Randi Fain

Efficacy and safety of perampanel in adolescent patients with drug-resistant partial seizures in three double-blind, placebo-controlled, phase III randomized clinical studies and a combined extension study

OBJECTIVE Assess perampanels efficacy and safety as adjunctive therapy in adolescents (ages 12-17) with drug-resistant partial seizures. METHODS Adolescent patients enrolled in multinational, double-blind, placebo-controlled, phase III core studies (studies 304, 305, or 306) completed 19-week, double-blind phase (6-week titration/13-week maintenance) with once-daily perampanel or placebo. Upon completion, patients were eligible for the extension (study 307), beginning with 16-week, blinded conversion, during which placebo patients switched to perampanel. Patients then entered the open-label treatment. RESULTS Of 1480 patients from the core studies, 143 were adolescents. Pooled adolescent data from these core studies demonstrated median percent decreases in seizure frequency for perampanel 8 mg (34.8%) and 12 mg (35.6%) were approximately twice that of placebo (18.0%). Responder rates increased with perampanel 8 mg (40.9%) and 12 mg (45.0%) versus placebo (22.2%). Adolescents receiving concomitant enzyme-inducing antiepileptic drugs (AEDs) had smaller reductions in seizure frequency (8 mg:31.6%; 12 mg:26.8%) than those taking non-inducing AEDs (8 mg:54.6%; 12 mg:52.7%). Relative to pre-perampanel baseline, seizure frequency and responder rates during the extension (Weeks 1-52) improved with perampanel. Most commonly reported adverse events in adolescents during the core studies were dizziness (20.4%), somnolence (15.3%), aggression (8.2%), decreased appetite (6.1%), and rhinitis (5.1%). Dizziness (13.2%), somnolence (11.6%), and aggression (6.6%) most often led to perampanel interruption/dose adjustment during the extension. SIGNIFICANCE Data demonstrated adjunctive perampanel treatment in adolescents with drug-resistant partial seizures produced better seizure control versus placebo, sustained seizure frequency improvements, and a generally favorable safety profile. Results were comparable to the overall study population. CLINICAL TRIAL REGISTRATION clinicaltrials.gov Identifiers: Study 304: NCT00699972; 305: NCT00699582; 306: NCT00700310; Study 307: NCT00735397.

Psychiatric and behavioral adverse events in randomized clinical studies of the noncompetitive AMPA receptor antagonist perampanel

Perampanel, a selective, noncompetitive α‐amino‐3‐hydroxy‐5‐methyl‐4‐isoxazolepropionic acid (AMPA) glutamate receptor antagonist, is indicated for adjunctive treatment of partial seizures in patients ≥12 years based on three phase III clinical studies. The perampanel U.S. Prescribing Information includes a boxed warning for serious psychiatric and behavioral adverse reactions. To provide context for this warning, detail on psychiatric and behavioral safety data from perampanel clinical studies is presented.

Safety and Efficacy of Lorcaserin: A Combined Analysis of the BLOOM and BLOSSOM Trials

Abstract Background: Lorcaserin, a novel selective 5-HT2C receptor agonist, is approved by the US Food and Drug Administration (FDA) for weight management in combination with lifestyle modification for adults with obesity and adults with overweight and ≥ 1 weight-related comorbid condition. The safety and effectiveness of lorcaserin in adult patients without type 2 diabetes mellitus was established based on 2 phase III clinical trials of similar design: Behavioral Modification and Lorcaserin for Overweight and Obesity Management (BLOOM) and Behavioral Modification and Lorcaserin Second Study for Obesity Management (BLOSSOM). This report presents a prespecified analysis of pooled data from these trials. Methods: Co-primary end points in this analysis include the proportion of patients with a reduction in baseline body weight of ≥ 5% and ≥ 10%, and a change in weight from baseline. Key secondary end points include changes from baseline values in lipid parameters, quality-of-life measures, glycemic indicators, and vital signs. Results: At week 52, more than twice as many lorcaserin-treated patients achieved a weight loss of ≥ 5% compared with placebo (lorcaserin, 47.1%; placebo, 22.6%), and lorcaserin-treated patients lost significantly more body weight (lorcaserin, −5.8%; placebo, −2.5%). A significantly greater proportion of lorcaserin-treated patients achieved a weight loss of ≥ 10% (lorcaserin, 22.4%; placebo, 8.7%). There were statistically significant improvements in lipid parameters, glycemic indicators, quality-of-life measures, and vital signs in the lorcaserin group compared with placebo. The most common adverse events associated with lorcaserin treatment were headache, upper respiratory tract infection, and nasopharyngitis. Lorcaserin-treated patients had a rate of FDA-defined valvulopathy similar to placebo. Conclusions: This pooled analysis of the phase III BLOOM and BLOSSOM trials shows that lorcaserin 10 mg twice daily, in combination with diet and exercise, is safe and tolerable, and is associated with statistically significant weight loss and clinically relevant improvements in cardiometabolic parameters.

