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Health See other Health Articles Title: Multiple Sclerosis: New Treatments, Tough Decisions Andrew N. Wilner, MD: I am Dr Andrew Wilner, and I am here today with Dr Stephen Krieger, Assistant Professor of Neurology and Director of the Neurology Resident Program at the Icahn School of Medicine at Mount Sinai Medical Center in New York City. Dr Wilner: Today, we will discuss several key studies from among the roughly 1000 presentations at this meeting. Dr Krieger, which ones are the most important for clinicians? Dr Krieger: This has been a very busy conference, as you said. Roughly 9000 people were here for those 1000 presentations. When we look at what will be applicable in the near future for those of us taking care of people with multiple sclerosis (MS), several clinical trials stand out. For example, at this meeting we saw the first presentation of the phase 3 trial data[1] for daclizumab, a new drug for MS. Daclizumab is a monoclonal antibody that went through a placebo-controlled phase 2 study in the past, with positive results. This phase 3 study was a direct head-to-head comparison with interferon beta-1a, given once a week by intramuscular injection. This was a positive trial. Even though daclizumab was compared head-to-head against an existing, approved medicine, this new monoclonal antibody proved to be superior on all of the main outcome endpoints—preventing relapses; preventing MRI lesions of MS; and even one of the disability metrics, preventing the accumulation of disability—against the active comparator in this trial. Daclizumab is injected subcutaneously once a month. Dr Wilner: The interferons are basic, proven, safe therapies for MS. Many patients are still taking interferons. Dr Krieger: Interferons were at the forefront of the MS treatment era. They have been around for 20-plus years. But now we are beginning to see more head-to-head trials than placebo-controlled trials, because it is not enough to show that an MS medicine can beat a placebo when we have so many more effective medicines. Thus, the fact that daclizumab was found to be superior to one of our existing medicines is strong data in favor of the new agent. Dr Wilner: Right. And it was superior in every domain. What about safety? Were there any safety concerns? Dr Krieger: There always are. The advantage from a dosing perspective is that this is a simple once-a-month injection that can be given at home. From the perspective of injection-site reactions and things of that nature, it is obviously better than medications that are injected more frequently. But there were other skin side effects with daclizumab; not only injection-site reactions, but rashes and other cutaneous issues with this drug. That had been a concern going into this trial. Mild skin reactions were seen in a decent number of patients, but they were only severe in a very small number, according to these data. The hope is that this will be a small safety issue, rather than a pervasive one. Another safety issue we will have to watch with this drug is liver function abnormalities. Some patients in this trial experienced elevated liver function tests slightly beyond what we have seen with the interferons. And because this was a head-to-head comparison, we can gauge that risk to some extent. If this drug reaches approval—and I know the manufacturer will be seeking approval on the basis of this trial—undoubtedly there will be some blood monitoring involved, and liver function tests in particular. Dr Wilner: I spoke with one of the company representatives, and it is my understanding that these data has been or will shortly be submitted to the US Food and Drug Administration (FDA). I guess within 6 months to a year, we may have a new treatment option. Dr Krieger: That is correct. And because this is a totally new modality, a new mechanism of action, it potentially opens up new avenues of treatment for patients with MS. Even though daclizumab is a monoclonal antibody, we have no similar drug for MS. It is a new mechanism for us. Dr Wilner: Are there any other drugs in the pipeline that are going forward? Dr Krieger: There certainly are. We have more than we can talk about in the time we have now. A couple of these are new iterations of existing strategies. For example, a pegylated form of interferon was recently approved by the FDA, just before this meeting. New data[2-6] presented at this meeting looked at further efficacy and safety outcomes for pegylated interferon, which look good. This agent should become available in the fall. Dr Wilner: And that will be an injection? Dr Krieger: Yes. I should say that pegylated interferon is advantageous because pegylation allows the drug to be absorbed more gradually. This means that rather than a 3-times-a-week injection or even a once-a-week injection, this can be administered every 2 weeks—twice a month. But the pegylation allows it to be absorbed more slowly. In principle, this keeps the patient consistently exposed to interferon, which is what we want, but with an every-other-week injection. Dr Wilner: I went to an evening session devoted to adherence. I was stunned that even given the severity of this disease and knowing that this is a progressive disease, adherence is a real clinical problem. If we can make the administration of the disease-modifying therapies (DMTs) more palatable, more tolerable, and less frequent, this may contribute to better adherence. Dr Krieger: One of the problems with this disease is that it is lifelong, with treatment that needs to be given all of the time. We have seen a few efforts to help adherence in that way. Glatiramer acetate, which has been a daily injection, was approved this past year to be given 3 times a week—half as often—and this new pegylated interferon will be given every 2 weeks, which is also half as often. Daclizumab is given once a month, so that is even less frequent. We hope that will translate into better adherence for all of these modalities. Dr Wilner: We now have a choice of treatments for MS. That brings a new problem: How does one choose? As yet, there is no formal algorithm. If you speak with 10 experts, you may hear 11 different suggestions. One idea is that perhaps a biomarker will be discovered—that eventually we will test a patient and say, "Aha! This drug will work for you." Are we making any progress in that direction? Dr Krieger: We certainly are. We are making progress, but it has proved to be a tougher nut to crack than we may have thought a decade ago. It is certainly true that we have an array of options now for our patients, and having these choices is a wonderful problem. But trying to make the right choices for the right patient will require biomarkers. We have seen many attempts to do this. For the drug that we talked about earlier, daclizumab, there may be a biomarker based on its mechanism of action with a certain type of lymphocyte. We may then be able to assay for that lymphocyte and see whether the drug is working or likely to work. For our existing medicines, a number of attempts have been made to identify biomarkers that will help us make that decision. Suhayl Dhib-Jalbut gave a very nice review of this at this meeting.[7] Other efforts include studies with glatiramer acetate. Investigators have been trying to identify particular genetic features, single-nucleotide polymorphisms (SNPs), that can be used to predict who will be an excellent responder or a nonresponder to glatiramer. One of those studies[8] was presented here as part of the late-breaking news, identifying a panel of 11 such genetic markers that did seem, in many cases, to predict who would be a great responder or who would not. That is being moved forward to potentially make it available. Dr Wilner: So we might have that in the office? Dr Krieger: It would be wonderful. That was actually my question for them at that late-breaking panel, and they said that they are definitely moving forward with it. That would be wonderful. What we really need is testing that we can do before we start these medicines, so we know which drug is the right one for the individual patient. Drug & Reference Information Multiple Sclerosis Brain Imaging in Multiple Sclerosis Ophthalmologic Manifestations of Multiple Sclerosis Post Comment Private Reply Ignore Thread
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