- Email: [email protected]
Sustained-release fampridine in Multiple Sclerosis
Multiple Sclerosis and Related Disorders (2014) 3, 17–21
Available online at www.sciencedirect.com
journal homepage: www.elsevier.com/locate/msard
REVIEW
Sustained-release fampridine in Multiple Sclerosis S. Hadavi, M.D. Baker, R. Dobsonn Blizard Institute, Queen Mary University of London, Barts and the London School of Medicine and Dentistry, London, UK Received 2 November 2012; received in revised form 30 May 2013; accepted 3 June 2013
KEYWORDS
Abstract
Multiple Sclerosis; Fampridine; Clinical trials; Safety; Walking; Disability
Sustained-release fampridine, a slow release formulation of 4-aminopryridine, is a voltagedependent potassium channel blocker licensed for the treatment of walking difficulties in multiple sclerosis (MS). Studies have demonstrated that approximately one-third of MS patients respond with a clear benefit to their walking speed. Sustained-release Fampridine is not currently available on the National Health Service (NHS), although it has been approved by the Food and Drug Administration (FDA) in the USA and European Medicine Agency (EMA). It appears to have an acceptable adverse event profile, with data from open-label extension studies now becoming available. Concerns have been raised that the use of fampridine may increase the risk of seizures, which were seen at higher rates in patients treated with high doses of sustained-release fampridine. The rate of seizures in those patients on lower doses has not been found to be significantly increased. There are significant barriers at present to the widespread use of fampridine in the UK, which have limited its use in clinical practice to date. Patients with MS are in need of interventions to improve walking and many clinicians feel that this drug may have a role in the symptomatic management of MS. & 2013 Elsevier B.V. All rights reserved.
Contents 1. 2. 3. 4. 5. 6. 7.
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Role of 4-aminopyridine . . . . . . . . . . . . . . . . . . . . . . . Efficacy and trial evidence for sustained-release fampridine Pitfalls of responder analysis . . . . . . . . . . . . . . . . . . . . Safety of SR-fampridine . . . . . . . . . . . . . . . . . . . . . . . Regulatory decision. . . . . . . . . . . . . . . . . . . . . . . . . . Conclusions. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
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Correspondence to: Blizard Institute, Queen Mary University of London, Barts and the London School of Medicine and Dentistry, 4 Newark Street, London E1 2AT, UK. Tel.: +44 207 882 2285; fax: +44 207 882 2180. E-mail address: [email protected] (R. Dobson). 2211-0348/$ - see front matter & 2013 Elsevier B.V. All rights reserved. http://dx.doi.org/10.1016/j.msard.2013.06.003
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Conflict of interest statement. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 21 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 21
1.
Introduction
Multiple Sclerosis (MS) is a complex disorder of the central nervous system (CNS), the cause of which is unknown. It is characterized by progressive demyelination and axonal degeneration within the CNS. MS is a disease of young people, particularly women, with an average age of onset of 25–30 years. It is estimated that there are currently 100–120 people per 100,000 living with MS in England and Wales (NICE, 2012). MS leads to a variety of symptoms including walking impairment, which is one of the most disabling features. Up to 75% of MS patients suffer from clinically significant walking disturbance (Heesen et al., 2008; Hobart et al., 2001; Swingler and Compston, 1992); 50% of MS patients require assistance with walking 20 years after their first symptom (Coles, 2009). During a normal gait cycle an individual is supported by a single leg 80% of the time with bilateral support during 20% of the gait cycle (Cuccurullo, 2012). In people with MS, the proportion of time spent with bilateral support is greater and therefore the speed of walking is slower (Remelius et al., 2012). Walking impairment in MS is complex and multifactorial. Factors affecting walking in MS include weakness and spasticity of the lower extremities, sensory impairment and fatigue. Walking disability has a high impact on the personal, professional and social burden of the disease (Phan-Ba et al., 2012). There are many drugs used in the symptomatic management of MS, but until recently none were licensed for the specific treatment of walking impairment.
2.
Role of 4-aminopyridine
The neurophysiology underlying the possible mechanism (s) of action of 4-aminopyridine (4-AP) is discussed in the accompanying article (Baker, in press). There has been increasing interest in the use of 4-AP as a therapeutic intervention to improve walking in MS. A randomised, double-blind, placebo-controlled study conducted by Bever et al. (Bever et al., 1994), focused on the pharmacokinetics of immediate-release 4-AP, together with the degree of clinical improvement and the adverse effects experienced by MS patients. It was demonstrated that clinical improvement was related to total 4-AP exposure, and adverse events to peak serum levels. 4-AP has a narrow therapeutic window; so to improve safety, limit the peak-dose side effects including seizures and acute encephalopathy (Murray and Newsom-Davis, 1981), and to generate prolonged adequate serum levels, the sustained-release Kv channel blocker, sustained-release (SR) fampridine, was developed.
