Multiple Sclerosis News Today interviewed Dr. Linard Filli, an MS researcher at the University Hospital Zurich involved in clinical studies of prolonged release Ampyra (dalfampridine), on walking ability in MS patients, and Dr. Andrew Blight, chief scientific officer at Acorda Therapeutics, the treatment’s developer.
Here is a full transcript of that interview. An in-depth article based on these questions and answers can be found here.
Dr. Filli , a neurologist, leads a team of scientists at University Hospital Zurich investigating the motor deficits, motor adaptation and functional recovery in patients with multiple sclerosis, and also in Parkinson’s disease, stroke and spinal cord injury. [Ampyra is known as Fampyra (fampridine) in Europe.]
Q: Your study shows that long-term Ampyra treatment significantly improves ambulatory function in gait-impaired MS patients, namely walking speed and endurance. Where these benefits clinically meaningful for the patients? In other words, did patients perceive these benefits, and did the treatment positively impact their functioning and daily life over the long term?
A: Indeed, patients of our study reported a significant Ampyra-induced improvement in self-perceived (i.e. subjective) walking function as measured by the widely-used 12-item Multiple Sclerosis Walking Scale (MSWS-12) questionnaire. In average, patients improved by 7.4 points in the MSWS-12 during the double-blind treatment phase with Ampyra compared to the treatment phase with Placebo, which is considered to be clinically meaningful based on earlier studies (Hupperts et al., 2016; Hobart et al., 2013; Mehta et al., 2015).
In accordance with these findings, we found a significant correlation between functional improvements in the clinical gait tests (Timed 25-Foot walk, 6-Minute Walk Test) and the self-perceived walking ability (MSWS-12), again underlining that the improvements in walking function as induced by Ampyra are perceived by patients and seems to be clinically meaningful for many of them. Moreover, a previous study of our lab (Zörner et al., 2016) demonstrated that Ampyra had a positive effect on daily activity in patients with MS as measured by wearable accelerometer devices attached to the ankles: double-blind treatment with Ampyra significantly enhanced the intensity of daily activity in the responder group compared to the treatment phase with Placebo.
Taken together, these results imply that the functional improvements as observed in walking speed and endurance are perceived by the patients and seem to positively influence daily activity / life over the long term.
Q: In your study, marked differences were observed in response to Ampyra treatment, with patients having either an initial good or a poor response, and with responsiveness changing in many over time. What do you think causes this range of responses? Are you planning to further investigate the potential mechanisms underlying these differences in response?
A: The mechanisms underlying the change in responsiveness to Ampyra over time remain speculative for the moment and need to be investigated in future large-cohort trials. Potential explanations for the longitudinal changes in drug responsiveness might include dynamic alterations in de-myelination versus neuronal degeneration in a given patient: whereas de-myelination of axons should enhance the efficacy of Ampyra (facilitated access to potassium channels located on the axon), axonal/neuronal degeneration might interfere with the efficacy of the drug.
Hence, we are planning to correlate changes in drug responsiveness with structural alterations in the central nervous system integrity as measured by, e.g., magnetic resonance imaging on the single subject level. Alternative mechanisms of improved responsiveness to Ampyra over time might include long-term training effects as induced by Ampyra that are not observed during short-term treatment (e.g., muscle reinforcement by improved mobility).
Q: Some patients who were initial good responders showed a possible growing resistance to the drug over the longer term. Is this an area of particular concern?
A: We observed both patients with increasing and decreasing responsiveness to Ampyra over time. In average, however, the results of our study demonstrated that the responsiveness in the total study population generally increased over time.
The fact that patients change their responsiveness to Ampyra in either direction emphasizes the importance of regular re-evaluation of drug efficacy over time. Hence, periodic drug holidays seem to be crucial to adapt / optimize the therapy with Ampyra, i.e., stopping treatment in patients losing their responsiveness over time. On the other hand, regular assessments of the efficacy of Ampyra in a given patient might also help to uncover drug efficacy in initially non-responding patients.
