COLLEEN E. MILLER, RN: Hello and welcome to MS Conversations. I'm Colleen Miller. I'm a doctorly prepared nurse practitioner at the Baird Multiple Sclerosis Research Center in Buffalo, New York. I have been doing this for about 12 years, just to give you an idea of who you're talking to here.

Now neutralizing antibodies to multiple sclerosis treatments is the topic of our discussion this evening, focusing on issues and situations more relevant to nurses who counsel and care for people with multiple sclerosis.

How are neutralizing antibodies formed? What is their significance, and how do they impact treatment decisions? These are some of the questions we hope to address during tonight's conversation.

Joining me for this discussion is one of my long-term friends and mentors, who has more experience than almost anybody in multiple sclerosis. My friend's name is Marie Namey, who is a clinical nurse specialist advanced practice nurse at the Cleveland Clinic Foundation. Thank you for joining us Marie.

MARIE A. NAMEY, RN: Thanks Colleen, it's a pleasure to be here tonight.

COLLEEN E. MILLER, RN: Before we start our discussion tonight, I would like to encourage everyone who is listening to send in questions via e-mail or telephone.

Marie, let's start by explaining what neutralizing antibodies are and why they develop to some medications like interferons?

MARIE A. NAMEY, RN: That's a real basic question. I think as nurses we need to have this information at hand and understand it a bit.

Neutralizing antibodies are a subset of binding antibodies that interfere or neutralize the function of the molecule that they bind to. Usually, neutralizing antibodies work by binding to an important part of the foreign substance and therefore render the medication pretty much ineffective.

COLLEEN E. MILLER, RN: Is this a problem with all medications, do you think Marie?

MARIE A. NAMEY, RN: Well, neutralizing antibodies develop to certain medications. Some of the medicines that have been developed over the past 10 years are protein-based and are derived from a large number of cultured cells.

These proteins are slightly different than normal proteins and can be recognized as foreign when they are injected into the body. So an immune response is mounted against them. So the neutralizing antibody thought has been more a concern, as I said, in the past 10 years since we have developed these more sophisticated medications which have been delivered through intramuscular or subcutaneous route.

I think what I would like to ask you Colleen is, "Why do you think this is an important topic for nurses at this particular time in providing care for folks who have multiple sclerosis?"

COLLEEN E. MILLER, RN: Well, our patients often ask us questions, and they look to us for guidance. As we all know, MS is a progressive disease. So the patients will often say, "I'm having relapses or I'm getting worse. Does this mean that the medicine is not working for me?" At that point in time, they often say, "You know, I've heard about this neutralizing antibody situation. Do you think that the medicine isn't working because my body is fighting it?" So then I often discuss that yes, neutralizing antibodies is a real hot topic now. We're not completely certain as to whether it makes a huge impact or not. As we know, the medications that patients are on now to prevent disease progression and relapse are primarily the interferons, such as Avonex, Rebif and Betaseron. Then there is also Copaxone.

Now the thought is that Copaxone and antibodies are not really a problem, although that is coming into question. It's the interferons that tend to form the neutralizing antibodies.

MARIE A. NAMEY, RN: You know, I think you bring up an important point about the patients asking you questions about the neutralizing antibodies. They ask them almost in the same breath where they ask, "Well, why can't these medicines be given as pills?" On the same response that we give them, "Because they are proteins and proteins tend to be utilized in the body in a different way when they're given in pill form than they're given in injection. When these medicines are given in injection, there is this tendency to create a neutralizing antibody because they are the protein. So, you know, it's a big education -- information for the patients when they start to ask about how do these medicines work, I guess.

COLLEEN E. MILLER, RN: Yeah. It brings up another theory in this whole discussion as to why do injections in certain areas cause more antibody formation than other injections, such as it has long been thought that the subcutaneous injections may, in fact, cause more antibodies because the subcutaneous tissue is more active.

MARIE A. NAMEY, RN: My understanding is that there is more reactivity when the medication is given subcutaneous than in the muscle because the receptors of the skin are such that they respond more to these proteins.

MARIE A. NAMEY, RN: What then, are the interferon preparations that lead to the production of neutralizing antibodies? I mean, you said that we have Avonex and Rebif and Betaseron. Are there differences in the reactions and the creation of neutralizing antibodies in the different interferon preparations?

