Fampridine (Fampyra ) in multiple sclerosis

Fampridine (Fampyra ) in multiple sclerosis NHS Regional Drug & Therapeutics Centre (Newcastle) March 2012

Summary Fampridine is a first-in-class oral potassium channel blocker licensed to improve walking ability for specific patients with multiple sclerosis. The efficacy and safety of fampridine in MS has been demonstrated in two large phase 3 randomised placebo-controlled studies. Fampridine demonstrated greater efficacy in a number of outcome measures compared with placebo. However, a substantial proportion of patients were non-responders and mean treatment effects in responder patients were often of small magnitude and uncertain clinical significance. The primary outcome evaluated in phase 3 studies was walking speed, which demonstrated a gain of about 0.15 feet per second for fampridine compared with placebo. Other measures of walking ability such as endurance and balance also demonstrated small but significant gains for fampridine compared with placebo. Fampridine appears to present an acceptable adverse effect profile with most effects being mild or moderate in severity, consisting predominantly of gastrointestinal disorders or sensory disturbances. Of concern is the rare incidence of seizure, although the modified-release formulation of fampridine has been developed in part to overcome this. Fampridine is a costly treatment, with treatment costs estimated at about 4,700 per patient per annum once established on treatment and using homecare arrangements. Of critical importance is the initial screening of patients to identify responders who will benefit from continued treatment. Replicating the process used in clinical studies will require intensive supervision and prove onerous for clinical teams. Using a less rigorous process will probably, however, result in a larger than expected proportion of patients being identified as responders. No evidence was found for the cost-effectiveness of fampridine in MS. Given the high cost of treatment and small treatment effect on only a narrow aspect of the condition it is unlikely that fampridine would meet conventional limits for cost-effectiveness within the NHS. North East Treatment Advisory Group, Mar 2012 1

Introduction Multiple sclerosis (MS) is a chronic and progressive inflammatory disorder affecting the brain. Common symptoms include fatigue, blurred vision, numbness and tingling, problems controlling bladder and bowel movements, mental (cognitive) problems, muscle spasticity, pain and impaired mobility and balance. The extent and severity of symptoms vary from patient to patient but are generally considered to reflect the underlying extent of neuronal damage. Walking impairment is the most prominent disability with about half of patients within 20 years after the first symptoms requiring a stick to aid walking. Recent surveys suggest that 64% of patients experience trouble walking and 63% of those report that it is very disruptive to their overall daily life. Life expectancy is reduced by about 10 to 15 years compared with age and gender matched controls. 1-5 Most patients (80 to 90%) are diagnosed with relapsing-remitting disease (RRMS) which is characterised by episodes of neurological dysfunction (relapse) interspersed by periods of complete or partial recovery (remission). 1 As the disease progresses the frequency, duration and severity of relapses will generally increase. Recovery from each subsequent relapse often diminishes resulting accumulation of disability over time. 2 Following an initial period of RRMS, which may last a number of years, patients will usually enter a secondary progressive phase in which symptoms rapidly worsen with infrequent and relatively minor remission. This is known as secondary progressive MS (SPMS). Primary progressive MS (PPMS) affects around 15% to 20% of patients and is characterised by a rapid and severe progression of symptoms and disability with relatively short periods of remission. 2 The progression of MS is commonly measured using the Expanded Disability Status Scale (EDSS) which aims to quantify disability in MS. This is described in detail in appendix 1. MS is the most common neurological disease in young adults. First onset symptoms typically occur at a young age of < 50 years. Females are affected three times more frequently than males. The annual incidence is estimated at 3 to 7 per 100,000 and prevalence estimated at 100 to 120 per 100,000 in England and Wales. 3 Transposing these figures to NHS North East lead to an estimated population of 2,650 to 3,200 MS patients and annual incidence of 80 to 200 patients. 6 Current approaches to the management of MS include: Non-drug treatments such as physiotherapy, occupational therapy, and speech therapy; drugs for symptom control such as baclofen and tizanide for spasticity and anticholinergic agents for bladder symptoms; steroids for relapse; disease modifying treatments (DMT) which aim to reduce relapse rates, severity, and prevent and delay disease progression. North East Treatment Advisory Group, Mar 2012 2

Licensed DMT include interferon beta, glatiramer acetate, natalizumab and fingolimod. Immunosuppressant drugs such as mitoxantrone and alemtuzumab are sometimes used outside of their product license as DMT in MS. 6,7 Several drugs are used in the management of MS although none are specifically licensed for improving walking ability. Fampridine (Fampyra, Biogen Idec) is a modified-release (MR) tablet licensed for improvement of walking in adult patients with MS with walking difficulty (EDSS 4-7). 8 Fampridine is an oral potassium channel blocker which has been shown to improve the conduction of nerve signals across damaged (demyelinated) nerve axons such as those seen in MS. 9 It became available in the UK in Autumn 2011. The NHS North East Treatment Advisory Group has received a request to conduct an appraisal of, and issue a recommendation for, the use of fampridine 10 mg MR tablets within their product license in MS. The National Institute of Health and Clinical Excellence (NICE) is not currently planning to conduct a technology appraisal of fampridine. 10 North East Treatment Advisory Group, Mar 2012 3

