearly nine months ago. So without further delay, I yield the floor to Anna, who will tell us about her experience of returning to her low phenylalanine diet. Hello Anna! The topic of our interview today is new treatments for individuals who have phenylketonuria. I believe you will have a lot to tell us about this topic.
Yes, definitely. My experiences have lasted my whole life, that s for sure. I would like you to tell us a little bit about your experience, because if I recall correctly, when we first met each other, you had started the diet when you were around 8 years old. No, I started when I was 18. 18 years old. Yeah. Then after that, it wasn t possible to go off it. After that, you came back to see me because you wanted to get pregnant. And I know that even my colleagues here told me that because of how hard it is to follow the diet, they said that you would need a lot of coaching in order to go back on the diet. And I think that, with everything I showed you and everything that happened, you were very surprised. Yes, definitely. I was really surprised, like you said. I was a very difficult patient when I was younger, but when I think back, that was because I didn t understand my situation and the consequences. So once I put it into my head that I had to do it because I wanted to get pregnant, it became much easier for me. Yes, it s true that someone who wants to get pregnant is motivated, but I think you were surprised at how the formula flavours had changed, and all of the new products that were on the market. Yeah, it didn t work anymore for me when I was younger, but now I m a little older. When I was younger, Cambrooke didn t exist, or at least I didn t know about it. So when it comes to meals, food, Cambrooke definitely makes a huge difference. A huge difference in what sense?
A positive difference. I m not saying that it s super good, but it s pleasant, and it s possible to live my life on the diet with no problems. OK, is it the same with the formulas? Yes, of course. When I was young, I didn't want to have anything to do with the formulas. But now, well they still involve some work, depending of the formula, and I can find one or two that work and that I can drink and am able to take. It makes a big, big difference. So Anna, are you also aware of the other treatments that are coming, such as KUVAN and PEG-PAL? Have you ever heard of them? Yes, I have heard a lot about KUVAN. I would like it, I am very interested, and if I am not mistaken, it is possible that it will be in Canada in the near future, I think, in a year for sure, to give you enough time. I have to say that I would like to try it. I went to a type of seminar that talked about KUVAN, that it s a little AD so that you can follow the diet more easily. And that is something that I absolutely want to try once my children are, once I have had all my children and I don t want anymore. So have you also heard of PEG-PAL, the injected enzyme? Yeah, I have heard of it, but I have to say that, unfortunately, the way I think and operate, it isn t something that I would be interested in. I haven t been looking at it. Right now, it s KUVAN, I m more interested in KUVAN than other things. Anna, have you had a chance to go on the website and hear other interviews with patients, or patients stories that have inspired you? Yes, definitely. For sure, I went on the Patient Power site and found the personal stories of people who deal with it and everything that goes with it every day, and I found it really interesting. I also read a story about a girl who, I forget now, she was 8 or 9, and I found it amazing how she followed the diet, because at that age, I didn t follow it. It s definitely a good site. For me, it s for the personal stories, because you can have all the information possible, you can read the books and talk to the doctors, but you really get to understand what we are dealing with from the personal stories. It really is a good site, and I advise everyone to visit it.
Well, thank you very much, Anna, and the good news is that you are going to be involved in it too. Thank you very much for your contribution. Thank you! So let me continue we would like you to listen to Dr. Mitchell and myself, because today we are going to tell you about KUVAN, and I can tell you right now that KUVAN is already available in Canada. It's just a matter of determining who is going to cover the costs. But a lot of work is being done on that. So I also urge you to contact your team, your doctor and dietician, to really find our where we are on this. We will also talk a little bit about where we are in terms of research into PEG-PAL, and other products that I think might help you. I think that s what happened, the new products they really revolutionized things, and that s what made it possible for you to give birth to a beautiful daughter, I think. Yes, yes, yes. It allowed me to have my daughter. She is nine years and nine months old now. And that is why, and I know that with Dr. Mitchell and the team, we discussed the possibility of a KUVAN trial, but I would wait, I think, we are talking about trying for a second baby. I don t want it to take long. As for the diet, it s easy, I know. I know what to do. I just have to focus on it. But after the second pregnancy, I want to look into where things are with KUVAN. At any rate, Anna, I like hearing you tell us now how easy the diet is, because people tell us that the diet isn t easy, but I think you have been able to compare the entire evolution of what s going on. So thank you very much, Anna. Thank you! I would now like to ask Dr. Mitchell a few questions. I know some of you want to know exactly what phenylketonuria is. So just to be sure that we are all on the same page, can you please tell us what phenylketonuria is? Yes, hello Marie! Phenylketonuria is a disease in which the body is missing a very important enzyme that is required for metabolizing amino acids. What are amino acids?