COLLEEN E. MILLER, RN: Well yes. If we go back to our clinical trials, we see that the Betaseron has approximately a 45% rate for neutralizing antibody formation. Keep in mind, binding antibodies are not necessary neutralizing antibodies. Binding antibodies are antibodies that get in the way. But the neutralizing antibodies turn off the response of the medication or the effect.

But back to our products that we're concerned about, we have Betaseron at about a 45% neutralizing antibodies level, and next comes Rebif. If you look at the EVIDENCE trial, which is the most recent, their formation rate was about 24%. The Avonex is now between 2% and 5%.

This is a little change that people aren't aware of. Back when we first started the phase III trial -- and I know you were involved in that as well as I was Marie -- the Avonex was actually made by a different process. It had a higher neutralizing antibody level. The process has now been refined to the point where the antibody level is the lowest of all the products at about 2-5%. So this is a change in the labeling in the package insert that people are asking questions about now.

MARIE A. NAMEY, RN: I remember when folks were in the phase III study for Avonex here. They frequently had blood draws to test for neutralizing antibodies. Those were monitored quite closely over time. But after hearing what you said, it seems that the manufacturing process and the route of administration and the frequency of injection can add to the reasons why patients develop neutralizing antibodies to interferon.

COLLEEN E. MILLER, RN: Yes, but it also has been tied into the formulation itself and how close the formulation is to the actual human interferon-beta. Without the glycosylation and with adding some mannitol and some of the other things that are used to adjust the pH, the substance that's actually injected is a little bit different than what the body is used to. It's thought that that in itself may actually stimulate the body's response in saying, "Hey, this stuff isn't right. I'm going to make a neutralizing antibody to kill it."

MARIE A. NAMEY, RN: You know, I think this stuff is complicated. I think it's complicated not only for patients, but for some of our nurse colleagues.

COLLEEN E. MILLER, RN: Oh absolutely.

MARIE A. NAMEY, RN: I recall that chemistry and biochemistry were some of my more difficult classes in school. I think that helps with some of the understanding of how complex these medications really are. It helps us appreciate the fact that all interferons aren't alike, and that Avonex is created more like a human interferon to help in terms of the treatment effect and decrease the side effects, and also then has the benefit of a lower amount of neutralizing antibodies.

COLLEEN E. MILLER, RN: And the other thought is that the Avonex is actually made from a mammalian cell, as is Rebif from the Chinese hamster ovary cell. The Betaseron is made from E. coli, which is a bacteria cell that many pharmaceutical products are made from.

MARIE A. NAMEY, RN: You know, often when I tell patients that Avonex and Rebif were made from the Chinese hamster ovary cell, they find it incredulous and begin to laugh. I don't think that they have an appreciation of some of the background research and work that goes into creation of some of these medications. I think it's easier almost to understand how a medicine is made from a bacteria or some growth on a cheese than it is from a Chinese hamster ovary cell.

I think that this is important information to share with our patients so that they understand the complexities of how the medications are created, what goes into the work of developing medications to make them safe and effective for patients.

COLLEEN E. MILLER, RN: Yes. I think one thing that has kind of bothered me through the years is sometimes people will say, "Well, that Betaseron stuff is made from E. coli, and you know, you get sick from E. coli and it's in your colon." It's a very common process, and it's not an infective type substance that they work with. I think that's a common misconception.

MARIE A. NAMEY, RN: Well back to the neutralizing antibody topic specific, how do they affect the effectiveness of the treatment intervention and disease progression in MS?

COLLEEN E. MILLER, RN: Well Marie, that's a very, very good question, as you know. It's a question that is debated daily in the field of multiple sclerosis. It used to be thought that people could develop neutralizing antibodies and they could go away and it would make no difference. But we know now that when people really develop high levels of antibodies, they say that a cutoff level is 20, but really, if somebody develops a level well over 100, those levels don't tend to go away. What happens, as we can see in some of the clinical trials such as the Betaseron and the Avonex trial and in the PRISMS-4 data for Rebif, that number one, the antibodies take about nine months to twelve months to begin to develop, so you don't see any effect of the neutralizing antibodies early in any clinical trials.

MARIE A. NAMEY, RN: Can I interrupt and ask, how do you see them? What kind of test is done to really measure neutralizing antibodies?

