Relative Efficacy in Multiple Sclerosis

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The MD Magazine Peer Exchange “Strategies in the Management of Relapsing-Remitting Multiple Sclerosis” features a panel of physician experts discussing the importance of early therapy in multiple sclerosis treatment, factors that affect choice of management strategy, the need for ongoing monitoring, and other aspects of treating patients with multiple sclerosis.

This Peer Exchange is moderated by Fred D. Lublin, MD, FAAN, FANA, Saunders Family Professor of Neurology and director of the Corinne Goldsmith Dickinson Center for Multiple Sclerosis at Icahn School of Medicine at Mount Sinai, New York.

The panelists are:

• Patricia K. Coyle, MD, professor and vice chair (Clinical Affairs) and director of the Multiple Sclerosis Comprehensive Care Center at Stony Brook University Medical Center, New York
• Clyde E. Markowitz, MD, associate professor of neurology and director of the Multiple Sclerosis Comprehensive Care Center at Perelman School of Medicine, University of Pennsylvania, Philadelphia,
• Claire S. Riley, MD, assistant professor of neurology and director of the Columbia University Multiple Sclerosis Clinical Care and Research Center, Department of Neurology, Columbia University, New York

Claire S. Riley, MD: Looping back to what we were talking about before, about early disease activity and its impact on long-term function: I think it does call into question this idea of escalation based on breakthrough disease activity. Maybe we need to throw out that paradigm and instead recommend early, highly effective therapy, followed up by more modestly effective, more safety-acceptable treatment—which is not our way of doing things often here in the United States, I think it’s a bit more of a European model, sort of an induction—and then follow up with a better safety profile for longer term.

But, I think we need to know what the impact of having early relapses on long-term prognosis is. It might be that if that factor truly drives the risk of developing secondary progression, perhaps taking a few years of a high-efficacy, maybe a higher-risk therapy early on, will pay dividends 20 years down the road.

Fred D. Lublin, MD, FAAN, FANA: Clyde, with relative efficacy, we used to have none and now we have some. And this is kind of important because unless you study 2 drugs together in the same study, head-to-head, you can’t compare them across clinical trials.

Clyde E. Markowitz, MD: It’s a mess.

Fred D. Lublin, MD, FAAN, FANA: You say everybody does it, but it’s a mistake. And I think the tests of time have told us that placebo groups in this century do better than treated groups did in the 90s. So, you need to do comparative efficacy, real phase III head-to-head studies. What sort of information have we got?

Clyde E. Markowitz, MD: Not a lot. Most of the clinical trials that have been designed in the more recent past have included arms that may have a comparator arm, but aren’t designed for an efficacy outcome. This makes it a little bit challenging even though there’s lots of marketing around that conversation to say, “Well, you know, they had a lower rate of relapses in this group versus this group.”

But the problem is that you’re not looking at apples and apples. People are not necessarily blinded in the clinical trials, or maybe the study design was not randomized for certain things. So, you’re looking at a lot of data now that is comparison-like but not good data. That makes it very challenging for us. You do a double dummy trial where everybody is blinded in that kind of randomization scheme. That makes more sense, but it’s a big study with lots of patients over many years and we can’t convince a lot of sponsors to go down that pathway these days to do that kind of work.

There are a couple of studies that are up-and-coming that may go down that pathway. Your study was a great study trying to address that, with interferons and glatiramer in a combination, but I think we’re at a lax. Everything we do now to make a comparison is our best guess, and we’re sometimes guessing toward things that were, 20 years ago, guesses in efficacy.

Fred D. Lublin, MD, FAAN, FANA: What we have on the market is alemtuzumab, which when assessed head-to-head against high-dose, high-frequency interferon, you’re pointing out some of the design difficulties there. But it’s pretty much accepted as being superior—not a perfect design—but I think the data will support that.

We have fingolimod in a 1-year study against low-dose, low frequency interferon. And again, it succeeded for a reasonable one-year metric, which was relapse rate and also MRI. And then, in the pipeline, we have some that have done even a better job. We do have the comparator arm, so I don’t think they help nearly as much as we would have thought. We have altered data; high-dose, high-frequency interferon. They’re pretty much similar to glatiramer acetate but better than low-dose, low frequency interferon. But we need more, right?

Patricia K. Coyle, MD: The MS-based Registry is a huge global registry, and it certainly wasn’t randomized. But they attempted to look at MS patients who were switched for breakthrough activity. Then, they tried to do a propensity analysis to match comparable groups. Granted, it wasn’t randomized, but it’s sort of a common sense result.

They looked at people breaking through on the first-line parenterals—interferon-beta or GA (glatiramer acetate)—and if you would switch them within that class or go to fingolimod. The fingolimod group did better. Then, they looked at a group where they broke through on the interferon-betas, GA, and they stuck with that class and went to natalizumab. Natalizumab did better.

They looked at breakthrough patients on the interferon-betas or GA that went to fingolimod or natalizumab. The natalizumab group did better than fingolimod. Granted, it’s not a randomized study, but it sort of clicked with common sense and our feeling that the second-line parenterals are the most efficacious—higher efficacy but higher risk. With the orals, about equal or maybe a little bit better than the first-line parenterals. So, it kind of matched what I would have expected.