In this full-length interview, Marco Rizzo, M.D., Ph.D., explains how a new drug could reinstate the immune system in MS patients.
April 14, 2003
Ivanhoe Broadcast News Transcript with
Marco Rizzo, M.D., Ph.D., Neurologist,
Yale University School of Medicine, New Haven, Connecticut,
TOPIC: Protecting MS Patients
What is the definition of multiple sclerosis?
Dr. Rizzo: Multiple sclerosis is a disease in which the immune system misbehaves and attacks the brain and spinal cord. The disease comes in the form of attacks in which the immune system is inappropriately activated or turned on and it attacks specific parts of the brain or parts of the spinal cord and causes neurologic deficit.
Is there a cure?
Dr. Rizzo: There is no cure for multiple sclerosis.
What are the most commonly prescribed treatments right now for multiple sclerosis?
Dr. Rizzo: Right now, there are four standard therapies that are referred to as disease modifying therapies. These therapies are intended to decrease the number of attacks or the number of relapses that patients experience, and the big four are so-called ABCR drugs, which are Avonex® (biogen), Betaferon®/Betaseron® (berlex), Copaxone®, and Rebif® (serono). They may be divided coarsely into the so-called Interferon group, which is Avonex, Betaseron, and Rebif, vs. Copaxone, which is a slightly different philosophy of therapy.
How effective are the ABCR drugs in keeping a patient’s MS condition at a certain level and not allowing it to progress or deteriorate?
Dr. Rizzo: Not very effective. Unfortunately, those patients that are on the drug very often do continue to have relapses even though the relapses are decreased in frequency, and it's unclear at this time if any of these medications prevent the so-called secondarily progressive phase.
You were part of a drug trial, which is in its final phase of testing -- an experimental drug that may be an addition to the current drugs that you talked about for treating MS. What is this new drug and why was it chosen? What is its potential?
Dr. Rizzo: Antegren (natalizumab), is quite an interesting drug. Before I go into what the drug does, you should know that as part of the disease multiple sclerosis, lymphocytes, those portions of the immune system that misbehave, lymphocytes traffic from the blood into the brain and spinal cord and that’s actually a very important blunder that the body allows or that the body makes in the disease multiple sclerosis. Antegren prevents the trafficking of these destructive lymphocytes from the blood into the brain.
How does it do that?
Dr. Rizzo: In order for a lymphocyte to go from the blood into the brain, it has to recognize, it has a key to a lock so-to-speak, and it has to turn the key to go into the brain through the blood/brain barrier. What this drug does is essentially changes the lock so the key doesn’t fit, so to speak.
Does it, in a sense, correct the immune system?
Dr. Rizzo: It doesn’t correct the immune system, per se. Antegren is a drug that keeps the immune system from entering the spinal cord and brain and reeking destruction.
Explain to me the parameters of the drug trial. How many people were involved, what are the goals, and where is it now?
Dr. Rizzo: The one that was published was a trial of a few hundred patients. The current trial is about 700 patients.
There are three phases, right?
Dr. Rizzo: Yes. So, the current phase, the phase III trial, which is a large, North American trial, includes about 700 patients. These patients are being randomized to either Antegren or placebo and they’re being followed, both in terms of their clinical disease and the brain MRIs are being sequentially viewed and evaluated to determine how the drug affects the disease in the brain as well as the individual patients.
What do the 700 patients have to do? Do they have to come in every month to get an injection?
Dr. Rizzo: Yes, exactly. It’s a lot of work to participate in the drug trial. When a patient participates in a trial, what they’re doing is essentially taking their disability and contributing to the greater good or they’re contributing to hopefully benefit their friends, colleagues and strangers who also have multiple sclerosis down the road. A patient does not enter a clinical trial because they think they’re getting the most advanced therapy. The FDA allows us to conduct placebo-controlled trials because medications for multiple sclerosis don’t work that well. So, when a patient decides to participate in a trial, they have to work hard. They have to come to whatever research center they’re affiliated with once a week and then once a month. They get frequent MRI scans, they get blood draws, and it’s a lot of work, agonizing.
The 700 patients, half of them get placebo, half of them get the drug?
Dr. Rizzo: Yes.
What do the 700 patients need to do for this particular phase III trial?
Dr. Rizzo: What happens is they first come in and they’re screened, so they’re examined by a physician like myself or one of my colleagues to determine if they have relapsing and remitting multiple sclerosis. If they do, then they have to meet the other criteria, for instance, they can’t be a pregnant female, they can’t be too old, or have other superimposed medical diseases that might preclude them from participating. Once they pass through the screening phase, then they get a baseline MRI scan, a baseline neurologic examination, and after I think two or three MRI scans, I don’t remember. But after a number of MRI scans, they begin the study drug and that drug might be a placebo or the Antegren.
If Antegren is found at the end of all of this testing to be a successful treatment, what would be the significance of that for MS patients?
Dr. Rizzo: It gives MS patients more options for treatment. Right now, we essentially have two classes of compounds -- there are the interferons, there’s Copaxone, not even talking about chemotherapy in certain forms of multiple sclerosis. This gives us another option. Not only is it going to be demonstrated to be effective as monotherapy, we hope, but because it has a unique mechanism, it may be complementary to our current treatments.
Were you looking for typically mild MS patients?
Dr. Rizzo: Well, the enrollment criteria in this trial and in many trials include patients that are not too sick and not too well. We want to get patients who are actively experiencing relapses because otherwise we have no way of really telling in the short term of the drug is effective at all.
If Antegren is found to be an effective treatment, what significance does that hold for multiple sclerosis patients?
Dr. Rizzo: It provides another treatment option. Treatment options right now are quite limited. It will provide an additional modality of treatment and may provide complementary treatments and provide a venue for possible combination therapies.
How does Antegren work to restore the immune system in a person suffering from multiple sclerosis?
Dr. Rizzo: Right now, there are no therapies that really restore the immune system. Restoration occurs only by the body itself. What these medications do and what Antegren does is modify the immune system, and in Antegren’s case, decreases the ability of the immune system to go into the brain, to actually enter the brain and cause damage.
So Antegren alone has been found to do what?
Dr. Rizzo: Antegren, in the phase II trial, the outcome measure, that is the barometer that we used to determine if the drug was effective, was primarily by using the brain MRI scan. The brain MRI scan, we looked for active lesions, areas where the multiple sclerosis was actively attacking the brain and we do that by what’s called enhancement or gadolinium enhancement in the brain MRI scans. What we did was we selected patients that actively had gadolinium enhancement, that is they had active disease, and randomized those patients to placebo or Antegren, and then we studied all these patients and studied the MRI scans in blinded fashion so that the evaluators, the clinical evaluators, and also the radiologists who read the MRI scans were unaware of who was getting drug and who was getting placebo.
What did the MRIs taken of patients after they received Antegren show?
Dr. Rizzo: In the phase II trial, the primary measure that we used to determine that the Antegren worked had to do with the brain MRI scans, so we took brain MRI scans of our study patients before and after treatment with the study drug. What that demonstrated was that those patients on Antegren had a significant improvement in the MRI scans compared to those patients who received placebo.
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