3. Efficacy and trial evidence for sustainedrelease fampridine There have been previous studies examining the therapeutic use of 4-AP, but this article focuses on sustained-release
4-AP, SR-fampridine. Trial evidence for the use of SRfampridine is summarised in Table 1. The first pilot double-blind placebo-controlled, crossover study of SR-fampridine of 10 MS patients with stable motor deficits (Expanded Disability Status Scale, EDSS 6.0–7.5) was in 1997 (Schwid et al., 1997). There was a wide range of walking impairment in this relatively small proof-of-concept trial, which nonetheless managed to reach statistical significance. 9 out of 10 patients in the treatment group demonstrated an objective improvement in speed of walking compared to placebo based on a timed test (p=0.02), and 7 felt subjectively better. A randomised, double-blind, placebo-controlled, parallelgroup trial of SR-fampridine in 25 MS patients was published in 2007 (Goodman et al., 2007). This trial, performed in 2000–2001, was a dose-escalation trial focussing on both dose-related efficacy and safety. The primary analysis, the change from baseline in the timed 25-foot walk (T25FW), did not achieve statistical significance. However, post-hoc analysis demonstrated a significant improvement in walking speed (in feet/second) in the SR-fampridine group (p= 0. å03). Convulsions were seen in 2 patients receiving high dose (425 mg twice-daily) SR-fampridine. The efficacy and dose response characteristics of SRfampridine were explored in a phase II multicentre, randomised, placebo-controlled, parallel trial with 206 participants – MS-F202 (Goodman et al., 2008). Patients were randomised 1:1:1:1 to placebo, SR-fampridine 10 mg twice daily, 15 mg twice daily and 20 mg twice daily. The primary outcome measure was the percentage change from baseline in average walking speed measured by the T25FW. The proportion of patients demonstrating a 420% improvement in walking speed did not reach statistical significance between any of the doses of SR-fampridine and placebo (SR-fampridine 10 mg, 23.5%; 15 mg, 26.0%; 20 mg, 15.8%; vs. placebo, 12.8%). In a post-hoc analysis, 36.7% patients treated with SR-fampridine demonstrated a consistent improvement in the T25FW versus 8.5% of the placebo group. The sub-group of the SR-fampridine group demonstrating a consistent improvement in walking speed was designated a “responder” group. There was a consistent mean improvement of 25–29% in walking speed for fampridine-treated responders over the double-blind treatment period. The use of the T25FW as a marker of treatment response was thought to be validated by the fact that the responder group also demonstrated improvements in the self-assessed measure of ambulation, the 12-item multiple sclerosis walking scale (MSWS-12). There was also a non-significant trend towards an improvement in the clinician global impression (CGI) scores in the responder group (p= 0.056). Treatment discontinuations secondary to adverse effects such as seizures, chest discomfort and balance disorders were more commonly seen in the higher dose treatment groups (≥15 mg). Post-hoc analysis of the above study, demonstrated that patients who met a responder criterion for a consistent response (increase in walking speed in ≥3 visits on drug
Sustained-release fampridine in Multiple Sclerosis compared to the fastest walking speed in several pre-treatment sessions) did not have a reduction in the treatment effect during the treatment period. This highlighted the fact that in those patients who showed an initial response to SR-fampridine, the response was sustained throughout follow-up (Goodman et al., 2008). Following this, two phase III trials were designed using a responder-analysis model. This design was a first for MS trials, and this is discussed in more detail below. MS-F203 (Goodman et al., 2009) and MS-F204 (Goodman et al., 2010) were multicentre, double blind, placebo-controlled trials. MS-F203 randomised 301 MS patients who were able to walk 25 feet in between 8 and 45 s in a 3:1 ratio of SR-fampridine 10 mg twice daily to placebo. The duration of this study was 21 weeks; consisting of one week of screening, two weeks of placebo run-in, fourteen weeks of double-blind treatment and four weeks of follow up. The second trial, MS-F204, randomised 239 MS patients with similar disability in a 1:1 ratio to SRfampridine 10 mg twice daily or placebo. This study included one week of screening, two weeks of placebo run-in, nine weeks of double-blind treatment and two weeks of follow up. Both studies used walking speed (in feet/second) as measured by the T25FW to define the primary clinical endpoint. The primary efficacy analysis was based on the proportion of responders in the SR-fampridine and placebo groups. Responders were differentiated from non-responders based on faster walking speed in at least three of the four on-treatment visits compared to off-treatment. The MSWS12 was used to validate whether the criteria chosen to define responders was clinically meaningful, using a comparison between responders and non-responders regardless of treatment allocation, to control for those who showed a marked response to placebo. To examine the FDA concern regarding the possibility of a gradual loss of response, responders were assessed for a significant improvement in walking speed at the last observed double-blind visit. There were a higher proportion of responders in the SRfampridine group. 34.8% (78/224; po0.0001) (Goodman et al., 2009) and 42.9% (51/119; po0.0001) (Goodman et al., 2010) patients in the SR-fampridine groups were responders versus 8.3% (6/72) and 9.3% (11/118) in the placebo group. In a subgroup analysis of responders, there were increases of 25.2% (95% confidence interval (CI) 21.5–28.8%) (Goodman et al., 2009) and 24.7% (95%CI 21.0–28.4%) (Goodman et al., 2010) in walking speed compared to 4.7% (95%CI 1.0–8.4%) and 7.7% (95% CI 4.4–11.0%) in the placebo group. Responders demonstrated significant improvements in perceptions of walking, based on the MSWS-12 (p=0.0002). The increase in walking speed was maintained throughout active treatment (po0.001), but reversed on treatment discontinuation. The non-responders to treatment in MS-F203 demonstrated a small increase in walking speed during the first treatment visit, however this was lost during the subsequent visits. The non-responders in MS-F204 had no significant initial response compared to placebo. The combined results of these two trials support the efficacy of 10 mg twice-daily SR-fampridine in those who showed an initial response to treatment, through an improvement in both walking speed and patients' subjective perception of their ambulatory deficits. However, there are limitations to these trials. They are based on walking speed over a short distance, but walking stability and endurance are also important. There is a clear
19 learning effect with the T25FW (Larson et al., 2013), although this should been seen to an equal degree in the placebo and active treatment arms. It is unclear as to whether the increased walking speed over 25 feet translates over longer distances, as although walking speed is different over different distances, evidence exists that there are strong correlations between walking speed as measured by longer and shorter duration tests in multiple sclerosis (Dalgas et al., 2012). Dose response with respect to SR-fampridine efficacy at lower doses has not been fully evaluated. No increase in efficacy with higher doses was found in earlier trials, and to date there is limited evaluation of doses lower than 10 mg twice daily.
