IGOR J. KORALNIK, MD: Natalizumab belongs to a new class of medications called selective adhesion molecule inhibitors.

It is a humanized monoclonal antibody which is directed against the alpha-4 subunit of integrins.

Integrins are adhesion molecules that are present on the surface of lymphocytes and monocytes and are necessary for the leukocytes to be able to come out of the bloodstream into the tissues.

Integrins will bind with other molecules on the surface of the blood vessel, either VCAM in the brain vessel or MAdCAM in the gut vessels and that will initiate the process of extravasation of these leucocytes inside of the tissue and outside of the blood vessels.

When natalizumab binds on the monocytes and leucocytes it prevents this interaction and basically sequesters the leucocytes inside of the bloodstream.

IGOR J. KORALNIK, MD: There have been various therapies used for multiple sclerosis. First line of medication was global immunosuppressants, like steroids, for example, or various types of chemotherapies. Another wave of medication includes immunomodulators, like interferon, different types of interferons or glatiramer acetate, which modulate immune response by various mechanisms including cytokine production, for example, or even migration of lymphocytes in the tissues. But natalizumab has a more specific type of action, which is directed toward the migration of leucocytes inside of the body.

ROBERT J. FOX, MD: The benefits of targeting your immunomodulation with a monoclonal antibody is that you can very specifically target what you want to do. The interferons, although they're very effective in MS, they lead to a very wide array of immune responses, and by targeting one specific area, we can in a very careful way modulate how we're affecting this disease. So, it's a silver bullet, if you will, to try to just derail a small part of it so that we're not overly suppressing the immune system.

IGOR J. KORALNIK, MD: The benefit of targeted antibody immunotherapies are to be very selective for one specific target, hoping that this target is going to be a major component of MS pathogenesis. But since MS pathogenesis is not thoroughly understood and there may be more, different forms of MS that have different pathogenic mechanism, obviously we will need to try these medications one after the other in order to see if it's really effective for a certain type of MS.

Natalizumab Efficacy and Safety Data

J. THEODORE PHILLIPS, MD, PhD: Two phase III studies were performed that led to the ultimate approval of Tysabri for relapsing forms of MS.

The first study performed was called the AFFIRM study and looked at, over a two-year period of study, the effect of Tysabri as monotherapy versus placebo in relapsing individuals with MS. The second, sister study to this that was carried out at about the same time looked at people with relapsing MS who were already on interferon beta-1a, Avonex, and who continued to be on this treatment throughout that two-year study. Half of those patients were treated with Tysabri in addition to Avonex. The other half were treated with placebo. So those two studies comprised the two phase III studies that-both of which were successful, that led to Tysabri's ultimate FDA approval in November 2004.

The AFFIRM study looked at a little over 900 individuals with relapsing MS, two thirds of which were placed on Tysabri, the other third on placebo for a study duration of approximately two years. The results from the AFFIRM study were positive even as early as one year into the study, where an interim look was performed. Whereas there was an important, statistically significant reduction in relapse rate at one year, even more importantly at two years, this prominent effect on relapse rate reduction was sustained with an overall 68 percent effect in relapse rate reduction for the entire two-year study.

To me, I think even more important than that, and what actually was-represented the primary endpoint for the full two-year study-was the determination of the effect on Tysabri on the long-term progression of sustained disability in this disease. As troublesome as relapses are, it is the sustained progression in disability of this disease that- in which it takes- this disease takes its biggest socioeconomic toll.

This study showed a 42 percent reduction versus placebo in Tysabri-treated individuals as far as the development of sustained EDSS change occurred. This is greater than we have seen in other studies to this date, and very encouraging in its own right.

IGOR J. KORALNIK, MD: There was also an increase in quality of life measures in natalizumab-treated patients and a marked decrease in new MS lesions on MRI.

MRI parameters were looked at also and were-each of them were robustly positive and highly statistically significant.

At two years there was a 92 percent reduction in gadolinium enhancement on cranial MRI. There was an 83 percent reduction in new or enlarging T2 hyperintense lesions, and there was a 76 percent reduction in T1 hypointense black holes. This array of positive MRI results using conventional measures for disease activity surpasses that which has been reported for other agents in the treatment of MS, and again, concurrent with the prominent clinical results, leads to a very encouraging and hopeful picture for the future use and effectiveness of this drug in treating MS.

