Epilepsy Research (2012) 102, 117—121

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SHORT COMMUNICATION

Safety and efficacy of ezogabine (retigabine) inadults with refractory partial-onset seizures:Interim results from two ongoing open-label studies

Antonio Gil-Nagela,∗, Martin J. Brodieb,1, Robert Leroyc,2, Tracy Cyrd,3,Susan Halld,3, Mary Castigliae,4, Colleen Twomeye,4,Kevan VanLandinghame,4

a Epilepsy Program, Department of Neurology, Hospital Ruber International, La Maso 38, 28034 Madrid, Spainb Epilepsy Unit, Western Infirmary, G11 6NT Glasgow, Scotland, UKc Neurological Clinic of Texas, 7777 Forest Lane, Dallas, TX 28034, USAd Valeant Pharmaceuticals International, 406 Blackwell St, Suite 410, Durham, NC 27701, USAe GlaxoSmithKline, Moore Drive, PO Box 13398, 5.4600.4A, Research Triangle Park, NC 27709, USA

Received 27 January 2012; received in revised form 15 May 2012; accepted 20 May 2012Available online 5 July 2012

KEYWORDSRetigabine;

Summary Interim results of two open-label extension studies assessed ezogabine/retigabinesafety and tolerability for partial-onset seizures. At data cutoff, 336 (60%) patients received≥12 months’ open-label ezogabine/retigabine. The most common TEAEs included dizziness

Ezogabine;

Long-term trial;Partial-onsetseizures;Potassium channels;Antiepileptic drugs

(22%), somnolence (19%), headache (14%), and fatigue (10%). Change in seizure frequencyfrom baseline (median reduction, 53%) and responder rate (52.5%) was maintained in patientsremaining on ezogabine/retigabine. Continuous 6-month and 12-month seizure-free rates forezogabine/retigabine exposures ≥12 months were 13.1% and 7.1%, respectively.© 2012 Published by Elsevier B.V

∗ Corresponding author. Fax: +34 913875250.E-mail addresses: agnagel@ruberinternacional.es

(A. Gil-Nagel), mjb2k@clinmed.gla.ac.uk (M.J. Brodie),rfleroy@airmail.net (R. Leroy), tracy.cyr@valeant.com (T. Cyr),susan.hall@valeant.com (S. Hall), mary.x.castiglia@gsk.com(M. Castiglia), colleen.k.twomey@gsk.com (C. Twomey),kevan.x.vanlandingham@gsk.com (K. VanLandingham).

1 Fax: +44 141 211 2072.2 Fax: +1 972 566 7023.3 Fax: +1 919 294 3097.4 Fax: +1 919 315 0943.

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0920-1211/$ — see front matter © 2012 Published by Elsevier B.V.http://dx.doi.org/10.1016/j.eplepsyres.2012.05.007

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ntroduction

zogabine (EZG; United States adopted name)/retigabineRTG; international nonproprietary name) is an antiepilep-ic drug (AED) that has been approved in the United Statesnd the European Union as adjunctive therapy in adultsith partial-onset seizures. EZG/RTG enhances the activ-

ty of neuron-specific voltage-gated potassium channels,

hich enhances the M-current and suppresses epileptiformctivity (Shieh et al., 2000; Wuttke et al., 2005). Twoompleted multicenter, randomized, double-blind, placebo-ontrolled trials demonstrated the efficacy and safety of

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ZG/RTG 600—1200 mg/day in adults with partial-onseteizures (Brodie et al., 2010; French et al., 2011). Thiseport describes the integrated interim safety and efficacyesults of the respective long-term open-label extensionsOLEs).

ethods

tudies 303 and 304 (NCT00310375 and NCT00310388)re ongoing OLEs of Studies 301 and 302, respectivelyBrodie et al., 2010; French et al., 2011). The interimata cutoff date for this analysis was October 2, 2009.oth studies complied with the Declaration of Helsinki,

nternational Conference on Harmonisation, Good Clin-cal Practice guidelines, and applicable country-specificegulations. Independent ethics committees approved therotocols at each site, and informed consent was obtainedefore enrolment.

tudy design

he primary objective of Studies 303/304 was to evaluatehe long-term safety and tolerability of EZG/RTG in adultsith partial-onset seizures; a secondary objective was toetermine the long-term efficacy of EZG/RTG.

