Historical overview of the rationale for the pharmacological use of prolonged-release fampridine in multiple sclerosis

Figures & data

Figure 1. Disability progression in people with multiple sclerosis as defined by the Expanded Disability Status Scale.

A 2.0 score indicates minimal clinical disability and fully ambulatory. A 7.0 score indicates the need for a wheelchair for mobility.

^†After median times of 8, 20 and 30 years following disease onset, most patients with multiple sclerosis will reach EDSS scores of ≥4.0, ≥6.0 and >7.0, respectively [3,4,7].

^‡Almost 50% of patients with multiple sclerosis will reach an EDSS of 6.0 within 25 years of disease evolution and approximately 50% will reach an EDSS score of 7.0 within 30 years [8].

EDSS: Expanded Disability Status Scale.

Figure 2. Chemical structure of 4-aminopyridine.

Figure 3. Time course of current blocked by 4-aminopyridine (fampridine).

Net membrane current (inward current plotted downwards) at the start of a stretch of continuous conduction (as in a demyelinated fiber). Horizontal dashed lines indicate the zero net current. (A) Control; (B) after application of 5 mM 4-aminopyridine; (C) change in net membrane current attributable to 4-aminopyridine derived by subtracting curve B from curve A.

Reproduced with permission from [27].

Figure 4. Incremental increases in walking speed among prolonged-release fampridine- and placebo-treated patients and the association between increased walking speed and self-reported walking ability.

(A) Significantly more patients treated with prolonged-release fampridine experience ≥10 to ≥40% improvements in walking speed on the Timed 25-Foot Walk compared with placebo. (B) Improvements in ≥20% objectively measured walking speed are associated with clinically meaningful improvements in subjectively measured walking ability.

*p < 0.05.

**p < 0.001 versus placebo.

^†Measured using the Timed 25-Foot Walk.

MSWS-12: 12-item MS Walking Scale; PR: Prolonged release.

Data taken from [61,62].

Figure 5. Prolonged-release fampridine Timed-Walk Responder rate by baseline characteristics.

DMT: Disease-modifying therapies; EDSS: Expanded Disability Status Scale; GA: Glatiramer acetate; LEMMT: Lower extremity manual muscle test; PPMS: Primary–progressive multiple sclerosis; PRMS: Progressive–relapsing multiple sclerosis; RRMS: Relapsing–remitting multiple sclerosis; SPMS: Secondary–progressive multiple sclerosis.

Data taken from [69].

Table 1. Existing drug labels of fampridine across the world.

Country	Date of approval	Trade name	Generic name	Dose (mg twice daily)	Indications	Contraindications	Ref.
USA	January 2010	AMPYRA^®; Acorda Therapeutics, Inc.	Dalfampridine extended release	10	Indicated to improve walking in patients with MS, demonstrated by an increase in WS	History of seizure; moderate or severe renal impairment	[104]
Australia and New Zealand	May 2011	FAMPYRA^®; Biogen Idec, Inc.	Modified-release fampridine	10	Indicated for the symptomatic improvement of walking ability in adult patients with MS who have shown improvement after 8 weeks of treatment	History of seizure (patients should be preassessed for seizure risk and excluded if at high risk); moderate or severe renal impairment (creatinine clearance <50 ml/min or eGFR <59 ml/min/1.73 m^2); concurrent treatment with other forms of 4-AP; hypersensitivity to fampridine or any of the excipients	[106]
EU	July 2011	FAMPYRA^®	Prolonged-release fampridine	10	Indicated for the improvement of walking in adult patients with MS with walking disability (EDSS: 4.0–7.0)	History or current presentation of seizure; mild, moderate or severe renal impairment (creatinine clearance <80 ml/min); hypersensitivity to fampridine or any of the excipients; concurrent treatment with other forms of 4-AP; concomitant use of FAMPYRA with medicinal products that are inhibitors of the OCT2 transporter (e.g., cimetidine)	[107]
Canada	February 2012	FAMPYRA™	Sustained-release fampridine	10	Indicated for the symptomatic improvement of walking in adult patients with MS with walking disability (EDSS: 3.5–7)	Hypersensitivity to fampridine or any of the excipients; history of mild, moderate or severe renal impairment (creatinine clearance <80 ml/min); history of seizure or medically assessed as at high risk of seizure; concurrent treatment with other forms of 4-AP; concurrent treatment with inhibitors of renal OCT2 (e.g., cimetidine and quinidine)	[108]

4-AP: 4-aminopyridine; eGFR: Estimated glomerular filtration rate; EDSS: Expanded Disability Status Scale; MS: Multiple sclerosis; OCT2: Organic cation transporter 2; WS: Walking scale.