J. THEODORE PHILLIPS, MD, PhD: In the SENTINEL study, the patient population that were studied in that study were all individuals who had been on interferon beta-1a, Avonex, for a period of at least a year, and despite being on an effective treatment like interferon, this was a set of people that were selected for continued disease activity despite being on an effective therapy.

ROBERT J. FOX, MD: It's unclear if the interferon was failing the patient, in that it wasn't working at all, but they were clearly responding suboptimally compared to the way we would want them to respond.

J. THEODORE PHILLIPS, MD, PhD: In the SENTINEL study then, these people were divided into two groups. Half of the people were randomized to receive Tysabri, the other half randomized to receive placebo. Everybody continued throughout the entire two-year study on their-on their regular interferon beta-1a Avonex treatment.

IGOR J. KORALNIK, MD: 1,171 patients were enrolled in this study, which was carried for a period of two years. The major result of this study was a 53 percent reduction in relapses in natalizumab and interferon-beta-treated patients versus interferon-beta-treated patients alone. There was improvement in quality of life measures in natalizumab and interferon-treated patients and as well as a marked decrease in the number of new MRI lesions of multiple sclerosis.

ROBERT J. FOX, MD: The safety assessment from both the AFFIRM and the SENTINEL trials looked very encouraging initially in that patients tolerated the infusions quite well. There were some side effects, but it was generally quite well tolerated. There was a proportion of patients who developed an infusion reaction to the infusion, but other than that it was generally a well tolerated therapy until the development of PML.

And this was certainly a surprise to all of us in the field of multiple sclerosis.

Progressive Multifocal Leukoencephalopathy (PML)

IGOR J. KORALNIK, MD: The first patient who developed PML under natalizumab therapy was not an MS patient. It was a patient with Crohn's disease, which is an inflammatory disease of the gut. This patient was 60-years-old and he was treated with a variety of immunosuppressive therapy, including infliximab and azathioprine. This patient then received eight injections of natalizumab and started to develop neurologic problems characterized by behavioral abnormalities, withdrawn affect that were noticed by the family first and when he was brought to medical attention for these problems it was found that he had bilateral lesions in the frontal lobe white matter on MRI.

The thought of the clinicians at that time was that he may have malignancy of the brain, a tumor of the brain, and a biopsy of the brain was performed, which was interpreted at that time as an astrocytoma. And the patient died soon thereafter. It's only retrospectively that this histology of this patient was reexamined after the two other cases of PML in natalizumab-treated patients were discovered and that the correct diagnosis of PML was actually ascertained.

IGOR J. KORALNIK, MD: The two MS patients who developed PML during natalizumab treatment were in their mid-40s. One of them had been diagnosed with relapsing MS five years prior to presentation. The other one had been diagnosed with relapsing MS approximately more than 20 years actually prior to presentation. They both had been treated with natalizumab for at least two years. They developed neurologic deficits which were unlike their usual MS manifestations and were diagnosed by MRI as having white matter lesions that were different than the MS lesions, which were expanding rapidly.

One patient who had been diagnosed with relapsing MS five years ago had a very aggressive form of brain disease which turned out to be PML, including cavitated lesions in the brain, which started in the left frontal lobe.

IGOR J. KORALNIK, MD: The autopsy showed a lot of PML lesions in all the histological sections that were examined. Interestingly no MS lesions were found in this histological material. The other MS patient who developed PML had his first PML lesion diagnosed on a routine MRI scan, which was interesting because when he started to develop behavioral abnormalities, which were unlike his usual MS presentation, clinicians were alerted that something strange was happening in this patient, and natalizumab was stopped early in this patient.

The diagnosis of PML was established by PCR detection of JC virus, the agent of PML in the cerebral fluid. And a variety of treatments were started in this patient in the hope of stopping the progression of PML.

IGOR J. KORALNIK, MD: There were three patients out of 3,000 natalizumab-treated patients who developed PML. The manufacturer of natalizumab decided to pull out the medication from the market, which I think was the safe thing to do, because it was the first time that PML had been diagnosed in both MS patients, or Crohn's patients for that matter. There was a need to understand the reason for this happening, the mechanism of reactivation of the virus, JC, that causes PML.

J. THEODORE PHILLIPS, MD, PhD: In spring 2005, at the annual Academy of Neurology meetings, the full two-year data of the AFFIRM monotherapy natalizumab study were discussed. Not only clinical efficacy, but also MRI measures of efficacy, statistically significant quality of life measures in natalizumab-treated patients, but also, and most importantly, safety profiles, as well. I think it can be said accurately from the full two-year study that in general, natalizumab has a very good safety profile in the vast majority of individuals.