Patients successfully completing the maintenance phasef Studies 301 (EZG/RTG 1200 mg/day) and 302 (EZG/RTG00—900 mg/day) and who were, in the opinion of the inves-igator, expected to benefit from participation in an OLEtudy entered a 6- (Study 301) or 4-week (Study 302) double-lind transition phase to a target dose of 1200 (Study 303) or00 mg/day (Study 304). Patients unable to tolerate the finalose of the transition phase could begin open-label treat-ent at 900 mg/day (Study 303) or 600 mg/day (Study 304).linic visits took place at 1, 2, 3, 4, 6, 8, 9, 10, and 12onths during the first year of the OLEs and every 4 months

hereafter.Key exclusion criteria included any condition that would

revent compliance with study procedures. The use ofelbamate, vigabatrin, monoamine oxidase inhibitors, andedications known to lower seizure threshold (e.g. neu-

oleptics) was prohibited.

tudy medication

ZG/RTG was administered in three doses at approximately-h intervals, either as monotherapy or adjunctive to 1—3pproved AEDs with/without vagus nerve stimulation. Toptimize efficacy and tolerability, the investigator coulddjust the dose of EZG/RTG by 150 mg/day each week andodify the dose to unequal doses and/or twice-daily admin-

stration within the range 600—1200 mg/day. BackgroundEDs could be modified, tapered and/or discontinued iflinically indicated. If EZG/RTG was discontinued, patientsnderwent a 3-week tapering period.

afety assessments

he type, severity, and duration of spontaneous andeported adverse events (AEs) were coded using the Medical

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ictionary for Regulatory Affairs (Version 9.1). AEs wereeported by the patient and/or caregiver at periodic clinicisits, recorded in seizure diaries, or observed by thenvestigator. Relationship to study drug was assessed by thenvestigator. Treatment-emergent AEs (TEAEs) were defineds AEs that began after the first dose of open-label EZG/RTG.

fficacy assessment

atients recorded the date, number, and description ofeizures in a daily diary. At each visit, investigators reviewedhe diary and classified seizure types. Efficacy was evalu-ted by comparison of 28-day seizure frequency during the-week baseline period with the 28-day seizure frequencyuring open-label treatment.

tatistical analysis

ontinuous endpoints were summarized using descriptivetatistics (i.e. mean, standard deviation, median, minimumnd maximum, and number of observations). Categoricalata were summarized by the number of patients provid-ng data at the relevant time point (n), frequency counts,nd percentages. Baseline was defined as the parent studyaseline value for each endpoint.

The duration of exposure was summarized for patientsontinuing in the studies at data cut off. The probability ofetention over time was plotted using Kaplan—Meier esti-ates.Efficacy was assessed using the safety population, which

omprised all patients who successfully completed the tran-ition phase of Studies 301 or 302 and received at least 1ose of EZG/RTG in the open-label extension.

The number, percentage, and severity of AEs, the numberf AEs leading to withdrawal, and the number of serious AEsere tabulated by body system and preferred term.

The percent change from baseline to data cutoff in 28-ay total partial-seizure frequency and responder rates wereummarized for patients overall and with at least 3, 6,2, 24, and 32 months of open-label exposure. Seizure-reedom rates for any continuous 6- and 12-month periodere summarized and presented by duration of exposure

o open-label EZG/RTG. A patient was considered seizure-ree if no seizures were reported during the time period ofnterest.

esults

atient disposition and baseline characteristics

f the patients who completed Studies 301/302, 81% and 92%ntered Studies 303 and 304, respectively. As of October 2,009, 556 patients received ≥1 dose of open-label EZG/RTG,42 (44%) and 314 (56%) of whom had received placebond EZG/RTG, respectively, in Studies 301/302. At datautoff, 336 (60%) patients received ≥12 months’ open-

abel EZG/RTG. The mean (SD) age was 36.6 (11.87) years;hree (<1%) patients were aged ≥65 years. Most patientsn = 446; 80%) were receiving two or three concomitant AEDst baseline. The overall rate of study discontinuation was

Safety and efficacy of ezogabine (retigabine) in adults 119

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analyzing the duration between the first dose in the open-labelRTG, retigabine.

60% (n = 334); 104 patients discontinued due to an AE. Ofthe patients continuing in the study, 190/222 (85.6%) and141/222 (63.5%) were exposed to at least 18 and 24 monthsof treatment, respectively. The probability of retention overtime is presented in Fig. 1.

