Transcript The Implications of Tysabri Q & A session
Posted: Wed Jan 19, 2005 8:24 am
Transcript
The Implications of Tysabri (Natalizumab) for Multiple Sclerosis (MS) Therapy
Q & A session
The Implications of Natalizumab for Multiple Sclerosis (MS) Therapy Previously Recorded on December 15, 2004
J. THEODORE PHILLIPS, MD, PhD: Hello, this is Dr. Ted Phillips. I hope you've enjoyed our discussion on the implications of natalizumab for MS therapy and we're happy that you've stayed for this Q&A conference. I'm pleased to be joined again by Shirley O'Leary, JULIE FARACE and Rick Munschauer.
We've received quite a few questions, so let's get started. Now, what we did was we received so many questions that it would be impossible to cover all of the questions asked in a reasonable time. So we have binned a number of similar questions together and so we'll kind of cover them like that.
And so we're going to start off with a question that I'm going to direct towards Dr. Rick Munschauer and this one is from Sharon in New York and Martha from Indiana and George from Illinois who all want to know something about combining natalizumab with Rebif® or Betaseron®, but also the possibility of combining natalizumab with mitoxantrone. Rick, what do you have to say about that?
FREDERICK MUNSCHAUER, MD: Well, Ted, the SENTINEL study, the large phase III clinical trial, was indeed done adding Tysabri® or natalizumab to Avonex® or beta-interferon-1a. So, on a purely scientific basis, it's going to be questionable to compare the results that we got with Avonex® plus Tysabri® with another beta-interferon product plus Tysabri®.
However, on a clinical basis, I think it makes some sense. We know that the mechanisms of action of the type-1 interferons, interferon ß-1a or interferon ß-1b really are quite similar. And so I do feel that there is likely to be a therapeutic benefit of adding Tysabri® to any of the interferons, just as was demonstrated with Avonex®.
The caveat to that might be that, with the interferon ß-1b, Betaseron®, or with Rebif®, the incidence of neutralizing antibodies to interferon is quite a bit higher. And from previous MS leaders at teleconferences, we've really shown that the emergence of anti-interferon antibodies is associated with an attenuation of therapeutic effect.
So I think that, if somebody is on a beta-interferon and they're antibody-negative, then, from a clinical perspective, it's quite likely that adding Tysabri® will indeed produce the same sort of benefit as we see with Avonex®.
But I'd like to ask you a question, Ted. What do you think about adding Tysabri® to Copaxone®?
J. THEODORE PHILLIPS, MD, PhD: Well, indeed, and that was a question that was asked by a number of folks, including Victor from Kentucky and Lillian, a nurse from Colorado, and Connie, a nurse from Florida, wanted to know about that.
And, now, although we don't have the detailed answer to that important question right at this second, we'll at least have some safety data in no more than a few months from now. Some of you may know that there was a small phase II study carried out with natalizumab plus Copaxone® versus natalizumab plus placebo. It was phase II, so it wasn't an efficacy study, but rather it was a safety study. That study has completed and those people, like the other people in the two phase III studies going on, have rolled over into open-label natalizumab.
So, it's intriguing to think about the possibility of combining agents with different or possibly complementary modes of action. It -- theoretically, because we've got data on low-dose interferon, Avonex® plus natalizumab, that at least makes the concept that Rick was talking about of higher-dose interferon, Rebif® and Betaseron®, at least in the same ballpark.
Copaxone®, or glatiramer acetate, and natalizumab's a different ballpark. It's intriguing and we will have some safety data coming up, I think, in just a few months, but efficacy data will be later.
FREDERICK MUNSCHAUER, MD: Ted -
J. THEODORE PHILLIPS, MD, PhD: Rick -- no, go ahead.
FREDERICK MUNSCHAUER, MD: No, I was going to ask you, Ted, if the trial that adds Tysabri® to glatiramer acetate, or Copaxone®, shows that MRI data is reduced, is this something that you'd recommend to your patients, if they're fewer, newer enlarging T2 lesions, fewer gadolinium-enhancing lesions? In other words, since we won't have any primary outcome measure, because it's a relatively small trial, will you look to the MRI measures during that trial as a way of trying to facilitate your clinical decision-making?
J. THEODORE PHILLIPS, MD, PhD: Yeah. Well, great question and I guess my best answer to that is: If I split my patients down into two general categories, those people who are on a therapy and doing okay, maybe not optimally, but are not doing horribly, if I switch from what they are on to -- if I consider adding a Tysabri®, I think I am of the philosophical bent that I am going to be switching to natalizumab monotherapy and giving that a try, rather than adding it to preexisting.
Now, the other group of people who are doing very badly on whatever it is that I've tried and it seems like, you know, this person, the most likely issue, if there is any issue at all that will improve their situation, is going to be combination. Well, you know, in a certain sense, all bets are off. I think I would feel safe in combining Copaxone® with natalizumab, from what I know about this, although, like I said, the data hasn't actually been analyzed and made public yet. But do I intrinsically feel that this would be more effective, even if the MRI markers showed improvement? Well, that's hard to say. MRI markers, I expect to show improvement from Tysabri® alone.
FREDERICK MUNSCHAUER, MD: Yes, that's a good point. I skipped the -- to the second part of the question that you asked me and it was intentional. What about mitoxantrone, Ted, Novantrone®? Let's say you have a patient who is rapidly getting worse. The kind of patient that you and I both normally think is a candidate for major immunosuppressive therapy with mitoxantrone. What do you think is the role of Tysabri® and mitoxantrone or switching those patients from a rather potent immunosuppressive agent to the more immunomodulatory action of Tysabri®? How are you going to handle that?