Of course, we also discussed at that Academy meeting the three individuals, the two in the MS studies and the one in the Crohn's study, who came down with progressive multifocal leukoencephalopathy. The details of each of those patients as they were known to us then were discussed in detail, and indeed, even some discussion, panel discussion was had with a PML expert that the Academy moderators invited to be part of that session.

ROBERT J. FOX, MD: We learned a lot about the development and the treatment attempts that were performed on these patients, and also the surveillance data from the balance of the patients who were treated with natalizumab was reviewed, and showed that there were no additional cases. There was no additional suggestion of JC virus infection in the brain or of PML. And that was very encouraging, that there were not more cases of PML in these patients.

IGOR J. KORALNIK, MD: What was also presented at the ECTRIMS meeting in relation to the safety data of the AFFIRM and SENTINEL trials, were detection of JC virus in the plasma or serum of natalizumab-treated patients, which indicates that in this patient population and in these samples there was little evidence of JC virus reactivation. However, these researchers did not have the cells of the patients, the peripheral blood mononuclear cells for testing because they were not stored prospectively. There is data indicating that the JC virus may be associated with lymphocytes in the blood and, therefore in the future, it would be very important to test for viral load of JC virus in both the plasma serum sample and the cell samples of the blood.

ROBERT J. FOX, MD: PML, or progressive multifocal leukoencephalopathy, is a disease in which a virus, the JC virus-the name JC was named for the index patient from which the virus was initially isolated-it infects the brain. Usually it lives in most of us. About 80 percent of us carry this virus. It lives in our kidneys and in the bone marrow. And when the immune system is compromised, it can make its way into the brain, where it infects resident brain cells and causes those cells to die.

IGOR J. KORALNIK, MD: When PML occurs in a patient there is demyelination which occurs at certain places in the brain. By definition, it is a multifocal disease so multiple places in the brain are going to suffer from demyelination. Depending where the lesions are, it's exactly like MS, the neurological presentation is going to be very variable. In patients who survive from PML, they may be left with a variety of neurological deficits which pertains to the location of the lesions.

J. THEODORE PHILLIPS, MD, PhD: Where PML has been seen before has been actually limited to individuals who are severely immunosuppressed, either as a consequence of infection with HIV, AIDS or in organ transplants who have been pharmacology immunosuppressed or in cancer patients who are immunosuppressed because of their cancer and/or the medications used to treat it. Those have really been the only instances in which we have seen the central nervous system complication of JC virus reactivation. And even in those individuals, this is a rare occurrence. So most people who are immunosuppressed still don't have this as a complicating feature of their immunosuppression.

It was completely unexpected, in my view-I think in most people's views-that this study with Tysabri would be complicated by the occurrence of this particular infection.

Pathogenesis of PML

IGOR J. KORALNIK, MD: PML is caused by the reactivation of JC virus which is a benign polyomavirus that infects everybody in the normal adult population and remains quiescent throughout lifetime in normal individuals. When JC virus reactivates, most cases in the setting of profound immunosuppression, it will go to the brain and infect special cells of the brain called oligodendrocytes, the myelin-producing cells. It will cause a lytic infection of oligodendrocytes in the central nervous system.

What oligodendrocytes are doing, they are providing the myelin sheath, the white matter of the brain that coats axones. And when there is demyelination the normal signal transduction cannot occur within the brain and patients develop neurological deficits, including dementia, hemiparesis, sensory deficits, problems swallowing and breathing and usually this disease is fatal in weeks to months after disease onset.

ROBERT J. FOX, MD: Some people have wondered if the development of PML in these two patients really represents just a form of MS, and that a lot of MS may actually be PML that just hasn't gotten out of control, like the typical PML cases. The evidence for this hypothesis is quite scant. There really is very little data to support the presence of the JC virus in MS plaques or the involvement of JC viral infections in MS. And indeed, under the microscope, PML looks more like an astroglial tumor than it does a demyelinating plaque like multiple sclerosis. So, I think the likelihood of the JC virus being the underlying cause of multiple sclerosis, I think, is very unlikely.

