Drug Evaluation

Pharmacology and clinical efficacy of dalfampridine for treating multiple sclerosis 1. 2.

Introduction/overview of the market

Alessandra Lugaresi

Introduction to the

University “ G. d’ Annunzio” of Chieti-Pescara, Department of Neuroscience, Imaging and Clinical Sciences, Chieti, Italy

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compound 3.

Chemistry

4.

Pharmacokinetics

5.

Pharmacodynamics

6.

Clinical efficacy

7.

Safety and tolerability

8.

Regulatory affairs

9.

Conclusion

10.

Expert opinion

Introduction: Multiple sclerosis (MS) is the most frequent cause of neurological impairment and sustained disability in young adults. Currently approved disease-modifying drugs do not directly ameliorate the most common symptoms, such as walking impairment. Dalfampridine (DAL), currently approved in all forms of MS, might represent an answer to unmet needs in the symptomatic treatment of MS. Areas covered: The main pharmacological and clinical properties and safety issues of DAL, an extended-release formulation of 4-aminopyridine (4-AP), a broad-spectrum voltage-dependent potassium channel blocker, are described. Relevant publications were identified from a search of PubMed from 1966 to June 2014 (search terms ‘dalfampridine OR fampridine OR 4-aminopyridine). DAL, 10 mg twice daily, improves walking ability in approximately one-third and walking speed in about 25% of patients, independently from disease course, compared with placebo; it also improves leg strength. Treatment is generally well tolerated, although there is a dose-dependent increased risk of seizures, especially with dosages > 10 mg twice daily. Expert opinion: DAL represents an option in the symptomatic treatment of MS. Improved ambulation can impact quality of life, motivation and adherence, enhancing the successful management of MS. It has still to be established whether this favorably impacts costs associated with MS. Keywords: dalfampridine, extended-release, multiple sclerosis, risk, safety, walking impairment, walking speed Expert Opin. Drug Metab. Toxicol. (2015) 11(2):295-306

1.

Introduction/overview of the market

Multiple sclerosis (MS) is estimated to affect > 2.3 million people worldwide and is the most common disease of the CNS in young adults. Inflammatory demyelination and axonal damage characterize the disease since the earlier phases [1]. MS often causes neurological impairment and sustained disability including visual, motor and sensory disturbances, ataxia and walking impairment, fatigue, bowel and bladder dysfunction and cognitive impairment [2-6]. Gait disturbances affect approximately 75% of people with MS and are considered among the most disabling symptoms [7,8]. MS is characterized by demyelination within the CNS causing a delay or blockage of action potential conduction. Although the etiopathogenesis of MS has not yet been fully clarified, it is generally thought that an immune-mediated response to one or more myelin antigens causes axonal injury leading to MS clinical manifestations [1,4-7]. The goals of therapy in MS are reducing relapse frequency, delaying disability progression and cognitive dysfunction [1]. Currently approved drugs act on the immune system, but do not directly target the damaged nervous system and do not necessarily ameliorate many of the most common symptoms, such as walking impairment [2,4-7]. 10.1517/17425255.2015.993315 © 2015 Informa UK, Ltd. ISSN 1742-5255, e-ISSN 1744-7607 All rights reserved: reproduction in whole or in part not permitted

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A. Lugaresi

Box 1. Drug summary.

4.

Drug name (generic) Phase Indication

4.1

Mechanism of action Route of administration Chemical structure

Dalfampridine Launched Improvement in walking ability (as demonstrated by an increase in walking speed) in patients with multiple sclerosis Potassium channel antagonist Oral C5H6N2

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NH2

N

Pivotal trial(s)

2.

2 Phase II trials [18,19] and 2 Phase III trials [20,21]

Chemistry

The chemical structure of DAL, a small lipid-soluble, broadspectrum potassium channel-blocking agent belonging to the family of monoamino and diamino pyridine derivatives, is depicted in Box 1. 296

Absorption After oral administration, DAL is rapidly and completely absorbed through the gastrointestinal tract: compared with the aqueous oral solution, the relative bioavailability is 96%. The gastrointestinal absorption and bioavailability of DAL are not affected by food intake [1]. In 24 MS patients treated with DAL, at doses ranging between 5 and 20 mg, the mean maximum 4-AP plasma concentration (Cmax) and area under the plasma concentrationtime curve (AUC) were proportional to dosage. After 5, 10, 15 and 20 mg doses of DAL, separated by 4-day washout periods, mean Cmax values were 13.1, 25.2, 37.0 and 49.2 ng/ml, and mean AUC values were 122.1, 252.2, 394.4 and 511.3 ng . h/ml, respectively. Following single 5, 10, 15 and 20 mg doses of DAL, the mean apparent elimination half-life was 5.76, 5.55, 5.50 and 5.05 h, respectively [10]. Distribution DAL has a lipophilic structure and readily crosses the blood-brain barrier. Its plasma protein binding is low (range 1 -- 3%) and the apparent volume of distribution is 2.6 l/kg: this corresponds to a wide distribution in body tissues, including the CNS [1,2]. 4.2