Early weight loss while on lorcaserin, diet and exercise as a predictor of week 52 weight-loss outcomes.

To identify an early treatment milestone that optimizes sensitivity and specificity for predicting ≥5% weight loss at Week (W) 52 in patients with and without type 2 diabetes on lorcaserin or placebo.

Perampanel efficacy and tolerability with enzyme-inducing AEDs in patients with epilepsy

Objective: Evaluate the impact of concomitant enzyme (CYP3A4)-inducer antiepileptic drugs (EIAEDs) on the efficacy and safety of perampanel in patients from the 3 phase-III clinical trials. Methods: Patients with pharmacoresistant partial-onset seizures in the 3 phase-III clinical studies were aged 12 years and older and receiving 1 to 3 concomitant antiepileptic drugs. Following 6-week baseline, patients were randomized to once-daily, double-blind treatment with placebo or perampanel 8 or 12 mg (studies 304 and 305) or placebo or perampanel 2, 4, or 8 mg (study 306). Results: Treatment response assessed by median percent reduction in seizure frequency and responder rates improved with perampanel compared with placebo. However, at 8 and 12 mg, the treatment response was significantly greater in patients receiving non-EIAEDs. The treatment effect (perampanel–placebo) also demonstrated a dose-dependent increase in all patients. The overall incidence of treatment-emergent adverse events was similar regardless of the presence of EIAEDs. Occurrence of some adverse events, such as fatigue, somnolence, dizziness, irritability, was greater in patients receiving non-EIAEDs, as was discontinuation because of adverse events. Conclusions: Perampanel shows efficacy and safety in the presence and absence of EIAEDs. As systemic exposure to perampanel increases, so does efficacy. Given the extensive metabolism of perampanel, systemic exposure is clearly reduced with concomitant administration of CYP3A4 inducers. This supports the strategy of dosing perampanel to clinical effect. Recognition of these pharmacokinetic interactions will be important in the optimization of this novel medication. Classification of evidence: This study provides Class II evidence that 2 to 12 mg/d doses of perampanel reduced seizure frequency and improved responder rate in the presence and absence of EIAEDs.

Evaluating the cognitive effects of donepezil 23 mg/d in moderate and severe Alzheimer’s disease: analysis of effects of baseline features on treatment response

BackgroundTreatment of Alzheimer’s disease with acetylcholinesterase inhibitors can result in symptomatic benefits, but patients often show variable responses. The objective of this post hoc analysis was to investigate relationships between easily identifiable baseline characteristics/demographics and cognitive response in patients treated with either donepezil 23 mg/d or 10 mg/d and to identify factors potentially influencing response.MethodsA post hoc analysis was conducted using data from a large, 24-week, randomized, double-blind, international study enrolling patients with moderate to severe Alzheimer’s disease (baseline Mini-Mental State Examination [MMSE], 0-20) (NCT 00478205). Cognitive changes in subgroups of patients based on selected baseline and demographic characteristics were compared using the least squares mean changes in Severe Impairment Battery scores at Week 24. Univariate and multivariate analyses were also performed.ResultsDonepezil 23 mg/d provided statistically significant incremental cognitive benefits over donepezil 10 mg/d irrespective of baseline functional severity, measured by scores on the Alzheimer’s Disease Cooperative Study-Activities of Daily Living-severe version (P < 0.05). When patients were categorized by baseline cognitive severity (MMSE score), significant benefits of donepezil 23 mg/d over 10 mg/d were seen in both subgroups when based on MMSE scores of 0-9 versus 10-20 (P < 0.02 and P < 0.01, respectively), and in the more severe subgroup when based on MMSE scores of 0-16 versus 17-20 (P < 0.0001 and P > 0.05). Statistically significant incremental cognitive benefits of donepezil 23 mg/d over 10 mg/d were also observed regardless of age, gender, weight, or prestudy donepezil 10 mg/d treatment duration (P < 0.05). In the multivariate analysis, the only significant interaction was between treatment and baseline MMSE score.ConclusionsThe cognitive benefits of donepezil 23 mg/d over 10 mg/d were achieved regardless of the patient’s age, gender, weight, duration of prior donepezil 10 mg/d, and functional severity. The influence of baseline cognitive severity on response seemed to be dependent on the level of impairment, with cognitive benefits of donepezil 23 mg/d over 10 mg/d most apparent in those patients at a more advanced stage of disease. These data may be useful in helping practicing physicians make informed decisions for their patients with advanced Alzheimer’s disease.