Efficacy Fampridine in MS has been evaluated in two phase 3 trials known as MS-F203 11 and MS-F204. 12 Both studies had similar design and were double-blind, randomised, and placebo-controlled (combined n = 533). The key difference was study duration being 14 and 9 weeks respectively. The primary efficacy outcome in both studies was the responder rate, based on the timed 25 foot walk test. To be defined as a treatment responder, a patient needed to have demonstrated an increase in walking speed as measured using the timed 25 foot walk test, on at least three out of four assessment visits during the double-blind treatment phase. Other outcomes included the 12-item multiple sclerosis walking scale (MSWS-12), the Ashworth disability score, and patient and clinician global impressions. Outcome measures are described in more detail in appendix 2. 11,12 At baseline, patients had a mean EDSS score of about 6.0 (range 1.5 to 7.0). About half of patients had SPMS, a third RRMS, and most of the remainder had PPMS. Patients were able to walk at about 2.0 to 2.2 feet per second at baseline (i.e. about 10 to 15 seconds of walking to cover the distance). At the end of the treatment phases walking speed had increased by about 0.2 feet/s (~6.0 cm/s) with fampridine and by 0.05 to 0.11 feet/s (~1.5 to 3.4 cm/s). Thus the incremental mean gain in walking speed with fampridine is about 2.5 to 4.5 cm/s. If this is maintained for 60 seconds (1 minute) then the expected gain is about 1.5 to 2.7 metres. 11,12 The proportion of patients in MS-F203 who were classed as responders was 35% (78 of 224) in the fampridine group and 8% (six of 72) in the placebo group (p < 0.0001). 11 In MS-F204 this was 43% (51 of 119) and 9% (11 of 118) respectively (p < 0.0001). 12 Table one summarises results of the walk test in both studies. Increases in walking speed seen in fampridine responders in both studies were maintained throughout active treatment but reversed on treatment discontinuation. 11,12 Non-responders to fampridine in MS-F203 exhibited a small significant increase in walking speed compared with placebo at first treatment visit however there was no difference seen at subsequent visits. 11 Non-responders in MS-F204 showed no significant change in walking speed compared with placebo. 12 Table two summarises results of the MSWS-12 which assesses patient perceptions of walking problems on daily life. Fampridine patients in MS-F203 did not show a significant difference in MSWS-12 compared with placebo however there was a clear trend in favour of fampridine. There was significant gain in responders compared with non-responders in both studies. Changes from baseline in both trials were significant for total responders versus non-responders (both p < 0.001). Since a statistically significant improvement in MSWS-12 in responders compared to nonresponders in this measure serves to validate the clinical meaningfulness of the walk test, the 25% change in walk test seen in the fampridine responder group in both trials was judged to be clinically significant. 13 North East Treatment Advisory Group, Mar 2012 4

Table 1. Results of the walk test in studies MS-F203/4 11,12,14,15 MS-F203 MS-F204 Placebo (n = 72) Fampridine (n = 224) p Placebo (n = 118) Fampridine (n = 119) p Double-blind phase baseline (feet/s) 2.12 2.14 0.88 2.28 2.21 0.55 End of double-blind phase (feet/s) 2.16 2.35 0.19 2.39 2.42 0.73 Absolute difference (feet/s) 0.05 0.21 0.03 0.11 0.22 0.04 Gain relative to baseline (%) (95% confidence Interval) Responders 4.7 (1.0 to 8.4) 25.2 (21.5 to 28.8) 7.5 (5.0 to 10.0) 7.7 (4.4 to 11.0) 24.7 (21.0 to 28.4) 6.0 (2.2 to 9.7) Table 2. Results of the MSWS-12 in studies MS-F203/4 11,12,16 Placebo (n = 72) MS-F203 Fampridine (n = 224) p Placebo (n = 118) MS-F204 Fampridine (n = 119) Double-blind phase baseline 67.0 69.1 0.526 67.6 73.3 0.015 End of double-blind phase 72.1 69.1 0.411 68.4 70.7 0.379 Absolute difference 5.1-0.04 0.060 0.8-2.6 0.036 Mean change from baseline (95% confidence Interval) Responders* Nonresponders Nonresponders* -6.84 (-9.65 to -4.02) 0.05 (-1.48 to 1.57) < 0.001 * Includes patients from both treatment groups -6.04 (-9.57 to -2.52) 0.85 (0.72 to 2.43) p < 0.001 Other outcomes from studies MS-F203/4 are summarised in appendix 3. Data from MS-F203/4 extension studies has been presented at a recent conference. 17 Of 349 patients randomised in the MS-F203/4 studies, 310 entered the extension studies and received open-label fampridine 10 mg MR twice daily with follow-up of up to 60 months (five years). 191 patients completed the extension studies. The evidence indicates that mean relative change in walking speed compared with baseline declines through most follow-up assessments over time. Mean gains for responders remains consistently elevated relative to non-responders although mean gains do converge over time. By about two years, the difference in mean walking speed relative gain from baseline between responders and nonresponders is less than 10%, and for responders the mean gain is less than 10% above baseline. However the numbers of patients which constitute the data sets at two years or beyond is relatively small compared with the original patient cohorts. 17 North East Treatment Advisory Group, Mar 2012 5

