July 4, 2016
GW Pharmaceuticals released results of a
randomized, double-blind, placebo-controlled
phase III trial of Epidiolex (cannabidiol or CBD)
for Lennox-Gastaut syndrome (LGS), a rare
and severe form of childhood-onset epilepsy.
The trial randomized 171 patients into two
arms, where Epidiolex 20mg/kg/day (n=86)
or placebo (n=85) was added to current antiepileptic
drug (AEDs) treatment. The average
age of trial participants was 15 years (34%
were 18 years or older). During the treatment
period, patients taking Epidiolex achieved a
median reduction in monthly drop seizures
of 44% compared with a reduction of 22% in
patients receiving placebo, and the difference
between treatments was statistically significant
(p=0.0135). Epidiolex has Orphan Drug
Designation from the FDA for the treatment
of LGS and Dravet syndrome. The company
anticipates advancing Epidiolex toward NDA
submission with the FDA in the first half of
2017. In addition to this first phase III trial of
Epidiolex in LGS, GW is conducting a second
phase III dose-ranging trial of Epidiolex for the
treatment of LGS.
March 28, 2016
GW Pharmaceuticals reported results of the first pivotal phase III study of Epidiolex (cannabidiol or CBD) for the treatment of Dravet syndrome. The study randomized 120 patients into two arms, Epidiolex 20mg/kg/day (n=61) and placebo (n=59). Epidiolex or placebo was added to current anti-epileptic drug (AED) treatment regimens. On average, patients were taking approximately three AEDs, having previously tried and failed an average of more than four other AEDs. The average age of trial participants was 10 years and 30% of patients were less than 6 years of age. The median baseline convulsive seizure frequency per month was 13. Patients taking Epidiolex achieved a median reduction in monthly convulsive seizures of 39% compared with a reduction on placebo of 13%, which was highly statistically significant (p=0.01). The difference between Epidiolex and placebo emerged during the first month of treatment and was sustained during the entire treatment period. Epidiolex was generally well-tolerated in the study. The most common adverse events (occurring in greater than 10% of Epidiolex-treated patients) were somnolence, diarrhea, decreased appetite, fatigue, pyrexia, vomiting, lethargy, upper respiratory tract infection and convulsion. Of those patients on Epidiolex that reported an adverse event, 84% reported it to be mild or moderate. GW is currently conducting a second phase III trial in Dravet syndrome, which is recruiting 150 patients. Epidiolex has both Orphan Drug designation and Fast Track designation from the FDA in the treatment of Dravet syndrome.
June 2, 2014
Eisai reported results of a phase III
extension study (n=1,218) of Fycompa
(perampanel) for the treatment of epilepsy.
Patients aged greater than or equal to 12
years with partial-onset seizures, despite
treatment with one to three antiepileptic
drugs at baseline, were titrated to 12mg/day
(or their individual maximum tolerated
dose) during the blinded conversion period,
followed by open-label maintenance. The
study showed perampanel was well-tolerated
for up to three years of treatment at a
median daily dose of 10.6mg/day. The most
frequent AEs, which were reported in greater
than or equal to 10% of patients, were
dizziness, somnolence, headache, fatigue,
irritability and weight increase. Only dizziness
and irritability caused discontinuation
of the study in >1% of patients (3.9% and
1.3%, respectively). After titration/conversion,
responder rate and median percentage
change from baseline in seizure frequency
were stable: 46% for both measures at nine
months (in 980 patients with greater than
or equal to nine months’ exposure) and
58% and 60%, respectively, at two years (in
the 337 patients with two years’ exposure).
Among 1,216 patients, median exposure
was 1.5 years (range, one week to 3.3
years), with >300 patients treated for over
two years. Up to 90% of patients achieved
a reduction in secondarily generalized
seizures and 5% of patients achieved seizure
freedom lasting at least one year.
