Andrew N. Wilner, MD; Bruce Cree, MD, PhD, MCR; Fred D. Lublin, MD; Lawrence Steinman, MD


May 15, 2014

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Laquinimod: How Does It Work?

Andrew Wilner, MD: Greetings. I am Dr. Andrew Wilner, reporting for Medscape from the 66th Annual Meeting of the American Academy of Neurology in Philadelphia, Pennsylvania. I am here today with Dr. Bruce Cree, Associate Professor of Neurology at the University of California in San Francisco; and Dr. Fred Lublin, Saunders Family Professor of Neurology at the Icahn School of Medicine in Mount Sinai in New York City and Director of the Corinne Goldsmith Dickinson Center for Multiple Sclerosis at Mount Sinai Medical Center. I am also joined by Dr. Lawrence Steinman, Professor, Department of Neurology and Neurological Sciences, and Department of Pediatrics, at Stanford University School of Medicine in Stanford, California. Welcome, gentlemen.

We are here today in Philadelphia where there have been lots of presentations on multiple sclerosis (MS). For our viewers who are clinicians and researchers, from your point of view, what were the most exciting presentations?

Bruce Cree, MD: I found Dr. Comi's presentation[1] on laquinimod quite interesting. This was an integrated analysis taking the 2 large phase 3 studies that were done in relapsing MS and asking the question about disability progression in these cohorts. Those studies previously read out as being positive, showing an impact of laquinimod on disability and also on brain volume loss, but less of an impact on new lesion formation and relapses. It raises the question of whether laquinimod could have a neural protective property in MS. They did an analysis in which they first looked at a sustained disability progression, not just at 3 months; they also looked at 6 months, 9 months, and 1 year. They found the same effect of laquinimod in disability progression, confirming the change in disability progression at each of these time intervals.

The next question was whether you could take apart the group of patients who experience relapses during the course of the trial and separate them from the patients who didn't experience relapses to try to understand the mechanism of disability progression. It was interesting that there was also an impact in the group of patients who had no relapses. That group of patients did experience some degree of disability progression which was then attenuated by treatment with laquinimod. That is interesting because patients who are getting worse without relapses are patients who have progressive MS, so this raises the question of how we use laquinimod in patients with progressive forms of MS. He left the end of his presentation with a proposal for a trial in primary progressive MS, and it looks like that is going to move forward. Following those results will be a larger study in secondary progressive MS. I would be very interested to see any treatment that works in progressive forms of MS.

Dr. Wilner: Laquinimod is not yet approved; is that right?

Dr. Cree: That's right. It's not approved yet. It is under review in Europe but not approved in the United States, and it remains to be seen when or if it will be approved.

Dr. Wilner: It sounds like it has great potential.

Dr. Cree: It has potential. The results that [Comi] presented were quite provocative and I would be in support of any trial in secondary progressive MS with an agent that has shown promise in patients who are progressing without relapses.

Dr. Wilner: Dr. Lublin, what did you see that was important?

Fred D. Lublin, MD: Before I tell you what was important, continuing on that theme, we had discussed at the meeting the measures of durable worsening over time. We found, as an aside, that whether you had relapsing disease or were worsening without relapses, the measures were the same. In fact, most of our measures are not very good for predicting durability of response; there are ways to do better but the numbers drop down.

There is a report from the Mayo Clinic that, after a severe attack, whether it is your first or a subsequent attack, you are more than likely to go on to progressive disease. So, there is this relationship between attacks and progression and what is going on, separate from progression. In general, there is a lot of interest in progressive disease in the field, so these findings inform that area.

Risk Factor Scores: Combining Genes and Environment

Dr. Lublin: The part of the meeting that I latched onto were some studies looking at risk factor scores.[2] This involves integrating the information that we have from genetic studies, primarily using the HLA-DRB*1501 susceptibility gene, along with risk factors such as smoking, a history of infectious mononucleosis, antibodies to the Epstein-Barr virus, vitamin D levels, and sun exposure. Putting those together and looking primarily at families, we are trying to develop risk scores and what the odds would be for someone who doesn't yet have the disease to go on to develop the disease. This is early work, but it is kind of exciting because it does have the potential of developing ways of better predicting, and if we can better predict, then we can start to think about preventive measures.