J. THEODORE PHILLIPS, MD, PhD: Well, speaking for myself, I think I'm going to handle that extremely carefully. I personally would be reluctant to go just blindly into mitoxantrone plus natalizumab. That isn't saying that it couldn't be a good combination, but I think that that potent immunosuppressant plus the potent immunomodulatory actions of natalizumab, I think that really needs a safety study before that can just be launched into. There might be unexpected not-so-good complications from adding those two together, so I don't know.
I personally am just going to kind of put that one on the back burner and I'm also asking myself how it was that I ask you that question, but you ended up asking me that question.
We actually have a question that came in just now from Amy in Illinois, who wants to know if any of us -- well, I say "if any of us," I'm sure every one of us have thoughts about natalizumab, Tysabri®, and what to tell patients who may wish to become pregnant. So, Shirley, what are you going to tell -- I mean, you know, this is not an uncommon type of question to come up.
SHIRLEY O'LEARY, RN, MSCN: Oh, you're right, it's a very common question. And, of course, we would be very erring on the side of caution and have our patients, if they're planning on becoming pregnant, to stop therapy, most likely, in their best interest, I think. And, of course, I'm sure the package insert is agreeing with that, too.
Now, I know that there were some pregnancies that resulted in the study and I don't know necessarily all of the final outcomes. I think most of the people did just great, but it certainly wasn't something that was hoped to happen during the studies. We practiced very good -- hopefully, all the patients practice very good birth control and we, as research coordinators, constantly reminded them about that.
So we really don't have much data on pregnancy and natalizumab, so I think that my advice, from a nursing perspective, would be to have my patient stop therapy, if they were interested in becoming pregnant.
J. THEODORE PHILLIPS, MD, PhD: Right. I -- I think probably -- I mean, that is the safest answer. Just a momentary followup: The data on the people -- people in both placebo and natalizumab treatment groups, there were a handful in both studies, people who got pregnant. There were, as I recall, there were no obvious adverse outcomes in either group of pregnancies. I actually think there have maybe been a very few natalizumab births now and, again, to my best knowledge, no problems, no issues.
Nonetheless, it still is a category C pregnancy drug and I think it's very well-advised that -- for this drug and pretty much -- at least in my opinion, pretty much most any drug, to discontinue during the relatively protective, MS-wise, time of pregnancy.
Let's see. Got a question here from Joanie in Washington State who is wondering what kind of monitoring needs to be done during and in the one-hour observation period after infusion and is this documented on any kind of a standard flowsheet. Shirley, I'm going to shoot this one to you again, since you've been doing this for so long.
SHIRLEY O'LEARY, RN, MSCN: Well, yes, of course, with all of our natalizumab infusions that we've done thus far with regard to research, there is the one hour of infusion followed by the one hour of observation afterwards. And, actually, I -- the package insert also states that they -- that you are to monitor the patient for an hour, post-infusion.
Usually, within our research protocols, we take about ten minutes of flush in that second hour. So the ten minutes of that post- -- the first hour post-infusion is generally used up with flushing the line. And then, normally, I think what might be recommended is to go ahead and leave your line in, leave your saline lock in place and then just have the patient in the room with you and you're observing them for the next forty minutes, completing that one hour post-infusion. And then, taking out the saline lock at the end and doing concluding vital signs and then allowing the person to leave.
As far as the monitoring and then documenting on a flowsheet, a flowsheet is great, because you can capture all of that information, from the time the patient walks in and that's going to include a little bit of an assessment of them, how are they doing, any particular problems, doing vital signs. And then documenting your insertion of your catheter and the beginning of the infusion, vital signs and just all your monitoring throughout and then finally ending with completion of vital signs, a second set of vital signs and then discontinuing the saline lock.
So, yes, you can capture everything on one sheet in a very organized fashion, so I think that is a really excellent idea.
J. THEODORE PHILLIPS, MD, PhD: Great, okay. Julie, here's a question for you, still more kind of into the nuts and bolts of infusion. Inasmuch as with any therapeutic monoclonal antibody with natalizumab, there has been a reported low, but nonetheless detectable incidence of infusion-related reactions. Any ideas -- Elizabeth a nurse from New York asks if there are any suggestions, maybe to help minimize the likelihood of infusion reactions, perhaps just in general.
JULIE FARACE, RN, CNRN: Well, one thing that we have to think about when we need -- when we're looking to minimize these infusion reactions is that the people -- the patients who have been treated with natalizumab, they are showing a higher incidence of reactions if they have this neutralizing antibody to the drug, which I believe we're going to get into in a few minutes. So it's kind of a question as to whether or not should we treat this prophylactically or should we allow this to happen, so that we can tell whether or not this is something the patient will tolerate.
I think, in other infusions that I've given myself, we treat prophylactically only because we know more about the infusions, whereas, with Tysabri®, we're still getting that data. So, a lot of times, we will treat patients with things like Tylenol® and Benadryl® prophylactically to prevent, a lot of times, just even mild fever, flushing, chills, things like that. But I think it's also important to remember that this is because we know more about those drugs, so we need to kind of do that with caution at first, especially with a new patient who hasn't received this yet.
J. THEODORE PHILLIPS, MD, PhD: A somewhat related question from Jean in Delaware and I'll kind of address this to both you, Julie, and Shirley. Jean asks -- or comments that "We are setting up a small infusion center in our office to accommodate Tysabri® infusion. Is there anything special we should have available to assist our patients during infusion, in order to handle any sort of discomfort of side effect?" Any kind of general comments or suggestions, in terms of, I guess, creature-comfort types of issues for an infusion area?
