Lynn Kramer

Topiramate placebo-controlled dose-ranging trial in refractory partial epilepsy using 600-, 800-, and 1,000-mg daily dosages

We conducted a multicenter, double-blind, randomized, parallel, placebo-controlled trial in 190 patients to evaluate the safety and efficacy of three dosages of topiramate (600, 800, and 1,000 mg/day) as adjunctive therapy for patients with refractory partial epilepsy. During an 18-week double-blind treatment period, median percent reductions from baseline in average monthly seizure rates were 1% for placebo, 41% for topiramate 600 mg/day and topiramate 800 mg/day, and 38% for topiramate 1,000 mg/day. There was a 50% or greater reduction from baseline in seizure frequency in 9% of patients in the placebo group and in 44% for topiramate 600 mg/day, 40% for topiramate 800 mg/day, and 38% for topiramate 1,000 mg/day. No placebo patients were improved by 75 to 100% in seizure frequency, whereas 20% of the topiramate patients were improved to this degree. All intent-to-treat drug-placebo comparisons including seizure reduction, percent responders, and investigator and patient global evaluations significantly (p <or=to 0.02) favored topiramate. Treatment-emergent adverse events consisted mainly of neurologic symptoms commonly observed during antiepileptic drug (AED) therapy. Sixteen percent of patients on topiramate discontinued therapy due to adverse events. Results of this study indicate that topiramate is a highly efficacious and generally well tolerated new AED. When large groups of patients are compared, incremental efficacy in the add-on setting is not observed at topiramate dosages above 600 mg/day; however, higher doses may prove beneficial to individual patients who tolerate them. NEUROLOGY 1996;46: 1678-1683

Double-Blind, Placebo-Controlled Trial of Topiramate as Add-On Therapy in Patients with Refractory Partial Seizures

Summary: In a double‐blind, randomized, parallel‐group trial, we compared topiramate (TPM) with placebo as addon therapy in patients with refractory partial epilepsy. TPM was titrated either to the target dosage of 800 mg/ day [400 mg twice daily (b. i. d.)] or to the maximal tolerated dose if lower. Twenty‐eight (28) patients were randomized to each treatment group. In the intent‐to‐treat analysis, the net median percent reduction relative to placebo in average monthly seizure rate was 54% for patients in the TPM group (p < 0.001). None of the placebo‐treated patients and 43% of the patients treated with TPM experienced 250% reduction in seizures (p = 0.001), and 36% of patients assigned to TPM had a 75–100% reduction in seizures (p < 0.01). Secondarily generalized seizures were also significantly reduced in the TPM group (p = 0.044). The most common adverse events (AE) reported in the TPM group were fatigue, impaired concentation, weight loss, dizziness, and paresthesias. AE occurring either during the rapid titration of TPM or at high dosages led 21% of TPM‐treated patients to withdraw from the study. Half of these occurred during the titration study period. No serious AE or clinically important changes in clinical laboratory measures were observed. The present study further establishes the favorable profile and good benefithisk ratio of TPM in resistant partial epilepsy.

Efficacy and safety of adjunctive perampanel for the treatment of refractory partial seizures: a pooled analysis of three phase III studies.

Three phase III studies (304 [ClinicalTrials.gov identifier: NCT00699972], 305 [NCT00699582], 306 [NCT00700310]) evaluated perampanel, an α‐amino‐3‐hydroxy‐5‐methyl‐4‐isoxazolepropionic acid (AMPA) receptor antagonist, as adjunctive therapy for refractory partial seizures. We report post hoc analyses of pooled study data by randomized dose.

Perampanel for adjunctive treatment of partial‐onset seizures: A pooled dose–response analysis of phase III studies

To better understand the relationship between efficacy and perampanel dose, integrated actual (last) dose data from three phase III trials and an extension study (blinded Conversion Period; open‐label Maintenance Period) were analyzed.

Development of perampanel in epilepsy

Alpha‐amino‐3‐hydroxy‐5‐methyl‐4‐isoxazolepropionic acid (AMPA)‐type glutamate receptors play a key role in mediating glutamatergic transmission in the cortex. Perampanel (2‐[2‐oxo‐1‐phenyl‐5‐pyridin‐2‐yl‐1,2‐dihydropyridin‐3‐yl] benzonitrile) is a potent, orally active, highly selective, non‐competitive AMPA‐type glutamate receptor antagonist, identified via a focused discovery program at Eisai Research Laboratories. Development of perampanel as adjunctive therapy for the treatment of partial‐onset seizures was planned in keeping with regulatory guidance and guidelines on antiepileptic drug (AED) development. This is the first AED with a specific action on glutamate‐mediated excitatory neurotransmission to show evidence of efficacy and tolerability in reducing treatment‐refractory partial‐onset seizures in Phase III clinical trials. Perampanel (Fycompa®) has been approved in the EU and the United States for adjunctive treatment of partial‐onset seizures.

Time to prerandomization monthly seizure count in perampanel trials A novel epilepsy endpoint

Objective: To determine whether a novel endpoint of time to prerandomization monthly seizure count could be used to differentiate efficacious and nonefficacious therapies in clinical trials of new add-on antiepileptic drugs (AEDs). Methods: This analysis used data from 3 randomized, double-blind, placebo-controlled phase III trials of perampanel as an add-on therapy in patients with epilepsy who were experiencing refractory partial seizures: studies 304 (ClinicalTrials.gov identifier NCT00699972), 305 (NCT00699582), and 306 (NCT00700310). Time to prerandomization monthly seizure count was evaluated post hoc for each trial, and findings were compared with the original primary outcomes (median percent change in seizure frequency and 50% responder rate). Outcomes were assessed for all partial-onset seizures, secondarily generalized (SG) tonic-clonic seizures only, and complex partial plus SG (CP + SG) seizures. Results: Perampanel 4–12 mg significantly prolonged median time to prerandomization monthly seizure count, generally by more than 1 week, compared with placebo, across all 3 studies, consistent with the original primary outcomes. Analysis of SG seizures only, and CP + SG seizures, also indicated a significantly prolonged median time to prerandomization monthly seizure count with perampanel 8 mg and 12 mg compared with placebo. Conclusions: Time to prerandomization monthly seizure count is a promising novel alternative to the standard endpoints of median percent change in seizure frequency and 50% responder rates used in trials of add-on AEDs. Use of this endpoint could reduce exposure to placebo or ineffective treatments, thereby facilitating trial recruitment and improving safety.

Perspective of the Pharmaceutical Industry

New drugs in general, and anticonvulsants in particular, may be discovered through serendipity or through specific scientific design. The efforts leading to drug discovery are spearheaded primarily by the pharmaceutical industry. The compounds discovered possess physical and pharmacologic properties that are categorized. For many years, the task of anticonvulsant design was approached by modifying the heterocyclic ring structure of existing agents (hydantoins and barbiturates), in an attempt to develop agents of either greater efficacy or greater safety. Thus drug development was slow and agents offering insignificant differences were developed. More recently, an expansion in theoretical scientific knowledge has stimulated the development of new agents of diverse chemical structure. Many of these agents have been designed to fill specific roles. However, despite this, safe and efficacous anticonvulsant agents have been slow to enter the marketplace.