Introduction to the compound

Dalfampridine (DAL) is the extended-release (ER) formulation of 4-aminopyridine (4-AP) (Box 1), also known outside the USA and before 2010 as fampridine. DAL, a broadspectrum voltage-dependent potassium channel blocker, has been shown to improve walking speed in approximately one-third of MS patients in pivotal studies and is the first drug specifically approved to ameliorate walking ability [1,2,4]. As 4-AP has a narrow therapeutic window, being associated with an increased risk of epileptic seizures at high peak concentrations, an ER formulation has been developed to obtain lower peak plasma concentrations [1]. The effects of DAL can complement those of diseasemodifying treatments (DMTs) by addressing walking, a primary concern among many patients. DAL can be safely associated with first-line DMTs and does not preclude their use in MS [9]. Clinically significant interactions with fingolimod (based on CYP system metabolism pathway) have not yet been reported. Here, the main pharmacological and clinical properties and the safety issues of DAL will be reviewed. Publications were identified from a search of PubMed from 1966 to June 2014, using the search terms ‘dalfampridine OR fampridine OR 4-aminopyridine’ AND ‘pharmacokinetics’ OR ‘pharmacodynamics’ OR ‘multiple sclerosis’. Furthermore, recent relevant publications and contributions to meetings held in 2014 have also been reported and commented on. 3.

Pharmacokinetics

Metabolism In vitro studies in human liver microsomes showed that DAL is minimally metabolized by the hepatic CYP-2E1 through 3-hydroxylation in two inactive metabolites: 3-hydroxy4-AP and 3-hydroxy-4-AP sulfate [1]. DAL does not affect the in vitro activities of human hepatic isoenzymes of CYP, and is unlikely to induce human hepatocytes at therapeutic concentrations or to alter the pharmacokinetics of other drugs metabolized by these enzymes. DAL is not a substrate for or an inhibitor of the p-glycoprotein transporter in vitro and is unlikely to pharmacokinetically interact with other drugs that are substrates for or inhibitors of this transporter [1]. 4.3

Elimination DAL is almost completely eliminated as unchanged drug via the kidneys (95.9% of a DAL dose recovered in the urine within 24 h). Creatinine clearance (CrCl) and DAL levels are significantly correlated with an increase in drug exposure in subjects with renal impairment. A study in 20 subjects with renal dysfunction, treated with a single 10 mg dose of DAL, showed that the geometric mean Cmax was 68 -- 101% higher and CrCl was 43 -- 73% lower in those with renal impairment than in healthy volunteers [11]. Recently, these data were confirmed by Samara et al., who evaluated both single-dose and steady-state pharmacokinetics in healthy controls (HC, n = 13) and subjects with mild (n = 17) and moderate (n = 12) renal impairment. Plasma concentrations, after a 7.5 mg dose were consistently higher in subjects with renal 4.4

Expert Opin. Drug Metab. Toxicol. (2015) 11(2)

Dalfampridine

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Table 1. Pharmacokinetic properties of dalfampridine extended-release. Dosage and administration Mean maximum plasma concentration (Cmax)* Mean time to Cmax* Bioavailability Effect of food on bioavailability Mean AUC* Mean apparent elimination T½* Plasma protein binding Apparent volume of distribution Distribution in CNS Hepatic metabolism Renal excretion Renal impairment

Hepatic impairment

10 mg per os b.i.d. 25.2 mg/ml 3.92 h 96% No 252.2 ng . h/ml 5.55 h 1 -- 3% 2.6 l/kg Yes Low (3-hydroxylation) 95.9% Caution; contraindicated in moderate-to-severe renal impairment No dose adjustment

Modified from [1]. *Pharmacokinetics of a single dose of dalfampridine ER 10 mg in healthy volunteers. b.i.d.: Twice daily; ER: Extended-release.

impairment compared with HC, with a highly significant (p < 0.0001) inverse linear correlation between CrCl and drug exposure. Steady-state AUC0 -- 12 was 74 and 151% higher with mild and moderate renal impairment, respectively [12]. Therefore in patients with moderate or severe renal impairment (CrCl £ 50 ml/min), DAL is contraindicated [1]. DAL should be used with caution in elderly patients who may have impaired renal function and is also contraindicated during pregnancy (category C in the USA) and lactation. Hepatic impairment is not expected to alter the pharmacokinetics of DAL [1]. Table 1 summarizes pharmacokinetic properties of DAL. The more favorable pharmacokinetic profile of DAL is consistent with twice a day (b.i.d.) dosing, which provides an additional advantage over the four-times daily dosing required to avoid fluctuations with immediate-release formulations; less frequent dosing could result in greater patient adherence and improved outcomes, although it would not reduce costs compared with immediate-release formulations [13]. 5.

