COMMENTARY

New Data, New Drugs, and...a Vitamin for MS?

Bruce Cree, MD, PhD, MCR; Stephen Krieger, MD

Disclosures

May 01, 2015

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A Promising Phase 3

Bruce Cree, MD, PhD, MCR: Hello. I'm Bruce Cree, associate professor of clinical neurology from the University of California, San Francisco. With me is Stephen Krieger, associate professor of neurology at the Corinne Goldsmith Dickinson Center for Multiple Sclerosis at Mount Sinai in New York.

Today we will be discussing multiple sclerosis (MS) highlights from the 67th Annual American Academy of Neurology meeting in Washington, DC. What do you find interesting at this meeting?

Stephen Krieger, MD: This was a great meeting. We heard a lot of results from research in MS that will be important for us over the coming years. For example, we heard the daclizumab clinical trial results.[1] This was a phase 3 trial, a direct comparison with weekly intramuscular interferon injection.

Dr Cree: What did the trial show?

Dr Krieger: Daclizumab is a new candidate medicine for MS, with a new mechanism of action. It was superior to interferon in preventing relapses, preventing MRI lesions, and even preventing the accumulation of disability. It was positive on all three of those metrics.

Dr Cree: How long was the trial?

Dr Krieger: This was a 2-year primary core endpoint trial, a decent-length, robust, phase 3 trial.

Dr Cree: What does daclizumab do? What is its supposed mechanism of action?

Dr Krieger: We are still learning. It's a monoclonal antibody, given monthly by subcutaneous injection. Daclizumab is a modulator of CD25, which works on interleukin receptors and seems to modulate the immune system through that mechanism.

Dr Cree: It has some interesting properties because it seems to induce a type of natural killer cell, the NK56 (bright) cell, which has suppressor activity. Do you think it might work as a biomarker for a therapeutic response?

Dr Krieger: That would be something we don't yet have. If we look at these CD56 (bright) cells and gauge whether the mechanism is having the desired biological effect, it could give us the ability to know whether a drug is working or will work without waiting to see in a given patient.

Dr Cree: Daclizumab isn't yet approved, and we have heard some of the efficacy data. Were any safety signals associated with this? These days, many MS products have potential risk/benefit considerations that are somewhat different from the days when we started working in MS, when we had only the interferons and glatiramer acetate that were so safe. What are the safety characteristics of daclizumab? Is there anything that we should be looking out for?

Dr Krieger: Yes. This is a new mechanism of action, and with anything that works on the immune system in a novel way, we need to take a step back and look at some of the other consequences.

Liver function test abnormalities are going to be important here. There were a significant number of elevated liver function tests, including those that crossed Hy's law. Neurologists will have to review Hy's law if this drug is approved. Liver function test abnormalities were twice as common as we have seen with interferon, so we have to monitor those levels.

There are also some cutaneous side effects and adverse events. These were not only injection-site reactions but more diffuse skin reactions. It remains to be seen how often those will be serious, but we will need to look at that.

Dr Cree: With these considerations, in your practice, do you imagine that this drug will be used as a front-line therapy or in people who haven't done well on front-line therapy? Would it be used in an escalation treatment paradigm? What are your thoughts about using this agent in patients who test positive for the JC virus?

Dr Krieger: I'm not yet sure how I am going to use this in practice. My supposition is that I won't use it preferentially as a first-line drug because we have an array of well-known medicines, many of which are very safe.

But this does have superior efficacy to one such first-line drug, so it might be useful in patients who have had breakthrough disease. If that CD56 biomarker proves to be useful, it could give us a more rational way to choose patients for this medicine, and that's something that we don't have for our other drugs.

Dr Cree: To sum up, this is a drug that seems to have better efficacy, but with some safety issues that will have to be considered as we think about the application of this drug in clinical practice.

Enduring Results From the BENEFIT Trial

Dr Cree: Did you find anything else interesting at this meeting?

Dr Krieger: We have been talking about front-line medicines and safe, more longstanding medicines. It's worth looking at the extensions of some of those core trials. One was the BENEFIT trial of interferon beta-1b.[2]

Dr Cree: What was the original BENEFIT study? Which patients were investigated?

Dr Krieger: This is an 11-year follow-up from what was a clinically isolated syndrome (CIS) trial. First-attack patients who met MRI criteria were randomly assigned to interferon or placebo and followed for a couple of years, and now it has been extended out to 11 years, looking at conversion to clinically definite MS (second attack) and subsequent disability.

This trial is useful because it is the longest-term, best-quality post-CIS data that we have. The main takeaway is that the patients did very well. Very little disability was accumulated, even over 11 years, among the patients in this group—certainly in the early treatment group that received interferon-beta up front.

Dr Cree: Was there a difference between those patients and the ones who got the treatment a little bit later?

Dr Krieger: This trial showed that starting interferon at the time of the first attack significantly delayed the occurrence of second attacks. The difference between starting early and waiting a year or two is maintained for the entire 11 years. People who weren't treated early never quite caught up. That's an important lesson, 11 years after that trial.

Dr Cree: So, early intervention seems to be of benefit for our patients.

Dr Krieger: And people can do well for a long time, which is inspiring, as well as being a goal as we start treating people at the first signs of disease.

Dr Cree: Both of these treatments—daclizumab and interferon beta-1b—are being developed for relapsing MS or are already approved for relapsing MS and CIS.

Dr Krieger: Right.