Dr. Cree: Would you say that with all of the attention that has been given to genome-wide association studies, that they haven't given us any real risk stratification other than if you have the HLA-DRB1*1501 allele? The other factors that we have heard so much about increase risk only by 1.1 or 1.2, and they don't help us at all in the clinic.

Dr. Lublin: The risk is extremely low compared with the general population, and they [SNPs] are up to 110. They have another 100 waiting to be published as well but you are absolutely right. They are extremely low-risk. What will be more interesting, if we can ever properly do it because the numbers needed are so high, is to look at severity and genes that may be expressing severity, because there is very good reason to see that they are separate from susceptibility. Other than the HLA variant, the others don't add anything, and we have known about the HLA for a long time.

Dr. Cree: A couple of studies are being planned to look at disease severity. The large genome-wide association study that was done looked at an MS severity scale, a marker of disease severity combined with disease duration. They could not find an association with any of those initial 62 genes or any single-nucleotide polymorphism elsewhere in the genome that was clearly associated with disability progression, but the MS severity scale is perhaps not the best metric. Other things may need to be looked at, and maybe we will find something at the radiographic level related to disease onset, or other phenotypes that may be relevant to MS, that will relate back to the genome.

Dr. Lublin: The problem with those pooled databases is that the clinical data -- other than "yes, they have MS" -- are not nearly as good as what you try and get prospectively.

Dr. Cree: To get the numbers up, you have to have a lot of patience. It is a real challenge over time when you are looking at such things as MRI or spinal fluid. It is very difficult.

Smoking: Most Modifiable Risk

Dr. Wilner: Fred, you mentioned smoking. That sounds like something that is pretty easy to modify one way or the other, so how does smoking affect your risk?

Dr. Lublin: You are absolutely right. You hit on it and that is exciting, because modifiable risk factors are what we are looking for, and certainly smoking is one of those. We used to say to people, "Don't smoke. It's not good for you." But now several studies suggest that smoking is associated with MS and with worsening of MS. It raises some very interesting questions (not yet explored that I know of) about bronchial mucosal immunity. Just like we have been looking at gut immunity -- there are other biomes -- the mucosa of the lungs may be interacting with the immune system during smoking, but there are also toxins and other things. It is modifiable and it is something that we now stress very strongly with our patients.

Lawrence Steinman, MD: This is the second disease where a strong effect has been shown. It has an undeniably strong effect on rheumatoid arthritis, both for susceptibility and for course of the disease. You mentioned the lung as another area where the smoking interaction with the immune system can occur, and one of the messages is that we know that lymphocytes traffic into the brain. If we can stop that, we can modify the disease. If you look at natalizumab or the effect of sphingosine-1-phosphate receptor modulators, it turns out that en route to the brain, these cells pass through the lung, and that is where the interaction could come from cigarette smoke and other environmental factors.

Dr. Wilner: Dr. Steinman, what did you find of particular interest at this meeting?

Dr. Steinman: The issues of risk mitigation, and what we can do to actually tell a patient how a change in lifestyle or habit could lead to a better outcome, is very important. As far as the different medications either approved or in the process of being approved, it is the drugs about which we know the mechanism of action, and we can think rationally about interpreting some of the results. One of the problems I had with the very interesting study presented by Comi is that I don't know exactly how laquinimod works, as opposed to how a monoclonal works or how a sphingosine-1-phosphate modulator works. If we could gain more information about that, then I could integrate the mechanism of action into some of these outcomes.

Dr. Cree: It's the same with dimethyl fumarate (DMF); we don't really understand the mechanism of action of DMF, although we have some ideas on the table.

Dr. Steinman: Right.

Dr. Wilner: Gentlemen, I would like to thank you very much for sharing your insights here at the 66th annual meeting of the American Academy of Neurology. This is Dr. Andrew Wilner, reporting for Medscape. Thank you for your attention.


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