The Art and Science of Natalizumab Therapy
Editor's Note:
Andrew Wilner, MD, discusses the art and science of natalizumab treatment with Thomas Leist, MD, PhD, director of the Multiple Sclerosis Center at Thomas Jefferson University in Philadelphia, Pennsylvania. They spoke on June 2, 2012, at the Consortium of Multiple Sclerosis Centers and Americas Committee for Treatment and Research in Multiple Sclerosis (ACTRIMS) meeting in San Diego, California.
Dr. Wilner: Dr. Leist, natalizumab is among the multiple options we now have for treating patients with multiple sclerosis. When do you decide to use this drug, and how do you use it?
Dr. Leist: At this point, I think we have 2 different scenarios for using natalizumab: one for patients who test negative for the JC virus antibody, and another for patients who test positive for the JC virus antibody. These 2 patient groups obviously have a significantly different risk profile with respect to developing progressive multifocal leukoencephalopathy (PML), which has been associated with natalizumab.
In patients who are JC virus-negative and have aggressive disease, I view natalizumab as a first-line medication. I will also use this as a second-line treatment in JC virus-negative patients whose disease has broken through the usual first-line medications.
In patients who are JC virus-positive, additional factors must be considered. If the patient been exposed to multiple treatment options and this really represents a last resort, or risks of other treatment options are considered greater than risks of natalizumab, it may be an option, but it must be used judiciously.
Dr. Wilner: If a patient becomes JC-antibody positive during the course of therapy, what do you do then?
Dr. Leist: To date, we have not had a lot of experience with patients who seroconvert during treatment. But in that case, there is certainly the potential that the primary infection could be associated with occurrence of PML, as we have seen with other opportunistic infections. For example, toxoplasmosis as a primary infection can be associated with cerebral involvement in the appropriate setting.
If the patient becomes JC-positive at some point during treatment, I probably would look for another medication for this particular patient, unless the patient has run through the gamut of medications and this is the last option for the patient, or other medications cannot be considered because of particularities of this patient. For patients who are JC-positive and belong to this very high-risk group, after 2 years of treatment with natalizumab, the risk for PML is 1 in 250. If the patient has previously been on immunosuppressive therapy, the risk is closer to 1 in 90. In these patients, we need to have reasons to persist with therapy. I mentioned the patient who has run through other medications, for example.
Adjustments in the dose frequency are at least a theoretical concept that one could entertain. It has become clear over the past few years that the longer the patient is on the medication, the higher the risk is for PML. In addition, there is speculation that the levels of natalizumab that persist in a patient may actually creep up with long-term use. Therefore, less frequent dosing maybe a potential alternative to forestall development of PML.
Dr. Wilner: Can you provide an example of such dosing?
Dr. Leist: Every 6 or 8 weeks rather than every 4 weeks. Dr. Carlo Tornatore from Georgetown University presented a poster at the American Academy of Neurology meeting describing a practice that uses natalizumab every 8 weeks. I belong to a group that switches patients to every 6-7 weeks after 18 months to 2 years of natalizumab therapy with less frequent in dosing in mind. Having said this, no clinical trials have proven this regimen to be safer than every-4-week dose administration.
Dr. Wilner: Reducing the frequency is a strategy that allows you to prolong the time beyond 1 or 2 years, when normally you would feel compelled to stop the drug. Is that correct?
Dr. Leist: Reducing the frequency of administration is, in my mind, a way to perhaps get closer to the minimally effective dose that would enlarge the therapeutic window of the medication.
In my practice, for example, I have patients who have been on mitoxantrone but had return of significant disease activity even after completing the lifetime dose of mitoxantrone. They are on natalizumab after a very "Hail Mary" medication. These patients are unwilling to move to another medication because of their previous experience, so in these patients, I have moved to a regimen of infusions every 6-8 weeks in an attempt to provide a certain pulsatility of treatment, with the hope that for at least part of the month, there is a greater immune surveillance that hopefully protects the patient from occurrence of PML.
Obviously, I am making certain assumptions with this. However, in the phase 2 trial of natalizumab, doses of 3 mg/kg and 6 mg/kg were equally effective. That means to me that the lower dose could have been explored to see whether it potentially will be equally effective, but with greater safety. At the time of the phase 2 trial, however, PML was not a consideration.
Dr. Wilner: Dr. Leist, thank you very much for sharing your experience in the treatment of patients with multiple sclerosis.
