As the community faces ongoing challenges in the setting of progressive multiple sclerosis (MS), Clyde E. Markowitz, MD, shares how the EXPAND trial introduced new data that might impact the treatment paradigm.
Clyde E. Markowitz, MD
PUBLISHED December 17, 2018
Current Series: Multiple Sclerosis: A Disease of an Immune System Gone Awry
Clyde E. Markowitz, MD: The main problem for secondary-progressive multiple sclerosis has been that it’s a little bit of a slower progression. When you look at a relapsing population of patients, you can measure attacks. One of the outcomes for many of our clinical trials is attack rate. You can measure that. People come in, they have new symptoms, and you can actually say, “You’ve reached this level of EDSS [Expanded Disability Status Scale] abnormality on the scoring system, so you’ve had an attack.”
The problem we have with secondary-progressive MS is that there are not as easily defined events. Early in the course of secondary-progressive disease, you can still have attacks; but as the disease progresses, you may no longer have attacks and just slowly get worse over time. When I say “slowly,” our ability to measure that change on EDSS scoring is very difficult because the change can occur over years. A small inability to move with a normal gait to requiring a cane may take years. We sometimes design clinical trials with the idea that you want to measure something in 2 years or possibly 3 years in some trials. The problem with that is that most patients may not progress so much in that time.
If you’re going to take a group of patients and put half of them on placebo and the other half on an active treatment, you may have difficulty, in a short amount of time, of demonstrating a meaningful difference between these 2 groups. That has been a huge problem for the MS community, dealing with progressive patients period. That includes both primary-progressive and secondary-progressive groups. That metric of measuring disability on the EDSS scoring system is not sensitive enough to those changes over time. That has been the big problem.
Most recently, we’ve been doing a clinical trial with a molecule called siponimod, which is very similar to fingolimod. Fingolimod is the drug that’s approved for relapsing disease, and it’s an S1P [sphingosine-1-phosphate receptor] modulator. It’s an agonist. It binds to a receptor that is present on your lymphoid cells, and it causes internalization of the receptor. That receptor is actually required for lymphocytes to migrate out of lymph nodes and get into the blood circulation and do their thing.
When you look at the fingolimod molecule, it hits many different receptors. There are 5 receptors, or subtypes, and it hits all of them. We believe that the side effect profile for fingolimod exists in part because those receptors are so ubiquitous throughout the body: They’re on your lungs, they’re on your heart, and they’re on pretty much most tissues in your body. That is why fingolimod has many more requirements for monitoring. You have to have cardiac monitoring. You need to have your eyes checked. You may need to have liver tests, lung tissue tests, and pulmonary function tests. There are a number of things that go on with that compound.
We thought about doing a trial for a more selective molecule, one that only binds to the S1P1 [sphingosine-1-phosphate receptor 1]receptor and the S1P5 [sphingosine-1-phosphate receptor 5]receptor, where you might be able to get rid of some of the other side effects with this drug. There have been a number of companies out there trying to develop compounds that are more selective to be able to get efficacy, but not require all of that monitoring and safety concern.
Siponimod was one of these. They’ve done trials, and they did a trial in secondary-progressive MS. The study was designed with the idea that they could look at slowly progressive disease in secondary-progressive patients who met certain entry criteria. They needed to have a certain level of neurologic disability. Two-thirds of them would go on to active treatment, and one-third would be in the placebo group. They went ahead and did a 2-year trial to try and see how these patients did. But 2 years may not be enough to answer the question. So, they devised the trial to make it an event-driven trial. What that means is that you need to have a certain number of events of people progressing in the trial before you could say this trial was complete.
They completed the trial, and the data were impressive because this is the first compound that was able to show a benefit in secondary-progressive disease. It showed about a 21% reduction in disability progression. It hit on all the other metrics of relapse for people who were still having relapses, including MRI [magnetic resonance imaging] activity. It looked very similar to what we had with fingolimod, in terms of the benefit, but it also hit the disability progression piece that we were not able to see in other trials with secondary-progressive patients. This is really the first time that we’ve seen this kind of a benefit.