Safety and tolerability

Of the 477 (86%) patients who experienced a TEAE (Table 1),411 (74%) events were assessed as at least possibly related tostudy drug. TEAEs and those leading to withdrawal are pre-sented in Table 1. The majority of TEAEs were CNS-related(62% of patients) and categorized as mild or moderate.Psychiatric disorder TEAEs were reported in 133 (24%)patients. Cardiac and vascular TEAEs were uncommon (2%and 3%, respectively). Of the 65 (12%) patients who expe-rienced TEAEs categorized as urinary and renal disorders,15 (3%) patients reported urinary retention, 14 (3%) uri-nary hesitation, 2 (<1%) urinary tract disorder, and 2 (<1%)decreased urine flow. Other TEAEs categorized as urinaryand renal disorders (all ≤1%) included dysuria, nephrolithi-asis, proteinuria, haematuria, pollakiuria, bladder disorder,bladder spasm, oliguria, urinary incontinence, bladder pain,bladder prolapsed, calculus bladder, chromaturia, costover-tebral angle tenderness, hydronephrosis, leukocyturia, toxicnephropathy, neurogenic bladder, renal pain, and strangury.Four patients withdrew due to urinary retention, and oneeach withdrew due to hydronephrosis, toxic nephropathy,and urinary hesitation.

Serious TEAEs were reported in 88 (16%) patients, themost common of which were in the categories nervoussystem disorders (n = 37 [7%]; experienced by >1 patient:convulsion, epilepsy, complex partial seizures, grand malconvulsion, status epilepticus, coma, and partial seizurewith secondary generalization); injury, poisoning and proce-dural complications (n = 14 [3%]; experienced by >1 patient:head injury); psychiatric disorders (n = 14 [3%]; experienced

by >1 patient: confusional state and conversion disorder),and infections and infestations (n = 9 [2%]; experienced by>1 patient: pneumonia). Four deaths were reported: twowere described as possible sudden unexpected death in

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nsion study and the taper dose at start date. EZG, ezogabine;

pilepsy (SUDEP), one as probable SUDEP, and anothers multiple myeloma. After data cutoff, two additionaleaths considered unrelated to EZG/RTG were reported1 asphyxia, 1 cardiac arrest). No clinically abnormal trendsn other laboratory values, ECGs, vital signs, or physical andeurologic examinations were indicative of safety issues.

fficacy

our patients (2 from Study 301 and 2 from Study 302) had noeizure information recorded during the open-label exten-ion period and were not included in the efficacy analyses.he percent change in 28-day total partial-seizure frequencyrom baseline to data cutoff was a median reduction of3% (median reduction from 10.4 to 5.1 seizures). Percenteductions from baseline in total partial-seizure frequencynd responder rates were stable over time (Fig. 2A and B).he responder rate (≥50% reduction in 28-day total partial-eizure frequency) from baseline to OLE period (52.5%)ncreased over time with decreasing number of patientsemaining on EZG/RTG (Fig. 2B).

Continuous 6-month seizure-free rates for patientsxposed to 6, 12, or 24 months of EZG/RTG treatment were0.6% (n = 46), 13.1% (n = 44), and 19.1% (n = 35), respec-ively. Twelve-month seizure-free rates for patients exposedo 12 or 24 months of EZG/RTG treatment were 7.1% (n = 24)nd 11.5% (n = 21), respectively.

iscussion

pen-label, long-term, observational trials can providealuable information for the clinician and better reflectlinical practice than randomized, double-blind, placebo-ontrolled trials (Ben-Menachem, 2005; Mohanraj androdie, 2003; Zaccara et al., 2006). In Studies 303/304,oth EZG/RTG dose and concomitant AEDs could bedjusted, more closely reflecting actual clinical practice

ut also introducing limitations to data interpretation.atients previously randomized to EZG/RTG treatment inhe parent study or during the transition phase may havexperienced minimal or tolerable AEs which did not lead to

120 A. Gil-Nagel et al.

Table 1 Number (%) of patients reporting treatment-emergent adverse events (≥3%) and treatment-emergentadverse events leading to withdrawal.