Adverse effects Immediate-release preparations of fampridine have been associated with an increased risk of seizure. Convulsions have been rarely reported in phase 2 trials of fampridine MR tablets in MS and to date there has been only one report of a focal seizure in phase 2 and 3 trials. 11,12,18,19 The most frequent adverse effects seen in patients enrolled in the phase 3 studies are summarised in table three. Table 3. Adverse effects reported > 5% fampridine patients in phase 3 studies 11,12 MS-F203 MS-F204 Adverse Effect Placebo n = 72 Fampridine n = 228 Placebo n = 119 Fampridine n = 120 Fall 11(15%) 36 (16%) 20 (16.8%) 14 (11.7%) Urinary tract infection 10 (14%) 31 (14%) 10 (8.4%) 21 (17.5%) Dizziness 4 (6%) 19 (8%) 1 (0.8%) 10 (8.3%) Insomnia 3 (4%) 14 (6%) 2 (1.7%) 12 (10.0%) Fatigue 2 (3%) 14 (6%) Nausea 3 (4%) 14 (6%) 1 (0.8%) 10 (8.3%) Asthenia 4 (6%) 13 (6%) 5 (4.2%) 10 (8.3%) Back pain 0 13 (6%) 3 (2.5%) 7 (5.8%) Balance disorder 2 (3%) 13 (6%) 2 (1.7%) 7 (5.8%) Headache 4 (6%) 13 (6%) 1 (0.8%) 11 (9.2%) In study MS-F203 eight fampridine patients discontinued study medication due to treatment-emergent adverse effects. Two events were regarded as possibly related to treatment; one focal seizure in a patient suffering from sepsis secondary to pneumonia, and one episode of severe anxiety. 11 In MS-F204, 25 fampridine patients experienced adverse effects which were considered to be treatment-related although no further details were provided. 12 Unpublished data relating to longer-term safety, with follow-up of up to five years, indicates that no new adverse effects emerged compared with the randomised studies. Cumulative adverse effect rates are, however, elevated compared with the relatively short randomised studies and this is not an unexpected observation. The most common effects were urinary tract infection, fall, disease relapse, and arthralgia. These are symptoms typical of established MS. 17 Fampridine is contraindicated in patients with renal impairment (creatinine clearance < 80 ml/min) and in patients with a history of seizure. 8 North East Treatment Advisory Group, Mar 2012 6

Cost analysis Costs include VAT at 20% where applicable unless otherwise indicated The recommended dose of fampridine (Fampyra ) in MS is 10 mg twice daily. 8 Fampyra is available in packs of 28 and 56 tablets at 217.20 and 434.40 respectively, corresponding to a daily treatment cost of 15.51. 20 For those patients maintained on Fampyra the annual cost of treatment is estimated at 5,661 per patient. The manufacturer is able to provide Fampyra to NHS patients via homecare arrangements at no additional cost. 21 As well as potentially being more convenient for patients, this would also negate the addition of VAT to drug costs. The annual cost of Fampyra without VAT is 4,720. 20 The manufacturer offers a scheme which provides sufficient Fampyra for 28 days treatment at no cost. This is specifically designed to permit the assessment of treatment response, such that treatment is only continued at cost to the NHS in those patients deemed responders. 22 Thus the screening of a comparatively large number of patients to identify treatment responders can be achieved at reduced drug cost to the NHS. The manufacturer has estimated, seemingly based on the mean responder rate observed in MS-F203, that only 35% of patients will continue therapy beyond the two week assessment period. 11,21 The responder rate in MS-F204 was 43%; 12 a weighted mean rate is about 37%. However, the response rate in the MS-F203/4 studies was achieved with four assessments over a minimum period of up to eight weeks (i.e. two-weekly assessments as per MS-F204). 11,12 In order to obtain zero-cost Fampyra before identifying treatment responders would require that responders would be identified after a maximum of four weeks. 22 This could only be achieved with a reduced between-test frequency or a reduced number of sequential tests or a combination of both. Either way, there is no evidence to indicate that this would yield the same or similar responder rates as observed in the MS-F203/4 studies. The Fampyra summary of product characteristics recommends that patients are initially prescribed only two weeks of medication to enable the identification of responders. 8 This is a more severe divergence from the clinical evidence than that which might be imposed by a four-week assessment period corresponding to the maximum availability of zero-cost Fampyra. 22 Each patient assessment is estimated to cost 136 (excluding market forces factor uplift, typically about 2% for NHS North East provider trusts) based on the indicative cost of a multi-professional neurology outpatient visit. 23 Therefore the cost of four such assessments as utilised in the MS-F studies is estimated at 544. An additional consideration is the burden of responder assessments, which may require a significant number of outpatient appointments in a short period of time. North East Treatment Advisory Group, Mar 2012 7

