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This activity is not sanctioned by, nor a part of, the American Academy of Neurology.

Medscape Conference Coverage, based on selected sessions at the:

This activity is not sanctioned by, nor a part of, the American Academy of Neurology.

Highlights From Two Pivotal Trials in Multiple Sclerosis Presented at AAN 2008: PreCISe and BEYOND, an Expert Interview With Giancarlo Comi, MD

Authors: Giancarlo Comi, MD; Stephanie Kushner, PhDFaculty and Disclosures


Editor's Note:

New data from 2 key trials in multiple sclerosis, the PreCISe trial and the BEYOND trial, were presented at the 60th Annual Meeting of the American Academy of Neurology held from April 12-19, 2008, in Chicago, Illinois. Medscape Group Scientific Director, Stephanie Kushner, PhD, interviewed Giancarlo Comi, MD, about the results of these trials and what implications these results may have on clinical practice and the future management of patients with MS.

Medscape: Dr. Comi, thank you for taking the time to talk with Medscape about the data from 2 key pivotal trials that were presented at the 60th Annual Meeting of the American Academy of Neurology: the Study to Evaluate the Effect of Early Glatiramer Acetate Treatment in Delaying the Conversion to CDMS in Subjects Presenting With a Clinically Isolated Syndrome (PreCISe trial)[1] and the Betaferon/Betaseron Efficacy Yielding Outcomes of a New Dose (BEYOND) trial.[2] Let's begin with the PreCISe trial. What was the primary objective and design of the study?

Dr. Comi: The PreCISe trial was performed in patients with clinically isolated syndromes (CIS).[1] Events suggestive of a diagnosis of CIS are a first attack suggestive of multiple sclerosis (MS) and the presence of lesions on brain magnetic resonance imaging (MRI). So, the presence of CIS was essentially the primary inclusion criteria, after having excluded other potential causes of disease.

There are currently 2 categories of pharmacologic agents available for first-line treatment of MS, interferons (including interferon beta-1a administered intramuscularly (IM), interferon beta-1a administered subcutaneously (SC), and interferon beta-1b, administered SC), and glatiramer acetate which is administered SC. The interferons and glatiramer acetate are disease-modifying therapies.

The results of 3 previous trials indicate that the beta interferons may delay the onset of clinically definite MS (CDMS).[3-5] The PreCISe trial is the first trial exploring the effects of glatiramer acetate in patients with CIS on conversion to CDMS.[1]

The study was a 3-year, multicenter, randomized, double-blind, placebo-controlled design. Four hundred eighty-one patients were randomized into one of two parallel-treatment groups. One group of patients received daily glatiramer acetate 20 mg SC and the other group received daily SC injections of placebo. After evaluating the available data (81% of the global exposure, which corresponds to a global exposure of 2.4 years) from an interim analysis, the Drug Monitoring Committee recommended that the double-blind, placebo-controlled phase of the trial be stopped and that all patients from the placebo arm be moved to active treatment. The data presented at AAN this year are the available data from the interim analysis.

Medscape: What were the results of the study?

Dr. Comi: The clinical and demographic characteristics of the patients were similar in each of the two groups (active treatment and placebo), indicating that the randomization process was efficient, resulting in a normal balance.

Conversion to CDMS was considered to have occurred when the patient experienced a second attack. Forty-three percent of the patients in the placebo group converted to CDMS compared with 25% of the patients in the group receiving glatiramer acetate 20 mg SC, which is highly statistically significant (P < .0001). This translates into a 45% reduction in risk for conversion to CDMS in patients receiving active treatment. Additionally, the 25th percentile time to CDMS was 336 days in the group receiving placebo and 722 days in the patients receiving glatiramer acetate. That translates into a 115% increase in time to CDMS in patients on active treatment compared with the placebo arm.

Additionally, most of the secondary endpoints (MRI endpoints) were also found to be positive in the patients receiving glatiramer acetate. There was a significant reduction in the total number of new T2 lesions, which is a measure of the new lesions that accumulated in the brain during the observation period. The mean number of new T2 lesions was significantly reduced by 61% in the glatiramer acetate arm compared with the placebo arm (P < .0001). The same is true for the total number of new gadolinium-enhanced lesions seen at the last scan; patients receiving glatiramer acetate had a 61% decrease compared with patients receiving placebo (P < .0001). Again, this was a highly significant decrease. Finally, new T1 hypointense lesions were also decreased in the patients receiving active treatment compared with those receiving placebo.

Nothing unexpected was observed with regard to safety, as glatiramer acetate is a well-known drug that has been available for more than 15 years. Glatiramer acetate was well tolerated, with adverse events similar to those already observed in previous trials, including local injection-site reactions and transient postinjection reactions such as chest pain, flushing, dyspnea, palpitations, and anxiety.

In conclusion, the results of this study demonstrate that we have here a second option for the treatment of patients in the very early phase of the disease. And, as already demonstrated with the interferon betas, when therapy is initiated in the very early phase of the disease, patients do better than when therapy is initiated later in the disease course. The results of this study confirm the proof of concept of the importance of early treatment.

Medscape: Thank you, Dr Comi. I would now like to discuss the BEYOND study.[2] What was the primary objective and design of this study?

Dr. Comi: The BEYOND trial was designed based on some preliminary observations that increasing the dose of interferon beta-1b could increase the magnitude of its therapeutic effect. Like glatiramer acetate, interferon beta-1b is a very well-known drug. The drug entered the market in 1993 in the United States and a couple of years later in Europe.