SHIRLEY O'LEARY, RN, MSCN: Well, I think, actually, there's a number of things we can do. Certainly, a comfortable chair, being in a position to elevate a patient's legs, some just comfort techniques such as that. Hopefully, the IV insertion has gone smoothly, those sorts of things are always positive in any IV setting, I think. And with regard to natalizumab, we've been very fortunate and have seen few side effects from the drug thus far and that's not to say that we shouldn't always be prepared. Certain, we should be.
And I think it's also important to -- as we were talking a little bit before, in doing your assessment when your patient comes in, to determine, right off the bat, if there -- if there's anything going on before you even begin your infusion, such as a headache or a stomachache or an upper respiratory infection, so they're congested, anything that might maybe be troublesome a little bit down the road in that one-hour infusion for them. And so if we can address those things upfront, that's going to enhance their comfort quite a bit, too.
And then, again, being prepared and having on site any medications that you would need to address any reactions or anything that would come up during the infusion would also be important. What do you think, Julie?
JULIE FARACE, RN, CNRN: Yeah, I -- that's pretty much the answer I was going to give, except for I've found that my patients, in our infusion center, really like the fact that we have a much more relaxed setting in our infusion center.
SHIRLEY O'LEARY, RN, MSCN: Mm-hm.
JULIE FARACE, RN, CNRN: Where we have actual like lamps that you would have in your house that have a -- that provide a dimmer light, so that, once the infusion has started and the patient is allowed to relax a little more, not feeling so much in the stark hospital setting. Things like blankets and pillows to keep them comfortable, that really helps. And, sometimes, even the nurse at our infusion center brings in a relaxing CD, that can be helpful to them. Anything to kind of minimize their anxiety during the infusion.
J. THEODORE PHILLIPS, MD, PhD: Great, great. Rick, I got a question for you. This is from Marianne, a physician in Arkansas. A more general question. She asks, "Can it or has it been shown that the prevention of relapses is truly an indication of delay in progression of the disease?"
FREDERICK MUNSCHAUER, MD: It's a very good question and it's one that I know you've thought about a lot, Ted.
We really believe -- and this is data, I think, that Tom Scott has published in Neurology. We believe that exacerbations early on in the course of relapsing MS are indeed predictive of future disability. So if you have someone who generally has a disease duration that's shorter than about six, seven years and who has not yet achieved a certain level of disability that results in a significant impairment in their ability to ambulate, for instance, a EDSS rating of 5 or below. That group of people, early in the disease with less disability, relapses probably are correlated with progression in disability later on.
In data that Confavreux has published in Europe, it's quite clear that, when people are seven, eight, nine, ten, eleven years into the illness or have significant difficulty with walking, then exacerbation rates in those patients tend to be less. As people evolve from an early relapsing form of the disease to a more secondarily progressive forms of the disease, exacerbations tend to go away. So he had a very interesting article that showed, if you're disability score was greater than 4 or you were having difficulty walking long distances, that exacerbations themselves may not be predictive of long-term disability.
I know that sounds complicated, but the way I think about it, if you have minimal disability early on in your disease, if you have a high exacerbation rate, you're likely to become -- more likely to become impaired over the next few years. While, later on in the disease, exacerbation rate doesn't really predict how much more ground you'll lose, from a point of view of disability. Would you agree with that, Ted, or do you want to modify that?
J. THEODORE PHILLIPS, MD, PhD: No, I do agree with that, in general. I think the nature of the question asked itself kind of speaks to a larger question of what is what in MS, clinically speaking. Are relapses just relapses? Is progression the same or is it different? And I think that there -- I think this is an evolving area in MS and I think that there is accruing evidence that what -- that there may be a -- an underlying progression to the disease that is not so apparent early in the disease, where the disease early on is punctuated by the more dramatic exacerbation followed by whatever degree of improvement there is.
And, yet, having said that, it seems quite intuitive that the more attacks one has with less than 100% recovery from each, over time, that will amount to accruing neurological problems and could translate into increasing disability.
We've got so many more questions here and yet I'm told that we have relatively not much time left, so I want to try to get to maybe two or three other questions.
Rick, let me ask you about -- let's talk just a second about neutralizing or we should call blocking antibodies and Tysabri®. A physician from Texas asks, "What are the recommendations for antibody testing? What will be used and who will do it?" And, also, Faith from California wants to know, "Does antibody formation to Tysabri® produce diminished response to treatment?"
FREDERICK MUNSCHAUER, MD: Well, the second question is much easier to answer. Tysabri® is a humanized IgG. It's a protein and whenever you inject proteins into people, there is the potential for developing an antibody against this protein. In the case of Tysabri®, which is an antibody itself, you have an antibody against an antibody. And we do know that about 9% of people on Tysabri® develop an anti-Tysabri® antibody. And about 6% of those, that antibody just is persistent, it doesn't go away.
We also know, from both the AFFIRM and the SENTINEL trial and the one-year data has been looked at, is that, if you're going to develop an antibody to Tysabri®, you do so in the first three months. And, once you've developed the antibody, if it's persistent, it will be there three months later or at six months. And we also know that, once you've developed an antibody to Tysabri®, gee, you know, we see a regression in terms of exacerbation rates, in subsequent months over the first year, to resemble the exacerbation rates of the people in the placebo group. So the emergence of anti-Tysabri® antibodies is associated with a loss of efficacy of Tysabri®. The exacerbation rates increase up to almost the level of somebody who was a placebo person.
However, if you are one of those 3% that have transient Tysabri® antibodies, well, as the antibodies go away, then the efficacy of the drug, in terms of reducing exacerbation rates, is seen again.