January 13, 2014
Upsher-Smith Laboratories released results
of a phase III trial of USL255 for the treatment
of epilepsy patients with refractory
partial-onset seizures (POS). The randomized,
multicenter, double-blind, placebocontrolled,
parallel-group study enrolled 249
patients at 66 centers globally. During the
three-week titration phase, USL255-treated
subjects demonstrated a significantly greater
median reduction from baseline in weekly
POS frequency as compared with placebotreated
subjects (33.9% v 8.6%, P<0.001). This
significant treatment effect was sustained
during the eight-week maintenance phase
(45.7% v. 22.1%, P=0.001). USL255 significantly
reduced POS frequency as early as
week one when compared with placebo and
sustained this efficacy. The 50% responder
rate during the 11 weeks of treatment also
was greater with USL255 compared with placebo
(37.9% v. 23.2%, P=0.013). USL255 reduced
median weekly complex partial seizure
frequency (P=0.001) and was associated with
a higher responder rate (P=0.003). USL255
was shown to be effective in both complex
partial seizures (CPS) and partial secondarily
generalized seizures (PSG). USL255 was most
effective in subjects taking more than two
antiepileptic drugs (AEDs) and demonstrated
improvement, even in the most refractory
of patients (≥7 AEDs tried). Treatment with
USL255 resulted in a significant improvement
in time to seizure freedom (P=0.004), and
a higher percentage of subjects achieved
seizure freedom for at least 21 days prior to
the last dose of study drug as compared with
placebo (16.1% v. 5.6%, P=0.006). The overall
incidence of treatment-emergent adverse
events was 66% (USL255) and 50% (PBO)
(P=0.015). Upsher-Smith’s NDA for USL255
has been accepted for review by the FDA.
November 4, 2013
Upsher-Smith Laboratories reported results of a phase I trial of USL255 (extended-release topiramate) for the treatment of epilepsy. The randomized, placebo-controlled, double-blind study planned to enroll 60 healthy subjects into six dose cohorts (600mg, 800mg, 1000mg, 1200mg, 1400mg and 1600mg). Each cohort enrolled 10 subjects of which eight subjects received USL255 and two subjects received matching placebo. Blood samples were collected and tolerability was evaluated for 14 days post-dose. USL255 displayed consistent plasma exposure up to 24 hours after administration, with low inter-subject variability in total plasma exposure and maximal topiramate plasma concentrations. AUC and C(max) were dose proportional and linear from 600mg to 1400mg. Single doses of USL255 generally were well-tolerated from 600mg to 1200mg, with MTD established at 1200mg. The NDA for USL255 has been accepted for review by the FDA.
March 4, 2013
Pfizer released results for a phase III trial of Lyrica (pregabalin) capsules CV compared to levetiracetam for the treatment of seizures. This randomized, double-blind, parallel-group, multi-center, comparative, flexible-dose study enrolled adult patients experiencing refractory partial onset seizures caused by epilepsy and who also were unresponsive to treatment with at least two, but no more than five, prior antiepileptic drugs. Subjects received Lyrica 300mg, 450mg or 600mg daily or levetiracetam 1,000mg, 2,000mg or 3,000mg daily for 12 weeks. The top-line results indicate the study met its primary endpoint by demonstrating a comparable proportion of patients on Lyrica achieved at least a 50% reduction in the 28-day seizure rate during the maintenance phase relative to levetiracetam. Lyrica was well tolerated. The most frequent adverse events were headache, dizziness, insomnia, somnolence, nausea and fatigue. Based on these results, Pfizer will be submitting data for presentation at upcoming scientific congresses and for publication in a peer-reviewed medical journal.