COLLEEN E. MILLER, RN: Well, that's important because you need -- some of the labs, when you order antibodies for interferon, they will give you a level of binding antibodies.

MARIE A. NAMEY, RN: This is a blood test?

COLLEEN E. MILLER, RN: A blood test. It is a blood test. But it is important that you order neutralizing antibodies, not binding antibodies. Again, binding antibodies are like going to the mall at Christmas time. There are a lot of people in your way, but you can still get what you need to get. Neutralizing antibodies are kind of like going shopping at Christmas time and the store is wiped out. So no matter how hard you try, you're not going to get what you want to get. So when you order the antibodies, it has to be neutralizing antibody levels.

But back to the effect. Some of the controversy has been that these clinical trials only run for two years, so you really don't see the effect until the second year. You're just beginning to see the effect of these neutralizing antibodies. In the two year trial, we start to see a drop off of clinical effect. You see progression of the disability, and you see increase in MRI activity in T2 lesion load and in gadolinium enhancement.

But what's really kind of interesting is one of the longer-running studies that went for four years out, was the PRISMS-4 data, which was a European trial looking at Rebif.

In the first two years of the trial, they really didn't see any effect of neutralizing antibodies. However, in the last two years, in years three and four, they noted that people who developed neutralizing antibodies lost the clinical effect of the interferon in terms of disease progression, MRI activity and some mention of relapse rate, but it's kind of a vague mention.

MARIE A. NAMEY, RN: Yeah. I don't think we have hard enough evidence to say that there is an effect definitely on the relapse rate. But it sounds like the antibodies can occur within the first 9-12 months of treatment, but the effects may not be apparent until later. Correct?

COLLEEN E. MILLER, RN: Correct. That is my understanding and I believe that is where the current level of research is pointing.

MARIE A. NAMEY, RN: So we still need to do more research?

COLLEEN E. MILLER, RN: Absolutely.

MARIE A. NAMEY, RN: To find out exactly what's really true about these long-term effects of increased neutralizing antibodies and then what we need to do in terms of treatments for patients.

COLLEEN E. MILLER, RN: Uh huh. So then Marie, if somebody comes in and says, "You know, I don't think this stuff is working. I'm getting worse. I think I'm having more relapses, what do you tell them?" I know that we tell them, "Well, maybe we'll look at antibodies, but what else could it be?"

MARIE A. NAMEY, RN: Well, we all know that MS is a progressive disease, and all the treatments we have are partially effective. They're good treatments, and there are certainly more treatments available now than when I started working in this field 17 years ago. But we always have to look. We have to keep our eyes open as to what might be the intervening variable that caused the disease to get worse over time. So it's prudent to look at clinically how the patient is doing, certainly listen to the patient and pay careful attention to what they think is happening, monitor the MRI. If you're index of suspicion is high enough and they're on interferon they may be developing neutralizing antibodies, so certainly check that.

Certainly, I think there is a consideration if a patient is on Avonex and is hearing about other treatment options that are available, and if their disease is also progressing, we need to check neutralizing antibodies before we make a switch to another agent. Because if what you're saying is true, that because of the pharmacokinetics of Avonex and the route of administration and the frequency, there is a lower neutralizing antibody titer, than changing to another interferon isn't going to help.

COLLEEN E. MILLER, RN: You know, that brings up a very interesting point, and something that's very important to get across is the cross-reactivity of neutralizing antibodies. For instance, if I am on Betaseron and I develop neutralizing antibodies to Betaseron, what are my options?

MARIE A. NAMEY, RN: Well, there is some thought that a different route of administration of medication might not create as high a titer. People have been known to level off over time. A neutralizing antibody titer might be quite high and off the charts, and then you take it later and it might be within normal limits. You might want to monitor that over time to see what's going on.

I don't necessarily think switching a medicine is necessarily the best way to go. We have data that tells us the natural history of the disease is that it's a progressive disease. Again, going back to the fact that these medications are partially effective, some individuals or many individuals are going to have breakthrough disease and may need to have combination therapy then, consider other therapies that are available.

COLLEEN E. MILLER, RN: There are...

MARIE A. NAMEY, RN: So it's very individual.

COLLEEN E. MILLER, RN: Yeah. And there are experts in our field that believe that once somebody has established a level, a very high level, like 500 of neutralizing antibodies to one interferon, that they are, in fact, going to cross react and have neutralizing antibodies and less of an effect of the other interferons. So this is a concern when we're teaching our patients upfront about what their options are.