This may present an onerous burden for patients and clinics as well as being clinically inappropriate. In order to replicate the same responder-status assessments as used within clinical studies, assessments would need to be spread over a minimum period of up to eight weeks (i.e. two-weekly assessments as per MS-F204) incurring drug costs of up to 869 per patient before all non-responders were identified. 20,23 Those costs would be reduced to 434 if the Fampyra responder scheme was utilised, and further reduced again if Fampyra was provided via homecare arrangements. Of course, some non-responders could be identified at the 2 nd or 3 rd assessment although data indicating the relevant proportions is not available. Table three demonstrates the different costs of treating patients to identify responders based on varying assessment intensities and with or without the Fampyra responder scheme. It must be remembered that any assessment of responder patients which is less rigorous than that used in the MS-F203/4 studies could lead to a higher proportion of patients being maintained on treatment, some of which could therefore be considered inappropriate. Table 3. Cost of identifying treatment responders with various assessment intensities 20,23 Assessment period Two weeks Four weeks Four weeks Eight weeks* Number of assessments 1 2 4* 4* Cost of assessments 136 272 544 544 Cost of drug**: Responder scheme 0 0 0 362 Total 136 272 544 906 Cost of drug**: 181 362 362 724 Total 317 634 906 1,268 * As utilised in clinical studies. ** Assumed drug provided via homecare and no VAT At initiation, therefore, fampridine is associated with an non-drug costs stemming from clinical appointments although it is not possible to determine the incremental effect over and above the expected level of supervision that such patients may receive anyway. The cost of trialling fampridine in all eligible patients for eight weeks with four outpatient appointments is estimated at up to 1,413 (assuming provision of Fampyra including VAT). 20,23 Of these, only 35 to 40% are estimated to remain on therapy. 11,12 The mean cost of treatment per annum per patient will be greater than the long term drug costs alone as the value will need to be adjusted to allow for a larger volume of patients who are trialled on the treatment initially. This cost has been estimated at North East Treatment Advisory Group, Mar 2012 8

up to 8,829 per patient for the first year including the cost of four assessment appointments. 20-23 Another uncertainty in this cost analysis is the cost of an outpatient appointment. This has been assumed at 136 per appointment based on an indicative neurology outpatient tariff for the proceeding financial year. 23 However, locally agreed tariffs are currently in place with NHS North East mental health trusts and these may diverge substantially. One trust has a tariff for its multiple sclerosis service ranging from about 120 to 1,200 per appointment depending on how the episode is categorised. 24 Only one relevant economic report was identified relating to fampridine for MS. This was a conference abstract which assessed the net budget impact from the introduction of fampridine (Fampyra ) to the UK. The analysis used an annual cost per patient of 3,800 which is less than the actual cost. The analysis assumed a patient population of 35,000 based on EDSS scores of 4.0 to 7.5 and annual uptake over the first three years of 3%, 10% and 16%, with a withdrawal rate of 2.2%. The incremental costs were estimated at 3.4 million, 10.9 million and 18.2 million for years 1, 2 and 3 after launch. 25 Adjusting the figures for a conservatively estimated cost of 4,720 and the NHS North East population (approximately 4.5% of the UK population) 6 the corresponding values are 190,000, 609,000 and 1.017 million respectively. Costs are described as being incremental to usual care alone although this is not described. The prevalence of MS in the UK is estimated at about 110 patients per 100,000. 3 Approximately 57% of these patients will have an EDSS score of 4 to 7, corresponding to about 63 patients per 100,000. 21 Of these around 64% will have walking impairment, corresponding to about 40 patients per 100,000. 5 It is expected that about 35% of patients who have an EDSS score of 4 to 7 with walking impairment will respond to fampridine treatment, corresponding to about 14 patients per 100,000. 21 Transposed to the population of NHS North East this corresponds to a potential patient population of up to 370 patients. 6 Of course, not all potentially eligible patients will be trialled with therapy but no evidence was identified to reliably estimate the proportion of eligible patients who might receive treatment with fampridine. For this reason reliable estimates of the expected patient population for NHS North East PCTs have not been estimated. North East Treatment Advisory Group, Mar 2012 9