Efficacy and safety of perampanel in patients with drug-resistant partial seizures after conversion from double-blind placebo to open-label perampanel

OBJECTIVE To evaluate the efficacy and safety of perampanel in patients with drug-resistant partial seizures after the conversion from double-blind placebo in three phase III studies to open-label perampanel, and to assess the impact of perampanel titration rates through a comparison of weekly vs biweekly dose increases. METHODS Patients who completed the three multinational, double-blind, placebo-controlled, phase III core studies (studies 304, 305, or 306) were eligible to enroll in the extension study (study 307). Patients completing the double-blind treatment (6-week titration, 13-week maintenance) with placebo (DB-PBO) or perampanel (DB-PER) began the extension study with a 16-week blinded conversion period, during which DB-PBO patients were switched to perampanel. Doses were titrated in 2-mg increments (biweekly) to an individualized maximum tolerated dose of perampanel (up to 12 mg/day). Patients then entered a planned, open-label treatment period. RESULTS Perampanel treatment during the extension study reduced total seizure frequency/28 days relative to the double-blind prerandomization baseline regardless of prior perampanel or placebo treatment in the core studies. In the DB-PBO patients, median percent reductions in seizure frequency at the end of the double-blind period, at the end of the conversion period, and at Weeks 40-52 in the open-label maintenance period were 18.6%, 44.3%, and 55.0%, respectively. Seizure control was also improved in the DB-PER patients during the extension period compared to the end of the double-blind period. Responder rates were similar between the 2 patient groups at the end of the conversion period. Perampanel was well tolerated, with the most common treatment-emergent adverse events being dizziness, somnolence, weight increase, irritability, fatigue, and headache. For those patients randomized to the 12 mg group (DB-PER 12 mg), 78.4% reached the daily dose of 10 or 12 mg by the end of the 6-week titration period of the double-blind phase. By the end of the 16-week conversion period of the extension study, 64.0% of DB-PBO patients reached the daily dose of 10 or 12 mg. Seizure frequency reduction was greater after the first 13-week maintenance period of the extension study in the DB-PBO group compared to patients assigned to DB-PER 12mg during the 13-week maintenance period of the double-blind study. CONCLUSION Patients who received placebo in the phase III core DB studies and transitioned to perampanel in the open-label extension study (DB-PBO) achieved seizure control at the end of the conversion period similar to that of patients who had been previously exposed to perampanel (DB-PER) as well as comparable safety outcomes. Patients who received perampanel during the core studies and continued with treatment during the extension study (DB-PER) also showed sustained improvements in seizure control with long-term exposure to perampanel.

Coadministration of lorcaserin and phentermine for weight management: A 12-week, randomized, pilot safety study

To assess the short‐term tolerability of lorcaserin alone or with two dose regimens of phentermine.

Effect of lorcaserin on glycemic parameters in patients with type 2 diabetes mellitus.

Lorcaserin, a 5‐HT2C receptor agonist approved for chronic weight management, is also associated with improvements in glycemic parameters in patients with/without type 2 diabetes mellitus (T2DM), but the extent to which these effects are mediated by weight loss is unknown. This post hoc analysis further examines glycemic data from the Phase III BLOOM‐DM study stratified by weight changes.

Safety and tolerability review of lorcaserin in clinical trials.

Lorcaserin is a novel selective serotonin 2C receptor agonist indicated by the US Food and Drug Administration for chronic weight management in adults with obesity or overweight with ≥1 comorbidity. The safety and efficacy of lorcaserin were established during two Phase III clinical trials in patients without diabetes (BLOOM and BLOSSOM) and one Phase III clinical trial in patients with type 2 diabetes (BLOOM‐DM). Headache was the most common adverse event experienced by patients during all Phase III trials. Additional adverse events occurring in >5% of patients receiving lorcaserin included dizziness, fatigue, nausea, dry mouth and constipation in patients without diabetes, and hypoglycaemia, back pain, cough and fatigue in patients with diabetes. In a pooled analysis of echocardiographic data collected during the three lorcaserin Phase III trials, the incidence of FDA‐defined valvulopathy was similar in patients taking lorcaserin and the placebo. Here, the safety profile of lorcaserin at the FDA‐approved dose of 10 mg twice daily is reviewed using data from the lorcaserin Phase III programme, with a focus on theoretical adverse events commonly associated with agonists of the serotonin receptor family. Based on the lorcaserin Phase III clinical trial data, lorcaserin is safe and well tolerated in the indicated patient populations.