Amino acids are found in proteins, or in other words, in meat. Every meal we eat contains phenylalanine. The problem with people who have phenylketonuria is that they are not able to metabolize this protein. Just so we understand correctly, metabolizing means converting phenylalanine or properly digesting it? Yes, that s right. And that is because an enzyme called PAH, or phenylalanine hydroxylase, is missing. This enzyme normally serves to break down proteins, to break down phenylalanines, and that is what is referred to as metabolizing this amino acid. If this amino acid cannot be broken down, the result is an increase in this amino acid in the blood and in the brain. This accumulation causes problems for a child or adult who has this condition. In children, it is important to limit this amino acid. Otherwise, it can cause mental delays. In other words, if the problem is not detected at birth, the infant will be given normal milk that contains a lot of phenylalanines, just like any other dairy product, and this amino acid will accumulate in the brain and cause developmental problems. Are these developmental and mental delay problems irreversible? At this point, yes. If the child is not diagnosed before the damage is done, it cannot be reversed. Well, I think we are lucky here in Canada, because all infants are screened. Yes, screening is carried out on all newborns throughout most of the developed world before they even leave the hospital, and a small blood sample is taken in order to determine whether the phenylalanine level is elevated. If it is elevated, it is very important for this child to be seen by a specialized team, which means a metabolic clinic, in order to change his or her diet. However, that is more your role than mine, so please go ahead. Yes, I can talk about it a little later. Right now, we are talking about children who may have brain disorders, but what could happen to me as an adult? Well, in the past we thought that it was only important to limit phenylalanines during childhood. But this is not the case at all. Of course, when adults consume a diet that is full of phenylalanines, other problems can emerge. I don t mean that there could be
developmental problems, but there can also be memory problems or problems formulating thoughts. And this can cause what seems like clouds in the brain. The person can t think Like being in a fog. In a fog, that s it. It isn t permanent like with babies that have developmental problems. These types of problems can be reversed, and things can be improved if we continue on a diet that is low in phenylalanine. Okay, thank you for this clarification Dr. Mitchell. Now, what level is ideal, because often when patients come to see us, we bombard them with this number. So what is the ideal level? Why do we have to keep the phenylalanine as low as possible, but in a zone called the treatment zone? That s the completely safe zone. It means that we think we want to keep the phenylalanine at below 360 most of the time, but the problem is that we don t have a system for measuring phenylalanine levels every day. There isn t a machine that can measure phenylalanine levels at home. This means that we have to be tested for phenylalanine levels every week or so, and set a goal of keeping the level below 360, because we know that people with numbers like that have better development. This means that if we can keep the level below 360, most of the time we are giving our patient the best possible chance for development. It is also important for the stability of the phenylalanines. We know that, with things like fevers, we want to break down the proteins and add to our phenylalanine, and this can push the phenylalanine level much higher. This means that we want minimal fluctuation of the phenylalanine. Most of the time, we want numbers that are quite stable. This isn t always possible, and it s hard to maintain good control, because some people do not have a lot of the enzyme, and the tiniest increase in phenylalanine in the diet can cause a huge increase in phenylalanine in the system. So Dr. Mitchell, what you re saying is that it isn t easy, that you want the levels to stay low, but you also need stability. But I think these are the things we want, but we also know, for instance, if I consider the diet, that we are asking people to make major changes, and it isn t a diet that is easy to follow. We mustn t forget that phenylalanine is something that is known as an essential amino acid, which means that my body cannot produce this amino acid, and I have to get it from an external source. Unfortunately for our patients, and for anyone with PKU, there are many foods that contain proteins. Of course we always we tell patients to avoid major sources of protein, like meat, eggs, chicken, fish, all dairy products, peanut butter - so it isn t easy to live with a diet like that,
