The Pipeline 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

Patricia K. Coyle, MD: So, there are very interesting things in the pipelines. One, there’s a humanized monoclonal antibody and anti-CD25 in front of the FDA right now. This is daclizumab. This is against the IL-2 receptor alpha chain.

They have a daclizumab high-yield product (HYP), DAC HYP, that’s given subcutaneously on a monthly basis. In a phase III trial, that was superior to IM (intramuscular) interferon-beta-1a given weekly. It had very good suppression of relapses and good suppression of MRI disease activity. It did not meet the specified 3 months confirmed disability, although there was clearly a trend. In terms of side effects, there was a little bit of concern about cutaneous reactions, an increase in liver enzymes—particularly ALT (alanine transaminase)—and increase in infections. But, it was very well tolerated. So, that’s sitting in front of the FDA. We should be hearing about it shortly.

There has also been great excitement about the anti-CD20 humanized monoclonal antibody, ocrelizumab, which has had two major phase III trials—two in relapsing MS, OPERA 1 and 2, and a phase III trial in primary progressive MS, ORATORIO. The 2 relapsing trials were outstandingly successful in suppressing relapses, disability, and MRI compared against an interferon-beta comparator.

In the primary progressive trial, it was randomized against placebo. For the very first time, the primary outcome (slowing progression) confirmed EDSS (expanded disability status scale) worsening over 3 months, and it was met. It was statistically significant. I think that’s going to raise a big issue. It’s clear that they are going to go to the FDA for approval for progressive MS. They’ve been fast-tracked. They’ve not submitted yet, but there has to be a ruling within 6 months. So, it’s going to be very interesting to see what happens with that.

Then, we have an interesting oral agent, laquinimod (son of linomide), that’s currently in trials. This is an immunomodulator agent. We’re not really sure how it works. But, for the first time in its prior phase III trials, we saw an agent that didn’t have a great effect in suppressing relapses or MRI lesion activity but seemed to have a stronger effect on disability and atrophy—as though it might have a neuroprotective effect. That actually led to its being studied in a phase II trial, currently, in primary progressive MS. There is also a current ongoing relapsing trial where confirmed disability is the primary outcome.

They’ve had a little glitch, though. The 2 phase III trials, that have been completed, looked at 0.6 mg of laquinimod and there was a sense that as you went higher, you had greater efficacy. In the current phase III trial, they looked at 0.6 and 1.2 mg, and then in the primary progressive trial, they were studying 0.6 and 1.5 mg. They needed to abandon the higher dose. They’ve abandoned the 1.5 and 1.2 mg doses because some cardiac issues cropped up. That’s exactly what we had seen with linomide, the precursor back in the 1990s. That was a very promising oral treatment that was aborted because of cardiac toxicity. So, these are just 3 of the agents in the pipeline. I think it’s very exciting.

Claire S. Riley, MD: I think that with ocrelizumab B cell-directed therapy that is just about as excited as I’ve seen a group of neurologists get—when data was presented, particularly, the ORATORIO presentation, at the ECTRIMS meeting. I think the hope for an effective therapy for primary progressive MS is really galvanizing and exciting for a community that, at times historically, could tend to act a little bit toward therapeutic nihilism. I think this is a good moment for our patients and for us.

Patricia K. Coyle, MD: Here’s the problem—it would almost look like an anti-inflammatory effect. You saw the progression curves separating the first 6 months, and then they were simply parallel. They entered primary progressive patients—26% had contrast enhancement. Now, they showed an analysis, very recently, of the enhancing and the non-enhancing cohort. Both clearly seemed to have treatment effects, although nothing was statistically significant. I’m just a little bit concerned that this was actually an anti-inflammatory effect as opposed to a true neurodegenerative effect, which would be earth shaking.

Claire S. Riley, MD: This was the ECTRIMS presentation?

Patricia K. Coyle, MD: Yes.

Claire S. Riley, MD: It will be interesting to see that data published because I think there’s a lot to be learned.

Patricia K. Coyle, MD: Remember, they entered primary progressive MS patients that had abnormal spinal fluid, which is an inflammatory marker, and capped them at age 55.

Fred D. Lublin, MD, FAAN, FANA: Yes, they were younger.

Clyde E. Markowitz, MD: This actually brings up an interesting resurgence of the need to do a spinal tap, potentially. Right?

Patricia K. Coyle, MD: Thank you, Clyde.

Clyde E. Markowitz, MD: I look at that data as well. I agree that maybe it’s mostly of an anti-inflammatory effect, but there’s no reason to think that your primary progressive patients aren’t inflammatory, as well. And, there are probably subgroups within who are more inflammatory and who will get a benefit, as opposed to some who won’t. That’s just the reality. But, if you look at the data from the relapsing-remitting trials with that compound, it is very robust.

They were tested against the high-dose, high-frequency interferon, and it was a very well designed trial. The two studies were almost perfectly overlapping in terms of their benefits. It’s a very convenient treatment—every 6 months getting an infusion.

The question with all these new compounds is, what’s the long-term safety? If you go back and remember when the drug was being studied in some of the other rheumatologic conditions, they ended up stopping some of the clinical trials because of these opportunistic infections that showed up in the patient population. We don’t see that yet in MS, to any large degree, and we hope there won’t be any PML (progressive multifocal leukoencephalopathy). But these are always a concern when you have a new compound that’s coming to market—what’s the long-term safety going to look like?

Patricia K. Coyle, MD: Very true. Those were opportunistic infections in Asians in the rheumatologic trials.

Clyde E. Markowitz, MD: True.

Patricia K. Coyle, MD: But, you almost feel greater comfort because we have some experience with rituximab, which is a chimeric anti-CD20 used for neuromyelitis optica spectrum disorder, currently.

Clyde E. Markowitz, MD: We do.

Patricia K. Coyle, MD: It’s very exciting. It had superb data in relapsing MS.