Table 2. Early clinical trials of immediate-release fampridine (4-aminopyridine) for the treatment of multiple sclerosis.

Study (year)	Study design	Patient characteristics (n, mean age [years], male [%])	Drug formulation, administration route, dosing regimen	Efficacy measure	Study purpose	Principle findings/outcome	Ref.
Jones et al. (1983)	Longitudinal crossover study	Group 1: MS patients with optic neuritis (n = 5, 34 years). Group 2: MS patients with spastic paraparesis (n = 5, 50 years)	Group 1: oral 4-AP sulfate 10 mg followed by 20 mg if the first dose was tolerated. Group 2: oral 4-AP sulfate 60 mg per day for 7 days (reduced to 20 mg if the higher dose was not tolerated)	Group 1: visual acuity change from baseline at 1, 2 and 3 h postdose. Group 2: Disability rating change from baseline at 7 days	To evaluate the efficacy of 4-AP as a potential treatment for MS	Improvement in some visual tests; no change in disability rating	[54]
Stefoski et al. (1987)	Placebo-controlled time-course study	Temperature-sensitive MS patients (n = 12, 100% male), five men without MS and five MS patients received placebo	Intravenous dose titration of 7–35 mg of 4-AP in 1–5-mg doses every 10–60 min	Static quantitative perimetry, motor function, flicker-fusion frequency, visual acuity and videotaped neurological examinations	To assess the efficacy of 4-AP to improve clinical signs of MS	Vision improved in seven patients, oculomotor function in five patients and motor function (power, coordination and gait) in five patients. Improvements developed quickly for improvements in flicker frequency (within minutes of the injection) at doses as low as 2 mg	[73]
Davis et al. (1990)	Follow-up, double-blind, placebo-controlled, dose-ranging study	Temperature-sensitive MS patients (n = 20, 100% male). Randomized to three treatment arms (n = 15 receiving 4-AP)	Single, oral dosing of 10–25 mg of 4-AP or lactose placebo capsules	Static quantitative perimetry, motor function, critical flicker-fusion, visual acuity, visual-evoked potentials and videotaped neurological examinations	To further assess the potential of 4-AP as a practical symptomatic treatment of MS	Motor functions (power, coordination and gait) improved in nine out of 13 patients receiving 4-AP, vision in 11 out of 13 patients and oculomotor functions in one out of two patients at doses as low as 10 mg	[53]
Stefoski et al. (1991)	Double-blind, placebo-controlled study	Temperature-sensitive MS patients (n = 17, median age 41 years, 47% male)	One to three doses of 7.5–52.5 mg of oral 4-AP at 3–4-h intervals over 1–5 days	Static quantitative perimetry, critical flicker-fusion, visual acuity, visual-evoked potentials and videotaped neurological examinations	To assess whether efficacy could be safely prolonged	76.5% of patients treated with 4-AP showed clinically important motor and visual improvements. Responses seen with a dose of 7.5 mg. No serious adverse events occurred	[74]
van Diemen et al. (1992)	24-week crossover trial	MS patients (n = 70), 42 years, 39%	Randomized to 4-AP and placebo for 12 weeks each (maximum dose: 0.5 mg/kg of bodyweight), mean daily dose of 31.2 mg at the end of treatment	Primary efficacy measure: EDSS score	To assess whether treatment with 4-AP is beneficial in MS	16.4% responded with a 1.0 point decrease in EDSS score	[75]
Polman et al. (1994)	Open-label extension study. Follow-up varying from 6 to 32 months	MS patients (n = 31), 48 years, 26%	Daily doses of 4-AP up to 0.5 mg/kg of bodyweight	EDSS score and patient self-reporting	To assess long-term efficacy and safety of 4-AP in patients with MS	>50% of patients who continued treatment for >6 months showed subjective improvement in ambulation. Seizures were experienced by two patients	[45]
Bever et al. (1994)	Double-blind, placebo-controlled crossover study	Temperature-sensitive MS patients with visual and motor detects (n = 8), 46 years, 50%	Oral dosing to achieve 4-AP target concentration ranges: low: 30–59 ng/ml and high: 60–100 ng/ml	Contrast sensitivity, standard neurologic examination, videotaped neurologic examinations, quantitative strength assessment, flicker-fusion frequency, visual-evoked response latencies and EDSS scores	To compare the safety and efficacy of two target peak serum concentration ranges	Standard neurologic examination, ratings of videotaped neurologic examinations and quantitative strength (hamstring and quadriceps) assessment all improved versus placebo. However, flicker-fusion frequency, visual-evoked response latencies and EDSS scores did not improve with treatment. Seizure and acute confusional episodes were seen in the high-dose group	[41]