DAL has the greatest affinity for slowly inactivating potassium channels and occludes the pore from the cytoplasmic side. As a consequence, it reduces potassium current, increases action-potential duration so that a larger amount of calcium enters in presynaptic nerve terminals and increases transmitter release, delays repolarization and improves conduction in non-myelinated fibers [2,3,15]. Figure 1 shows the proposed mechanism for the therapeutic action of DAL, which may occur through the blockade of potassium channels that become exposed during demyelination. In demyelinated axons, potassium channels have been shown to redistribute along the axon in a manner similar to sodium channels: this could explain the increased sensitivity of these axons to the drug [7,16]. In addition to the direct axonal potassium-channel blockade, other mechanisms have been hypothesized to explain the activity of DAL in MS: remyelination (through oligodendrocyte precursor cell progression and proliferation) and enhanced pre-synaptic transmission. Remyelination of damaged axons is possible to a certain degree in MS and depends on proliferation of oligodendrocytes, derived from oligodendrocyte precursor cells. Some potassium channel subtypes play a role in oligodendrocyte precursor cells cell-cycle progression and proliferation: the blockade of these channels could hypothetically facilitate remyelination and restore neural conduction [2,15,17]. DAL can also enhance presynaptic transmission, with an increased neurotransmitter release, directly stimulating the high-voltage activated calcium channels, thereby increasing the end-terminal influx of calcium and the cytoplasmic free calcium [1,2,15]. Potassium channels are distributed across multiple cell lines both in the CNS (microglia, neurons and oligodendrocytes) and in the immune system (T and B cells, macrophages and dendritic cells) [15]. It is well known that the number of potassium channels is upregulated when these cells are activated, having a main role in activation and proliferation [2,15]. It can be hypothesized, but it has not been demonstrated that block of potassium channels by DAL in these cells might exert a therapeutic action in inflammatory demyelinating diseases, reducing the activity of these cells and dampening the inflammatory response (immunomodulatory effect) [2,15].

Pharmacodynamics 6.

In mammalian myelinated axons, voltage-dependent sodium channels prevail at the nodes of Ranvier, and potassium channels at the internode [7]. Demyelination of central axons leads to exposure of the paranodal and juxtaparanodal regions, rich in potassium channels and significantly contributes to hamper action potential propagation. Larger transmembrane voltage changes and increased potassium currents from the axon cause action potential conduction delay or block [3,14]. In addition, the exposure of slow potassium channels interferes with hyperpolarization, thus impairing axonal generation of repetitive impulses [2].

Clinical efficacy

Several key studies demonstrated the efficacy of DAL in restoring walking ability in MS patients. Phase II studies The first multicenter, randomized, double-blind, placebocontrolled Phase II study was conducted to determine the safety of sustained-release 4-AP in subjects with MS and to examine dose-related efficacy from 10 mg up to 40 mg b.i.d. Thirty-six patients with clinically definite MS (screening Expanded Disability Status Scale [EDSS] score < 6.5 and a 6.1

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A. Lugaresi

Fatigue Severity Score > 4.0) were observed during a 4-week baseline period and then randomly allocated to receive DAL (n = 25, doses ranging from 10 to 40 mg b.i.d., increasing in 5 mg increments weekly) or placebo (n = 11) for 8 weeks. The primary objective of the study was the safety of DAL assessed on reports of adverse events, brief physical examination, vital signs, standardized routine laboratory tests and electrocardiogram (ECG) measurements. The efficacy was mainly evaluated with the MS Functional Composite (MSFC), which includes a component of timed ambulation, and the Lower Extremity Manual Muscle Testing (LEMMT), measuring muscle strength, performed bilaterally, with the subject supine. Several other functional assessments were also performed [18]. The results showed an improvement in walking speed (post hoc analysis) and in lower extremity muscle strength (prospective analysis) in the DAL group compared with placebo. In the prospectively planned analysis, the change in the time required for the 25-Foot Walk across the study weeks from baseline did not achieve significance on the repeated measures analysis (p = 0.28). However, a post hoc analysis, evaluating the walking speed, in feet per second (ft/s), to normalize the variance, showed that the change from baseline in walking speed across the study weeks was significantly better in the group treated with DAL (p = 0.03). The effect on walking speed appeared to increase slightly with dose, and plateau above 20 -- 25 mg twice daily. The change from baseline in LEMMT across the study weeks showed significantly greater improvement in the DAL group compared with placebo (p = 0.01) with little evidence of additional dose-response at higher levels for leg strength. There were no significant differences in other MSFC measures or fatigue scores [18]. Another multicenter, randomized, double-blind, placebocontrolled, parallel-group Phase II study evaluated the efficacy and safety of three different doses of DAL (10, 15 or 20 mg b. i.d.) in 206 patients (aged 18 -- 70 years) with MS (according McDonald’s criteria) recruited at 24 centers in the USA and Canada. Participants were randomly assigned to four study treatment groups: DAL (10, 15 or 20 mg b.i.d.) or placebo, under double-blind conditions. The prospective primary efficacy variable was change in walking speed during treatment relative to baseline using the Timed 25-Foot Walk test (T25FW). Prospective secondary efficacy outcome measures were LEMMT test and other parameters. Safety was assessed by monitoring: adverse events, vital signs, clinical laboratory test results, ECG readings and physical examination [19]. According to the prospective analysis, a trend for increased walking speed was observed in all the groups treated with DAL versus placebo (10 mg b.i.d., 23.5%; 15 mg b.i.d., 26.0%; 20 mg b.i.d., 15.8%; placebo, 12.8%), although the difference was not statistically significant. There were improvements compared with placebo in mean LEMMT score during the stable-dose period for the groups receiving DAL 10 mg (p = 0.018) and 15 mg (p = 0.003), but not for the group treated with 20 mg b.i.d. There were no significant changes in other secondary assessments. A novel responder 298