Points to consider Fampridine is the only drug specifically indicated for improvement of walking ability in adult patients with MS. Fampridine is not licensed for the treatment of other aspects of MS such as reducing relapse rates, severity of relapse, reducing disease progression, or modifying the disease process. 8 Although there are currently no other drugs specifically licensed to improve walking in MS other treatments such as physical rehabilitation and other drugs may still have positive effects on a patient s ability to walk. Fampridine may be suitable for use as an add-on therapy, possibly in combination with currently available drugs or physiotherapy, in a select group of patients, within its licensed indication, in an area of unmet need. This use, although realistic, is not entirely evidence-based as only about two-thirds of patients in the pivotal studies were using other treatments such as interferon and glatiramer. 11,12 MS is a lifelong and progressive condition. The effects of fampridine have been demonstrated primarily in relatively short duration studies. It is not entirely clear how durable the effects of fampridine are in the longer term. The available evidence indicates that the effects may not be durable beyond about two years. 17 Fampyra is only licensed for patients within a specific window of disability and therefore patients will require regular review to ensure that the prescription remains appropriate. 8 Outcomes evaluated in the pivotal phase 3 studies of fampridine in MS are generally reported based on responder vs. non-responder status irrespective of treatment allocation. 11,12 This confounds and confuses the interpretation of study outcomes. Third parties have reported the outcomes based on original treatment allocations and these have demonstrated only small changes in most outcomes compared with baseline between active and placebo groups. 15,16 The primary outcome of the fampridine studies relates to walking speed. 11,12 Of equal or potentially greater importance to patients is the ability to sustain walking (endurance) or the stability of walking (balance). This was assessed primarily using the MSWS-12, which did demonstrate small incremental benefits for fampridine compared with placebo. 11,12 The incremental benefit of fampridine on walking speed is about 1½ to 2 inches per second, or 2 to 3 metres per minute. It is not clear how valuable this is to patients. Differences between subject global impression scores, fampridine vs. placebo groups, were small and not always significant. 11,12 Other outcomes were also somewhat limited in the size of their effect with small and often non-significant differences between fampridine and placebo groups. North East Treatment Advisory Group, Mar 2012 10

The distinction between fampridine responder and non-responder patients may be difficult to achieve in practice. Of concern is that this distinction and the attributed treatment effects could be partially explained by the regression to the mean phenomenon. Without evidence of longer follow-up it is difficult to distinguish whether the observed efficacy could be explained by a natural variation in disability or through a causal effect of fampridine. Fampridine appears to present an acceptable adverse effect profile, although again this is derived from only short-term studies with limited longer-term evidence. 11,12,17 Some neurological and gastrointestinal effects do occur at a substantially greater rate compared with placebo. Of particular concern are effects of dizziness and balance disorder which could negate the benefits of treatment. However there does not appear to be an obvious effect on the rate of falls experienced by patients. 11,12 A number of studies of fampridine in MS are still underway or are yet to publish results including follow-up studies to MS-F203 and F204. 26-28 Fampridine (Fampyra ) is a costly therapy at about 5,000 per patient per annum. 20 This is similar to the annual cost of some of disease modifying treatments such as glatiramer and interferon. 20 Additional costs will be incurred in identifying responder patients and continued assessment of efficacy although the incremental impact in a highly morbid population is not clear. The majority of patients commenced on fampridine are unlikely to remain on the treatment 21 and this represents a poor return on up-front costs as well as imposing constraints on both the healthcare system and patients. In addition all patients will be exposed to the risks of treatment. Mean patient costs in the first year of treatment will be inflated due to the high dropout rate and intensive assessment required at initiation. No evidence was found for the cost-effectiveness of fampridine in MS. Given the high cost of treatment and small treatment effect on only a narrow aspect of the condition it is unlikely that fampridine would meet conventional limits for costeffectiveness within the NHS. The initial license application for fampridine was rejected by the European Medicines Agency in January 2011 due to concerns that the effect on walking speed was not clinically meaningful, that benefits did not outweigh adverse effects, and the lack of longer-term safety and efficacy data. 29 Following further consideration a decision for license approval was made in May 2011. The EMA concluded: on the basis of quality, safety and efficacy data submitted, [the EMA] considers there to be a favourable benefit to risk balance for Fampyra,. The licensing authority issued the license on condition that long-term safety and efficacy data will become available. 30 Fampridine is likely to remain outside of the primary care domain due to the nature of the condition being treated. North East Treatment Advisory Group, Mar 2012 11

Acknowledgement This report is largely based on an original report produced by the NHS Regional Drug & Therapeutics Centre (Newcastle), published in September 2011. Authors declarations The lead author has no relevant interests to declare. The secondary author has participated in a non-promotional educational event sponsored by a company which produces a drug licensed for the treatment of spasticity in MS. The event did not concern that particular drug or MS. References 1. Tremlett H, et al. New perspectives in the natural history of multiple sclerosis. Neurology 2010;74:2004-15 2. Coles A. Multiple Sclerosis. Neurology in Practice 2009;9:118-26 3. NICE. Clinical Guideline 8: Management of multiple sclerosis in primary and secondary care 2003 4. http://text.mssociety.org.uk/textonly/about_ms/symptoms/index.html Accessed 19/07/2011. 5. Key findings from two new multiple sclerosis surveys. conducted by Harris Interactive. www.nationalmssociety.org/news/news-detail/download.aspx?id1018 Accessed: 19/07/2011. 6. NHS The Information Centre for Health and Social Care. Attribution dataset GP registered populations 2010.www.ic.nhs.uk/statistics-and-data-collections/population-and-geography/gpregistered-populations/attribution-dataset-gp-registered-populations-2010 7. NICE. Technology Appraisal 32: Beta interferon and glatiramer acetate for the treatment of multiple sclerosis. 2002 8. Summary of product characteristics for Fampridine (Fampyra, Biogen Idec). February 2012. www.medicines.org.uk 9. Belachew S, et al. Natalizumab induces rapid improvement of disability status and ambulation after failure of previous therapy in relapsing-remitting multiple sclerosis. European Journal of Neurology 2011;18:240-45 10. Personal communication, National Institute for Health and Clinical Excellence, January 2012. 10. NICE. Review of Clinical Guideline 8. www.nice.org.uk/nicemedia/live/10930/55083/55083.pdf Accessed: 29/08/2011 11. Goodman A, et al. Sustained-release oral fampridine in multiple sclerosis: a randomised, double blind, controlled trial. Lancet 2009;373:732-8 12. Goodman A, et al. A phase 3 trial of extended release oral dalfampridine in multiple sclerosis. Ann Neurol 2010;68:494-502 13. National Prescribing Centre. Prolonged-release fampridine improves measures of walking in some patients with multiple sclerosis. www.npc.nhs.uk/rapidreview/?p=1760 Accessed: 19/07/2011. 14. European Public Assessment Report. www.ema.europa.eu/docs/en_gb/document_library/epar_- _Public_assessment_report/human/002097/WC500109957.pdf Accessed: 08/08/2011. 15. Food and Drug Administration. NDA: 22-250 Fampridine AC Background. www.fda.gov/downloads/advisorycommittees/committeesmeetingmaterials/drugs/peripheralandcentr alnervoussystemdrugsadvisorycommittee/ucm185663.pdf Accessed: 19/07/2011 16. Food and Drug Administration. www.fda.gov/downloads/advisorycommittees/committeesmeetingmaterials/drugs/peripheralandcentr alnervoussystemdrugsadvisorycommittee/ucm191029.pdf Accessed: 19/07/2011. North East Treatment Advisory Group, Mar 2012 12