There were 3 parallel treatment arms in the BEYOND trial, and patients were randomized 2:2:1. That means that 20% of the patients were randomized to glatiramer acetate, 40% of the patients were randomized to interferon beta-1b 250 mcg SC (the "regular" dose) and 40% were randomized to interferon beta-1b 500 mcg SC, double the dose.

The study was double-blind with regard to the comparison between the 2 different doses of interferon beta-1b. In other words, patients receiving (and those administering) interferon beta-1b did not know which dose they were receiving (or administering). However, there was no "blinding" with regard to glatiramer acetate due to the dosing regimen: glatiramer acetate is administered every day while interferon beta-1b is administered every other day. So, in order not to complicate the design too much, there was this difference in the blinding. The minimum study duration was 24 months with a maximum of 42 months.

Medscape: What were the results of the study?

Dr. Comi: Unfortunately, it is very simple to summarize the results because the 3 arms were very similar in all of the clinical endpoints. The 500-microgram (mcg) dose of interferon beta-1b was no more efficacious than the 250-mcg dose of interferon beta-1b with regard to the primary endpoint, which was the relapse rate. So, there was no difference in the relapse rate between the 2 doses of interferon beta-1b, and there was also no difference in the relapse rate when comparing glatiramer acetate with each dose of interferon beta-1b.

I think this is quite interesting because this is the second study demonstrating the same effect of beta interferons and glatiramer acetate. There was an earlier study which showed that multiweekly injection with interferon beta-1a or interferon beta-1b produced the same effect essentially as glatiramer acetate with regard to relapse rate at 6 months.[6] So the 2 drugs have essentially the same therapeutic effects.

The only difference between the 2 agents observed in the BEYOND trial[2] is that interferon beta-1b was more powerful in reducing the cumulative number of new T2 lesions up to the last scan. The T2 lesion volume was also significantly reduced in the patients receiving each dose of interferon beta-1b compared with glatiramer acetate. This was the only difference in favor of interferon beta-1b.

These results are not surprising. If we look at the results of previous studies performed with the same drugs in patients with RRMS, it was already evident that the majority of the effects of the interferon betas were larger compared with glatiramer acetate.

And again, what about safety? Well the safety profile was very similar to what has been observed previously. All regimens, including the higher dose of interferon beta-1b, were well tolerated. However, because there was no gain in terms of efficacy, there is no reason to utilize higher doses of interferon beta-1b.

Medscape: I think you touched on this briefly before, but have there been any other trials examining the benefits of early treatment? And do they support the findings of PreCISe?

Dr. Comi: Yes. The first trial explored the effect of a single, weekly IM injection of interferon beta-1a.[3] The results of this trial demonstrated that the single injection of interferon beta-1a IM once weekly reduced the risk for conversion to CDMS. The second trial was a European study (the ETOMS study),[4] and again the trial showed that a once-weekly dose of interferon beta-1a administered SC was effective in reducing the risk for conversion to CDMS. The third was a trial exploring the effect of interferon beta-1b, and this trial demonstrated that the drug was significantly effective in reducing the risk for conversion to CDMS.[5] Therefore, we have 3 previous trials exploring 3 different types of interferons, and all 3 with the same conclusion. And this year, the PreCISe trial demonstrates the same conclusion, but with glatiramer acetate.

The cumulative data with the beta interferons and glatiramer acetate demonstrate that we have the possibility to make a choice among treatments for patients with CIS. We may prefer one or the other, but in any case we have the alternative.

Medscape: With regard to clinical implications of these findings, do they help clinicians make a choice about either when to initiate therapy and/or with what agent?

Dr. Comi: Well, I think there are 3 fundamental advantages here. The first is that it is now absolutely clear that if we combine the results of the head-to-head studies between the interferons and glatiramer acetate, including the results of the PreCISe study, we now have clear evidence that from the beginning of the disease and during the entire active phase of the disease, the interferons and glatiramer acetate may be active. Second, the same drugs when they are used very early do better than when they're used later. And third, the 2 drugs have very similar profiles. This is a big advantage, because some patients respond quite well to one of the drugs vs another, or some patients don't tolerate one of the drugs vs another. So, it is a real fundamental advantage now to have 2 options because the data demonstrate that we can really use one or the other.

Medscape: Do you think that it is possible that we may reach a point where patients are completely free from disease activity?

Dr. Comi: I think that the key point is that we still don't have the final solution. The currently available drugs reduce the risk for new events, and that is the classic prevention profile. For example, if you stop smoking you'll reduce the risk for cancer but you don't eliminate the risk. So here we are in the same situation: if we treat, and particularly if we treat extremely early, we can reduce the risk for new activity by about 50% with these drugs. It is probable that if a patient fails with either glatiramer or one of the interferons, if we switch to the other we may somewhat increase the proportion of patients free from disease activity. But, it's not the final solution for everybody. So what we need is to try to learn the best way to use these drugs, or how to combine them with other available drugs, because the new target is the ability to have a patient completely free from disease activity, something which was unbelievable even only 5 years ago. Now we have this possibility in front of us.

Medscape: Are there any concluding remarks that you'd like to make?

Dr. Comi: Well, to me the message is that now we have a much better knowledge about all of these treatments. Now, the new challenge is to use these treatments in a very clever manner with this new, very ambitious objective to control complicated disease. And I think the next step will be in the next couple of years, when 3 or 4 new drugs may be available. With the combination of the currently available treatments and the treatments that may be available in the near future, we can really change, in a significant way, the level of efficiency of the control of the disease.

Medscape: Thank you Dr Comi for sharing this information and your insights with us today.

This activity is supported by an independent educational grant from Teva Neuroscience.

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