IGOR J. KORALNIK, MD: I think that PML and MS are located at two extreme ends of the spectrum of immunological diseases, actually. MS is felt to be an autoimmune disease where there is too much immune response against normal component of the myelin, the brain white matter, leading to demyelination and neurologic deficit. On the other hand, PML only occurs in patients who are profoundly immunosuppressed. That means that their immune system is not working, especially the cellular immune response, which leads to the reactivation of this benign virus, JC virus, that leads to a lytic infection of oligodendrocytes and then creates demyelination with associated neurologic deficit. So, I think that these are extremely different diseases, actually.

The major clinical difference between MS and PML is that PML is not relapsing-remitting. It's always progressive unless patients are able to muster an immune response that is specific against JC virus and stabilize their disease. However, they never go back to a normal neurological exam, and they always will have some sort of neurologic deficit. On the other hand, you have MS patients who have a relapsing-remitting course and have necessarily no neurologic deficit between attacks.

J. THEODORE PHILLIPS, MD, PhD: One could ask the question, is it possible that it is the combination of natalizumab with other potent immunomodulatory or potent immunosuppressive medications that, in a certain susceptible individual, might predispose them for this unexpected opportunistic viral consequence. I think that is a reasonable hypothesis, and yet it's one for which we don't have additional data to really test that hypothesis with.

IGOR J. KORALNIK, MD: Patients that developed PML in these studies were treated with other immunosuppressant medication or immunomodulatory medications. The two MS patients who developed PML were treated by a combination of natalizumab and interferon-beta. It is possible that this double therapy led to an increase of JC virus replication that eventually led to its escape from immunosurveillance, spread to the central nervous system and developed into PML.

ROBERT J. FOX, MD: After the two MS patients with PML were published in the New England Journal of Medicine, there were some follow-up letters that were questioning whether these patients had MS at all. I think that's a little bit tough argument to convince one of. These patients met the standard inclusion criteria for developing multiple sclerosis for inclusion in the clinical trials. They had ongoing relapses despite having received interferon therapy, which is not uncommon in MS. One of the patients did not have significant disability, but that certainly does not exclude them from having multiple sclerosis. So I think at this point there's very little data to support that these two patients did not have multiple sclerosis. The other issue, these two patients were seen at excellent multiple sclerosis centers that are very good at diagnosing and managing multiple sclerosis. So, I think that there's very little compelling evidence to support the hypothesis that these patients did not have MS.

PML Detection

ROBERT J. FOX, MD: The JC virus can be detected in a variety of fashions. Most of us carry this virus, and intermittently over time it can very frequently be detected in our urine. And so we shed that into the urine, and PCR of the urine can detect it very, very commonly. Therefore, it's not very helpful in diagnosing PML.

JC virus can also be detected from time to time in the circulating blood of MS patients and healthy controls. In the three patients- the two MS patients and the one Crohn's disease patient-who developed PML, it was not very helpful in detecting PML, in that one of the patients did have JC virus detectable in their blood ahead of time, but the other two patients did not have JC virus detectable in their blood, even after the development of symptoms of PML.

So, the blood is probably not going to be a very useful surveillance tool for us to pick up PML. It's not even a very useful diagnostic tool.

The gold standard of diagnosis is really detecting JC virus through PCR in the spinal fluid. So in any patient in whom we are concerned about the development of PML, really a spinal tap with a PCR for JC virus is the test that should be done.

IGOR J. KORALNIK, MD: The question whether JC virus is present in the brain of healthy individuals is still under debate. The literature shows that there are as many studies that did not find JC virus in the brain of "normal" patients from studies that actually did find evidence of JC virus present in the brain of people who did not have PML. Obviously in order to have access to the brain you need to have either a brain biopsy for other diseases or an autopsy in patients who died from other causes or elderly patients.

Studies that found the presence of JC virus in the brain found the virus only by polymerase chain reaction, which is an amplification technique of the DNA of the virus. But did not show any evidence of infection of brain cells by immunohistochemistry or in situ hybridization, which would pinpoint in which cell the virus resides. So it is still unclear to me if the positive signal came from amplification of the virus that circulated in the blood vessels, in association with lymphocytes, for example, or if the virus was actually present in the brain parenchyma. It is also puzzling that as many studies did not find the presence of the virus in the brain of these patients.

IGOR J. KORALNIK, MD: Interestingly enough, in the Crohn's patient, a sample of intestine that was taken out by surgery a couple of years prior to PML presentation was reexamined and no JC virus was found to be present in the specimen.