especially when you have to take a lunch to work or to school, and the fact is, proteins are everywhere. When the dietary restrictions are so strict, it is virtually impossible to follow it, and the patient is forced to eat the proteins found in bread, pasta, cookies. So now our patients have fortunately come to understand the problem, and products that are low in proteins, and therefore low in phenylalanine, have been developed. And these products definitely do not cause reactions. So it s more, I don t want to use an egg to give my cake structure, so people have to learn to cook with these different products, and their particular taste. I recommend that parents try to avoid having their children taste regular bread or cake. A baby can have a small portion, but beyond that, it can cause more severe problems. The portion must be minimal. But fortunately, there are products that are low in protein. But we ask people to take an amino acid based formula to try to replace all of the proteins that they cannot eat. For example, with eggs and in meat, so that is when I take my amino acid formula. So there already, it s already difficult in terms of the taste. Also, the reason why we are asking you and why you must take this formula is to make sure that, because I am not drinking milk, I could have a serious calcium deficiency, and also because people with PKU already have trouble maintaining healthy bones. In addition, I don t eat meat, so I don t have enough iron and folic acid and zinc, so it really is an essential formula for preventing nutritional deficiencies. So it isn t easy, because if I were a teenager, I would want to go with my friends, and you just have to think of fast food restaurants. But even if we don t think about that, going for a sleepover at a friend's house and having breakfast the next morning, even that is difficult. Even school outings, I can t have ice cream like everyone else. So it's very restrictive. It s not easy. It requires a support system and motivation. We used to believe that, once you reached a certain age, you could go off the diet, because they said the brain had formed and there would be no consequences. But like Dr. Mitchell told us earlier, what we have come to realize now, because our patients who were diagnosed with PKU a long time ago and they were among the first to be diagnosed, well, now they are adults. So we have the benefit of hindsight, and when we see that these people experienced problems in terms of stress or mood swings or even problems concentrating, as we said earlier, with their head in a fog. So now we ask people to stay on the diet for their whole lives. And what is interesting as we do this follow up is that companies have made a great deal of progress, and the number of new products has increased exponentially. We should also mention the Cambrooke frozen products that make people s lives easier and add variety. And we have been working on the tastes, etc. So it s getting more and more interesting. But still, it isn t easy. It requires planning and everything. So Dr. Mitchell, are there any new treatments available to help our patients to maintain their levels and make their lives a little easier? Can you tell us about this?
Yes, it s very interesting. There have been a lot of changes in recent years. It s not only with the food. There are new medications arriving on the market. Like we discussed, there is a long history of treatment with diet. There has been a great deal of success with these treatments, but that s not all. Like you said, it s hard for teens and adults who have problems following the diet. But we know that, in terms of new treatments, there is a medication called KUVAN. I will explain what KUVAN is. KUVAN is a cofactor for the deficient enzyme. This means that we need this chemical to help the enzyme to work better. If we are deficient in this cofactor, the enzyme will not be able to work. It was recently discovered that taking a large amount of the chemical called tetrahydrobiopterin can be beneficial, but I prefer KUVAN, because it s easier. Yes, definitely, or BH4, right? It s easier. But if we give KUVAN, it can help the enzyme that is in the body of the person who has phenylketonuria to work better. This means that it can metabolize more phenylalanine if it responds to the KUVAN medication. So Dr. Mitchell, does that mean that now I could have a more liberal diet? That is very important. People who respond to KUVAN must continue to follow the diet, and that is very important. Because there are people who think that if they respond to KUVAN, they can stop everything else. But that is not the case for most people who respond to KUVAN. They may be able to make choices or add more phenylalanine to their diets. And the choices are, it s a way to count quantities of phenylalanine. And often, this gives patients a diet that is less restrictive in phenylalanine. What I observed from patients who were on KUVAN was that they were people who were unable to eat meat and eggs, of course, but there were also people who, instead of eating bread that is low in protein, they ate regular bread, or regular pasta. The same applies for restaurants. It s a little easier now. Yes, that s right. It often gives the individual more choice and flexibility. Like you said, when they go to a restaurant they can have more natural protein but they still have to be careful. You mentioned briefly that it is a little like a vitamin or something like that, which gives the enzyme a little boost to work better is that right?
