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23 August 2010
In a phase III, double-blind placebo-controlled trial, MS-F203, of 301 patients with multiple sclerosis (MS), prolonged-release fampridine improved walking speed in the 35% of patients who responded to treatment. Those patients also reported an improvement in a self-assessed, walking-related disability score. Prolonged-release fampridine was associated with insomnia, fatigue, back pain and balance disorders.
Level of evidence:
Level 1 (good quality patient-oriented evidence) according to the SORT criteria.
Action
Prolonged-release fampridine (dalfampridine) has been submitted for a licence to improve walking ability in patients with all types of MS. A related product, compounded 4-aminopyridine, is not widely used in the UK as it has a narrow therapeutic margin and has been associated with seizures. Whilst short-term phase III data suggests that the adverse effect profile does improve with the prolonged-release formulation this has yet to be demonstrated in clinical practice. Prolonged-release fampridine is not currently in NICE’s timetable. Should dalfampridine be marketed, local decision makers will need to bear in mind the limited evidence currently available when considering discussing with other stakeholders the possible place in therapy of this product.
What is the background to this?
MS is usually characterised by periods of relapse and remission but some patients have a single episode and others a progressive form of the disease. The exact prevalence is unknown, but it has been estimated that 85,000 people in the UK currently have MS, with 2,500 new cases diagnosed each year. Information on the management of MS can be found on the NICE website. The clinical guideline is due for review.
Progressive worsening of mobility is a major factor in the disability experienced by some patients with MS. Sustained-release fampridine (dalfampridine) is a potassium-channel blocker which has recently been approved in the US (under the name Ampyra (dalfampridine) for improving walking in patients with MS. However, there was concern expressed by medical reviewers that although more patients on fampridine appeared to walk faster, the magnitude of the improvement in walking speed suggested the improvement was of limited clinical significance. Prolonged-release fampridine has been submitted to the European Medicines Agency for a marketing authorisation and there is likely to be much patient interest if it reaches the market.
There are no licensed treatments specifically to improve motor function in patients with MS; other recent developments in this therapeutic area have focused on oral immunomodulators for relapse prevention. We have previously covered the published studies for fingolimod in patients with relapsing-remitting multiple sclerosis (RRMS) i.e. FREEDOMS and TRANSFORMS, and that for cladribine (CLARITY). Fingolimod was more effective than placebo and intramuscular interferon beta-1a, respectively, at decreasing relapse rate. Oral cladribine (given in short courses) was more effective at preventing relapse than placebo.
NICE has recently started appraising the evidence for cladribine in RRMS, but the date of publication for this single technology appraisal is not yet known. A NICE single technology appraisal for fingolimod for RRMS is due to commence in the near future and an appraisal for use in the primary-progressive form is proposed, but a timeline is still to be set. Prolonged-release fampridine is not yet in NICE’s timetable.
What does this study claim?
The primary outcome was responder status based on consistent improvement in walking speed (in feet/second) as measured by the timed 25-foot walk (T25FW). A timed-walk responder was defined as a subject with at least three of the four on-treatment walking speeds faster than the fastest walking speed achieved among five off-treatment visits. The proportion of timed-walk responders in each treatment group was 35% (n=78/224) in the fampridine group and 8% (n=6/72) for placebo patients (calculated odds ratio (OR) 4.75; 95% confidence interval (CI) 2.08 to 10.86; P<0.0001).
During the treatment period the average change from baseline in walking speed was 25.2% (95%CI 21.5% to 28.8%) in fampridine responders (n=78) and 4.7% (1.0% to 8.4%) for placebo (n=72) patients; P< 0.001. The average change for fampridine non-responders (n=146) was 7.5% (5.0% to 10.0%). The walking speeds at the end of the treatment period are not quoted in the paper. The increase in walking speed in fampridine-treated responders was maintained during 14 weeks of treatment but, as anticipated given the drug’s mechanism of action, returned to baseline during the four-week follow-up after treatment had ceased.
How does this relate to other studies?
A Cochrane Review of different aminopyridines for symptomatic treatment in MS found no robust clinical trials from which to draw conclusions regarding benefit. In small trials of fampridine, there was some benefit on motor function (measured using manual muscle testing) and patient subjective response, but no benefit on fatigue or cognitive function. The Cochrane Review found that a small number of patients had experienced seizures whilst taking aminopyridines. In MS-F203, patients were excluded if they had a history of seizures or evidence of epileptiform activity on electroencephalogram (EEG).
As there are no drugs licensed for the improvement of motor function in MS there are no active comparator studies ongoing. There does not appear to be any head-to-head studies comparing fampridine with established therapies for MS. The MS-F203 study discussed below has an ongoing open-label extension for up to 36 additional months and this should provide information about longer term adverse events.