analysis of the walking speed results was conducted retrospectively to assess consistency of walking-speed improvement, rather than percentage change in walking speed. This post hoc analysis demonstrated that the response rates in the DAL 10-, 15- and 20-mg twice-daily dose groups were 35.3, 36.0 and 38.6%, respectively, and 36.7% for the pooled DAL-dose groups, all individually and collectively greater than the 8.5% response rate in the placebo group (p < 0.001 for pooled vs placebo). Besides, among DALtreated timed-walk responders, the mean improvement in walking speed was consistently 25 -- 29% across the doubleblind treatment period, significantly greater than in the placebo group (2 -- 4%) at every visit, both for each DAL-dose group and for the pooled-dose groups [19]. Phase III studies According to the safety and efficacy results of these Phase II studies and the favorable risk-to-benefit profile, the 10 mg b. i.d. dosage of DAL was selected for the following Phase III studies. The randomized, multicentre, double-blind, controlled Phase III study by Goodman et al. assessed efficacy and safety of oral DAL in patients (aged 18 -- 70 years) with clinically definite MS, and able to complete two trials of the T25FW in an average time of 8 -- 45 s at screening. Three hundred and one patients with any type of MS were randomly assigned to 14 weeks of treatment with either DAL (10 mg b.i.d.; n = 229) or placebo (n = 72). The primary end point was the percentage of timed-walk responders (defined as patients who had a faster walking speed for at least three out of four visits during the double-blind treatment period than the maximum speed for any of the first five off-treatment visits) in each treatment group. Secondary end points included: LEMMT scores; the 12-item MS Walking Scale (MSWS-12, a patient-reported outcome used to evaluate the clinical significance of the timed-walk response criterion); the Ashworth score for spasticity; a subject global impression (SGI) and a clinician global impression (CGI) [20]. Efficacy analyses were based on a modified intention-totreat population (n = 296), which included all patients with any post-treatment efficacy data. Treatment groups were comparable for baseline demographics, disease characteristics and efficacy variables. The proportion of timed-walk responders was higher in the DAL group (78/224, 35%) than in the placebo group (6/72, 8%; odds ratio [OR]: 4.75; 95% CI: 2.08 -- 10.86; p < 0.0001). The average change from baseline in walking speed among the DAL-treated timed-walk responders was 25.2% (or 0.5 ft/s) compared with 4.7% (or 0.1 ft/s) in the placebo group. The increase in walking speed among the fampridine-treated timed-walk responders was maintained throughout the double-blind treatment period. Increase in walking speed among the non-responder population was small but significant versus placebo at visit 3, but no differences were noted at subsequent visits (Figure 2). Average changes from baseline in MSWS-12 score during the treatment period were -6.84 for timed during the treatment 6.2

Expert Opin. Drug Metab. Toxicol. (2015) 11(2)

Dalfampridine

A. K+

K+

B.

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K+

K+

Figure 1. Putative mechanism of action of dalfampridine. (A) Effect of demyelinization on exposure of potassium channels. (B) Blocking of potassium channels by dalfampridine. Reprinted [7],  2011 with permission from Informa Healthcare.

period were -6.84 for -walk responders and 0.05 for non-responders, independent of treatment assignment (p = 0.0002), indicating a reduced self-assessed ambulation-related disability in timed-walk responders; scores were consistently lower for all 12 items of the scale among timed-walk responders compared with non-responders. Timed-walk responders also had better mean SGI scores than non-responders (4.88 vs 4.43, respectively; p = 0.001), and better mean CGI scores (3.28 vs 3.74, respectively; p < 0.0001). Finally, the average improvement in the LEMMT scores among DAL-treated timed-walk responders was 0.18 compared with 0.04 for the placebo group (p = 0.0002). This study demonstrated that DAL improves walking ability in a proportion of subjects with MS. This improvement is associated with a reduction of patients’ reported ambulatory disability and provides a clinically meaningful therapeutic benefit [20]. The same authors performed another randomized doubleblind placebo-controlled study in patients with definite MS of any course type with the objective to confirm the efficacy results and to determine whether the improvement in walking is maintained between doses. Two hundred and thirty-nine patients aged 18 -- 70 years, enrolled in 39 centres in the USA and Canada, had clinically definite MS and a T25FW time between 8 and 45 s. Patients were randomized to double-blind treatment with placebo (n = 119) or DAL 10 mg (n = 120) b.i.d. for 9 weeks. The primary efficacy end point was based on walking speed, measured by the T25FW, performed according to the instructions for the MSFC. The only prospectively defined secondary outcome measure was the LEMMT test; additional efficacy parameters (Ashworth score for spasticity, MSWS-12, SGI and CGI) were evaluated to allow comparison with the results of previous studies [21]. The number of patients who met the primary efficacy end point was 51 out of 119 (42.9%) in the group treated with DAL and 11 out of 118 (9.3%) in the placebo-treated group