December 10, 2012
Upsher-Smith Laboratories reported results from a phase I trial of USL261 for the treatment of seizures in epilepsy. This randomized, open-label study enrolled 90 patients with epilepsy between the ages of 12 and 62 on stable antiepileptic drug (AED) regimens. Subjects received a single dose of 2.5mg, 5mg or 7.5mg USL261 by a unit-dose nasal spray device. Results demonstrated that maximum midazolam plasma concentrations were rapidly achieved after dosing with USL261. Furthermore, onset of pharmacodynamic effects were seen as early as 10 minutes, and scores of each instrument returned to near baseline levels by four hours after the administration of USL261. Investigators concluded that midazolam Cmax was rapidly achieved after dosing with USL261, and both midazolam and 1-OHMZ were rapidly eliminated, with mean t(1/2) between three and four hours. The drug was well tolerated. Upsher-Smith also is studying USL261 in an ongoing global phase III trial called ARTEMIS1.
September 5, 2011
Eisai reported results from a phase III trial of perampanel for partial-onset seizures. This global, randomized, double-blind, placebo-controlled study (305) enrolled 389 subjects who received 8 or 12 mg perampanel or placebo once daily for 19 weeks, on top of their regular therapy. The response rates, defined as 50 percent or greater reduction in seizure frequency, were 14.7% for placebo, 33.3% for 8mg (p≡0.002) and 33.9% for 12 mg (p≡<0.001). In addition. perampanel 8 mg and 12 mg once-daily reduced median seizure frequency by 30.5% and 17.6%, respectively versus 9.7% for placebo. The most common adverse events were dizziness, fatigue, headache and somnolence.
March 14, 2011
Vertex reported results from a phase II trial of VX-765 for epilepsy. This randomized, double-blind, placebo-controlled study enrolled 60 adults with treatment-resistant partial onset epilepsy. The subjects received VX-765 as a 300mg oral tablet three times a day (900mg total) or placebo, along with standard epilepsy treatment, for a six-week duration. The primary endpoints of safety and tolerability were reached. The secondary endpoints assessed the clinical efficacy and were based on the percent reduction in seizure frequency, percent of subjects with a 50 percent or greater reduction in seizure frequency (responder-rate) and percent of subjects who were seizure-free in the last two weeks of treatment. These endpoints were reached by 13% to 19% of the VX-765 arm versus 0% to 9% of the placebo arm.
August 30, 2010
Eisai released positive preliminary results from a phase III trial of perampanel for the treatment of epilepsy. This global double blind, placebo controlled parallel group study (306) enrolled 706 subjects who were randomized to placebo or one of three perampanel doses. All subjects in the perampanel arm started on 2 mg doses. They either remained on 2 mg or their dosage was increased weekly in 2 mg increments to their randomized doses of 4 mg or 8 mg. Perampanel was effective in reducing median seizure frequency and increasing responder rates, with statistical significance reached in the 4 mg and 8 mg arms compared to placebo. Treatment was well tolerated and the most common adverse events were dizziness, somnolence and headache.
March 22, 2010
Icagen released positive results from a phase II trial of ICA-105665 for the treatment of photosensitive epilepsy. This multi-center, single-blind, placebo-controlled study (ICA-105665-04) enrolled 12 subjects with epilepsy with a documented photoparoxysmal response to intermittent photic stimulation. The subjects received a single dose of ICA-105665 (50 to 400 mg) or placebo, each followed by intermittent photic stimulation. The primary endpoint was change in photosensitivity response beginning one hour post-dose and lasting 8 hours. At the top dose studied (400mg/day), two of four subjects demonstrated a positive response to treatment with ICA-105665, as specified by standard pre-defined criteria. At all dose levels tested, ICA-105665 was well tolerated, with no serious adverse events and no dose limiting toxicities.