So what?
In this phase III trial 35% of patients responded to prolonged-release fampridine on the basis of walking speed. The timed-walk test was validated by another patient-oriented outcome, namely the 12-item multiple sclerosis walking scale (MSWS-12). This assesses patients’ perceptions of the effect that walking difficulties are having on them. Hence the 25% improvement in walking speed seen in fampridine responders was considered to be a meaningful change. However, despite considerable work correlating walking speed to other measures of walking, it remains a less impressive patient-orientated outcome in MS than annualised relapse rates, for example.
Prolonged release fampridine is the first therapy for ambulatory dysfunction in development for the management of MS. In this trial it improved walking ability irrespective of the type of MS the patient had. Whilst it is clear that not all patients respond to treatment, as with most medicines for most conditions, it is not possible to identify in advance those subsets of patients who are likely to benefit. However, the company have informed us that patients respond to dalfampridine within 2 to 4 weeks and hence those patients who respond to treatment can be identified relatively quickly.
Fampridine has a narrow therapeutic margin and has been associated with seizures. Patients were excluded from the trial if they had a history of seizures or evidence of epileptiform activity on EEG. In the trial one patient experienced a focal seizure, involving one arm, at the same time as being treated for sepsis. In the US, the drug is contra-indicated in patients with a history of seizure. Although the prolonged-release formulation may improve the adverse effect profile over standard release formulations, further data is required to clarify the risk-benefit ratio.
Design: Phase III, randomised, double-blind placebo-controlled trial with concealed allocation.
Patients: Patients, with all forms of MS, were eligible for this trial if they were able to complete two trials of a timed walk within an average time of 8 to 45 seconds. The 301 patients randomised had a mean age of 51 years and had had MS for about 13 years. The mean timed 25-foot walk speed at baseline was 2.1 feet/second. The mean EDSS score was 5.8. 71% of placebo patients and 66% of those on fampridine were on stable immunomodulator therapy (interferon or glatiramer acetate). Patients were excluded if they had a history of seizures or evidence of epileptiform activity on an EEG.
Intervention and comparison: Following a two-week single-blind placebo run-in, patients were randomised to prolonged-release oral fampridine 10mg twice a day or placebo for 14 weeks. This was followed by four weeks of no treatment with assessments at two weekly intervals.
Outcomes and results: The primary outcome was response to therapy assessed by changes in walking speed measured by the T25FW. This was validated by the MSWS-12, which assesses patients’ perspectives on their walking disability. A lower extremity manual muscle test (LEMMT) and the Ashworth score for spasticity were included in the secondary outcomes.
The modified intention-to-treat population included all randomised patients who had at least one efficacy assessment during the double-blind treatment period. Patients were grouped into responders and non-responders on the basis of consistency of walking speed improvement. Responders were defined as patients with a faster walking speed, for at least three of the four visits, during the double-blind treatment period than the maximum speed for any of the five off-treatment visits. 35% of patients in the fampridine group (78/224) and 8% of placebo patients (6/72) met the responder criterion (calculated OR 4.75 [95%CI 2.08 to 10.86], P<0.0001). During the treatment period the average change from baseline in walking speed was 25.2% (95%CI 21.5% to 28.8%) or 0.51 feet/s (0.41 to 0.61) in fampridine responders and 4.7% (1.0% to 8.4%) or 0.10 feet/s (0.03 to 0.17) for placebo patients. As expected, walking speed returned to baseline during the four-week follow-up with no treatment.
The average change from baseline during the treatment period for MSWS-12 was ‑6.84 (-9.65 to –4.02) for responders and 0.05 (-1.48 to 1.57) for non-responders, independent of treatment assignment (P=0.0002). All 12 items in the test showed a reduced mean disability score in the responder group compared with that in the non-responder group. The average improvement in the LEMMT score was 0.18 for fampridine responders and 0.04 for placebo patients (P=0.0002).
5% (n=11) of fampridine patients withdrew from therapy due to adverse events, such as sepsis and balance problems although these events were not considered related to treatment. 84% of fampridine patients and 81% of the placebo group experienced an adverse event. Those patients receiving fampridine experienced insomnia, fatigue and back pain. Serious adverse events occurred only in the fampridine group (n=16, 7%): of these, two were judged as possibly related to treatment. One patient suffered severe anxiety and in the other case the patient, who had sepsis secondary to community- acquired pneumonia, experienced a focal seizure. This seizure was judged possibly related to fampridine.
Sponsorship: Acorda Therapeutics Inc. Biogen Idec will be marketing the product in the UK.
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