4.
Pitfalls of responder analysis
Criticisms have been raised regarding responder analysis, which is, in essence, an attempt to transform a continuous variable into a dichotomous variable. When using a responder analysis, care must be taken to ensure clinical relevance of the response cut-off if using it to inform decisions regarding patient care. The MSWS-12 was used in these studies to validate the criteria for defining responders. The MSWS-12 measures a patients' perception of their own walking, and so the use of this indicates that the increased speed of walking objectively demonstrated by the T25FW has an impact on patients' perception of their own disability. In this case, there is a need to validate the chosen responder definition against other tools that quantitatively measure ambulatory status, such as the Dynamic Gait Index and Timed Up and Go. The T25FW measures walking speed over a short distance, and the 6 minute walk provides important information regarding motor fatigue, yet the chosen responder definition has not been validated against this (Hersh and Rae-Grant, 2012). In addition to the points above, another important fact regarding the use of a responder analysis assumes equal variances between the two populations being studied (i.e. between treatment and placebo). Essentially, a responder analysis measures the proportion of each population over a certain cut-off. If the variances of the measure are interest are not equal between the treatment and placebo groups, a greater proportion of one population may be above the selected cut-off used to define response; however, there may not be a significant difference overall between the two populations (Snappin and Jiang 2007).
5.
Safety of SR-fampridine
4-AP has been used in various unregulated formulation for many years, and there is considerable awareness regarding potential side effects (Chaplin and Dobson, 2012). Patients with MS are at higher risk of seizures than the general population (Koch et al., 2008). A high systemic dose or plasma concentration of SRfampridine (≥20 mg twice-daily) is associated with an increased risk of seizures (Goodman et al., 2008). In the phase II clinical trial (Goodman et al., 2008), two patients in the treatment group taking 20 mg twice-daily experienced seizures (one patient experienced a generalized tonic-clonic seizure, and the other patient had two separate episodes of complex partial seizures; both complex partial seizures followed an accidental
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overdose of SR-fampridine). The frequency of seizures in clinical trials with low doses of SR-fampridine has been sufficiently low to make it impossible to estimate the magnitude of the increased risk. Only one focal seizure, in the context of systemic sepsis, has been reported among 228 patients taking SR-fampridine 10 mg twice-daily (Goodman et al., 2009), with one seizure also reported in the placebo group (119 patients) of the other phase III trial (Goodman et al., 2010). It is not clear whether SR-fampridine increases the risk of falls in MS patients. In the phase II trial (Goodman et al., 2008), the frequency of falls in the treatment group out-numbered the placebo group, however this was not statistically significant. The percentage of participants suffering from falls was 11% in the placebo group versus 19%, 20% and 9% in treatment groups taking 10 mg, 15 mg and 20 mg SR-fampridine twice-daily, respectively. MS-F203 and MS-F204 demonstrated falls in 16% and 11.7% of patients in the SR-fampridine group compared to 15% and 16.8% of patients in the placebo group respectively. Other frequent adverse effects seen in the phase III studies include urinary tract infection, dizziness, insomnia, fatigue, nausea, back pain, balance disorders and headache. Taken overall, these side effects were evident at a higher rate in the SR-fampridine treated group, but with no clear dose-related increase for most events. SR-Fampridine is contraindicated in patients with mild, moderate or severe renal impairment (creatinine clearance o80 ml mol/min), and/or a prior or current history of seizures.
6.
Regulatory decision
As the outcome of above phase III trials are based on responder and non-responder status, the FDA performed additional analyses to examine the clinical significance of
the primary results. They compared the whole treatment group to the placebo group, independent of responder status. An incremental benefit in most outcomes compared with baseline was demonstrated Food and Drug Administration (2013a,b). The clinical significance of this effect however remains unclear. The EMA rejected the initial license application for SRfampridine in January 2011 due to concerns regarding a lack of clinically meaningful effects on walking speed, that treatment benefit did not outweigh the potential side effects, and insufficient data on long-term safety and efficacy European Medicines Agency (2013). Following reexamination the Committee for Medical Products for Human Use (CHMP) decided that the drug could benefit patients with significant walking disability, and that the benefit in these patients would outweigh the risk of rare side effects. Therefore SR-fampridine is now licensed for the improvement of walking disability in MS patients with an EDSS of 4–7. As only a fraction of patients appear to benefit from SRfampridine, it is necessary to assess treatment response 2 weeks after starting the medication. Identifying responders, together with defining the best outcome measure for demonstrating the efficacy of SR-fampridine, is of considerable clinical importance and has proved difficult. Currently patients undergo a timed walk test such as the T25FW to evaluate the efficacy of the drug. If no objective improvement is observed, the drug should be discontinued. However, there is still no consensus as to the best method for assessing treatment response in patients. The annual cost of SR-fampridine is approximately £5000 per patient. However, additional costs are incurred in identifying responders and assessing efficacy. According to the North East Treatment Advisory Group (NETAG) North
Table 1
Summary of clinical trial evidence for the use of SR-fampridine in multiple sclerosis.