So, I think antibodies are important to Tysabri® and I think a cheap, inexpensive assay is down the road and I think it will be available commercially. Certainly, all of us who've used the drug feel it would be an important thing. It only happens in about 6 to 9% of people. And probably the optimal time to measure it, if you were going to measure it just once would be at six months, because the majority of people will become positive at three months and those people that are persistently positive will be positive again at six months.
So, I'm thinking -- and we haven't worked all this out, but, as I look at the data, my personal approach will be to do Tysabri® antibodies after six months of therapy. If they're positive, then I will assume those are the people that have persistently positive antibodies and I also know those are the people whose exacerbation rates will resemble those of people who weren't treated at all and then I would move to an alternate therapy. Is that how you read the data, Ted?
J. THEODORE PHILLIPS, MD, PhD: Pretty much the same way. I hope we won't have to wait too terribly long for an antibody assay. As you point out, it's a straightforward binding assay and I'm told that, hopefully, by this Spring, no later than this Spring, that assay will be available.
As you point out, it -- the results are ultimately only important to, fortunately, a minority of people, not exceeding 9% total and then the more persistent area, the 6%. But, of course, to those 6% who tend to be more persistent, it's a critically important test, because it means, as you pointed out, that Tysabri® in that person may not be the best treatment for them. And exactly how persistent these, quote-unquote, "persistent" antibodies are is something that we're going to be getting more data about in the longer-term followup studies and I think that will be important as well.
Let's see, we probably have time for one last question and so I'm looking through my list here. You know, I think that the last question that -- is going to be one from Joy in New Jersey who asks, "Does natalizumab ameliorate cognitive as well as physical symptoms?" And if we can expect -- or is it reasonable to expect any improvement cognitively on Tysabri® as, say, compared to Avonex®?
FREDERICK MUNSCHAUER, MD: Tough question, isn't it? And, in fact, I am of the belief that MS is a whole-brain inflammatory disease and that the majority of the inflammatory cells come from the intravascular space, invade the brain and participate in immunologically mediated brain injury in a very diffuse way.
So it's a leap of faith, but I really do believe that, if you show that Tysabri® not only reduces exacerbation rates but also decreases gadolinium-enhancing and decreases newer enlarging lesions, then I would say, with a reasonable degree of medical certainly (sorry to sound legalistic about it) that it is probable that Tysabri® will slow cognitive impairment, too.
We don't have the data. The AFFIRM and the SENTINEL try did not measure cognitive function prospectively like the Avonex® trial did. So I think it's one of those things that we have to begin to use some clinical judgment on and I'll ask Shirley and I'll ask you, Ted, and Julie, too, about experience with this drug, in terms of what you feel about how patients subjectively feel on it. Do they feel like they are not progressing, either cognitively or physically?
J. THEODORE PHILLIPS, MD, PhD: Well, the -- I'll -- for the sake of time, I'll answer this one quickly.
You know, incorporated into these studies, the phase III studies is the MSQLI. And whereas at one year, there are some -- there's a statistically significant benefit in both studies favoring a sense of physical improvement, as measured on the short form 36, there -- it's less clear in other areas having to do with things, for instance, cognition, fatigue, so forth and so on. There are some positive trends, but there's also a lot of noise in the data. That may be a function of the testing itself, it may be a function of just one years' data and the infrequency in testing. We'll have more data in the Spring.
We'll also have -- although this is limited data, we'll have the PASAT data from the MSFC, which -- we'll have data on that at the end of the study.
I wish, truly wish we had more time to go into detail, but I am getting the signal that it is time to wrap it up. I know I can speak for all of us in saying that we have very much enjoyed doing this. I'd like to particularly thank Dr. Rick Munschauer, Shirley O'Leary and JULIE FARACE for providing their expert opinion and Dr. Mariko Kito, who couldn't be with us tonight, for her expert opinion on the video and our audience for all of these insightful questions.
If you have any more questions on natalizumab or any MS issue, you certainly can submit them to the experts exchange at the website, www.msleaders.org.
Thank you for joining us. I'm Dr. Ted Phillips.
Douglas Kerr, MD, PhD (Course Director):To conclude, you have heard a review of the mechanisms of action of the existing and emerging MS therapeutic agents. We have discussed that since MS is likely a heterogeneous disorder, with several pathologic subtypes, the rationale for utilizing new, targeting immunotherapies that may be common to all forms of the disorder, is increasingly strong. Several targeted antibody immunotherapies, including alemtuzamab (Campath), daclizumab (Zenapax), rituximab (Rituxan) and natalizumab (Tysabri) are being investigated in the treatment of MS. Each has a distinct mode of action and may be appropriate for different subsets of patients. The first of these to be approved, natalizumab, has been shown in one-year data to be dramatically effective in terms of MRI disease activity and relapses. Based on that data, from the AFFIRM and SENTINEL studies, the FDA approved natalizumab to reduce the frequency of clinical relapses in relapsing forms of MS. Although comparisons with other therapies cannot reliably be done based on differences in study design and the fact that there are no head to head comparisons, the approval of natalizumab is very promising for the treatment of MS.
It is clear that natalizumab is safe in the short term (at least to 20 months), is well tolerated and is highly effective in the studied measures of disease activity. However, we do not know long term safety on the use of Tysabri and we do not have data supporting its role in modifying disability accrual in MS patients. Additionally, some patients develop neutralizing antibodies to natalizumab and, unlike the controversy with neutralizing antibodies and interferon therapy, it is clear that neutralizing antibodies to natalizumab interfere with efficacy of the drug. Therefore, although natalizumab and other antibody immunotherapies seem poised to markedly enhance our treatment of MS, more data is required before we know exactly where this class of medications belongs in the arsenal.
You will be presented with more data on natalizumab and other antibody immunotherapies in the future. We hope this presentation has been helpful in interpreting those data and how these therapies will be utilized in the treatment of MS patients.