IGOR J. KORALNIK, MD: The people who are susceptible for developing PML are those who will develop profound cellular immunosuppression, such as patients with AIDS, for example. But again, only a small percentage of patients with AIDS will develop PML. Only 5 percent of those patients will develop PML; that means that 95 percent of other patients with AIDS who are profoundly immunosuppressed do not develop PML. What we have found in my laboratory is that the cytotoxic lymphocytes, CD8+ T cells that are specific for defense against JC virus, have a crucial role for the prevention of PML and also for clinical outcome in patients who develop PML. What we have found is that those patients who are able to mount JC virus-specific cytotoxic T cell response against the virus that we can measure in the laboratory are those patients who have a better clinical outcome, are able to stabilize their brain disease and survive more than a year, and sometimes for extended period of time. Those patients where we cannot detect the cellular immune response against JC virus are those who importantly are going to have a progressive disease and a rapid fatal outcome in weeks to months after PML onset.

Treatment for PML

J. THEODORE PHILLIPS, MD, PhD: At this point in time, unfortunately, there is no reliable treatment for PML once it has occurred. That isn't to say that numerous treatments, including various antiviral therapies, have not been tried. They have been tried. They have been reported on in the literature, with no consistent beneficial effect.

One area, though, of encouragement is that it seems-and this is largely from the HIV/AIDS literature-that in those individuals in which their immune system can be reconstituted, one can, in some instances, see the ability of the previously suppressed immune system to mount an effective antiviral response against the JC virus, and that so-called immune reconstitution syndrome seems to lead to a better, ultimate, and not necessarily fatal, outcome for the individual with PML.

IGOR J. KORALNIK, MD: The hope of recovery from PML will depend greatly on the source of immunosuppression in these patients. If it's a patient treated with natalizumab, if the diagnosis can be established early and the medication be withdrawn, we hope that after three months no more trafficking of lymphocytes within the brain parenchyma is going to occur and that this patient is going to be able to contain the progression of PML.

ROBERT J. FOX, MD: That has given us hope that if we can diagnose PML very early in patients with MS who have been treated with natalizumab, that we may be able to intervene in a way to help convert PML from a very, very serious complication to a more manageable complication.

Looking Forward

ROBERT J. FOX, MD: What we need to have is additional studies. We need to learn what is the incidence of PML in patients treated with just natalizumab. Is it a lower incidence than compared to patients who are on combination therapy?

I think this is going to be an enduring, rare but real complication of this drug. I think it will remain a very small proportion of patients, but I think it will be there. But we need to get a better sense of what the incidence is. We will certainly be treating patients with monotherapy. We'll certainly be very cautious about our use of IV steroids in patients who develop neurologic symptoms while on therapy. But we need to learn, as well, how to treat these patients once they develop PML. And that's what these future studies will look at.

ROBERT J. FOX, MD: If natalizumab comes back onto the market, we need to have a way to try to detect PML early, and that's going to be a big challenge.

At this point, we don't have a great way to detect when patients are developing PML or at the very early stages. There has been some discussion about surveillance MRIs, intermittent surveillance MRIs, but the problem with that is that, to be effective, these MRIs would have to be done very, very frequently, perhaps every six or eight weeks, which is really not a practical way of doing surveillance for this complication, particularly for such a very rare incidence-real but rare-incidence of this complication.

IGOR J. KORALNIK, MD: I think it's going to be very important to be able to test for JC virus activation in patients taking immunomodulatory drugs such as natalizumab in the future. I want to emphasize that it's not only an important question for natalizumab itself and MS patients or Crohn's patients, but for this entire class of medication called selective adhesion molecule inhibitors, which are very attractive candidates for treatment of a variety of other autoimmune diseases, such as rheumatoid arthritis, psoriasis, asthma, allergic rhinitis, diabetes type 1, for example.

How are we going to prevent new cases of PML in this patient population?

By analogy with another polyomavirus, the polyomavirus BK, which affects renal transplant recipients and can cause a severe renal disease, I think it would be important to measure for the reactivation of JC virus in the blood sample of patients treated with integrin blockers.

So, the thought would be to do the same thing for patients on leukocyte migration inhibitors to try to detect ahead of time reactivation of JC virus from the stage of latency and viremia, the presence of the virus in the blood. In those patients who will develop high titer of viremia, for example, they will be probably at higher risk of spreading the virus to the brain and developing PML, and therefore, we can think that in the future those patients should stop the medication or at least decrease treatment with their medication and therefore we may hope to prevent the development of PML in the future in these patients.