(p < 0.0001; OR: 8.14; 95% CI: 3.73 -- 17.74). The average improvement from baseline in walking speed during the efficacy analysis period was 24.7% (or 0.51 ft/s) in DAL-treated responders group compared with 7.7% (or 0.17 ft/s) in the placebo group and 6% in DAL-treated non-responders group. The increase in walking speed among DAL-treated responders was maintained across the double-blind treatment and was reversed with treatment discontinuation. The improvement from baseline walking speed among DAL-treated responders at visit 7 (week 9) was 25.7% [21]. The average improvement in the LEMMT score for the DAL-treated responders during the double-blind period was 0.145 U compared with 0.042 U for the placebo group (p = 0.028). The mean improvement of 0.048 U for DALtreated non-responders was not significantly different from either the DAL-treated responders or the placebo group [21]. With regard to the additional efficacy parameters, timedwalked responders (independently of treatment assignment) had a better outcome compared with non-responders in average changes from baseline in MSWS-12 score (indicating a reduction in self-assessed ambulatory disability and an improvement across a wide range of daily life activities related to walking), in SGI score and in CGI score [21]. These two studies according to the authors suggest that DAL might represent a novel and potentially useful treatment for MS, as a modulator of neural function that may be complementary to approved immunomodulatory therapies. Extension studies and pooled data analysis Pooled results of the three trials (one Phase II and two Phase III) were consistent with those of the individual studies in demonstrating the efficacy of DAL 10 mg b.i.d. for the improvement in walking ability in patients with MS. The overall improvement from baseline in walking speed (13.4 vs 5.8%) and timed-walk responder rates (37.3 vs 8.9%) was significantly (p < 0.001) higher in DAL 10 mg b.i.d. recipients (n = 394) than in placebo recipients (n = 237) [22,23]. Limone et al., using data from the Phase III study by Goodman et al. [20] evaluated the effect of DAL on health utility in patients with MS by mapping subjects’ individual item scores from the MSWS-12 onto the Euroqol 5-Dimension health utility index, using mapping equations (one from a North American registry, the other from a UK registry). The results confirmed that DAL response was associated with an improvement in health utility, regardless of the equation used [24]. Long-term open-label extension studies of the two Phase III pivotal trials were implemented in order to evaluate the longterm safety, tolerability and efficacy of DAL. One hundred and ninety-seven patients (70 DAL responders and 127 non-responders) of the first study [20] and 109 patients (49 DAL responders and 60 non-responders) of the second study [21] entered the extension phases and received open-label DAL 10 mg b.i.d. As expected, improvements in walking speed achieved during the double-blind period of both parent 6.3

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Change from baseline (mean ± 95% CI) (%)

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35 30

*

*

Visit 5

Visit 6

*

*

25 20 15 ‡

10 5 0 -5 -10

Visit 3

Visit 4

14-week treatment period

Visit 7

Visit 8

4-week followup

Placebo (n = 72) Dalfampridine timed-walk nonresponders (n = 146) Dalfampridine timed-walk responders (n = 146)

Figure 2. Percentage change in walking speed as measured by the Timed 25-Foot Walk at each visit after randomization. Reprinted from [20],  2009 with permission from Elsevier. *p < 0.001 versus placebo and fampridine-treated timed-walk non-responders. z p < 0.001 versus placebo only.

studies were lost after DAL discontinuation: however, re-start of DAL in the extension phases resulted in prompt improvements in walking speeds, similar to that observed at the end of the double-blind treatment period; this recovery was maintained among responders compared with non-responders in the majority of protocol-defined assessment visits. Data from both long-term extension studies indicate that the subset of responders was able to maintain long-term improvements in walking speed compared with the non-responder group [25,26]. Post-marketing studies and surveillance Post-marketing studies are usually helpful in identifying an unselected population rare adverse events and the real effectiveness of a drug. However, many post-marketing studies are on a limited number of subjects and unblinded, therefore, we have to be cautious in interpreting the results, which might suffer from placebo effect and practice effect besides true effects of DAL. A recent open-label explorative trial by Jensen et al. evaluated the effect of DAL on multiple outcome measures reflecting different domains (walking ability, lower limb physical ability, upper limb function and cognition) and compared the responsiveness of T25FW and the Six Spot Step Test (SSST), an easily administered walking measure that was 6.4

300

designed to assess elements of walking other than speed, such as coordination and balance, having a lower floor effect and better discrimination than the T25FW, after 4 weeks of treatment. Other tests administered to the patients at baseline and after 4 weeks were the 9-hole peg test (9-HPT), the 5 times sit-to-stand test (5-STS) and the symbol digit modalities test (SDMT) [27]. One hundred and eight patients (48.6 ± 7.1 years, 58.3% women, mean EDSS 5.6 ± 0.9, mean disease duration 10.8 ± 7.2 years) with MS (McDonald’s criteria, EDSS 4 -- 7, with a pyramidal functional subscore of ‡ 2) were included in the study and treated with DAL 10 mg b.i.d. for 4 weeks. The results showed an improvement of all the tests performed following treatment with DAL, although a practice effect can’t be excluded. Mean changes on the T25FW, the SSST, the 5-STS, the 9-HPT and the SDMT were 1.2 ± 3.7 s (11.2 ± 17.1%, p < 0.001), - 3.4 ± 6.4 s (17.0 ± 19.6%, p < 0.001), - 3.4 ± 7.2 s (16.6 ± 20.7%, p < 0.001), - 1.2 ± 6.0 s (5.1 ± 10.3%, p < 0.001), 1.4 ± 4.8 a.u. (4.6 ± 15.4%, p = 0.003), respectively (Figure 3). Change on the SSST differed significantly from T25FW (SSST 17.0 vs T25FW 11.2, p = 0.0013). No significant correlation between the response to DAL on the SSST, the T25FW, the 9-HPT, the SDMT or the 5-STS and age, sex, EDSS score or disease duration was observed [27].