The Implications of Tysabri (Natalizumab) for Multiple Sclerosis (MS) Therapy
Q & A session
The Implications of Natalizumab for Multiple Sclerosis (MS) Therapy Previously Recorded on December 15, 2004
J. THEODORE PHILLIPS, MD, PhD: Hello, this is Dr. Ted Phillips. I hope you've enjoyed our discussion on the implications of natalizumab for MS therapy and we're happy that you've stayed for this Q&A conference. I'm pleased to be joined again by Shirley O'Leary, JULIE FARACE and Rick Munschauer.
We've received quite a few questions, so let's get started. Now, what we did was we received so many questions that it would be impossible to cover all of the questions asked in a reasonable time. So we have binned a number of similar questions together and so we'll kind of cover them like that.
And so we're going to start off with a question that I'm going to direct towards Dr. Rick Munschauer and this one is from Sharon in New York and Martha from Indiana and George from Illinois who all want to know something about combining natalizumab with Rebif® or Betaseron®, but also the possibility of combining natalizumab with mitoxantrone. Rick, what do you have to say about that?
FREDERICK MUNSCHAUER, MD: Well, Ted, the SENTINEL study, the large phase III clinical trial, was indeed done adding Tysabri® or natalizumab to Avonex® or beta-interferon-1a. So, on a purely scientific basis, it's going to be questionable to compare the results that we got with Avonex® plus Tysabri® with another beta-interferon product plus Tysabri®.
However, on a clinical basis, I think it makes some sense. We know that the mechanisms of action of the type-1 interferons, interferon ß-1a or interferon ß-1b really are quite similar. And so I do feel that there is likely to be a therapeutic benefit of adding Tysabri® to any of the interferons, just as was demonstrated with Avonex®.
The caveat to that might be that, with the interferon ß-1b, Betaseron®, or with Rebif®, the incidence of neutralizing antibodies to interferon is quite a bit higher. And from previous MS leaders at teleconferences, we've really shown that the emergence of anti-interferon antibodies is associated with an attenuation of therapeutic effect.
So I think that, if somebody is on a beta-interferon and they're antibody-negative, then, from a clinical perspective, it's quite likely that adding Tysabri® will indeed produce the same sort of benefit as we see with Avonex®.
But I'd like to ask you a question, Ted. What do you think about adding Tysabri® to Copaxone®?
J. THEODORE PHILLIPS, MD, PhD: Well, indeed, and that was a question that was asked by a number of folks, including Victor from Kentucky and Lillian, a nurse from Colorado, and Connie, a nurse from Florida, wanted to know about that.
And, now, although we don't have the detailed answer to that important question right at this second, we'll at least have some safety data in no more than a few months from now. Some of you may know that there was a small phase II study carried out with natalizumab plus Copaxone® versus natalizumab plus placebo. It was phase II, so it wasn't an efficacy study, but rather it was a safety study. That study has completed and those people, like the other people in the two phase III studies going on, have rolled over into open-label natalizumab.
So, it's intriguing to think about the possibility of combining agents with different or possibly complementary modes of action. It -- theoretically, because we've got data on low-dose interferon, Avonex® plus natalizumab, that at least makes the concept that Rick was talking about of higher-dose interferon, Rebif® and Betaseron®, at least in the same ballpark.
Copaxone®, or glatiramer acetate, and natalizumab's a different ballpark. It's intriguing and we will have some safety data coming up, I think, in just a few months, but efficacy data will be later.
FREDERICK MUNSCHAUER, MD: Ted -
J. THEODORE PHILLIPS, MD, PhD: Rick -- no, go ahead.
FREDERICK MUNSCHAUER, MD: No, I was going to ask you, Ted, if the trial that adds Tysabri® to glatiramer acetate, or Copaxone®, shows that MRI data is reduced, is this something that you'd recommend to your patients, if they're fewer, newer enlarging T2 lesions, fewer gadolinium-enhancing lesions? In other words, since we won't have any primary outcome measure, because it's a relatively small trial, will you look to the MRI measures during that trial as a way of trying to facilitate your clinical decision-making?
J. THEODORE PHILLIPS, MD, PhD: Yeah. Well, great question and I guess my best answer to that is: If I split my patients down into two general categories, those people who are on a therapy and doing okay, maybe not optimally, but are not doing horribly, if I switch from what they are on to -- if I consider adding a Tysabri®, I think I am of the philosophical bent that I am going to be switching to natalizumab monotherapy and giving that a try, rather than adding it to preexisting.
Now, the other group of people who are doing very badly on whatever it is that I've tried and it seems like, you know, this person, the most likely issue, if there is any issue at all that will improve their situation, is going to be combination. Well, you know, in a certain sense, all bets are off. I think I would feel safe in combining Copaxone® with natalizumab, from what I know about this, although, like I said, the data hasn't actually been analyzed and made public yet. But do I intrinsically feel that this would be more effective, even if the MRI markers showed improvement? Well, that's hard to say. MRI markers, I expect to show improvement from Tysabri® alone.
FREDERICK MUNSCHAUER, MD: Yes, that's a good point. I skipped the -- to the second part of the question that you asked me and it was intentional. What about mitoxantrone, Ted, Novantrone®? Let's say you have a patient who is rapidly getting worse. The kind of patient that you and I both normally think is a candidate for major immunosuppressive therapy with mitoxantrone. What do you think is the role of Tysabri® and mitoxantrone or switching those patients from a rather potent immunosuppressive agent to the more immunomodulatory action of Tysabri®? How are you going to handle that?