If you choose a medication that may cause a higher level of neutralizing antibodies, once those are formed it's going to limit our options. We won't necessarily be able to use any other interferon.

MARIE A. NAMEY, RN: Right. And again, I certainly think this is an area that needs to be explored with more studies and more effort.

I believe that the Consortium of MS Centers is going to get together a group of thought leaders to look into some of these issues in detail. It would be most likely a physician group to explore ways of maybe setting up some studies to specifically look at this area of once a person has developed high neutralizing antibody titer, how long does that last, what implications does this have for them to continue to gain benefit from the interferon?

So there is still a lot to be learned out there about this topic.

COLLEEN E. MILLER, RN: Absolutely. And if a patient develops neutralizing antibodies to the interferons and is getting worse in their disease, our options may include trying other medications that are not interferons, as well as some of the more aggressive treatments such as the chemotherapies like mitoxantrone and Cytoxan, etc., and of course, the steroids.

MARIE A. NAMEY, RN: Right. And I think the important point is that each person is an individual and needs to be treated as such. We have all this information. We have much information about the study design for all of the immunomodulatory therapies. We have information about the use of mitoxantrone and Cytoxan. We have information about methotrexate and Imuran. The clinician, in partnership with the patient, needs to decide what's the best treatment option for this patient at this particular time of the disease? And it can change. It can change. But it's done on an individual basis.

COLLEEN E. MILLER, RN: Marie, have you had patients come in when Rebif was the new guy on the block saying, "You know, I've been on Betaseron, I've been on Copaxone. I've been on Avonex," -- any of those -- and they're doing fine and they come and they say, "Well, I want to try the new stuff. I've heard so much about this." How do you address that?

MARIE A. NAMEY, RN: Yeah. Well, you know, that's sort of the common American way. The newer product is the better product. I mean, all the laundry detergents do this all the time. (Laughter) It happens with medications too.

You know, I'm going to digress a little bit, but it happens when a medication is coming to be generic. A lot of the medicines come out with an XL or an extended release or a long-acting form to have another prescription drug to get out to the market.

But anyway, the focus or the idea is not to switch medications. If a person is doing well on their current therapy, the idea is to try to encourage them to stay on that therapy because it obviously seems to be working for them. Switching is not necessarily recommended. Certainly if a person is having a lot of side effects and the side effects are outweighing the good effects, or if a person is not responding as well as everyone would have hoped to the drug, then you need, as we said earlier, to consider other options in terms of treatment, in terms of where the disease is going.

But to switch because something new has come along isn't really a thoughtful response in caring for the patient.

COLLEEN E. MILLER, RN: You know, you bring up another interesting point that is one close to our hearts. When a patient comes in and says, "You know, I'm having another exacerbation," you look at the MRI and they have some more activity, how often have you said, "You know, are you really taking your medicine? Are you taking it every time you're supposed to be taking it?"

We find out that are patients are not as adherent as we think they are. So that is, I think, a very important question to ask our patients.

MARIE A. NAMEY, RN: I think this adherence issue is a whole other hour long.

COLLEEN E. MILLER, RN: Oh yeah.

MARIE A. NAMEY, RN: But you're absolutely right. Three of these medications have been on the market for a number of years now, and people get lax. You know, they get a little bit more comfortable with the disease, they get comfortable with the injections, and they kind of skip a few or take a little vacation. You're absolutely right, we need to be questioning folks about whether or not they're taking the injections as prescribed, and actually we also need to be monitoring injection technique over time. Again, people get a little lax. It's our responsibility to make sure that things are done in the correct manner.

COLLEEN E. MILLER, RN: So it looks as though we've come to the end of our conversation.

MARIE A. NAMEY, RN: Okay.

COLLEEN E. MILLER, RN: I want to thank you Marie for helping me out here and participating. As always, it's a pleasure working with you, my dear.

MARIE A. NAMEY, RN: This was a good educational experience for me and also a lot of fun working with you. I think this is a great example of how nurses network and help teach each other and broaden our audience to those of you who are listening out there. So thank you all for taking the time to participate tonight.

COLLEEN E. MILLER, RN: Yeah. Thank you one and all. Good night now.