Author (year)
Method of study
Schwid et al. (1997) Goodman et al. (2007)
Randomised doubleblind, placebocontrolled crossover Randomised doubleblind, placebocontrolled, parallel design Goodman Phase II Randomised et al. parallel group, dose (2008) comparison trial
Number SR-Fampridine dose of patients
EDSS Outcome range
Serious Adverse Events
10
6.0– 7.5
Timed walk test (8meters)
No serious side effects reported
4.0– 6.5
Timed walk and lower extremity muscle strength
Two convulsions in 2 subjects at doses of 30 and 35 mg twice-daily
2.5– 6.5
Speed of walking in T25FW, patient-based self-assessment of walking capacity (MSWS-12) Speed of walking in T25FW; MSWS-12
Two seizures in two subjects taking20mg twice-daily; one accidental overdose
25
206
Goodman Phase III Randomised 301 et al. double-blind, placebo(2009) controlled, parallel group study (MS-F203) Goodman Phase III Randomised 239 et al. double-blind, placebo(2010) controlled parallel group study (MS-F204)
17.5 mg twicedaily and placebo for 1 week 10–40 mg twicedaily, increasing in 5 mg increments weekly or placebo 10, 15, or 20 mg twice-daily or placebo
10 mg twice-daily or placebo
2.5– 7.0
10 mg twice-daily or placebo
1.5– 6.5
Speed of walking in T25FW, MSWS-12, CGI, SGI
One severe anxiety in a patient on diazepam; one focal seizure in a subject being treated for sepsis One syncope; two infections; one seizure in a patient taking placebo
CGI, Clinical Global Impression; EDSS, Expanded Disability Status Scale; MSWS-12, 12-item MS Walking Scale; SGI, Subject Global Impression; T25FW, Timed 25-foot Walk test.
Sustained-release fampridine in Multiple Sclerosis East Treatment Advisory Group (2013), SR-fampridine is a costly drug and as it affects only a narrow aspect of the condition it is unlikely to meet the conventional limits for cost effectiveness within the National Health Service (NHS) framework. MS is a progressive and lifelong condition. All the studies have looked at the effect of SR-fampridine over a relatively short duration and therefore not clear how durable the effect of treatment over the long-term. There is an urgent need for further studies on both the long-term efficacy and side effects of this drug.
7.
Conclusions
There are no other licensed medications for walking disability in MS, and SR-fampridine may be useful in certain patients. It appears to have an acceptable adverse event profile. As there have not been any long-term studies of the efficacy of SR-fampridine it is not yet known whether the effect seen in responders is sustained over months, or even years, or whether the efficacy will wane over time. It remains unclear whether any additional treatmentdependent side effects will become apparent. The issue of responders versus non-responders provides a clinical dilemma as to how best to assess response. The clinical differentiation of responders from non-responders either by stage of disease or lesion location is not yet possible. However, given the magnitude of the problem of walking disability in MS, this treatment represents a glimmer of hope for people with MS.
Conflict of interest statement SH, MDB and RD have no conflicts of interest to declare. This work was not supported by any specific grant. RD is supported by an ABN/MS Society of Great Britain Clinical Research Fellowship.
References Baker, MD. Potential therapeutic mechanism of K+ channel block for MS. Multiple Sclerosis and Related Disorders, http://dx.doi.org/ 10.1016/j.msard.2013.01.005, in press. Bever Jr CT, Young D, Anderson PA, et al. The effects of 4aminopyridine in multiple sclerosis patients: results of a randomized, placebo-controlled, double-blind, concentration-åcontrolled, crossover trial. Neurology 1994;44(6):1054–9. Chaplin S, Dobson R. Fampridine for the improvement of walking in multiple sclerosis. Prescriber 2012;23(7):12–6. Coles A. Multiple sclerosis. Practical Neurology 2009;9(2):118–26. Cuccurullo S. Gait analysis: physical medicine and rehabilitation board review 2004. NCBI bookshelf. Available from: 〈http:// www.ncbi.nlm.nih.gov/books/NBK27235/〉; 2012 [accessed 5.07.12]. Dalgas U, Severinsen K, Overgaard K. Relations between 6 min walking distance and 10 m walking speed in patients with multiple sclerosis and stroke. Archives of Physical Medicine and Rehabilitation 2012 Jul;93(7):1167–72. European Medicines Agency. Refusal of the marketing authorisåation for Fampyra (fampridine). www.ema.europa.eu/docs/en_GB/doc ument_library/Summary_of_opinion_Initial_authorisation/human/ 002097/WC500101071.pdf; 2013 [accessed 03.03.13].