J. THEODORE PHILLIPS, MD, PhD: Well, speaking for myself, I think I'm going to handle that extremely carefully. I personally would be reluctant to go just blindly into mitoxantrone plus natalizumab. That isn't saying that it couldn't be a good combination, but I think that that potent immunosuppressant plus the potent immunomodulatory actions of natalizumab, I think that really needs a safety study before that can just be launched into. There might be unexpected not-so-good complications from adding those two together, so I don't know.
I personally am just going to kind of put that one on the back burner and I'm also asking myself how it was that I ask you that question, but you ended up asking me that question.
We actually have a question that came in just now from Amy in Illinois, who wants to know if any of us -- well, I say "if any of us," I'm sure every one of us have thoughts about natalizumab, Tysabri®, and what to tell patients who may wish to become pregnant. So, Shirley, what are you going to tell -- I mean, you know, this is not an uncommon type of question to come up.
SHIRLEY O'LEARY, RN, MSCN: Oh, you're right, it's a very common question. And, of course, we would be very erring on the side of caution and have our patients, if they're planning on becoming pregnant, to stop therapy, most likely, in their best interest, I think. And, of course, I'm sure the package insert is agreeing with that, too.
Now, I know that there were some pregnancies that resulted in the study and I don't know necessarily all of the final outcomes. I think most of the people did just great, but it certainly wasn't something that was hoped to happen during the studies. We practiced very good -- hopefully, all the patients practice very good birth control and we, as research coordinators, constantly reminded them about that.
So we really don't have much data on pregnancy and natalizumab, so I think that my advice, from a nursing perspective, would be to have my patient stop therapy, if they were interested in becoming pregnant.
J. THEODORE PHILLIPS, MD, PhD: Right. I -- I think probably -- I mean, that is the safest answer. Just a momentary followup: The data on the people -- people in both placebo and natalizumab treatment groups, there were a handful in both studies, people who got pregnant. There were, as I recall, there were no obvious adverse outcomes in either group of pregnancies. I actually think there have maybe been a very few natalizumab births now and, again, to my best knowledge, no problems, no issues.
Nonetheless, it still is a category C pregnancy drug and I think it's very well-advised that -- for this drug and pretty much -- at least in my opinion, pretty much most any drug, to discontinue during the relatively protective, MS-wise, time of pregnancy.
Let's see. Got a question here from Joanie in Washington State who is wondering what kind of monitoring needs to be done during and in the one-hour observation period after infusion and is this documented on any kind of a standard flowsheet. Shirley, I'm going to shoot this one to you again, since you've been doing this for so long.
SHIRLEY O'LEARY, RN, MSCN: Well, yes, of course, with all of our natalizumab infusions that we've done thus far with regard to research, there is the one hour of infusion followed by the one hour of observation afterwards. And, actually, I -- the package insert also states that they -- that you are to monitor the patient for an hour, post-infusion.
Usually, within our research protocols, we take about ten minutes of flush in that second hour. So the ten minutes of that post- -- the first hour post-infusion is generally used up with flushing the line. And then, normally, I think what might be recommended is to go ahead and leave your line in, leave your saline lock in place and then just have the patient in the room with you and you're observing them for the next forty minutes, completing that one hour post-infusion. And then, taking out the saline lock at the end and doing concluding vital signs and then allowing the person to leave.
As far as the monitoring and then documenting on a flowsheet, a flowsheet is great, because you can capture all of that information, from the time the patient walks in and that's going to include a little bit of an assessment of them, how are they doing, any particular problems, doing vital signs. And then documenting your insertion of your catheter and the beginning of the infusion, vital signs and just all your monitoring throughout and then finally ending with completion of vital signs, a second set of vital signs and then discontinuing the saline lock.
So, yes, you can capture everything on one sheet in a very organized fashion, so I think that is a really excellent idea.
J. THEODORE PHILLIPS, MD, PhD: Great, okay. Julie, here's a question for you, still more kind of into the nuts and bolts of infusion. Inasmuch as with any therapeutic monoclonal antibody with natalizumab, there has been a reported low, but nonetheless detectable incidence of infusion-related reactions. Any ideas -- Elizabeth a nurse from New York asks if there are any suggestions, maybe to help minimize the likelihood of infusion reactions, perhaps just in general.
JULIE FARACE, RN, CNRN: Well, one thing that we have to think about when we need -- when we're looking to minimize these infusion reactions is that the people -- the patients who have been treated with natalizumab, they are showing a higher incidence of reactions if they have this neutralizing antibody to the drug, which I believe we're going to get into in a few minutes. So it's kind of a question as to whether or not should we treat this prophylactically or should we allow this to happen, so that we can tell whether or not this is something the patient will tolerate.
I think, in other infusions that I've given myself, we treat prophylactically only because we know more about the infusions, whereas, with Tysabri®, we're still getting that data. So, a lot of times, we will treat patients with things like Tylenol® and Benadryl® prophylactically to prevent, a lot of times, just even mild fever, flushing, chills, things like that. But I think it's also important to remember that this is because we know more about those drugs, so we need to kind of do that with caution at first, especially with a new patient who hasn't received this yet.
J. THEODORE PHILLIPS, MD, PhD: A somewhat related question from Jean in Delaware and I'll kind of address this to both you, Julie, and Shirley. Jean asks -- or comments that "We are setting up a small infusion center in our office to accommodate Tysabri® infusion. Is there anything special we should have available to assist our patients during infusion, in order to handle any sort of discomfort of side effect?" Any kind of general comments or suggestions, in terms of, I guess, creature-comfort types of issues for an infusion area?