Dr. Leist: Thank you.
Editor's Note:
Andrew Wilner, MD, discusses the art and science of natalizumab treatment with Thomas Leist, MD, PhD, director of the Multiple Sclerosis Center at Thomas Jefferson University in Philadelphia, Pennsylvania. They spoke on June 2, 2012, at the Consortium of Multiple Sclerosis Centers and Americas Committee for Treatment and Research in Multiple Sclerosis (ACTRIMS) meeting in San Diego, California.
Dr. Wilner: Dr. Leist, natalizumab is among the multiple options we now have for treating patients with multiple sclerosis. When do you decide to use this drug, and how do you use it?
Dr. Leist: At this point, I think we have 2 different scenarios for using natalizumab: one for patients who test negative for the JC virus antibody, and another for patients who test positive for the JC virus antibody. These 2 patient groups obviously have a significantly different risk profile with respect to developing progressive multifocal leukoencephalopathy (PML), which has been associated with natalizumab.
In patients who are JC virus-negative and have aggressive disease, I view natalizumab as a first-line medication. I will also use this as a second-line treatment in JC virus-negative patients whose disease has broken through the usual first-line medications.
In patients who are JC virus-positive, additional factors must be considered. If the patient been exposed to multiple treatment options and this really represents a last resort, or risks of other treatment options are considered greater than risks of natalizumab, it may be an option, but it must be used judiciously.
Dr. Wilner: If a patient becomes JC-antibody positive during the course of therapy, what do you do then?
Dr. Leist: To date, we have not had a lot of experience with patients who seroconvert during treatment. But in that case, there is certainly the potential that the primary infection could be associated with occurrence of PML, as we have seen with other opportunistic infections. For example, toxoplasmosis as a primary infection can be associated with cerebral involvement in the appropriate setting.
If the patient becomes JC-positive at some point during treatment, I probably would look for another medication for this particular patient, unless the patient has run through the gamut of medications and this is the last option for the patient, or other medications cannot be considered because of particularities of this patient. For patients who are JC-positive and belong to this very high-risk group, after 2 years of treatment with natalizumab, the risk for PML is 1 in 250. If the patient has previously been on immunosuppressive therapy, the risk is closer to 1 in 90. In these patients, we need to have reasons to persist with therapy. I mentioned the patient who has run through other medications, for example.
Adjustments in the dose frequency are at least a theoretical concept that one could entertain. It has become clear over the past few years that the longer the patient is on the medication, the higher the risk is for PML. In addition, there is speculation that the levels of natalizumab that persist in a patient may actually creep up with long-term use. Therefore, less frequent dosing maybe a potential alternative to forestall development of PML.
Dr. Wilner: Can you provide an example of such dosing?
Dr. Leist: Every 6 or 8 weeks rather than every 4 weeks. Dr. Carlo Tornatore from Georgetown University presented a poster at the American Academy of Neurology meeting describing a practice that uses natalizumab every 8 weeks. I belong to a group that switches patients to every 6-7 weeks after 18 months to 2 years of natalizumab therapy with less frequent in dosing in mind. Having said this, no clinical trials have proven this regimen to be safer than every-4-week dose administration.
Dr. Wilner: Reducing the frequency is a strategy that allows you to prolong the time beyond 1 or 2 years, when normally you would feel compelled to stop the drug. Is that correct?
Dr. Leist: Reducing the frequency of administration is, in my mind, a way to perhaps get closer to the minimally effective dose that would enlarge the therapeutic window of the medication.
In my practice, for example, I have patients who have been on mitoxantrone but had return of significant disease activity even after completing the lifetime dose of mitoxantrone. They are on natalizumab after a very "Hail Mary" medication. These patients are unwilling to move to another medication because of their previous experience, so in these patients, I have moved to a regimen of infusions every 6-8 weeks in an attempt to provide a certain pulsatility of treatment, with the hope that for at least part of the month, there is a greater immune surveillance that hopefully protects the patient from occurrence of PML.
Obviously, I am making certain assumptions with this. However, in the phase 2 trial of natalizumab, doses of 3 mg/kg and 6 mg/kg were equally effective. That means to me that the lower dose could have been explored to see whether it potentially will be equally effective, but with greater safety. At the time of the phase 2 trial, however, PML was not a consideration.
Dr. Wilner: Dr. Leist, thank you very much for sharing your experience in the treatment of patients with multiple sclerosis.
Dr. Leist: Thank you.
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