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Dalfampridine

The study has the limitation to be uncontrolled and unblinded. These data, however, indicate that DAL might have a broader effect on MS-related impairment than merely walking speed and muscle strength of the lower limbs, because it seems to improve balance, coordination and cognition [27]. This is in line with experiences with 4-AP. The multicentre open-label single-arm Phase IV real practice ENABLE study evaluated the effect of long-term treatment with DAL on health-related quality of life in 901 MS patients. After 4 weeks, 84.5% of the patients showed a clinical benefit (faster walking speed and improvement of MSWS) and continued the treatment for a total of 48 weeks. At the end of the study, in this group of patients the authors reported that DAL treatment was able to significantly improve the physical functioning, the activity limitation and the general health status respect to baseline [28]. A recent update of this study, presented at the 2014 Joint ACTRIMS-ECTRIMS Meeting, showed a consistent and significant improvement also in the SF-36-derived SF-6D health index scores, a test which contains six score domains (physical functioning, role participation, social functioning, bodily pain, mental health and vitality) and health state utility scores [29]. Other recent local clinical experiences confirmed the therapeutic value of DAL in relieving MS symptoms. One small study in Oklahoma retrospectively evaluated the efficacy of DAL ER (10 mg b.i.d.) in 20 veterans with MS with limited ambulatory ability, and its impact on motor function in an outpatient setting. The authors reported a significant improvement in walking speed (increased by 33%) and endurance (increased by 31%, representing clinically meaningful improvement, p < 0.05). This improvement in mobility was associated with a clinically significant change in motor function [30]. Further small trials evaluated the long-term clinical benefit of DAL in a real-world setting. The first study, conducted in Austria in 2011, before the European launch of DAL, assessed the long-term effects of DAL in clinical practice in 67 patients (mean MS duration, 16.5 years; mean EDSS score, 4.8; mean T25FW, 13.9 s), with MS with walking impairment. After 4 weeks, 50.7 and 32.8% of patients walked ‡ 10 and ‡ 20% faster, respectively; and in 65.7% of patients, MSWS-12 scores improved. A higher proportion (65.7%) of patients demonstrated improvement in patient-reported walking ability during DAL treatment at 4 weeks. After 6 months, 38.8 and 16.4% of patients walked ‡ 10 and ‡ 20% faster versus baseline, respectively; and in 59.7% of patients, MSWS-12 scores improved. Patient-reported fatigue also improved on average by one point [31]. More recently, an open-label study conducted in Germany evaluated the short- and long-term effects of DAL on motor and cognitive parameters in 52 patients with MS (EDSS 4.0 -- 7.0 and impaired mobility) over 9 -- 12 months. Thirty out of 52 patients (~ 60%) were still on treatment after 9 -- 12 months. Two weeks after treatment initiation, significant ameliorations could be found for T25FW, maximum

walking distance as well as motor and cognitive fatigue, still present after 9 -- 12 months. A tendency towards improvement of somatosensory evoked potentials was found in a subset of patients [32]. A recently published prospective observational study also evaluated whether pre-treatment motor-evoked potentials, where an increased central motor conduction time (CMCT) suggests demyelination of the pyramidal tract, are suitable to predict a therapeutic response to DAL. Twenty-five patients with definite MS were treated with DAL 10 mg b.i.d. A significant overall improvement was observed for both T25FW (median difference - 1.0 s, p = 0.001) and 50 m walk (median difference - 5.0 s, p = 0.002). The analysis showed a significant difference of DCMCT between responders (n = 9, median baseline DCMCT 6.4 ms) and nonresponders (n = 11, median baseline DCMCT 0.9 ms; p = 0.007). Importantly, all patients with normal CMCT at baseline (n = 5) were non-responders, whereas all responders and a subpopulation of the non-responders demonstrated a pathological increase in CMCT before treatment. The authors concluded that MS patients with a normal pre-treatment CMCT are very unlikely to benefit from DAL, whereas patients with a prolonged CMCT have a higher chance to respond to treatment than non-stratified patients [33]. The single-center, double-blind, randomized, placebo-controlled, crossover, Phase II investigator-initiated trial FAMPKIN evaluated the efficacy of DAL on walking function and physical activity in daily life and kinematic gait parameters in 61 patients with definite MS and able to walk at least 50 meters. Subjects were randomized in 2 arms: DAL 10 mg b.i.d. for 6 weeks followed by placebo b.i.d. for 10 weeks (after a wash-out period of 2 weeks) or vice versa. The main results of FAMPKIN study were: beneficial effects of DAL treatment on walking speed and endurance (intensity rather than time with activity) in patients with MS; substantial changes in various kinematic gait parameters on the singlesubject level and good safety profile [34-36]. Subjects who completed the FAMPKIN trial entered the open-label FAMPKIN EXTENSION trial and were treated with DAL 10 mg b.i.d. for over 2 years, except for one treatment-free interval of 2 weeks per year. At the end of the study, DAL treatment had beneficial effects on walking function and cognitive performance (improved attention, psychomotor speed and executive function skills) [37,38]. Several local studies and post-marketing experiences on large case series, recently presented on occasion of the 2014 Joint ACTRIMS-ECTRIMS Meeting, confirmed the improvement of walking ability and speed, spasticity, fatigue and quality of life in DAL-responder patients as well as the good tolerability profile of DAL [39-42]. In particular, Savin et al. analyzed the impact of DAL on manual function (with tests evaluating strength, daily functions and handwriting performance) of 26 MS patients with ambulatory and manual function deficits. The study showed that DAL improved the manual function of these patients 1 month after treatment initiation [43].