Q: The study enrolled patients with relapsing-remitting, primary progressive, and secondary progressive MS. Were there any relevant differences in outcome and response to Ampyra based on MS type? Is it possible to say which subgroup benefitted the most from this therapy?
A: We did not find a valid correlation between patient’s responsiveness and their specific type of MS in our study. We found both well responding patients and non-responders in each of the different MS subtypes. In line with our results, a previous large-cohort study investigating more than 500 patients treated with Ampyra did not find any correlation between the responsiveness to Ampyra and the MS type (Goodman et al., 2014).
Importantly, the results of our study and previous trials demonstrate that Ampyra also exerts significant positive effects in patients with chronic progressive MS, where alternative treatment options to improve walking function are virtually absent. We are currently screening for demographic and clinical factors that might be used as predictors of patients’ (short- and long-term) responsiveness to Ampyra in the future.
Q: The study ran for two years. Are there plans to follow these patients for a longer period?
A: Yes, the FAMPKIN extension trial was extended for 3 more years and thus will run over a period of 5 years in total. The majority of participants are currently in their last year of the study.
Q: Physical activity and exercise are suggested as a possible way to prevent the onset and progression of mobility disability. Would it be relevant to investigate the possible combined effect of physical activity and Ampyra in MS patients?
A: Combinations of different treatment approaches have led to synergistic positive effects in many different fields of medicine in the past. Thus, it would be very interesting to combine Ampyra with e.g. physical exercise or alternative therapeutic approaches aiming to restore ambulatory function in patients with MS.
Dr. Andrew R. Blight is the chief scientific officer at Acorda Therapeutics and previous winner of the Inaugural Purchase College Scientific Entrepreneurship Award. He has held academic positions at Purdue University and New York University, and was professor and director of the Neurosurgery Research Laboratory at the University of North Carolina at Chapel Hill.
Q: A recent study showed that long-term treatment with Ampyra significantly improved ambulatory function in gait-impaired MS patients, namely walking speed and endurance. It also found that those who were poor respondents to the therapy in short-term responded in longer term (2 years), although efficacy can diminish over time. What general feedback are you receiving from healthcare providers and patients on this therapy?
A: Ampyra has been tried by more than 120,000 people with MS in the United States, and tens of thousands more around the world. It has a meaningful impact for many people who try it; walking is a basic function that affects many other aspects of our lives. Like most medicines, not everyone will benefit.
Because MS is both a variable and progressive disease, people who do not respond at one point to Ampyra may see improvements later on. The data from this study is important to help medical professionals in determining how to prescribe Ampyra and assess its value to a particular individual.
Q: Ampyra is FDA-approved to improve walking in adults with MS. Is Acorda planning to explore other medical conditions which could benefit from Ampyra?
A: We conducted clinical trials to assess whether Ampyra would improve walking in people who had experienced an ischemic stroke. Unfortunately, the data did not support continued studies. We currently are not studying Ampyra in other neurological disorders, but are very gratified at the impact this medication has made in the treatment of people with MS.
Q: Although MS occurs mostly in adults, it is also diagnosed in children and adolescents. In fact, studies suggest that 2 to 5 percent of all MS patients have a history of symptom onset before age 18. Is Acorda planning to assess whether Ampyra can also benefit this patient population?
A: We don’t have plans to study Ampyra in pediatric MS.
Q: Not all patients respond to Ampyra. Are future studies planned to evaluate possible combination treatment approaches that might improve response?
A: We tried to find those kinds of patterns in our clinical trials, to see if we could identify people who were most likely to benefit from therapy. We found that there was no good predictor of who would be a responder — we looked at background therapies, type of MS and a number of other factors.
Q: Is Acorda developing other potential treatments for MS? Which aspects of the disease or symptoms would Acorda like to target pharmaceutically?
A: We are currently studying a drug called rHIgM22, which may help to stimulate remyelination in damaged nerves. This would be a complementary therapy to disease-modifying drugs that try to halt the progression of disease. M22 is currently in Phase 1 testing, and we expect to complete our ongoing clinical trial by the end of the year.