21 Food and Drug Administration. NDA: 22–250 Fampridine AC Background. www.fda.gov/downloads/AdvisoryCommittees/Commit teesMeetingMaterials/Drugs/PeripheralandCentralNervousSys temDrugsAdvisoryCommittee/UCM185663.pdf;2013 [accessed 03.03.13]. Food and Drug Administration. www.fda.gov/downloads/Advisory Committees/CommitteesMeetingMaterials/Drugs/Peripheraland CentralNervousSystemDrugsAdvisoryCommittee/UCM191029. pdf;2013 [accessed 03.03.13]. Goodman AD, Brown TR, Cohen JA, Krupp LB, Schapiro R, Schwid SR, et al. Fampridine MS-F202 Study Group. Dose comparison trial of sustained-release fampridine in multiple sclerosis. Neurology 2008;71(15):1134–41. Goodman AD, Brown TR, Edwards KR, Krupp LB, Schapiro RT, Cohen R, et al. MSF204 Investigators. A phase 3 trial of extended release oral dalfampridine in multiple sclerosis. Annals of Neurology 2010;68(4):494–502. Goodman AD, Brown TR, Krupp LB, Schapiro RT, Schwid SR, Cohen R, et al. Fampridine MS-F203 Investigators. Sustained-release oral fampridine in multiple sclerosis: a randomised, doubleblind, controlled trial. Lancet 2009;373(9665):732–8. Goodman AD, Cohen JA, Cross A, Vollmer T, Rizzo M, Cohen R, et al. Fampridine-SR in multiple sclerosis: a randomized, double-blind, placebo-controlled, dose-ranging study. Multiple Sclerosis 2007;13(3):357–68. Heesen C, Bohm J, Reich C, Kasper J, Goebel M, Gold SM. Patient perception of bodily functions in multiple sclerosis: gait and visual function are the most valuable. Multiple Sclerosis 2008;14 (7):988–91. Hersh C, Rae-Grant A. Extended-release dalfampridine in the management of multiple-sclerosis-related walking impairment. Therapeutic Advances in Neurological Disorders 2012;5 (4):199–204. Hobart J, Lamping D, Fitzpatrick R, Riazi A, Thompson A. The Multiple Sclerosis Impact Scale (MSIS-29): a new patient-based outcome measure. Brain 2001;124(5):962–73. Koch M, Uyttenboogaart M, Polman S, De Keyser J. Seizures in multiple sclerosis. Epilepsia 2008;49(6):948–53. Larson RD, Larson DJ, Baumgartner TB, White LJ. Repeatability of the timed 25-foot walk test for individuals with multiple sclerosis. Clinical Rehabilitation 2013. [Epub ahead of print]. Murray NM, Newsom-Davis J. Treatment with oral 4-aminopyridine in disorders of neuromuscular transmission. Neurology 1981;31 (3):265–71. NICE. Management of multiple Sclerosis in primary and secondary care. National Institute for Health and Clinical Excellence 2008, London. Available from: 〈http://www.nice.org.uk〉; 2012 [accessed 5.07.12]. North East Treatment Advisory Group. Fampridine (Fampyras) in multiple sclerosis. 〈http://www.netag.nhs.uk/files/appraisalre ports/Fampridine%20in%20MS%20%20NETAG%20appraisal% 20report%20-Mar2012.pdf〉;2013 [accessed 03.03.13]. Phan-Ba R, Calay P, Grodent P, Delrue G, Lommers E, Delvaux V, et al. A corrected version of the Timed-25 Foot Walk Test with a dynamic start to capture the maximum ambulation speed in multiple sclerosis patients. Neurorehabilitation 2012;30(4):261–6. Remelius JG, Jones SL, House JD, Busa MA, Averill JL, Sugumaran K, et al. Gait impairments in persons with multiple sclerosis across preferred and fixed walking speeds. Archives of Physical Medicine and Rehabilitation 2012;93(9):1637–42. Schwid SR, Petrie MD, McDermott MP, Tierney DS, Mason DH, Goodman AD. Quantitative assessment of sustained-release 4-aminopyridine for symptomatic treatment of multiple sclerosis. Neurology 1997;48(4):817–21. Snappin SM, Jiang Q. Responder analyses and the assessment of a clinically relevant treatment effect. Trials 2007;8:31. Swingler RJ, Compston DA. The morbidity of multiple sclerosis. Quarterly Journal of Medicine 1992;83(300):325–37.
Available online at www.sciencedirect.com
journal homepage: www.elsevier.com/locate/msard
REVIEW
Sustained-release fampridine in Multiple Sclerosis S. Hadavi, M.D. Baker, R. Dobsonn Blizard Institute, Queen Mary University of London, Barts and the London School of Medicine and Dentistry, London, UK Received 2 November 2012; received in revised form 30 May 2013; accepted 3 June 2013
KEYWORDS
Abstract
Multiple Sclerosis; Fampridine; Clinical trials; Safety; Walking; Disability
Sustained-release fampridine, a slow release formulation of 4-aminopryridine, is a voltagedependent potassium channel blocker licensed for the treatment of walking difficulties in multiple sclerosis (MS). Studies have demonstrated that approximately one-third of MS patients respond with a clear benefit to their walking speed. Sustained-release Fampridine is not currently available on the National Health Service (NHS), although it has been approved by the Food and Drug Administration (FDA) in the USA and European Medicine Agency (EMA). It appears to have an acceptable adverse event profile, with data from open-label extension studies now becoming available. Concerns have been raised that the use of fampridine may increase the risk of seizures, which were seen at higher rates in patients treated with high doses of sustained-release fampridine. The rate of seizures in those patients on lower doses has not been found to be significantly increased. There are significant barriers at present to the widespread use of fampridine in the UK, which have limited its use in clinical practice to date. Patients with MS are in need of interventions to improve walking and many clinicians feel that this drug may have a role in the symptomatic management of MS. & 2013 Elsevier B.V. All rights reserved.
Contents 1. 2. 3. 4. 5. 6. 7.
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Role of 4-aminopyridine . . . . . . . . . . . . . . . . . . . . . . . Efficacy and trial evidence for sustained-release fampridine Pitfalls of responder analysis . . . . . . . . . . . . . . . . . . . . Safety of SR-fampridine . . . . . . . . . . . . . . . . . . . . . . . Regulatory decision. . . . . . . . . . . . . . . . . . . . . . . . . . Conclusions. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
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Correspondence to: Blizard Institute, Queen Mary University of London, Barts and the London School of Medicine and Dentistry, 4 Newark Street, London E1 2AT, UK. Tel.: +44 207 882 2285; fax: +44 207 882 2180. E-mail address: [email protected] (R. Dobson). 2211-0348/$ - see front matter & 2013 Elsevier B.V. All rights reserved. http://dx.doi.org/10.1016/j.msard.2013.06.003
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Conflict of interest statement. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 21 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 21
1.