SHIRLEY O'LEARY, RN, MSCN: Well, I think, actually, there's a number of things we can do. Certainly, a comfortable chair, being in a position to elevate a patient's legs, some just comfort techniques such as that. Hopefully, the IV insertion has gone smoothly, those sorts of things are always positive in any IV setting, I think. And with regard to natalizumab, we've been very fortunate and have seen few side effects from the drug thus far and that's not to say that we shouldn't always be prepared. Certain, we should be.
And I think it's also important to -- as we were talking a little bit before, in doing your assessment when your patient comes in, to determine, right off the bat, if there -- if there's anything going on before you even begin your infusion, such as a headache or a stomachache or an upper respiratory infection, so they're congested, anything that might maybe be troublesome a little bit down the road in that one-hour infusion for them. And so if we can address those things upfront, that's going to enhance their comfort quite a bit, too.
And then, again, being prepared and having on site any medications that you would need to address any reactions or anything that would come up during the infusion would also be important. What do you think, Julie?
JULIE FARACE, RN, CNRN: Yeah, I -- that's pretty much the answer I was going to give, except for I've found that my patients, in our infusion center, really like the fact that we have a much more relaxed setting in our infusion center.
SHIRLEY O'LEARY, RN, MSCN: Mm-hm.
JULIE FARACE, RN, CNRN: Where we have actual like lamps that you would have in your house that have a -- that provide a dimmer light, so that, once the infusion has started and the patient is allowed to relax a little more, not feeling so much in the stark hospital setting. Things like blankets and pillows to keep them comfortable, that really helps. And, sometimes, even the nurse at our infusion center brings in a relaxing CD, that can be helpful to them. Anything to kind of minimize their anxiety during the infusion.
J. THEODORE PHILLIPS, MD, PhD: Great, great. Rick, I got a question for you. This is from Marianne, a physician in Arkansas. A more general question. She asks, "Can it or has it been shown that the prevention of relapses is truly an indication of delay in progression of the disease?"
FREDERICK MUNSCHAUER, MD: It's a very good question and it's one that I know you've thought about a lot, Ted.
We really believe -- and this is data, I think, that Tom Scott has published in Neurology. We believe that exacerbations early on in the course of relapsing MS are indeed predictive of future disability. So if you have someone who generally has a disease duration that's shorter than about six, seven years and who has not yet achieved a certain level of disability that results in a significant impairment in their ability to ambulate, for instance, a EDSS rating of 5 or below. That group of people, early in the disease with less disability, relapses probably are correlated with progression in disability later on.
In data that Confavreux has published in Europe, it's quite clear that, when people are seven, eight, nine, ten, eleven years into the illness or have significant difficulty with walking, then exacerbation rates in those patients tend to be less. As people evolve from an early relapsing form of the disease to a more secondarily progressive forms of the disease, exacerbations tend to go away. So he had a very interesting article that showed, if you're disability score was greater than 4 or you were having difficulty walking long distances, that exacerbations themselves may not be predictive of long-term disability.
I know that sounds complicated, but the way I think about it, if you have minimal disability early on in your disease, if you have a high exacerbation rate, you're likely to become -- more likely to become impaired over the next few years. While, later on in the disease, exacerbation rate doesn't really predict how much more ground you'll lose, from a point of view of disability. Would you agree with that, Ted, or do you want to modify that?
J. THEODORE PHILLIPS, MD, PhD: No, I do agree with that, in general. I think the nature of the question asked itself kind of speaks to a larger question of what is what in MS, clinically speaking. Are relapses just relapses? Is progression the same or is it different? And I think that there -- I think this is an evolving area in MS and I think that there is accruing evidence that what -- that there may be a -- an underlying progression to the disease that is not so apparent early in the disease, where the disease early on is punctuated by the more dramatic exacerbation followed by whatever degree of improvement there is.
And, yet, having said that, it seems quite intuitive that the more attacks one has with less than 100% recovery from each, over time, that will amount to accruing neurological problems and could translate into increasing disability.
We've got so many more questions here and yet I'm told that we have relatively not much time left, so I want to try to get to maybe two or three other questions.
Rick, let me ask you about -- let's talk just a second about neutralizing or we should call blocking antibodies and Tysabri®. A physician from Texas asks, "What are the recommendations for antibody testing? What will be used and who will do it?" And, also, Faith from California wants to know, "Does antibody formation to Tysabri® produce diminished response to treatment?"
FREDERICK MUNSCHAUER, MD: Well, the second question is much easier to answer. Tysabri® is a humanized IgG. It's a protein and whenever you inject proteins into people, there is the potential for developing an antibody against this protein. In the case of Tysabri®, which is an antibody itself, you have an antibody against an antibody. And we do know that about 9% of people on Tysabri® develop an anti-Tysabri® antibody. And about 6% of those, that antibody just is persistent, it doesn't go away.
We also know, from both the AFFIRM and the SENTINEL trial and the one-year data has been looked at, is that, if you're going to develop an antibody to Tysabri®, you do so in the first three months. And, once you've developed the antibody, if it's persistent, it will be there three months later or at six months. And we also know that, once you've developed an antibody to Tysabri®, gee, you know, we see a regression in terms of exacerbation rates, in subsequent months over the first year, to resemble the exacerbation rates of the people in the placebo group. So the emergence of anti-Tysabri® antibodies is associated with a loss of efficacy of Tysabri®. The exacerbation rates increase up to almost the level of somebody who was a placebo person.
However, if you are one of those 3% that have transient Tysabri® antibodies, well, as the antibodies go away, then the efficacy of the drug, in terms of reducing exacerbation rates, is seen again.
So, I think antibodies are important to Tysabri® and I think a cheap, inexpensive assay is down the road and I think it will be available commercially. Certainly, all of us who've used the drug feel it would be an important thing. It only happens in about 6 to 9% of people. And probably the optimal time to measure it, if you were going to measure it just once would be at six months, because the majority of people will become positive at three months and those people that are persistently positive will be positive again at six months.