March 9, 2009
Marinus reported positive results from a phase II trial of ganaxolone for the treatment of partial onset seizures. This randomized, double-blind, placebo-controlled trial enrolled 147 adults with partial onset seizures, who continued to have seizures even while taking up to three antiepileptic drugs. The subjects were observed for baseline seizure activity for eight weeks and were then randomized to receive either ganaxolone or placebo in addition to their existing stable AED regimen. The arm receiving ganaxolone were titrated over one to two weeks to a maintenance dose of 1,500 mg/day, where they were maintained for an additional eight weeks. The primary endpoint, a statistically significant reduction of mean weekly seizure frequency versus placebo, was reached during the titration and maintenance period (p<0.0251). Subjects in the ganaxolone arm also showed an improvement on percent reduction in seizure frequency versus placebo (p<0.0144). Responder rates (a greater than 50 percent reduction in seizures) were numerically higher in the ganaxolone arm versus placebo but did not reach statistical significance (p<0.1926). Ganaxolone was generally well tolerated. Based on the results, Marinus plans to move the development of ganaxolone into phase IIb studies.
June 30, 2008
Sepracor reported positive results from three phase III trials of eslicarbazepine acetate for the treatment of partial epilepsy. These randomized, double-blind, placebo-controlled, multi-center studies enrolled 1,049 subjects with history of more than four partial seizures per month despite treatment with up to three concomitant anti-epileptic drugs. The subjects received eslicarbazepine acetate once-daily at doses of 800 mg and 1200 mg or placebo and were evaluated in 12-week maintenance periods. They were subsequently followed up in an open-label study for one year. Data revealed a 35.4% relative reduction in seizure frequency over the 12-week period for the 800 mg once-daily dosage regimen (p=0.0002) and a 38.8% reduction for the 1200 mg once-daily dosage regimen (p=0.0001) compared with placebo. In addition, 36.3% of subjects receiving 800 mg daily and 43.5% of subjects receiving 1200 mg daily experienced a 50 percent or greater reduction in seizure frequency over the 12-week maintenance period (p=0.0001 and p less than0.0001, respectively). Reduction in seizure frequency and responder rates were sustained over the 52-week treatment period. Eslicarbazepine acetate also led to statistically significant improvements in mean quality of life as measured by Quality of Life in Epilepsy Inventory-31 (QOLIE-31) scores at Week 52 compared with baseline measures. Based on the results Sepracor plans to file an NDA with the FDA in late 2008 or early 2009.
May 26, 2008
Eisai issued results from a clinical study of rufinamide for the treatment of Lennox-Gastaut syndrome (LGS). This multi-center, double-blind, placebo-controlled, randomized, parallel-group study enrolled 139 subjects between the ages of four and thirty years who were being treated with one to three concomitant stable dose antiepileptic drugs (AEDs). The subjects received either rufinamide (titrated up to 45mg/kg per day) or placebo in addition to their other AEDs. The trial met all the primary endpoints. The median percentage reduction in total seizure frequency from baseline was greater in the rufinamide therapy group than in the placebo group (32.7% versus 11.7%; p<0.002). The rufinamide-treated subjects had 42.5% median percentage reduction in tonic-atonic seizure (drop attack) frequency per 28 days from baseline as compared with 1.4% increase in the placebo-treated subjects (p<0.0001). The rufinamide group had a statistically significant improvement in seizure severity (p<0.005) and a higher percentage of subjects who experienced at least a 50% reduction in tonic-atonic seizure frequency per 28 days compared with placebo (42.5% versus 16.7; p=0.002). Treatment was generally well tolerated. An NDA for rufinamide is currently under review.
May 19, 2008
Valeant issued positive results from a phase III trial of retigabine for the treatment of epilepsy. This international, randomized, double-blinded, placebo-controlled, parallel group study was dubbed RESTORE-2 (Retigabine Efficacy and Safety Trials for Partial Onset Epilepsy) and enrolled 539 subjects. All subjects had refractory partial-onset seizures despite receiving one, two or three ant-epileptic drugs. The subjects received retigabine in fixed doses of 600 and 900 mg/day, administered in three divided doses, or placebo for thirty weeks. The co-primary endpoints were reached with statistical significance. These were 1) the percentage change in total partial seizure frequency per four weeks from baseline to the double-blind period, and 2) the proportion of responders, defined as a patient experiencing a greater than or equal to 50 percent reduction in total partial seizure frequency per four weeks from baseline to the double-blind period. The median reductions in twenty-eight day total partial seizure frequency were 15.9%, 27.9% and 39.9% in the placebo and retigabine 600 and 900 mg arms, respectively (p less than 0.01). The responder rates were 17.3%, 31.5% and 39.3% for the placebo and retigabine 600 and 900 mg arms, respectively (p less than 0.01). Treatment was generally well tolerated. Based on positive phase III results Valeant plans to file an NDA with the FDA and an MAA with the EMEA before the end of 2008.