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T M SD

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ST S 5-

SS ST

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Figure 3. Box plot showing the percentage change of T25FW, SSST, 5-STS, 9-HPT and SDMT. Reprinted from [27],  The Author(s), 2014 with permission from SAGE. 9-HPT: 9-Hole peg test; 5-STS: 5 Times sit-to-stand test; SDMT: Symbol digit modalities test; SSST: Six spot step test; T25FW: Timed 25-Foot Walk.

Finally, a retrospective observational study on the Health Core Integrated Research US Database evaluated the treatment pattern and the budget impact of DAL on MS. Nine hundred and thirty-eight patients met the inclusion criteria: most of these patients (82.6%) were adherent to DAL therapy. The economic preliminary estimates showed that the budget impact of DAL in this setting was small [44]. 7.

Safety and tolerability

Controlled clinical trials showed that DAL was usually well tolerated at the recommended dosage (10 mg b.i.d.). In the two dose-finding Phase II studies, the highest toxicity was observed with dosages > 20 mg. In the first study by Goodman et al., severe treatment-emergent adverse events on DAL occurred only at doses > 25 mg b.i.d. Five subjects discontinued DAL due to adverse events [18]. Similar results were found in the second study; serious adverse events occurred at higher rates in the 15- and 20-mg dose groups, and at a similar rate in the 10-mg dose group compared with the placebo group. Two patients experienced seizures while taking DAL 20 mg b.i.d., one following accidental overdose. Seizures have been associated with high systemic doses or high plasma 4-AP concentrations [19]. In the Phase III studies, urinary tract infections, falls, insomnia, dizziness, headache, nausea and fatigue were among the most common adverse events reported with DAL treatment in MS patients (Table 2) [20,21]. In the first Phase III trial, 11 patients (5%) treated with DAL were withdrawn from the study due to adverse events and 16 patients (7%) had one or more serious adverse events, but only 2 events were judged as possibly or probably related to treatment [20]. In the other study, four patients (3.4%) experienced at least one treatment-related adverse event leading to treatment discontinuation, and four patients (4.2%) one or more serious adverse events [21]. 302

In the Phase III pivotal trials, seizures occurred only in one case in the first study. They were associated with sepsis secondary to community-acquired pneumonia and led to treatment discontinuation [20]. Overall, it seems that when the extended-release preparation is used at the appropriate dosage (10 mg b.i.d.), the incidence of seizures is comparable to that of the MS population as a whole, as confirmed in the clinical overview by Haut et al. [2,45]. On this subject, some cases of seizures following accidental exposure was reported in literature, all caused by the administration of very high dosages of 4-AP. Burton et al. reported three cases treated with DAL, 10 mg tablets two or three times daily, and hospitalized with status epilepticus within minutes to hours after ingesting the first tablet of their new prescription. Liquid chromatography of the 4-AP tablets from the patients’ prescriptions revealed that the actual dose per 10-mg tablet was between 90.1 and 125.6 mg [46]. Another patient was hospitalized for the sudden onset of abdominal pain, vertigo, anxiety, profuse diaphoresis, hypersalivation, hypertension, bradycardia, agitation and choreoathetosis, followed by status epilepticus. Also in this case pills, prepared by a pharmacist, contained approximately 10 times the dose indicated on the label [47]. These findings strengthen the notion that seizures during DAL treatment are dose-related. In Belgium, no commercial preparation for 4-AP is available and the medication is compounded by the pharmacist, upon medical prescription. Ballesta Mendez et al. reported the case of a 58-year-old woman with progressive MS presenting with status epilepticus. She had used 4-AP for > 3 years, but seizures were time correlated to the ingestion of a single pill which, instead of 10 mg 4-AP, contained 100 mg 4-AP [48]. Regarding cardiotoxicity, no relevant effects have been reported at standard doses, suggesting that DAL has a low potential for QT prolongation and the development of drug-induced cardiac arrhythmias [2,7]. Besides, no new safety issues emerged in the open extension trials [25,26]. However, it has to be mentioned that a recent publication on the first dose effects of fingolimod on 906 MS patients, of whom 34 required prolonged observation, showed a QT prolongation in 5 patients treated with DAL, requiring prolonged monitoring in 2 patients [49]. Finally, a pharmacovigilance survey evaluated the postmarketing safety experience in approximately 46,000 patients treated with DAL in the USA, in order to provide a descriptive analysis of all spontaneously reported adverse events since product launch (March 2011). The most frequently reported post-marketing adverse events were: dizziness, insomnia, balance disorder, headache, nausea, urinary tract infection, asthenia and back pain. Seizures were reported in 85 (about 5.4/1000 patient-years), of which 82 were reported or confirmed by a healthcare practitioner (about 5.2/1000 patientyears). It is noteworthy that 62% of cases had an additional risk factor for seizures: history of convulsions, renal impairment, wrong dosing or use of concurrent medications with a labelled seizure risk. Spontaneous safety data from

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Table 2. Comparative safety profile of dalfampridine extended-release in the 2 Phase III clinical trials. Most frequent adverse events (%)

Goodman 2009 Goodman 2010

Urinary tract infections Falls Insomnia Headache Dizziness Nausea Asthenia Upper respiratory infections Back pain Balance disorders

14 16 8 6 8 6 6 6 6 6

17.5 11.7 10 9.2 8.3 8.3 8.3 5.8 5.8 5.8

Modified from [2].

the US post-marketing experience were consistent with the safety profile reported during clinical development [50]. Due to the well-defined clinical and safety profile of DAL, the MoSt Project (More Steps in MS: a Delphi method consensus initiative for the evaluation of mobility management of MS patients in Italy), recently published on Journal of Neurology, stated that the drug is considered the most appropriate treatment for motor dysfunction control by the interviewed clinicians, and is suitable for both primary and secondary progressive MS [51]. 8.