Discouraging Results From INFORMS

Dr Cree: What is going on with progressive MS? We had the results of the INFORMS study.[3]

Dr Krieger: This is an important point to talk about, albeit a somewhat discouraging one. Fingolimod, which is approved for relapsing MS, has been studied in a very well-designed, well-powered 3-year study in primary progressive MS. This was the INFORMS trial—fingolimod vs placebo. Unfortunately, this was a negative trial. It did not meet its endpoint of preventing disability for patients with primary progressive MS. If you look at the data from this trial, these curves follow each other perfectly. It's not that the trial was underpowered; it's just that fingolimod doesn't have an effect on disability in people with primary progressive disease.

Dr Cree: Similarly, there was no effect on brain atrophy. There was no effect on brain volume loss, which was surprising because fingolimod has such a robust effect on brain volume loss in relapsing MS.

If this drug has the same mechanism of action, we would see an impact on brain volume loss, even if we didn't see an impact on disability. This underscores that this pathologic process is quite different and that use of these anti-inflammatory medications isn't going to be of great value in patients with progressive MS.

Dr Krieger: That is the concern. The short-term effect of this trial is that we are not going to see fingolimod used or approved for primary progressive MS. The bigger lessons are going to be what we can learn about the true pathophysiology and etiology of primary progressive MS; what are the drivers of disability; and how can we look at molecules and design trials to show benefit in this area?

Provocative Results With RENEW

Dr Cree: We also saw some interesting and provocative results from the phase 2 study of anti-LINGO-1.[4] Do you want to comment on that?

Dr Krieger: Anti-LINGO-1 is an antibody that takes a totally different approach to MS treatment. This is a putative remyelination strategy. All of our other agents prevent relapses, lesions, and disability. This agent is intended to foster remyelination.

It was studied in the RENEW trial.[4] This trial looked at patients with acute optic neuritis as a model for MS relapse. The outcome was assessed with visual evoked potentials—how well or how quickly did a recovering optic nerve conduct electricity? It's a novel outcome from an MS trial perspective, and it showed that the patients who were treated with anti-LINGO-1 recovered faster conduction time in the affected optic nerve than patients who were treated with placebo.

Dr Cree: Was there any impact on visual function and recovery of function?

Dr Krieger: They didn't see that in this trial. There's a floor effect: People who have optic neuritis get better. There wasn't a real difference in seeing people recover their visual acuity because they recovered their visual acuity to a great degree anyway.

Dr Cree: With this potential remyelination of the optic nerve, was there any evidence of neuronal protection? Did the retinal nerve fiber layer seem thicker or less injured than in the placebo group?

Dr Krieger: They didn't see that. They saw a benefit on the electrical measure, but not on visual acuity nor on the structural assay looking at the thickness of the nerve fiber layer, which does seem to be affected by optic neuritis.

Dr Cree: It seems that there is proof of concept that this drug can get into the central nervous system.

Dr Krieger: Right.

Dr Cree: It is administered at quite a large dose, 100 mg/kg, and it seems to help with some degree of repair, but we don't have the right tools to translate that into clinical practice if there is no benefit on visual function. We have to rethink how to use this molecule and get a good clinical endpoint.

Dr Krieger: That's true. It's being looked at now in an ongoing trial in relapsing MS. That is going to take a couple more years. I'm encouraged (cautiously) by these results. It would have been wonderful to see a greater recovery in visual function, but the larger trial in relapsing MS will provide a better understanding of what it does for people clinically.

Surprising Results With Biotin

Dr Cree: Returning to progressive MS, we saw the disappointing results of the INFORMS study, another trial in primary progressive MS in which there was no benefit. Later today we are going to hear the results of the biotin study in secondary progressive MS.[5] My understanding is that that trial was positive.

Dr Krieger: That is my understanding too. This is perhaps the surprise of the meeting. This study looked at very high doses of biotin supplementation—300mg daily. In contrast, a normal biotin supplement would typically be 1 mg. They tested a dose of 300 mg of biotin daily vs placebo in secondary progressive MS.

They chose improvement in disability, as measured by the Expanded Disability Status Scale (EDSS), as the primary outcome. We know from the press release that the top-line result was met. It's a positive trial of approximately 150 patients. We are eagerly going to look at the data this afternoon, see what the side-effect profile looks like, and figure out where this could fit in in the treatment of progressive disease.

Dr Cree: It's remarkable, because typically we think about progressive trials in MS as trying to prevent worsening of disability. Here is a trial that looks at improvement in function, which is remarkable if this winds up being true. With respect to mechanism of action, are there any ideas about what this compound might be doing?

Dr Krieger: We are going to have to learn that as we go. There are a couple of hypothesized mechanisms of action. One relates to the effect of biotin on mitochondrial function and energy metabolism in the cells. Another relates to the possibility that it could stabilize lipid formation, which is obviously important in a demyelinating disease. But we don't know. And the trial is much smaller than the typical modern phase 3 trial. It's about one tenth of the size of other progressive phase 3 trials. We will have to see what the clinical impact of these data will be.

Dr Cree: It can still give hope to our patients with progressive MS.

To recap, we had a great meeting. We have seen results from the phase 3 trial with daclizumab, a head-to-head comparison with interferon beta-1a.

We have seen an extension of the CIS study with interferon beta-1b that shows sustained benefits and benefit of early treatment. We have seen provocative data with anti-LINGO and more data that will be presented this afternoon with biotin. And, unfortunately, we have seen some negative results for the INFORMS clinical trial.

Later this year, we are going to be looking at other studies that hopefully will be available, such as the ocrelizumab trials. We will be very eagerly looking to see how that study does, as well as the trials of natalizumab in secondary progressive MS.

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