February 18, 2008
Epicept released positive preliminary results from a phase II trial of NP-1 for the treatment of diabetic peripheral neuropathy (DPN). This double blind, placebo-controlled study, dubbed Neuracept, enrolled two hundred and fifteen subjects. The primary endpoint, the difference in changes in pain intensity between NP-1 and placebo over a four week trial duration, was reached (p=0.0715). Secondary endpoints were reached as well. Sixty percent of subjects in the NP-1 treatment arm achieved a reduction of pain scores of at least 30% compared with 48% of subjects in the placebo arm (p=0.076). In addition, 33% of subjects in the NP-1 treatment arm achieved a reduction in pain scores of at least 50% compared with 21% of subjects in the placebo arm (p=0.078). Based on the results, Epicept plans to move forward with phase III trials of NP-1 for this indication.
Valeant reported positive results from a phase III trial of retigabine for the treatment of epilepsy. This randomized, double-blinded, placebo-controlled, international, parallel group study was dubbed RESTORE-1 (Retigabine Efficacy and Safety Trials for Partial Onset Epilepsy). The study enrolled three hundred and six subjects with epilepsy who were experiencing refractory partial-onset seizures despite receiving one, two or three Anti-epileptic drugs. The treatment duration was thirty two weeks and consisted of a fixed dose of 1200 mg/day of retigabine, administered in three divided doses, or placebo. The following primary endpoints were reached with statistical significance. The median reduction in twenty eight day total partial seizure frequency was 44.3% in the retigabine arm compared to 17.5% in the placebo arm (p less than 0.0001). The median reduction in twenty eight day total partial seizure frequency during the maintenance phase was 54.5% in the retigabine arm compared to 18.9% in the placebo arm (p less than 0.0001). The responder rate, defined as greater than or equal to 50% reduction in twenty eight day total partial seizure frequency, was 45.0% and 18.0% for retigabine versus placebo, respectively, and the responder rate during maintenance phase was 55.5% and 22.6% for retigabine versus placebo, respectively, (p less than 0.0001). Additional phase III trials are currently underway and Valeant anticipates filing an NDA with the FDA and an MAA with the EMEA before the end of 2008.
December 10, 2007
UCB Pharma reported positive results from two phase II trials of lacosamide for the treatment of epilepsy. This double-blind, randomized, parallel-group, placebo-controlled study enrolled four-hundred and five subjects with refractory partial onset seizures, which were uncontrolled despite treatment with one to three anti-epileptic drugs. The subjects received lacosamide 400 mg/day or 600 mg/day (given in two doses), or placebo for twelve weeks. The median reduction in seizure frequency from baseline was significantly greater for lacosamide than placebo: 37.3%, 37.8% and 20.8% for lacosamide 400 mg/day, 600 mg/day, and placebo, respectively. Significantly more subjects achieved a 50% or greater reduction in seizure frequency with lacosamide than placebo: 38.3%, 41.2% and 18.3% for lacosamide 400 mg/day, 600 mg/day, and placebo, respectively. Nine subjects who completed the Maintenance Phase were seizure free throughout the entire twelve-weeks: four in the 400 mg/day group (2.5%) and five in the 600 mg/day group (8.1%). The subjects who completed the SP754 trial had the option to transition to an open-label extension study, which was designed to evaluate long-term the efficacy and safety profile of lacosamide. A total of three hundred and seventy subjects were enrolled and received a median lacosamide dose of 400 mg/day. Of the 370 subjects, 284 (76.8%) were exposed to lacosamide for more than twelve months, 224 (60.5%) for more than twenty-four months, and 140 (37.8%) for more than thirty six months. After 5.5 years the median percent reduction in seizure frequency across all prior treatment groups was 45.9%. Additionally, 46.6% of subjects had at least a 50% reduction in seizure frequency with lacosamide. The long-term use of lacosamide was determined to be safe and well tolerated. An NDA is currently under review by the FDA.