4-AP: 4-aminopyridine; EDSS: Expanded Disability Status Scale; MS: Multiple sclerosis.

Table 3. Demographics and baseline characteristics in two Phase III trials (MS-F203 and MS-F204).

Parameter	MS-F203 [56]		MS-F204 [50]
	Placebo (n = 72)	PR-fampridine (n = 229^†)	Placebo (n = 119)	PR-fampridine (n = 120)
Mean age in years ± SD	50.9 ± 8.9	51.5 ± 8.7	51.7 ± 9.8	51.8 ± 9.6
MS disease course, no. (%) – Relapsing–remitting – Primary–progressive – Secondary–progressive – Progressive–relapsing	21 (29) 14 (19) 35 (49) 2 (3)	62 (27) 31 (14) 125 (55) 10 (4)	40 (34) 21 (18) 56 (47) 2 (2)	43 (36) 10 (8) 62 (52) 5 (4)
Disease duration (years) ± SD	12.7 ± 8.2	13.4 ± 8.3	13.1 ± 8.7	14.4 ± 9.5
Mean EDSS score ± SD	5.8 ± 1.1	5.8 ± 1.0	5.6 ± 1.2	5.8 ± 1.0
Mean baseline T25FW, (ft/s) ± SD	2.1 ± 0.7	2.1 ± 0.7	2.2 ± 0.7	2.1 ± 0.8
Mean baseline LEMMT score ± SD	4.0 ± 0.7	4.1 ± 0.6	4.0 ± 0.6	3.9 ± 0.6
Mean baseline MSWS-12 score ± SD	68.5 ± 22.3	70.7 ± 18.6	67.7 ± 22.6	73.8 ± 17.8
Mean baseline Ashworth score ± SD	1.0 ± 0.7	1.0 ± 0.7	0.8 ± 0.7	0.9 ± 0.6

^†One subject randomized to this group did not receive intervention.

EDSS: Expanded Disability Status Scale; ft/s: Feet per second; LEMMT: Lower extremity manual muscle test; MS: Multiple sclerosis; MSWS-12: 12-item multiple sclerosis walking scale; PR: Prolonged release; SD: Standard deviation; T25FW: Timed 25-Foot Walk.

Table 4. The efficacy of prolonged-release fampridine as assessed in two Phase III trials (MS-F203 and MS-F204).

Parameter	MS-F203 [56]	MS-F204 [50]
Population size, n	301	239
ITT population (efficacy analysis), n (placebo:fampridine)	296 (72:224)	237 (118:119)
PR-fampridine TWRs, %	34.8	42.9
Placebo TWRs, %	8.3	9.3
T25FW average change from baseline
PR-fampridine TWRs, % (95% CI)	25.2 (21.5–28.8)	24.7 (21.0–28.4)
Placebo, % (95% CI)	4.7 (1.0–8.4)	7.7 (4.4–11.0)
PR-fampridine TWnRs, % (95% CI)	7.5 (5.0–10.0)	6.0 (2.2–9.7)
MSWS-12 average change from baseline^†
TWRs (95% CI)	-6.84 (-9.65 to -4.02) (p = 0.002)^‡	-6.04 (-9.57 to -2.52) (p = 0.001)^‡
TWnRs (95% CI)	0.05 (-1.48–1.57)	0.85 (-0.72–2.43)
LEMMT average change from baseline
PR-fampridine TWRs	0.18 (p = 0.002)^§	0.15 (p = 0.028)^§
Placebo	0.04	0.04
PR-fampridine TWnRs	0.11 (p = 0.046)^§	0.05

^†Negative change in MSWS-12 score indicates improvement.