17. Goodman AD on behalf of the MS-F203, MS-F204, and Extension Study Investigators. Updated analysis of open-label extension studies of dalfampridine extended release tablets in multiple sclerosis. Poster P566 presented at the 5th joint Triennial Congress of the European and Americas Committees for Treatment and Research in Multiple Sclerosis, October 2011 18. Goodman A, et al. Fampridine-SR in multiple sclerosis: a randomised, double blind, placebo controlled, dose ranging study. Multiple Sclerosis 2007;13:357-68 19. Goodman A, et al. Dose comparison trial of sustained-release fampridine in multiple sclerosis. Neurology 2008;71:1134-41 20. NHS dictionary of medicines and devices. www.dmd.nhs.uk February 2012 21. Personal communication with Biogen Idec. February 2012. 22. Fampyra Responder Identification Scheme.FM-PAN-0046b. September 2011. Biogen Idec. 23. Department of Health. Payment by results tariff 2011-12. www.dh.gov.uk/en/ Publicationsandstatistics/Publications/PublicationsPolicyAndGuidance/DH_122717 24. Data on file. NHS North East office of the North of England Specialised Commissioning Group. February 2012. 25. Pietri G, Miller DW, White J, Moorcroft E. Budget impact analysis of the introduction of fampridine to improve ambulation in patients with multiple sclerosis (MS) in the UK. Value in Health 2010;14(7):A319 26. Open-label extension study to evaluate the safety, tolerability and activity of oral fampridine-sr. http://clinicaltrials.gov/ct2/show/nct00649792?term=nct00649792&rank=1 Accessed: 19/07/2011 27. Study of fampridine-sr tablets in multiple sclerosis patients who participated in the MS-F203 trial. http://clinicaltrials.gov/ct2/show/nct00648908?term=ms-f203&rank=1 Accessed: 19/07/2011 28. Open label extension study to evaluate the safety and tolerability of oral fampridine-sr in Canadian subjects with multiple sclerosis who participated in the Acorda extension trials. http://clinicaltrials.gov/ct2/show/nct01235221?term=fampridine&rank=8 Accessed: 19/07/2011 29. European Medicines Agency. Refusal of the marketing authorisation for Fampyra (fampridine). www.ema.europa.eu/docs/en_gb/document_library/summary_of_opinion_- _Initial_authorisation/human/002097/WC500101071.pdf Accessed: 19/07/2011. 30. European Medicines Agency. Positive Opinion on the marketing authorisation for Fampyra (fampridine). www.ema.europa.eu/docs/en_gb/document_library/medicine_qa/human/002097/wc500106540.pdf Accessed: 19/07/2011 31. www.mult-sclerosis.org/expandeddisabilitystatusscale.html Accessed 19/07/2011 32. www.nationalmssociety.org/for-professionals/researchers/clinical-study-measures/t25- fw/index.aspx. Accessed: 19/07/2011 33. Lee K-C, et al. The Ashworth Scale: A reliable and reproducible method of measuring spasticity. Journal of Neurological Rehabilitation 1989;3:205-09 34. Compston A. Aid to the investigation of peripheral nerve injuries. Brain 2010;133:2838-44 35. Hobart J, et al. Measuring the impact of MS on walking ability. Neurology 2003;60 36. McGuigan C, et al. Confirming the validity and responsiveness of the multiple sclerosis walking scale (MSWS-12). Neurology 2004;62 North East Treatment Advisory Group, Mar 2012 13