But KUVAN activates an enzyme in the body called phenylalanine hydroxylase. This is the PAH that we discussed earlier. But the most important thing is that, even though we have a small amount of this enzyme, it isn't enough to metabolize the phenylalanine. But when KUVAN is there, it protects the enzyme. And this means that, if the enzyme is not catabolized, there are no remaining enzymes in the body to do their job to metabolize the phenylalanine. So if I create a mental picture, it s as if KUVAN allows the enzymes to grow up, to stay there longer and do their work - we use this word a lot. Yes, that s right. Now, can anybody take it? Does everyone respond to the medication? Not everyone responds to KUVAN, but depending on the studies, between 30% and 50% of people do respond. It is mostly people who have a milder form of phenylketonuria, and not really the classic patients. But that s not 100% either. There are classic patients who respond to the medication. And I think everyone should try it. It is very difficult to say who will respond before they try it. So ok, my doctor can t automatically know, based on my genetic mutation, whether or not I will respond. You really have to try the medication. It s difficult. There are mutations or changes in the genes where there is little response. But like I said, it's always better to try and see if there is a good response or not. Now when you talk about a good response, what do you mean by that? Well, that can also be difficult to explain, but if we try the KUVAN medication for a period of time, normally for a whole month, we will see at least a 30% decrease in phenylalanine. It may be difficult, for example, if you are already under control and you have to add food to see if you respond to this medication. Then the phenylalanine level is stabilized. But generally, the phenylalanine level will drop by 30%.
So people are asking if they can add food. So if at a given time you conduct the tests, I taste meat, and I like it, then what do I do? I will be able to answer that question once the KUVAN tests have been completed. What we do is add skim milk powder to the formula in order to determine the person s tolerance, to see how he or she responds, how much the enzyme can digest the phenylalanine. And at that point, after a period of time, when we see that everything is under control, we add the skim milk powder and remove that in exchange. So it s something that s easier for people instead of saying yes, try this, and then taking it away. It could be dangerous to not want to return to the diet after that. Yes, that s right. Now, can an infant or pregnant woman take KUVAN? Not much research has been done for pregnant women. You should speak to your doctor. There is no indication for testing KUVAN on pregnant women. However, we need to balance the risks of having a high level of phenylalanine during pregnancy against the risk of trying a medication with unknown effects during pregnancy. This is something that you really should talk over with your doctor. But can an infant or a newborn take KUVAN? Yes, we have a great deal of experience with this medication in newborns. But right now, the studies being conducted involve children aged 4 and over. We have not had a lot of experience, and we have not conducted studies on children under 4. But since we have used this chemical on this age, on infants, we know that it is very It s not dangerous? It s not dangerous for small infants. It s not dangerous for infants. The only problem I can see is how to administer it, because it is currently in pill form. Even if it can be dissolved in water or juice, infants aged 3 or 4 months don t drink juice. So I think it s a matter of working with your metabolic team.
So I think that, for newborns, we want to have a little stability before we start a new treatment. This means that we want to have good control over the diet. If you are considering trying this medication on a young child, speak to your team to determine the best process for starting out. What are the side effects of KUVAN? Well, as with all medications, there are side effects. The most frequent is sore throat, because it is a very acidic medication. But headaches also occur quite frequently. And like all other medications, it can cause digestive problems. So now, let s say I have PKU, then of course I will go and see my doctor, but how can I get started, how can I get KUVAN in Canada? In Canada, Health Canada has only given The green light? Yes, that s right. They gave the green light in April 2010. This means that we do not have a lot of experience in Québec. We have patients who participated in studies in the past. But we don t have many young patients or children who have taken the medication in Canada, because it wasn t available here in Canada before April. But now, there are ways to order the medication. You can t just go to the pharmacy and ask the pharmacist. It s a pretty specialized medication. There is a program called The KUVAN assistance program? Yes, that s right. When you speak to your doctor, he can write you a prescription for this medication, but he can also speak to you about the program. This would normally mean that, when you register for the program, you will receive the pills for 30 days at no cost. And this is really to see if you respond to it. After this period, this assistance program can help to determine if there are coverage solutions for this medication. We don t really know what the coverage is in other provinces for the moment, because it is relatively new. But this means that the program will work with your insurance company, and if you don t have