^‡Change from baseline compared with TWnRs, independent of treatment assignment.

^§Compared with placebo.

ITT: Intention to treat; LEMMT: Lower extremity manual muscle test; MSWS-12: 12-item multiple sclerosis walking scale; PR: Prolonged release; T25FW: Timed 25-Foot Walk; TWnR: Timed-Walk non-Responder; TWR: Timed-Walk Responder.

Table 5. Adverse events summary from the MS-F203 and MS-F204 trials, and combined analyses of the most common adverse events observed in the clinical trials of prolonged-release fampridine 10 mg twice daily.

AE	MS-F203 [56]		MS-F204 [50]
	Placebo (n = 72)	PR-fampridine (n = 228)	Placebo (n = 119)	PR-fampridine (n = 120)
Any AE, n (%)	58 (81)		79 (66)	103 (86)
Mild AEs, n (%)	16 (22)	59 (26)	36 (30)	39 (33)
Moderate AEs, n (%)	35 (49)	98 (43)	36 (30)	53 (44)
Severe AEs, n (%)	7 (10)	34 (15)	7 (6)	11 (9)
Serious AEs, n (%)	0 (0)	16 (7)	3 (3)	5 (4)
Possibly or probably treatment-related AEs, n (%)	19 (26)	62 (27)	15 (13)	25 (21)
Most frequent AEs^†, n (%)
Fall	11 (15)	36 (16)	20 (17)	14 (12)
Urinary tract infection	10 (14)	31 (14)	10 (8)	21 (18)
Insomnia	3 (4)	19 (8)	2 (2)	12 (10)
Dizziness	4 (6)	19 (8)	1 (1)	10 (8)
Headache	4 (6)	13 (6)	1 (1)	11 (9)
Nausea	3 (4)	14 (6)	1 (1)	10 (8)
Asthenia	4 (6)	13 (6)	5 (4)	10 (8)
Back pain	0 (0)	13 (6)	3 (3)	7 (6)
Balance disorder	2 (3)	13 (6)	2 (2)	7 (6)
Paresthesia	(<5)	(<5)	2 (2)	6 (5)
Nasopharyngitis	(<5)	(<5)	5 (4)	6 (5)
Arthralgia	(<5)	(<5)	5 (4)	6 (5)
Fatigue	2 (3)	14 (6)	(<5)	(<5)
Upper respiratory tract infection	7 (10)	14 (6)	8 (7)	7 (6)
Combined analyses throughout clinical development^‡
Most frequent AEs^§ (%)	Placebo (n = 238)		PR-fampridine (n = 400)
Urinary tract infection	8		12
Insomnia	4		9
Dizziness	4		7
Headache	4		7
Nausea	3		7
Asthenia	4		7
Back pain	2		5
Balance disorder	1		5
MS relapse	3		4
Paresthesia	3		4
Nasopharyngitis	2		4
Constipation	2		3
Dyspepsia	1		2
Pharyngolaryngeal pain	1		2

In the MS-F203 trial, values for AEs occurring in <5% of placebo and PR-fampridine patients and therefore not included in the previous publication [56] were: paresthesia 4 (6%), 10 (4%); nasopharyngitis 1 (1), 9 (4%); and arthralgia 5 (7%), 3 (1%), respectively. In the MS-F204 trial, values for AEs occurring in <5% of placebo and PR-fampridine patients and therefore not included in the previous publication [56] were: fatigue 4 (3%), 4 (3%), respectively.

^†Occurring in >5% of PR-fampridine-treated patients; ^‡Combined analyses of pooled data from MS-F202/203/204; ^§Occurring in >2% of PR-fampridine-treated patients and more frequently compared with placebo.

AE: Adverse event; MS: Multiple sclerosis; PR: Prolonged release.