Appendix 1. Expanded Disability Status Scale (EDSS) 31 Disability is measured across eight functional systems: pyramidal, cerebellar, brainstem, sensory, bowel/bladder, visual, cerebral and other. The scale is measured in half units from 0 to 10 ranging from no disability to death from MS. The EDSS scale is non-linear which means that a change of one unit from, say, 2.0 to 3.0 may not represent the same degree of disability as a change from, say, 6.5 to 7.5. Score Definition 0.0 Normal neurological examination 1.0 No disability, minimal signs in one FS 1.5 No disability, minimal signs in more then one FS 2.0 Minimal disability in one FS 2.5 Mild disability in one FS or minimal disability in two FS 3.0 Moderate disability in one FS, or mild disability in three or four FS. Fully ambulatory 3.5 4.0 4.5 5.0 5.5 6.0 6.5 7.0 7.5 8.0 8.5 Fully ambulatory but with moderate disability in one FS and more than minimal disability in several others Fully ambulatory without aid, self-sufficient, up and about some 12 hours a day despite relatively severe disability; able to walk without aid or rest for 500 metres Fully ambulatory without aid, up and about most of the day, able to work a full day, may otherwise have some limitation of full activity or require minimal assistance; characterised by relatively severe disability, able to walk without aid or rest for 300 metres Ambulatory without aid or rest for about 200 metres; disability severe enough to impair full daily activities (work a full day without special provisions) Ambulatory without aid or rest for about 100 metres; disability severe enough to preclude full daily activities Intermittent or unilateral constant assistance (cane, crutch, brace) required to walk about 100 metres with or without resting Constant bilateral assistance (canes, crutches, braces) required to walk about 20 metres without resting Unable to walk beyond approximately five metres even with aid, essentially restricted to wheelchair; wheels self in standard wheelchair and transfers alone; up and about in wheelchair for about 12 hours a day Unable to take more than a few steps; restricted to wheelchair; may need aid to transfer; wheels self but cannot carry on in standard wheelchair a full day; may require a motorised wheelchair Essentially restricted to a bed or chair or perambulated in wheelchair, but may be out of bed itself for much of the day; retains many self-care functions; generally has effective use of arms Essentially restricted to bed much of the day; has some effective use of arms and retains some self-care functions 9.0 Confined to bed; can still communicate and eat 9.5 Totally helpless bed patient; unable to communicate effectively, or eat/swallow 10.0 Death due to MS North East Treatment Advisory Group, Mar 2012 14

Appendix 2. Other outcome measures used to assess fampridine in MS The Timed 25 Foot Walk Test 32 The walk test is a quantitative measure of leg function, and therefore mobility. The patient is instructed to walk 25 feet as quickly as possible, whilst remaining safe. The time is calculated from the beginning of the instruction to begin, and ends when the patient has reached the 25-foot mark. The test is immediately repeated, with the average of the two times being taken as the result. Patients are permitted to use assistive devices such as canes and crutches whilst completing the task. The test must be completed within 3 minutes, if not, it is discontinued. Ashworth Score for Spasticity 33 Each passive movement is graded between 1 and 5: 1. Normal (no increase in muscle tone) 2. Slight increase in tone when affected part is moved in flexion or extension 3. More marked increase in tone but affected part is easily flexed 4. Considerable increase in tone; passive movement difficult 5. Affected part is rigid in flexion or extension Lower Extremity Manual Muscle Test (LEMMT) 34 The LEMMT measures strength across certain groups of muscles. The patient is asked to hold a limb at the end of its range of movement, while a clinician provides manual resistance. In the fampridine studies it was used across four muscle groups (ankle dorsiflexors, hip flexors, knee extensors and knee flexors). It is graded accordingly: 5. Muscle contracts normally against full resistance 4. Reduction in muscle strength but muscle contraction can still move the joint against resistance 3. Muscle strength is further reduced such that the joint can be moved only against gravity with the examiner s resistance completely removed. 2. Muscle can move only if the resistance of gravity is removed. 1. Only a trace or flicker of movement is seen or felt in the muscle or fasciculations are observed in the muscle. 0. No movement is observed. North East Treatment Advisory Group, Mar 2012 15

The 12-Item Multiple Sclerosis Walking Scale (MSWS-12) 35,36 This is a patient-rated measure of walking ability. The total score is generated and reported on a 0 to 100 scale, by subtracting the minimum score possible from 12 items (12) from the patients score, dividing by the maximum score (60), and then multiplying by 100. 36 The MSWS-12 is only relevant to patients who can walk. Patients are asked to circle the one number which best describes their degree of limitation, and to answer all questions. 35 In the past two weeks, how much has your MS.. Not at all A little Moderately Quite a bit Extremely 1. Limited your ability to walk? 1 2 3 4 5 2. Limited your ability to run? 1 2 3 4 5 3. Limited your ability to climb up and down stairs? 4. Made standing when doing things more difficult? 5. Limited your balance when standing or walking? 6. Limited how far you are able to walk? 7. Increased the effort needed for you to walk? 8. Made it necessary for you to use support when walking indoors (for example holding on to furniture, using a stick)? 9. Made it necessary for you to use support when walking outdoors (for example using a stick, frame etc)? 1 2 3 4 5 1 2 3 4 5 1 2 3 4 5 1 2 3 4 5 1 2 3 4 5 1 2 3 4 5 1 2 3 4 5 10. Slowed down your walking? 1 2 3 4 5 11. Affected how smoothly you walk? 1 2 3 4 5 12. Made you concentrate on your walking? 1 2 3 4 5 Subject Global Impression 11,12 Patients rate their perception of the effects seen with the medication they were taking. The effects were rated on a seven point scale, ranging from 1 (terrible) to 7 (delighted). Clinician Global Impression 11,12 The supervising clinician was asked to rate the patient s neurological condition on a seven point scale, ranging from 1 (very much improved) to 7 (very much worse), relative to the time of screening. North East Treatment Advisory Group, Mar 2012 16