Regulatory affairs

DAL has been marketed in the USA by Acorda Therapeutics, Inc., since 3 January 2010. In the EU, DAL is marketed by Biogen Idec, Ltd, since 20 July 2011 (renewal 27 July 2012). 9.

Conclusion

Walking impairment is a clinical hallmark of MS and has an adverse impact on most daily activities. It has been underrecognized as a therapeutic target for pharmacologic intervention. An extended-release formulation of 4-AP, a potassium channel blocker that improves axonal conduction and facilitates synaptic transmission, has been extensively studied in walking defects in MS. Treatment with DAL is usually well tolerated, but there is a dose-dependent increase in the risk of seizures with dosages higher than 10 mg b.i.d. DAL can be recognized as an important and innovative treatment of MS symptoms, complementing the actual standard therapy, which does not directly address walking speed. An improvement in ambulation could enhance patient motivation and compliance, favoring the success of the treatment plan and the management program of the disease and potentially favorably modify some direct and indirect costs associated with MS.

10.

Expert opinion

Although DMTs and mAbs have significantly improved the long-term prognosis of MS, we have to be aware that few therapeutic options are available for the progressive forms of MS, where motor impairment and cognitive problems prevail. Therefore, the importance of symptomatic treatments should not be underestimated. The ideal drugs should be devoid of serious side effects and, taking into account the economic burden of MS, have an affordable price. Unluckily, this has not been the case for recently launched symptomatics, such as DAL and delta-9-tetrahydrocannabinol/cannabidiol. Thanks to the ER formulation, DAL offers a clear advantage over immediate-release formulations in terms of safety and convenience at full dosage. In post-marketing studies, efficacy has been reported to be higher than in pivotal studies, reaching about 70% and no new safety signals have emerged. We have to be aware, however, that in post-marketing uncontrolled studies we lack a control group and do not account for the placebo effect, which in randomized controlled trial was consistently high. Another relevant issue is that not always statistically different results in treated patients translate into clinically meaningful improvements. With reference to seizures, the use of electroencephalographic screening before starting therapy might enhance safety, especially in patients with juxtacortical plaques. Caution should be used especially in advanced cases with confluent lesions and with patients needing co-medication with drugs known to have epileptogenetic effects. Caution should also be used in patients suffering from trigeminal neuralgia, marked spasticity and tonic spasms, which might be enhanced by treatment. As the dosage of DAL is standardized, an accidental overdosage will be prevented, differently from a galenic preparation, where a wrong dose can be dispensed by accident. On the other hand, it is common experience that, as patients rarely require 4-AP treatment at night, the total dosage can be often divided in two administrations, one in the morning and one after lunch, allowing for good adherence and limited toxicity. Another limitation is the fixed-dosage formulation, which does not permit a slow titration, contrary to what we were used to with the galenic formulation. In the author’s experience, the appearance of muscle spasms, sometimes painful, has represented a limitation and might be avoided with a titration starting kit and lower dose formulations. However, this would have to be first experimented in a clinical study, to obtain approval from the regulatory authorities. Lower dose formulations might also be useful in patients with renal impairment. Although theoretically promising, the drug has a limited market in countries such as Italy, where it is not reimbursed and the price is significantly higher than for the immediaterelease galenic preparation. This is particularly relevant, considering that only about 30% of patients have shown persistent

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benefits in pivotal trials and that it is still unclear who to treat, when to start and stop treatment and on the basis of which parameters. The possibility to prescribe the drug at no cost for the patient and payors (i.e., paid for by the pharmaceutical company), if a non-responder, might enhance the appropriate use of the DAL, as only responders would pay for the drug. However, even for responders the price is still high, although it has been recently reduced in Italy, as many MS patients with walking impairment retire early and have low income. The situation is probably different in the USA and other countries with different health systems. Data presented at the 2014 Joint ACTRIMS/ECTRIMS Meeting, although apparently exciting, may still be insufficient to demonstrate conclusively a clinically significant effect of DAL on daily activities. If new, robust and consistent data on the positive effects on other symptoms, such as visual and Bibliography

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Affiliation

Jara M, Barker G, Henney HR III. Dalfampridine extended release tablets: 1 year of postmarketing safety experience

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in the US. Neuropsychiatr Dis Treat 2013;9:365-70 Capra C, Battaglia MA, Gaudioso A, et al. The MoSt Project -- more steps in multiple sclerosis: a Delphi method consensus initiative for the evaluation of mobility management of MS patients in Italy. J Neurol 2014;261(3):526-32

Alessandra Lugaresi MD PhD University “G. d’Annunzio” of Chieti-Pescara, Department of Neuroscience, Imaging and Clinical Sciences, Via dei Vestini 31, Chieti, 66100, Italy E-mail: [email protected]