Fampridine Accord

Pharmacotherapeutic group: Other nervous system drugs, ATC code: N07XX07. Pharmacodynamic effects Fampyra is a potassium channel blocker. By blocking potassium channels, fampridine reduces the leakage of ionic current through these channels, thereby prolonging repolarization and thus enhancing action potential formation in demyelinated axons and neurological function. Presumably, by enhancing action potential formation, more impulses might be conducted in the central nervous system. Clinical efficacy and safety Three phase III, randomised, double-blind, placebo controlled confirmatory studies, (MS-F203 and MS-F204 and 218MS305) have been performed. The proportion of responders was independent of concomitant immunomodulatory therapy (including interferons, glatiramer acetate, fingolimod and natalizumab). The Fampyra dose was 10 mg twice a day (BID). Studies MS-F203 and MS-F204 The primary endpoint in studies MS-F203 and MS-F204 was the responder rate in walking speed as measured by the Timed 25-foot Walk (T25FW). A responder was defined as a patient who consistently had a faster walking speed for at least three visits out of a possible four during the double blind period as compared to the maximum value among five off-treatment visits. A significantly greater proportion of Fampyra treated patients were responders as compared to placebo (MS-F203: 34.8% vs. 8.3%, p< 0.001; MS-F204: 42.9% vs. 9.3%, p< 0.001). Patients who responded to Fampyra increased their walking speed on average by 26.3% vs 5.3% on placebo (p< 0.001) (MS-F203) and 25.3% vs 7.8% (p< 0.001) (MS-F204). The improvement appeared rapidly (within weeks) after starting the treatment. Statistically and clinically meaningful improvements in walking were seen, as measured by the 12- item Multiple Sclerosis Walking Scale. Table 2: Studies MS-F203 and MS-F204 STUDY * MS-F203 MS-F204 Placebo Fampyra 10 mg BID Placebo Fampyra 10 mg BID n of subjects 72 224 118 119 Consistent improvement 8.3% 34.8% 9.3% 42.9% Difference 26.5% 33.5% CI 95% P-value 17.6%, 35.4% < 0.001 23.2%, 43.9% < 0.001 ≥ 20% improvement 11.1% 31.7% 15.3% 34.5% Difference 20.6% 19.2% CI 95% P-value 11.1%,30.1% < 0.001 8.5%,29.9% < 0.001 Walking speed Feet/sec Ft per sec Ft per sec Ft per sec Ft per sec Baseline 2.04 2.02 2.21 2.12 Endpoint 2.15 2.32 2.39 2.43 Change 0.11 0.30 0.18 0.31 Difference 0.19 0.12 p-value 0.010 0.038 Average % Change 5.24 13.88 7.74 14.36 Difference 8.65 6.62 p-value < 0.001 0.007 MSWS-12-score (mean, sem) Baseline 69.27 (2.22) 71.06 (1.34) 67.03 (1.90) 73.81 (1.87) Average change -0.01 (1.46) -2.84 (0.878) 0.87 (1.22) -2.77 (1.20) Difference 2.83 3.65 p-value 0.084 0.021 LEMMT (mean, sem) (Lower Extremity Manual Muscle Test) Baseline 3.92 (0.070) 4.01 (0.042) 4.01 (0.054) 3.95 (0.053) Average change 0.05 (0.024) 0.13 (0.014) 0.05 (0.024) 0.10 (0.024) Difference 0.08 0.05 p-value 0.003 0.106 Ashworth Score (A test for muscle spasticity) Baseline 0.98 (0.078) 0.95 (0.047) 0.79 (0.058) 0.87 (0.057) Average change -0.09 (0.037) -0.18 (0.022) -0.07 (0.033) -0.17 (0.032) Difference 0.10 0.10 p-value 0.021 0.015 BID = twice a day Study 218MS305 Study 218MS305 was conducted in 636 subjects with multiple sclerosis and walking disability. Duration of double-blind treatment was 24 weeks with a 2 week post–treatment follow-up. The primary endpoint was improvement in walking ability, measured as the proportion of patients achieving a mean improvement of ≥ 8 points from baseline MSWS-12 score over 24 weeks. In this study there was a statistically significant treatment difference, with a greater proportion of Fampyra treated patients demonstrating an improvement in walking ability, compared to placebo-controlled patients (relative risk of 1.38 (95% CI: [1.06, 1.70]). Improvements generally appeared within 2 to 4 weeks of initiation of treatment, and disappeared within 2 weeks of treatment cessation. Fampridine treated patients also demonstrated a statistically significant improvement in the Timed Up and Go (TUG) test, a measure of static and dynamic balance and physical mobility. In this secondary endpoint, a greater proportion of fampridine treated patients achieved ≥ 15% mean improvement from baseline TUG speed over a 24 week period, compared to placebo. The difference in the Berg Balance Scale (BBS; a measure of static balance), was not statistically significant. In addition, patients treated with Fampyra demonstrated a statistically significant mean improvement from baseline compared to placebo in the Multiple Sclerosis Impact Scale (MSIS-29) physical score (LSM difference -3.31, p<0.001). Table 3: Study 218MS305 Over 24 weeks Placebo N = 318* Fampyra 10 mg BID N = 315* Difference (95% CI) p - value Proportion of patients with mean improvement of ≥ 8 points from baseline MSWS-12 score 34% 43% Risk difference: 10.4% (3% ; 17.8%) 0.006 MSWS-12 score Baseline Improvement from baseline 65.4 -2.59 63.6 -6.73 LSM: -4.14 (-6.22 ; -2.06) < 0.001 TUG Proportion of patients with mean improvement of ≥ 15% in TUG speed 35% 43% Risk difference: 9.2% (0.9% ; 17.5%) 0.03 TUG Baseline Improvement from baseline (sec) 27.1 -1.94 24.9 -3.3 LSM: -1.36 (-2.85 ; 0.12) 0.07 MSIS-29 physical score Baseline Improvement from baseline 55.3 -4.68 52.4 -8.00 LSM: -3.31 (-5.13 ; -1.50) < 0.001 BBS score Baseline Improvement from baseline 40.2 1.34 40.6 1.75 LSM: 0.41 (-0.13 ; 0.95) 0.141 *Intent to treat population = 633; LSM = Least square mean, BID = twice a day The European Medicines Agency has waived the obligation to submit the results of studies with Fampyra in all subsets of the paediatric population in treatment of multiple sclerosis with walking disability (see section 4.2 for information on paediatric use).