Appendix 3. Summary table of key studies Reference Design Intervention Patient numbers Inclusion criteria Exclusion criteria Primary outcome Results Safety MS-F203 11 DB, RCT, pbo control 2 week placebo run in period, 14 week treatment period 4 week follow up period Fam 10 mg twice daily vs. placebo Fampridine n = 228 Placebo n = 72 Patients were aged 18-70 years with clinically defined MS. They had to be able to complete 2 trials of the walk test in an average time of 8 to 45 seconds at screening Patients were excluded if they had: history of seizures; onset of MS exacerbation within 60 days of screening; evidence of epileptiform activity on screening electroenceph alogram; any condition which would interfere with conduct or interpretation of the study Primary Variable: Responder status (defined as a patient who had a faster walking speed for 3 out of 4 visits whilst on treatment, compared to the maximum speed for any of the offtreatment visits. Primary Outcome: Percentage change from baseline in walk test Secondary Outcome: Average change in Ashworth Scale; Average change in LEMMT Primary validation measure: Average change in MSWS-12 Responders: Fam R: n = 78 (35%) Pbo R: n = 6 (8%) (p<0.0001, OR: 4.75 (95% CI: 2.08 to 10.86) Walk test (95% CI): Fam R: 25.2% (21.5 to 28.8) Fam NR: 7.5% (5.0 to 10.0) Pbo: 4.7% (1.0 to 8.4) Ashworth Scale Fam R: -0.16 Pbo: -0.07 [p = 0.021] LEMMT Fam R: 0.18 Pbo: 0.04 [p=0.0002] MSWS-12 (95% CI) Total R: -6.84 (-9.65 to - 4.02) Total NR: 0.05 (-1.48 to 1.57) [p<0.0002] 2 patients discontinued treatment due to AEs which were regarded as possibly related to the treatment: 1 focal seizure in a patient suffering sepsis due to CAP; 1 episode of severe anxiety. The following AEs were reported at a higher rate in fampridine patients (Fam vs. pbo): Fall (16% vs. 15%) Dizziness (8% vs. 6%) Insomnia (6% vs. 4%) Fatigue (6% vs. 3%) Nausea (6% vs. 4%) Back pain (6% vs. 0) Balance disorder (6% vs. 3%) North East Treatment Advisory Group, Mar 2012 17

Reference Design Intervention Patient numbers Inclusion criteria Exclusion criteria Primary outcome Results Safety MS-F204 12 DB, RCT, pbo control 2 week placebo run in period, 9 week treatment period 2 week follow up period As previous Fampridine n = 120 Placebo n = 119 As previous Responders: Fam R: n = 51 (42.9%) Pbo R: n = 11 (9.3%) (p<0.0001, OR: 8.14 (95% CI: 3.73 to 17.74) Walk test (95% CI): Fam R: 24.7% (21.0 to 28.4) Fam NR: 6.0% (2.2 to 9.7) Pbo: 7.7% (4.4 to 11.0) Ashworth Scale Fam R: -0.18 Pbo: -0.06 [p = 0.0153] LEMMT Fam R: 0.145 Pbo: 0.042 [p=0.028] MSWS-12 (95% CI) Total R: -6.04 (-9.57 to -2.52) Total NR: 0.85 (0.72 to 2.43) [p<0.001] 25 patients discontinued treatment due to AEs which were regarded as possibly related to the treatment. The details of these are not given however, SAEs which occurred within the fampridine group include: Pneumonia, cellulitis, pyelonephritis and a combination of cholelithiasis and syncope. The following AEs were reported at a higher rate in fampridine patients (Fam vs. pbo): UTI (18% vs. 8%) Dizziness (8% vs. 1%) Insomnia (10% vs. 2%) Nausea (8% vs. 1%) Asthenia (8% vs. 4%) Back Pain (6% vs. 3%) Balance disorder (6% vs. 2%) Headache (9% vs. 1%) Key: AE adverse event; CAP community acquired pneumonia; DB double-blind; Fam fampridine; LEMMT lower extremity manual muscle test; MS multiple sclerosis; MSWS-12 12-Item Multiple Sclerosis Walking Scale; NR timed walk non-responder; pbo placebo; R timed walk responder; RCT randomised controlled trial; SAE serious adverse event; UTI urinary tract infection; Walk test timed 25 foot walk test. North East Treatment Advisory Group, Mar 2012 18