Introduction
Multiple Sclerosis (MS) is a complex disorder of the central nervous system (CNS), the cause of which is unknown. It is characterized by progressive demyelination and axonal degeneration within the CNS. MS is a disease of young people, particularly women, with an average age of onset of 25–30 years. It is estimated that there are currently 100–120 people per 100,000 living with MS in England and Wales (NICE, 2012). MS leads to a variety of symptoms including walking impairment, which is one of the most disabling features. Up to 75% of MS patients suffer from clinically significant walking disturbance (Heesen et al., 2008; Hobart et al., 2001; Swingler and Compston, 1992); 50% of MS patients require assistance with walking 20 years after their first symptom (Coles, 2009). During a normal gait cycle an individual is supported by a single leg 80% of the time with bilateral support during 20% of the gait cycle (Cuccurullo, 2012). In people with MS, the proportion of time spent with bilateral support is greater and therefore the speed of walking is slower (Remelius et al., 2012). Walking impairment in MS is complex and multifactorial. Factors affecting walking in MS include weakness and spasticity of the lower extremities, sensory impairment and fatigue. Walking disability has a high impact on the personal, professional and social burden of the disease (Phan-Ba et al., 2012). There are many drugs used in the symptomatic management of MS, but until recently none were licensed for the specific treatment of walking impairment.
2.
Role of 4-aminopyridine
The neurophysiology underlying the possible mechanism (s) of action of 4-aminopyridine (4-AP) is discussed in the accompanying article (Baker, in press). There has been increasing interest in the use of 4-AP as a therapeutic intervention to improve walking in MS. A randomised, double-blind, placebo-controlled study conducted by Bever et al. (Bever et al., 1994), focused on the pharmacokinetics of immediate-release 4-AP, together with the degree of clinical improvement and the adverse effects experienced by MS patients. It was demonstrated that clinical improvement was related to total 4-AP exposure, and adverse events to peak serum levels. 4-AP has a narrow therapeutic window; so to improve safety, limit the peak-dose side effects including seizures and acute encephalopathy (Murray and Newsom-Davis, 1981), and to generate prolonged adequate serum levels, the sustained-release Kv channel blocker, sustained-release (SR) fampridine, was developed.
3. Efficacy and trial evidence for sustainedrelease fampridine There have been previous studies examining the therapeutic use of 4-AP, but this article focuses on sustained-release
4-AP, SR-fampridine. Trial evidence for the use of SRfampridine is summarised in Table 1. The first pilot double-blind placebo-controlled, crossover study of SR-fampridine of 10 MS patients with stable motor deficits (Expanded Disability Status Scale, EDSS 6.0–7.5) was in 1997 (Schwid et al., 1997). There was a wide range of walking impairment in this relatively small proof-of-concept trial, which nonetheless managed to reach statistical significance. 9 out of 10 patients in the treatment group demonstrated an objective improvement in speed of walking compared to placebo based on a timed test (p=0.02), and 7 felt subjectively better. A randomised, double-blind, placebo-controlled, parallelgroup trial of SR-fampridine in 25 MS patients was published in 2007 (Goodman et al., 2007). This trial, performed in 2000–2001, was a dose-escalation trial focussing on both dose-related efficacy and safety. The primary analysis, the change from baseline in the timed 25-foot walk (T25FW), did not achieve statistical significance. However, post-hoc analysis demonstrated a significant improvement in walking speed (in feet/second) in the SR-fampridine group (p= 0. å03). Convulsions were seen in 2 patients receiving high dose (425 mg twice-daily) SR-fampridine. The efficacy and dose response characteristics of SRfampridine were explored in a phase II multicentre, randomised, placebo-controlled, parallel trial with 206 participants – MS-F202 (Goodman et al., 2008). Patients were randomised 1:1:1:1 to placebo, SR-fampridine 10 mg twice daily, 15 mg twice daily and 20 mg twice daily. The primary outcome measure was the percentage change from baseline in average walking speed measured by the T25FW. The proportion of patients demonstrating a 420% improvement in walking speed did not reach statistical significance between any of the doses of SR-fampridine and placebo (SR-fampridine 10 mg, 23.5%; 15 mg, 26.0%; 20 mg, 15.8%; vs. placebo, 12.8%). In a post-hoc analysis, 36.7% patients treated with SR-fampridine demonstrated a consistent improvement in the T25FW versus 8.5% of the placebo group. The sub-group of the SR-fampridine group demonstrating a consistent improvement in walking speed was designated a “responder” group. There was a consistent mean improvement of 25–29% in walking speed for fampridine-treated responders over the double-blind treatment period. The use of the T25FW as a marker of treatment response was thought to be validated by the fact that the responder group also demonstrated improvements in the self-assessed measure of ambulation, the 12-item multiple sclerosis walking scale (MSWS-12). There was also a non-significant trend towards an improvement in the clinician global impression (CGI) scores in the responder group (p= 0.056). Treatment discontinuations secondary to adverse effects such as seizures, chest discomfort and balance disorders were more commonly seen in the higher dose treatment groups (≥15 mg). Post-hoc analysis of the above study, demonstrated that patients who met a responder criterion for a consistent response (increase in walking speed in ≥3 visits on drug