private insurance, it will work with the provincial drug plan to see if you are covered for the medication. It is very new, but it is good news for some patients in Canada who have private or provincial insurance. If I am interested, I can go and see my genetic team and tell them that I have heard about KUVAN, and ask for some, because I think it is based on weight? Yes, that's right. So, 30 doses or the equivalent. And after that, there are assistance programs that can help us. You are talking about some patients who received favorable responses from their insurance. But we don't have much hindsight on KUVAN in Canada - we have a lot of experience with respect to its efficacy, but not with respect to how the costs are covered, because it has only been available since June. Yes, that's right, and we'll see what happens. I hope the government and the insurance companies will appreciate the benefits of this medication, because it can improve the quality of life for our patients. So now, while we are waiting for the government to make its move, because they don t move as fast as we would like them to sometimes, are there new treatments that exist right now or that are still being researched? Well there are other new medications, and new things on the way. There are some very interesting medications coming called Phenylalanine ammonia-lyase, which is an enzyme that is found in the plant that metabolizes phenylalanine, and we are close to starting real studies in a large area of the world among people with phenylketonuria to see if it can help to break down the phenylalanine in the body using a different method. Non-toxic products must be produced in the body, and it is very exciting. For people who do not respond to KUVAN, there are other treatments coming in the future. When you talk about phenylalanine ammonia-lyase, you are talking about what people refer to as PAL, right? That's right. PEG-PAL will be here soon. I think we need to do more research before we can prove that it is an effective medication for phenylketonuria, but for the time being, it looks pretty good.
So if I understand correctly, the trials involving humans have already started? They have already started, but we are early on in the process. And it isn't just something you take orally, you have to have a daily injection? Yes, it s injections. The problem is that the body does not have the enzyme, and the immune system tries to break down the protein that is taken orally, and by injection also. But there is a way to protect this enzyme against the immune system that has already been researched. It will provide a good way to fight the level of phenylalanine in the body and prevent it from getting too high. And I think that, to be clear, it is important to mention that this whole thing started at the McGill Health Centre. Right? Yes, a large number of studies have been conducted on animals here at McGill, and one of our students has conducted a great deal of research on the topic. Great. We really look forward to the results from the research on humans. Now, in the meantime, we often hear talk about large neutral amino acids. What do you think about these, and how do they work? Yes, large neutral amino acids are the other amino acids that are found in the body, and they use the same entrance as phenylalanine. If we administer a high number of amino acids that use the same door, they can prevent the phenylalanine from entering. This means that we must administer more large neutral amino acids than are in the diet, in pill form, and this can prevent the absorption of phenylalanine in the intestines. This means that, if we do not absorb too much phenylalanine, the phenylalanine level will logically be lower. I have also heard that there is some competition at the brain level. Yes, there is the other door that passes through the brain, and the same principle applies. If we use the other large neutral amino acids, this will prevent the phenylalanine from entering the brain.
So does this mean that if I go and see my doctor I could have a high level of phenylalanine in my blood and a lower level in my brain? In principle, yes, but it s too early to say if it's working properly. And one of the drawbacks of this treatment is that it is necessary to take a large number of pills with every meal. It isn't easy to take 10 to 12 pills with each meal. Yes, and on top of that, right now the pills are about the size of an aspirin. There is another thing, not a medication, but a product that s available on the market. Based on studies, using the whey that comes from making cheese, it has been discovered that it contains very little phenylalanine, and the Cambrooke company makes a product that could replace the formula, because it has been enriched with phenylalanine. Sorry, I mean, not with phenylalanine, but with vitamins and minerals, and it is low in phenylalanine, but it still contains phenylalanine, and this is Glycomacropeptide (GMP), and not many studies have been conducted on it so far. It s interesting, because this would not only mean formulas but also products and cheeses that would be made from the protein. And people would be able to reduce the quantity of formula they take, and could take these products that would essentially be normal products. And it's also a protein that is intact, so it could help in terms of nutrition also. But it is a little difficult to advise you about this, because all of this has only recently emerged. Please remember that the views expressed on Patient Power do not necessarily reflect the opinions of our sponsors, our partners, or Patient Power. Our discussions are not a substitute for seeking medical advice or care from your own doctor. Please have this discussion with your own doctor in order to receive the care that is most appropriate for you.