IGOR J. KORALNIK, MD: We do not know at the present time what the cutoffs are for the JC viral load in the blood, which is either peripheral blood mononuclear cells, or PBMC, or plasma sample from patients for the development of PML.

Healthy individuals should not have JC virus present in the blood, or less than 5 percent of them in trustworthy laboratory should be found to have JC virus in the blood. You can find, however, JC virus in the blood of 20 to 40 percent of HIV infected patients who do not have PML, and you can find it in the blood of 60 to 80 percent of patients who do have PML, which indicates that you may not have always the virus in the blood when a patient has PML, especially if those patients have stabilized their disease and do not have active JC virus replication in their brain.

On the other hand, this tells you that you may have JC virus in the blood in patients who are immunosuppressed, yet they will not develop necessarily PML.

So, I think it would be important to test for JC viremia in patients with MS or Crohn's disease before they start on integrin blocker medications and weed out those patients who already have JC virus detectable in the blood by PCR, quantified PCR.

The frequency of testing of blood sample for reaction of JC virus is still open. Obviously viremia, which may lead to hematogenic spread of the virus from the stage of latency in the kidney to the brain, may be a very transient event. If you take a blood sample in the morning, you may not find a viremic event in the afternoon. Patients who are treated with natalizumab get IV injections of the drug once a month so it's easy to take a blood sample at that time for measurement of JC virus titers. However, it's not clear that viremia is going to be picked up at that time, and therefore, the frequency of measurement is not clear at this point.

In those patients who do not have the virus in the blood, you would follow them prospectively by quantified PCR to estimate their viral load while they go on treatment. However, there is no data at the present time to tell you that after such threshold there is an increased risk of developing PML.

IGOR J. KORALNIK, MD: The role of serial MRIs for monitoring of patients who may be at risk of developing PML because they are treated with new immunomodulatory medication is going to be important especially in patients with multiple sclerosis because these patients will have relapsing neurologic deficits. And every time this happens, it will be a question is it a true MS flare or is it PML. So, it's going to be important to be able to have a look at the lesion by MRI and to decide if further testing is warranted.

However, although classical MS lesion may be looking differently by MRI than the classical PML lesion, it will still have some lesions where there is a doubt. Is it a new MS lesion or a new PML lesion?

In these patients, a spinal tap for measurement of JC virus by PCR, also quantified PCR if possible, is going to give you the answer, which is the diagnosis of PML. If it's negative it's reassuring. However you have to be aware of the fact that some patients develop PML with undetectable JC virus DNA in their cerebral spinal fluid

In addition to the MRI, spinal tap, a very close neurological followup of these patients is going to be necessary to decide if it's just a relapsing-remitting form of MS or if it's a new lesion, expanding lesion of PML.

J. THEODORE PHILLIPS, MD, PhD: Although no head-to-head comparative studies have been done with Tysabri versus the other agents, when one just looks at the raw data, it would appear as though, for instance, with regard to effect on relapse rate, that Tysabri's effect versus placebo is approximately two-fold greater than that seen with the other FDA available agents for relapsing MS.

J. THEODORE PHILLIPS, MD, PhD: There is a growing sense based on accumulating research that MS at a histopathological level may not be simply one immune-mediated disease, but could be as many as four loosely related diseases, based on immunopathology. If that is true, and to the extent that that model may be applicable to MS at large, it may mean that the future for effective MS therapeutics will be more targeted therapies dependent upon the pathology that exists in the individual patient.

If that's so, then that means that the future makes room for treatments that may target certain types of immune cells, but not others.

ROBERT J. FOX, MD: Natalizumab represents a very significant step forward in our ability to treat MS. It clearly is much superior to the standard injection therapies, and so represents a new generation of MS treatment. It does have significant complications, specifically PML, and that is of a concern. And when we use natalizumab, we need to be very careful in the type of patients that we consider for this drug and in counseling the patients regarding this very significant complication.

However, the market efficacy of this drug needs to be balanced carefully with the safety issues, and there are certainly many patients for whom our standard therapies are not working and are willing to accept the risk of PML for the benefit of this markedly superior drug.

However, this drug also suggests that there still is a need for the very effective and safe drug, and hopefully future drugs that are being developed down the line will be able to balance that to have that superior efficacy without the risk of serious side effects.