The experimental drug fampridine (4-aminopyridine) improves walking ability in some individuals with multiple sclerosis (MS). That is the conclusion of a multi-center Phase 3 clinical trial, the results of which were published today in the journal The Lancet.
“This study indicates that fampridine could represent an important new way to treat multiple sclerosis and perhaps become the first drug to improve certain symptoms of the disease,” said neurologist Andrew Goodman, M.D., chief of the Multiple Sclerosis Center at the University of Rochester Medical Center (URMC) and lead author of the study. “The data suggest that, for a sub-set of MS patients, nervous system function is partially restored while taking the drug.”
The study evaluated a sustained-release formulation of the drug, Fampridine-SR, which is being developed by Acorda Therapeutics, Inc. The company, which funded the study, announced that it had submitted a new drug application to the U.S. Food and Drug Administration earlier this month. Goodman has been a consultant and advisor to Acorda for its fampridine studies in MS.
Multiple sclerosis is a disease of the central nervous system and is the most common cause of neurological disability in young adults. Worldwide it is estimated that more than 2.5 million people are affected by MS which is typically characterized by recurrent relapses followed by periods of remission early in its course. The symptoms of the disease vary from person to person, but commonly consist of muscle weakness, gait difficulties, numbness or tingling in arms and legs, difficulty with coordination and balance, blurred vision, and slurred speech. Over time, the effects of the disease tend to become more permanent and debilitating.
While the precise cause is unknown, it is understood that the immune system in individuals with MS attacks myelin, a fatty tissue in the central nervous system that wraps the fibers – or axons – that connect nerve cells. Similar to the insulation on an electrical wire, myelin allows for the efficient conduction of nerve impulses. When myelin is lost or damaged in the disease, signals between nerve cells are delayed, disrupted, or even blocked.
It is believed that fampridine improves the transmission of signals in the central nervous system of some MS patients by blocking potassium ion channels. These channels serve as gates on the surface of cells and regulate normal electrical activity. In laboratory experiments involving nerve fibers with myelin that was damaged in a manner that mimics MS, scientists found that blocking these channels results in a recovery of signal conduction.
In the Phase 3 study published today, the effects of Fampridine-SR were tested in 301 adult MS patients at 33 locations in the U.S. and Canada over a 14-week period. Three quarters of the participants took the drug and the rest were given a placebo.
Typically, MS drugs have been evaluated based on the ability to prevent relapses. Because the goal of this study was to assess changes in function, the researchers instead sought to evaluate participants’ mobility and muscle strength – as opposed to the disease process. In prior studies, Goodman and his URMC colleague, the late Steven Schwid, M.D., had validated new methods to measure changes in gait, or walking speed over distance. Employing these methods in The Lancet study, they found that 34.8% of those receiving the drug experienced an improvement (an average of about 25% increase) in the speed they could walk 25 feet compared to only 8.3% in the placebo group.
“During the course of the disease, many MS patients experience a decline in mobility and this disability has a major impact in terms of quality of life,” said Goodman. “As a clinician, I can say that improvement in walking speed could have important psychological value; it may give individuals the potential to regain some of the independence that they may have lost in their daily lives.”
Several other drugs have been approved to treat MS. These treatments either counter the nervous system inflammation that is a characteristic of the disease or suppress the immune system generally. While these drugs can be effective at preventing new relapses and slowing the progression of the disease, there are no treatments currently available that improve impaired function, such as mobility problems, for people with MS. Participants in the trial were allowed to continue to take most other medications for MS and researchers did not observe any negative interactions. However, a total of eleven patients (4.8%) in the fampridine-treated group discontinued the study due to side effects. Only two of these were considered by the investigators to be possibly related to treatment.
Co-authors of the study include Schwid, Theodore Brown, M.D., M.P.H. with Evergreen Hospital Medical Center in Kirkland, WA, Lauren Krupp, M.D. with Stony Brook University, Randall Shapiro, M.D. with the Minneapolis Clinic of Neurology, and Ron Cohen, M.D., Lawrence Marinucci and Andrew Blight, Ph.D. all with Acorda Therapeutics.
There are already a number of approved treatments available for MS, how does fampridine differ?
The existing approved treatments for MS are what are called disease modifying agents. These are various therapies that address the fundamental disease process that cause damage to the central nervous system, specifically, damage to myelin – the fatty tissue that insulate nerve fibers – and damage to the nerve fibers themselves. These treatments all modulate, modify, or prevent the inflammation that is at the heart of the disease or suppress the immune system in a broad way in the hope that it will have an impact on the inflammation in the central nervous system.
Fampridine represents a new approach to therapy that impacts function, as opposed to the disease process. The specific types of functions we looked at in this and several other studies we have conducted with this drug are walking and leg strength. These are common problems people encounter with MS and are a major part of the overall impact and disability that MS causes.
This study represents hopefully a different, yet complementary approach to the existing disease modifying treatments. The idea of disease modifying is to prevent the damage in the central nervous system from happening. However, when the damage has already been done, fampridine represents for some patient an opportunity to potentially improve function while taking the drug.
What does the ability to improve walking speed mean for MS patients?
In this particular study what we observed was that among the people who met the criteria for consistently improved walking speed, they themselves were able to identify that they were better. And they were better in a whole realm of aspects of MS affecting their walking and ability to function on their feet. A 12 question scale that was used to evaluate things such as how far they could walk, how fast they could walk, and how long they could stay on their feet and all of these indicators improved. Not only did the timed-walk responders indicate that they were doing better, this was also apparent to the study clinicians even though they were blinded to who was receiving the drug.
The standard yardstick for evaluating MS treatments has been to use methods that measure the progression of the disease, including changes in MRI scans of the brain, clinical relapses, and the progression of disability over time. These have been used in measuring disease modifying treatments; however, this drug is different because it is intended to improve function.
In previous studies we found that the most consistent and sensitive measurement of changes in walking ability was the repeated timing of the 25 foot walk and that any change of more than 20 percent change (either better or worse) was significant. We also found that there was almost a 1 to 1 correlation between how fast someone could walk and how far they could walk. Furthermore, we found that there was a very strong correlation between the speed they could walk and the overall measurement of disability in a tool that is most commonly used in MS clinic trials called the Estimated Disability Status Score (EDSS) that looks at many aspect of disability.
The study shows that the drug improves walking ability for some but not all patients. How will clinicians determine which patients are appropriate for treatment?
The results so far have not given us a clear way to predict who will respond to treatment. The data show that for people who have clearly slowed walking as a result of MS roughly a third will improve to the point where we consider them as responsive to the drug.
Absent a way to predict who will respond to treatment, physicians will need to approach this in a practical manner. They would need to select people who have walking difficulties, prescribe the medication, and monitor how they do. This is a typical part of the practice of medicine. If a patient meets the criteria for a treatment then you try it and then make your best judgment as to how they are tolerating it and how effective it is and determine whether it is worth continuing.
Where there any notable side effects and negative interactions with other MS drugs that the patients may be taking?
We observed some common side effects such as dizziness, insomnia, and fatigue. In terms of negative interactions with other MS treatments, we actually specifically allowed and encouraged the use of other disease modifying and symptom treatments (e.g. bladder control medications) to see whether or not there would be negative interactions. We did not identify any in this study.