Preferred terma All EZG/RTG doses (n = 556)

TEAEs TEAEs leadingto withdrawal

Any event 477 (86) 117 (21)Dizziness 122 (22) 12 (2)Somnolence 108 (19) 11 (2)Headache 78 (14) 4 (<1)Fatigue 55 (10) 10 (2)Tremor 45 (8) 5 (<1)Convulsion 38 (7) 7 (1)Memory impairment 32 (6) 3 (<1)Amnesia 30 (5) 6 (1)Confusional state 30 (5) 6 (1)Influenza 30 (5) 0Coordination abnormal 29 (5) 2 (<1)Urinary tract infection 29 (5) 0Nasopharyngitis 27 (5) 0Speech disorder 24 (4) 3 (<1)Anxiety 23 (4) 2 (<1)Dysarthria 22 (4) 2 (<1)Diarrhea 21 (4) 0Diplopia 21 (4) 2 (<1)Vertigo 21 (4) 4 (<1)Asthenia 20 (4) 1 (<1)Nausea 20 (4) 2 (<1)Back pain 19 (3) 0Weight increased 19 (3) 3 (<1)Disturbance in attention 18 (3) 5 (<1)Upper respiratory tract

infection18 (3) 0

Paraesthesia 17 (3) 1 (<1)Abdominal pain 16 (3) 0Dysphasia 16 (3) 3 (<1)Gait disturbance 16 (3) 3 (<1)Vomiting 16 (3) 0Urinary retention 15 (3) 4 (<1)Insomnia 14 (3) 0Toothache 14 (3) 0Urinary hesitation 14 (3) 1 (<1)Vision blurred 14 (3) 2 (<1)

a Presented in declining order of incidence for all EZG/RTGdoses.TEAEs were defined as AEs that began on or after day 1 of open-label treatment.

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Figure 2 (A) Median percent reduction (from baseline ofdouble-blind phase to the open-label phase) in 28-day totalpartial-seizure frequency for patients treated with EZG/RTG forat least 32 months during the open-label extension. The 28-daytotal partial-seizure frequency is based on all data collectedcumulatively up to the visit in the open-label extension. (B)Responder rates (≥50% reduction in 28-day total partial-seizurefrequency). All data collected cumulatively up to the visit intp

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AE, adverse event; EZG, ezogabine; RTG, retigabine; TEAE,treatment-emergent adverse event.

iscontinuation; patients in the OLEs may therefore have aore favorable tolerability profile.The interim results of Studies 303/304 show long-term

fficacy of EZG/RTG and an acceptable safety profile forhe treatment of adults with partial-onset seizures. The

requency of TEAEs reported herein was within the rangeseported for the parent studies (73—92% in Studies 301/302).ZG/RTG was associated with TEAEs categorized as urinarynd renal disorders, some of which led to withdrawal.

Seda

he open-label extension are included, to determine whether aatient is a responder. EZG, ezogabine; RTG, retigabine.

verall, data from these ongoing OLE studies do not revealny new effects of EZG (RTG) on the bladder with long-termse not previously described in the regulatory trials (Brickelt al., 2012).

While several factors may contribute to continuing treat-ent with an AED, assessing the probability of retention canrovide useful information regarding the long-term com-osite of efficacy and tolerability (Wong et al., 1999).welve-month retention rate estimates for patients treatedith open-label EZG/RTG were higher than those reported

or gabapentin (20—25%), and similar to those for topiramatend lamotrigine (40—60%), and levetiracetam (60—75%)Zaccara et al., 2006).

The increase in efficacy observed at 24 months ofZG/RTG treatment may be explained by withdrawal ofatients due to lack of efficacy, TEAEs, or other reasons. Thefficacy outcomes observed are consistent with reports forther AEDs, such as levetiracetam (Abou-Khalil et al., 2003;

teinhoff et al., 2007), pregabalin (Ryvlin, 2005; Ryvlint al., 2010), and zonisamide (Wroe et al., 2008), althoughirect comparisons cannot be made. Seizure-free rates forny continuous 6-month period by duration of treatment

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Safety and efficacy of ezogabine (retigabine) in adults

exposure during the OLEs were similar to those reportedfor lamotrigine, pregabalin, levetiracetam, and topiramate(4.7%, 11.6%, 13.2%, and 16.1%, respectively) and similarto pregabalin for any continuous 12-month period (6.2%)(Zaccara et al., 2006; Uthman et al., 2010). Despite the rel-atively small total number of patients achieving continuousfreedom from seizures, the positive impact of this outcomefor a patient cannot be overemphasized.

In conclusion, these interim results support the long-term maintenance of efficacy and acceptable safety profileof EZG/RTG in adult patients with partial-onset seizuresremaining on treatment.

Acknowledgments

These studies were supported by Valeant PharmaceuticalsInternational. The preparation of this manuscript was sup-ported by GlaxoSmithKline and Valeant PharmaceuticalsInternational. Editorial support in the form of writing, draft-ing tables and figures, and collating author comments wasprovided by Dana Fox, PhD, CMPP (Caudex Medical Inc., NewYork, NY) and funded by GlaxoSmithKline and Valeant Phar-maceuticals International.

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