Sustained-release fampridine in Multiple Sclerosis compared to the fastest walking speed in several pre-treatment sessions) did not have a reduction in the treatment effect during the treatment period. This highlighted the fact that in those patients who showed an initial response to SR-fampridine, the response was sustained throughout follow-up (Goodman et al., 2008). Following this, two phase III trials were designed using a responder-analysis model. This design was a first for MS trials, and this is discussed in more detail below. MS-F203 (Goodman et al., 2009) and MS-F204 (Goodman et al., 2010) were multicentre, double blind, placebo-controlled trials. MS-F203 randomised 301 MS patients who were able to walk 25 feet in between 8 and 45 s in a 3:1 ratio of SR-fampridine 10 mg twice daily to placebo. The duration of this study was 21 weeks; consisting of one week of screening, two weeks of placebo run-in, fourteen weeks of double-blind treatment and four weeks of follow up. The second trial, MS-F204, randomised 239 MS patients with similar disability in a 1:1 ratio to SRfampridine 10 mg twice daily or placebo. This study included one week of screening, two weeks of placebo run-in, nine weeks of double-blind treatment and two weeks of follow up. Both studies used walking speed (in feet/second) as measured by the T25FW to define the primary clinical endpoint. The primary efficacy analysis was based on the proportion of responders in the SR-fampridine and placebo groups. Responders were differentiated from non-responders based on faster walking speed in at least three of the four on-treatment visits compared to off-treatment. The MSWS12 was used to validate whether the criteria chosen to define responders was clinically meaningful, using a comparison between responders and non-responders regardless of treatment allocation, to control for those who showed a marked response to placebo. To examine the FDA concern regarding the possibility of a gradual loss of response, responders were assessed for a significant improvement in walking speed at the last observed double-blind visit. There were a higher proportion of responders in the SRfampridine group. 34.8% (78/224; po0.0001) (Goodman et al., 2009) and 42.9% (51/119; po0.0001) (Goodman et al., 2010) patients in the SR-fampridine groups were responders versus 8.3% (6/72) and 9.3% (11/118) in the placebo group. In a subgroup analysis of responders, there were increases of 25.2% (95% confidence interval (CI) 21.5–28.8%) (Goodman et al., 2009) and 24.7% (95%CI 21.0–28.4%) (Goodman et al., 2010) in walking speed compared to 4.7% (95%CI 1.0–8.4%) and 7.7% (95% CI 4.4–11.0%) in the placebo group. Responders demonstrated significant improvements in perceptions of walking, based on the MSWS-12 (p=0.0002). The increase in walking speed was maintained throughout active treatment (po0.001), but reversed on treatment discontinuation. The non-responders to treatment in MS-F203 demonstrated a small increase in walking speed during the first treatment visit, however this was lost during the subsequent visits. The non-responders in MS-F204 had no significant initial response compared to placebo. The combined results of these two trials support the efficacy of 10 mg twice-daily SR-fampridine in those who showed an initial response to treatment, through an improvement in both walking speed and patients' subjective perception of their ambulatory deficits. However, there are limitations to these trials. They are based on walking speed over a short distance, but walking stability and endurance are also important. There is a clear
19 learning effect with the T25FW (Larson et al., 2013), although this should been seen to an equal degree in the placebo and active treatment arms. It is unclear as to whether the increased walking speed over 25 feet translates over longer distances, as although walking speed is different over different distances, evidence exists that there are strong correlations between walking speed as measured by longer and shorter duration tests in multiple sclerosis (Dalgas et al., 2012). Dose response with respect to SR-fampridine efficacy at lower doses has not been fully evaluated. No increase in efficacy with higher doses was found in earlier trials, and to date there is limited evaluation of doses lower than 10 mg twice daily.
4.
Pitfalls of responder analysis
Criticisms have been raised regarding responder analysis, which is, in essence, an attempt to transform a continuous variable into a dichotomous variable. When using a responder analysis, care must be taken to ensure clinical relevance of the response cut-off if using it to inform decisions regarding patient care. The MSWS-12 was used in these studies to validate the criteria for defining responders. The MSWS-12 measures a patients' perception of their own walking, and so the use of this indicates that the increased speed of walking objectively demonstrated by the T25FW has an impact on patients' perception of their own disability. In this case, there is a need to validate the chosen responder definition against other tools that quantitatively measure ambulatory status, such as the Dynamic Gait Index and Timed Up and Go. The T25FW measures walking speed over a short distance, and the 6 minute walk provides important information regarding motor fatigue, yet the chosen responder definition has not been validated against this (Hersh and Rae-Grant, 2012). In addition to the points above, another important fact regarding the use of a responder analysis assumes equal variances between the two populations being studied (i.e. between treatment and placebo). Essentially, a responder analysis measures the proportion of each population over a certain cut-off. If the variances of the measure are interest are not equal between the treatment and placebo groups, a greater proportion of one population may be above the selected cut-off used to define response; however, there may not be a significant difference overall between the two populations (Snappin and Jiang 2007).
5.
Safety of SR-fampridine
4-AP has been used in various unregulated formulation for many years, and there is considerable awareness regarding potential side effects (Chaplin and Dobson, 2012). Patients with MS are at higher risk of seizures than the general population (Koch et al., 2008). A high systemic dose or plasma concentration of SRfampridine (≥20 mg twice-daily) is associated with an increased risk of seizures (Goodman et al., 2008). In the phase II clinical trial (Goodman et al., 2008), two patients in the treatment group taking 20 mg twice-daily experienced seizures (one patient experienced a generalized tonic-clonic seizure, and the other patient had two separate episodes of complex partial seizures; both complex partial seizures followed an accidental