So, I'm thinking -- and we haven't worked all this out, but, as I look at the data, my personal approach will be to do Tysabri® antibodies after six months of therapy. If they're positive, then I will assume those are the people that have persistently positive antibodies and I also know those are the people whose exacerbation rates will resemble those of people who weren't treated at all and then I would move to an alternate therapy. Is that how you read the data, Ted?
J. THEODORE PHILLIPS, MD, PhD: Pretty much the same way. I hope we won't have to wait too terribly long for an antibody assay. As you point out, it's a straightforward binding assay and I'm told that, hopefully, by this Spring, no later than this Spring, that assay will be available.
As you point out, it -- the results are ultimately only important to, fortunately, a minority of people, not exceeding 9% total and then the more persistent area, the 6%. But, of course, to those 6% who tend to be more persistent, it's a critically important test, because it means, as you pointed out, that Tysabri® in that person may not be the best treatment for them. And exactly how persistent these, quote-unquote, "persistent" antibodies are is something that we're going to be getting more data about in the longer-term followup studies and I think that will be important as well.
Let's see, we probably have time for one last question and so I'm looking through my list here. You know, I think that the last question that -- is going to be one from Joy in New Jersey who asks, "Does natalizumab ameliorate cognitive as well as physical symptoms?" And if we can expect -- or is it reasonable to expect any improvement cognitively on Tysabri® as, say, compared to Avonex®?
FREDERICK MUNSCHAUER, MD: Tough question, isn't it? And, in fact, I am of the belief that MS is a whole-brain inflammatory disease and that the majority of the inflammatory cells come from the intravascular space, invade the brain and participate in immunologically mediated brain injury in a very diffuse way.
So it's a leap of faith, but I really do believe that, if you show that Tysabri® not only reduces exacerbation rates but also decreases gadolinium-enhancing and decreases newer enlarging lesions, then I would say, with a reasonable degree of medical certainly (sorry to sound legalistic about it) that it is probable that Tysabri® will slow cognitive impairment, too.
We don't have the data. The AFFIRM and the SENTINEL try did not measure cognitive function prospectively like the Avonex® trial did. So I think it's one of those things that we have to begin to use some clinical judgment on and I'll ask Shirley and I'll ask you, Ted, and Julie, too, about experience with this drug, in terms of what you feel about how patients subjectively feel on it. Do they feel like they are not progressing, either cognitively or physically?
J. THEODORE PHILLIPS, MD, PhD: Well, the -- I'll -- for the sake of time, I'll answer this one quickly.
You know, incorporated into these studies, the phase III studies is the MSQLI. And whereas at one year, there are some -- there's a statistically significant benefit in both studies favoring a sense of physical improvement, as measured on the short form 36, there -- it's less clear in other areas having to do with things, for instance, cognition, fatigue, so forth and so on. There are some positive trends, but there's also a lot of noise in the data. That may be a function of the testing itself, it may be a function of just one years' data and the infrequency in testing. We'll have more data in the Spring.
We'll also have -- although this is limited data, we'll have the PASAT data from the MSFC, which -- we'll have data on that at the end of the study.
I wish, truly wish we had more time to go into detail, but I am getting the signal that it is time to wrap it up. I know I can speak for all of us in saying that we have very much enjoyed doing this. I'd like to particularly thank Dr. Rick Munschauer, Shirley O'Leary and JULIE FARACE for providing their expert opinion and Dr. Mariko Kito, who couldn't be with us tonight, for her expert opinion on the video and our audience for all of these insightful questions.
If you have any more questions on natalizumab or any MS issue, you certainly can submit them to the experts exchange at the website, www.msleaders.org.
Thank you for joining us. I'm Dr. Ted Phillips.
Douglas Kerr, MD, PhD (Course Director):To conclude, you have heard a review of the mechanisms of action of the existing and emerging MS therapeutic agents. We have discussed that since MS is likely a heterogeneous disorder, with several pathologic subtypes, the rationale for utilizing new, targeting immunotherapies that may be common to all forms of the disorder, is increasingly strong. Several targeted antibody immunotherapies, including alemtuzamab (Campath), daclizumab (Zenapax), rituximab (Rituxan) and natalizumab (Tysabri) are being investigated in the treatment of MS. Each has a distinct mode of action and may be appropriate for different subsets of patients. The first of these to be approved, natalizumab, has been shown in one-year data to be dramatically effective in terms of MRI disease activity and relapses. Based on that data, from the AFFIRM and SENTINEL studies, the FDA approved natalizumab to reduce the frequency of clinical relapses in relapsing forms of MS. Although comparisons with other therapies cannot reliably be done based on differences in study design and the fact that there are no head to head comparisons, the approval of natalizumab is very promising for the treatment of MS.
It is clear that natalizumab is safe in the short term (at least to 20 months), is well tolerated and is highly effective in the studied measures of disease activity. However, we do not know long term safety on the use of Tysabri and we do not have data supporting its role in modifying disability accrual in MS patients. Additionally, some patients develop neutralizing antibodies to natalizumab and, unlike the controversy with neutralizing antibodies and interferon therapy, it is clear that neutralizing antibodies to natalizumab interfere with efficacy of the drug. Therefore, although natalizumab and other antibody immunotherapies seem poised to markedly enhance our treatment of MS, more data is required before we know exactly where this class of medications belongs in the arsenal.
You will be presented with more data on natalizumab and other antibody immunotherapies in the future. We hope this presentation has been helpful in interpreting those data and how these therapies will be utilized in the treatment of MS patients.