December 11, 2006
Ovation reported positive results from a phase II trial of clobazam for the treatment of Lennox-Gastaut syndrome (LGS). This randomized, double-blind, dose-finding trial enrolled 68 subjects, aged 2-26 years, who were placed into one of two clobazam treatment groups, a low dose (target of 0.25 mg/kg/day) or a high dose (target of 1.0 mg/kg/day), for a total duration of up to 10 weeks. Treatment was well tolerated, with all adverse events mild to moderate in nature. Efficacy results revealed that in the high dose clobazam group more than 83% of the subjects experienced 50 percent or greater reduction in weekly drop seizures from baseline (p=.0001) and 67% experienced a reduction of 75 percent or greater (p=.0006). In addition, nearly 15% of the subjects experienced complete elimination (100 percent reduction) of drop seizures during the course of the study, however this did not reach statistical significance (p=.0629). Based on the results, Ovation plans move forward with the development of clobazam.
Schwarz Pharma issued positive results from a phase III trial of lacosamide for the treatment of epilepsy. This multi-center, double-blind, placebo-controlled trial enrolled 485 subjects who were on a stable regimen of 1-3 concomitant AEDs, in Europe and Australia. Subjects received adjunctive treatment with placebo, 200 mg or 400 mg of oral lacosamide, in two equally divided doses per day. The primary endpoint was reduction of seizure frequency and a 50% responder rate. Treatment was generally well tolerated, with no reported serious adverse events. The most common adverse events were dizziness, headache and double vision. Statistical significance over placebo was reached in the reduction of seizure frequency from baseline to maintenance endpoint. The observed percent reduction over placebo was 14.4% (P=.02) for the lacosamide 200 mg/day group and 15.0% (P=.03) for the lacosamide 400 mg/day group. In addition, the 50% responder rate for the 400 mg/day group was 40.5% versus 25.8% for the placebo group (P=.006). Schwarz plans to use this trial as part of the marketing authorization application to be filed in Europe and the US.
September 13, 2004
Neurocrine Biosciences issued positive results of their phase III study of the modified release formulation of indiplon, their investigational treatment for insomnia. Data indicated that the study met its primary endpoint, with a highly significant increase in total sleep time (p<0.0001), compared with placebo. The study also met its secondary endpoints with significant improvements in all parameters: total wake time, wake after sleep onset, number of awakenings after sleep onset, latency to sleep onset, and sleep quality. The double-blind, placebo-controlled, multi-center, parallel-group outpatient study randomized a total of 229 elderly patients with a history of sleep disturbances; all subjects received nightly doses of either indiplon modified-release or placebo for 14 days. Neurocrine announced plans to submit an NDA for indiplon modified-release bases upon these results.
Schwarz Pharma has reported positive results of a phase II b study of their anti-epileptic investigational drug harkoseride. Trial data demonstrated that the drug produced a significant observed reduction in seizure frequency, and a greater than 50% response rate among participants, compared with placebo. Harkoseride treatment was also found to be safe and generally well tolerated. The multi-center, double-blind, placebo-controlled trial enrolled a total of 497 subjects suffering from partial seizures suffering due to treatment-refractory epilepsy. Subjects were randomized to receive either harkoseride or placebo twice daily for 12 weeks, adjunct to standard anticonvulsant treatment. Schwarz is currently conducting an open-label extension study in this patient population, in addition to an ongoing phase III investigation.