Motl RW, McAuley E. Association between change in physical activity and short-term disability progression in multiple sclerosis. J. Rehabil. Med. 43(4), 305–310 (2011).

 PubMed Web of Science ®Google Scholar

Bostock H, Sears TA, Sherratt RM. The effects of 4-aminopyridine and tetraethylammonium ions on normal and demyelinated mammalian nerve fibres. J. Physiol. (Lond.) 313, 301–315 (1981).

 Google Scholar

Stourac P, Putzki N. Prolonged-release fampridine shows consistent efficacy across subgroups of multiple sclerosis patients. Presented at: The 22nd meeting of the European Neurological Society. Prague, Czech Republic, 9–12 June 2012.

 Google Scholar

Acorda Therapeutics, Inc. AMPYRA® [dalfampridine] extended release tablets prescribing information, 2010. http://ampyra.com/home (Accessed 21 June 2012)

 Google Scholar

Australian Government, Department of Health and Ageing, Therapeutic Goods Administration. Australian Public Assessment Report for fampridine, 2012. www.tga.gov.au/auspar/auspar-fampridine-110615.htm (Accessed 17 October 2012)

 Google Scholar

European Medical Agency. EPAR. Summary of opinion (initial authorisation) for FAMPYRA (fampridine), 2011. www.ema.europa.eu/ema/index.jsp?curl=pages/medicines/human/medicines/002097/human_med_001432.jsp&mid=WC0b01ac058001d124 (Accessed 30 November 2011)

 Google Scholar

Health Canada. Drugs and healthcare products, 2012. www.hc-sc.gc.ca/dhp-mps/prodpharma/sbd-smd/drug-med/sbd_smd_2012_fampyra_132859-eng.php (Accessed 17 October 2012)

 Google Scholar

Jones RE, Heron JR, Foster DH, Snelgar RS, Mason RJ. Effects of 4-aminopyridine in patients with multiple sclerosis. J. Neurol. Sci. 60(3), 353–362 (1983).

 PubMed Web of Science ®Google Scholar

Stefoski D, Davis FA, Faut M, Schauf CL. 4-aminopyridine improves clinical signs in multiple sclerosis. Ann. Neurol. 21(1), 71–77 (1987).

 PubMed Web of Science ®Google Scholar

Davis FA, Stefoski D, Rush J. Orally administered 4-aminopyridine improves clinical signs in multiple sclerosis. Ann. Neurol. 27(2), 186–192 (1990).

 PubMed Web of Science ®Google Scholar

Stefoski D, Davis FA, Fitzsimmons WE, Luskin SS, Rush J, Parkhurst GW. 4-aminopyridine in multiple sclerosis: prolonged administration. Neurology 41(9), 1344–1348 (1991).

 PubMed Web of Science ®Google Scholar

van Diemen HA, Polman CH, van Dongen TM et al. The effect of 4-aminopyridine on clinical signs in multiple sclerosis: a randomized, placebo-controlled, double-blind, cross-over study. Ann. Neurol. 32(2), 123–130 (1992).

 Google Scholar

Polman CH, Bertelsmann FW, van Loenen AC, Koetsier JC. 4-aminopyridine in the treatment of patients with multiple sclerosis. Long-term efficacy and safety. Arch. Neurol. 51(3), 292–296 (1994).

 PubMed Web of Science ®Google Scholar

Bever CT Jr, Young D, Anderson PA et al. The effects of 4-aminopyridine in multiple sclerosis patients: results of a randomized, placebo-controlled, double-blind, concentration-controlled, crossover trial. Neurology 44(6), 1054–1059 (1994).

 PubMed Web of Science ®Google Scholar

Goodman AD, Brown TR, Krupp LB et al.; Fampridine MS-F203 Investigators. Sustained-release oral fampridine in multiple sclerosis: a randomised, double-blind, controlled trial. Lancet 373(9665), 732–738 (2009).

 PubMed Web of Science ®Google Scholar

Goodman AD, Brown TR, Edwards KR et al.; MSF204 Investigators. A Phase 3 trial of extended release oral dalfampridine in multiple sclerosis. Ann. Neurol. 68(4), 494–502 (2010).

 PubMed Web of Science ®Google Scholar