20
S. Hadavi et al.
overdose of SR-fampridine). The frequency of seizures in clinical trials with low doses of SR-fampridine has been sufficiently low to make it impossible to estimate the magnitude of the increased risk. Only one focal seizure, in the context of systemic sepsis, has been reported among 228 patients taking SR-fampridine 10 mg twice-daily (Goodman et al., 2009), with one seizure also reported in the placebo group (119 patients) of the other phase III trial (Goodman et al., 2010). It is not clear whether SR-fampridine increases the risk of falls in MS patients. In the phase II trial (Goodman et al., 2008), the frequency of falls in the treatment group out-numbered the placebo group, however this was not statistically significant. The percentage of participants suffering from falls was 11% in the placebo group versus 19%, 20% and 9% in treatment groups taking 10 mg, 15 mg and 20 mg SR-fampridine twice-daily, respectively. MS-F203 and MS-F204 demonstrated falls in 16% and 11.7% of patients in the SR-fampridine group compared to 15% and 16.8% of patients in the placebo group respectively. Other frequent adverse effects seen in the phase III studies include urinary tract infection, dizziness, insomnia, fatigue, nausea, back pain, balance disorders and headache. Taken overall, these side effects were evident at a higher rate in the SR-fampridine treated group, but with no clear dose-related increase for most events. SR-Fampridine is contraindicated in patients with mild, moderate or severe renal impairment (creatinine clearance o80 ml mol/min), and/or a prior or current history of seizures.
6.
Regulatory decision
As the outcome of above phase III trials are based on responder and non-responder status, the FDA performed additional analyses to examine the clinical significance of
the primary results. They compared the whole treatment group to the placebo group, independent of responder status. An incremental benefit in most outcomes compared with baseline was demonstrated Food and Drug Administration (2013a,b). The clinical significance of this effect however remains unclear. The EMA rejected the initial license application for SRfampridine in January 2011 due to concerns regarding a lack of clinically meaningful effects on walking speed, that treatment benefit did not outweigh the potential side effects, and insufficient data on long-term safety and efficacy European Medicines Agency (2013). Following reexamination the Committee for Medical Products for Human Use (CHMP) decided that the drug could benefit patients with significant walking disability, and that the benefit in these patients would outweigh the risk of rare side effects. Therefore SR-fampridine is now licensed for the improvement of walking disability in MS patients with an EDSS of 4–7. As only a fraction of patients appear to benefit from SRfampridine, it is necessary to assess treatment response 2 weeks after starting the medication. Identifying responders, together with defining the best outcome measure for demonstrating the efficacy of SR-fampridine, is of considerable clinical importance and has proved difficult. Currently patients undergo a timed walk test such as the T25FW to evaluate the efficacy of the drug. If no objective improvement is observed, the drug should be discontinued. However, there is still no consensus as to the best method for assessing treatment response in patients. The annual cost of SR-fampridine is approximately £5000 per patient. However, additional costs are incurred in identifying responders and assessing efficacy. According to the North East Treatment Advisory Group (NETAG) North
Table 1
Summary of clinical trial evidence for the use of SR-fampridine in multiple sclerosis.
Author (year)
Method of study
Schwid et al. (1997) Goodman et al. (2007)
Randomised doubleblind, placebocontrolled crossover Randomised doubleblind, placebocontrolled, parallel design Goodman Phase II Randomised et al. parallel group, dose (2008) comparison trial
Number SR-Fampridine dose of patients
EDSS Outcome range
Serious Adverse Events
10
6.0– 7.5
Timed walk test (8meters)
No serious side effects reported
4.0– 6.5
Timed walk and lower extremity muscle strength
Two convulsions in 2 subjects at doses of 30 and 35 mg twice-daily
2.5– 6.5
Speed of walking in T25FW, patient-based self-assessment of walking capacity (MSWS-12) Speed of walking in T25FW; MSWS-12
Two seizures in two subjects taking20mg twice-daily; one accidental overdose
25
206
Goodman Phase III Randomised 301 et al. double-blind, placebo(2009) controlled, parallel group study (MS-F203) Goodman Phase III Randomised 239 et al. double-blind, placebo(2010) controlled parallel group study (MS-F204)
17.5 mg twicedaily and placebo for 1 week 10–40 mg twicedaily, increasing in 5 mg increments weekly or placebo 10, 15, or 20 mg twice-daily or placebo
10 mg twice-daily or placebo
2.5– 7.0
10 mg twice-daily or placebo
1.5– 6.5
Speed of walking in T25FW, MSWS-12, CGI, SGI
One severe anxiety in a patient on diazepam; one focal seizure in a subject being treated for sepsis One syncope; two infections; one seizure in a patient taking placebo
CGI, Clinical Global Impression; EDSS, Expanded Disability Status Scale; MSWS-12, 12-item MS Walking Scale; SGI, Subject Global Impression; T25FW, Timed 25-foot Walk test.
Sustained-release fampridine in Multiple Sclerosis East Treatment Advisory Group (2013), SR-fampridine is a costly drug and as it affects only a narrow aspect of the condition it is unlikely to meet the conventional limits for cost effectiveness within the National Health Service (NHS) framework. MS is a progressive and lifelong condition. All the studies have looked at the effect of SR-fampridine over a relatively short duration and therefore not clear how durable the effect of treatment over the long-term. There is an urgent need for further studies on both the long-term efficacy and side effects of this drug.
7.
Conclusions
There are no other licensed medications for walking disability in MS, and SR-fampridine may be useful in certain patients. It appears to have an acceptable adverse event profile. As there have not been any long-term studies of the efficacy of SR-fampridine it is not yet known whether the effect seen in responders is sustained over months, or even years, or whether the efficacy will wane over time. It remains unclear whether any additional treatmentdependent side effects will become apparent. The issue of responders versus non-responders provides a clinical dilemma as to how best to assess response. The clinical differentiation of responders from non-responders either by stage of disease or lesion location is not yet possible. However, given the magnitude of the problem of walking disability in MS, this treatment represents a glimmer of hope for people with MS.
Conflict of interest statement SH, MDB and RD have no conflicts of interest to declare. This work was not supported by any specific grant. RD is supported by an ABN/MS Society of Great Britain Clinical Research Fellowship.
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