Efficacy of HP-3070, A Once-Daily Asenapine Transdermal System, in the Treatment of Adults with Schizophrenia: A PANSS Five-Factor Analysis.

Introduction: HP-3070, a once-daily asenapine transdermal system, is the first antipsychotic "patch" formulation FDA approved for adults with schizophrenia. Positive and Negative Syndrome Scale (PANSS) score items can be grouped into a five-factor structure to describe specific schizophrenia symptom domains. This post hoc analysis of data from a pivotal study evaluated HP-3070's efficacy by examining these factors. Methods: In a phase 3 study, adults with an acute exacerbation of schizophrenia were randomized to six weeks of treatment with HP-3070 3.8mg/24h, 7.6mg/24h, or placebo. An analysis was performed using the five PANSS factor domains (negative symptoms, positive symptoms, disorganized thought, uncontrolled hostility/excitement, anxiety/depression). Mixed-model repeated-measures (MMRM) analysis included change from baseline (CFB) in PANSS factor score as the repeated dependent variable, with country, treatment, visit, treatment by visit interaction, and baseline PANSS score as covariates. Results: The analysis included 607 patients. Treatment with HP-3070 3.8mg/24h resulted in a statistically significant LS mean CFB (improvement) vs placebo at Weeks 4-6 for all domains except for anxiety/depression, where a numerical difference was observed in favor of active treatments. Among the domains, the positive symptom factor demonstrated the numerically greatest LS mean (SE) difference from placebo in CFB, which for HP-3070 7.6mg/24h was -2.0 [0.57] and for HP-3070 3.8mg/24h was -2.3 [0.57]; P<0.001 for both. Treatment effect size for the positive symptom factor using Cohen's d (95% confidence intervals) was 0.39 (0.17, 0.61) for HP-3070 7.6mg/24h and 0.45 (0.20, 0.64) for HP-3070 3.8mg/24h. Discussion: Post hoc analysis using a PANSS five-factor model suggests that HP-3070 may address a broad range of symptoms in people with schizophrenia.

d-Amphetamine Transdermal System in Treatment of Children and Adolescents with Attention-Deficit/Hyperactivity Disorder: Secondary Endpoint Results and Post Hoc Effect Size Analyses from a Pivotal Trial.

Objectives: Amphetamines are a preferred treatment for attention-deficit/hyperactivity disorder (ADHD), with the dextroamphetamine transdermal system (d-ATS) providing an alternative to oral formulations. A pivotal trial of d-ATS in children and adolescents with ADHD met primary and key secondary endpoints. This analysis reports additional endpoints and safety findings from the pivotal trial and evaluates effect size and number needed to treat (NNT) for d-ATS. Methods: In this study, a 5-week, open-label dose-optimization period (DOP) preceded a 2-week, randomized, crossover double-blind treatment period (DBP). Eligible patients received d-ATS 5 mg during the DOP, with weekly evaluations for increase to 10, 15, and 20 mg (equivalent to labeled doses of 4.5, 9, 13.5, and 18 mg/9 hours, respectively) until reaching and maintaining the optimal dose, which was utilized for the DBP. Secondary endpoints included assessment of Attention-Deficit/Hyperactivity Disorder Rating Scale IV (ADHD-RS-IV), Conners' Parent Rating Scale Revised Short Form (CPRS-R:S), and Clinical Global Impression (CGI) scores. NNT was calculated for ADHD-RS-IV and CGI-Improvement (CGI-I). Safety assessments included treatment-emergent adverse events (TEAEs) and dermal safety. Results: In total, 110 patients entered the DOP, with 106 patients randomized (DBP). During the DBP, the least-squares mean (95% confidence interval) difference for d-ATS versus placebo in ADHD-RS-IV total score was -13.1 (-16.2 to -10.0; p < 0.001), with effect size of 1.1 and NNT of 3 for ADHD-RS-IV remission, ≥30% improvement, and ≥50% improvement. Significant differences between placebo and d-ATS were also observed for CPRS-R:S and CGI-I scales (p < 0.001), with NNT of 2 for CGI-I response. Most TEAEs were mild or moderate, with three leading to study discontinuation in the DOP and none in the DBP. No patients discontinued due to dermal reactions. Conclusions: d-ATS was effective in treating ADHD in children and adolescents, meeting all secondary endpoints, with a large effect size and NNT of 2-3 to achieve a clinically meaningful response. d-ATS was safe and well tolerated, with minimal dermal reactions. Clinical Trial Registration: NCT01711021.

Efficacy and Safety of Dextroamphetamine Transdermal System for the Treatment of Attention-Deficit/Hyperactivity Disorder in Children and Adolescents: Results from a Pivotal Phase 2 Study.

Objectives: To assess efficacy and safety of the new Dextroamphetamine Transdermal System (d-ATS) to treat children and adolescents (aged 6-17 years) with attention-deficit/hyperactivity disorder (ADHD). Methods: In this phase 2, randomized, placebo-controlled study, 4 d-ATS patches of differing doses (5, 10, 15, and 20 mg) were evaluated. Patients began a 5-week, open-label, stepwise dose-optimization period in which they received a 5-mg d-ATS patch (applied to hip) for 9 hours. During weekly visits, patients were evaluated for possible adjustments to the next dose level based on efficacy and safety. Once at the optimal dose, that dose was maintained during a 2-week, crossover double-blind treatment period. Primary endpoint was to assess efficacy of d-ATS versus placebo as measured by Swanson, Kotkin, Agler, M-Flynn, and Pelham Scale (SKAMP) total score; key secondary endpoints included assessing onset and duration of efficacy by SKAMP total score, and additional secondary endpoints included Permanent Product Measure of Performance (PERMP) scores. Safety was assessed throughout. Results: d-ATS treatment resulted in significant improvements versus placebo in ADHD symptoms as measured by SKAMP total score, with overall least-squares mean difference (95% confidence interval) versus placebo of -5.87 (6.76, -4.97; p < 0.001) over the 12-hour assessment period. Onset of efficacy was observed at 2 hours postdose (p < 0.001), and duration of effect continued through 12 hours (patch removed at 9 hours), with significant differences between d-ATS and placebo at all time points from 2 hours onward (all p ≤ 0.003). Significant improvements versus placebo in PERMP-A and PERMP-C scores were also observed from 2 to 12 hours postdose with d-ATS treatment. d-ATS was safe and well-tolerated, with a systemic safety profile similar to that observed with oral amphetamines. Conclusions: This study demonstrates that d-ATS is an effective and well-tolerated treatment for children and adolescents with ADHD. These data indicate that d-ATS can deliver sustained levels of efficacy along with the advantages of transdermal drug delivery, making it a beneficial new treatment option. Clinical Trial Registration no.: NCT01711021.

Pharmacokinetic Profile of the Asenapine Transdermal System (HP-3070).

PURPOSE/BACKGROUND: The asenapine transdermal system (HP-3070) is the first antipsychotic patch approved in the United States for treatment of adults with schizophrenia. METHODS/PROCEDURES: Three phase 1, open-label, randomized studies characterized the pharmacokinetic (PK) profile of HP-3070 by assessing its relative bioavailability compared with sublingual asenapine, its single-/multiple-dose PK and dose proportionality, and the effects of application site, ethnicity, and external heat on bioavailability. Two studies were conducted in healthy subjects, and 1 was conducted in adults with schizophrenia. FINDINGS/RESULTS: During single HP-3070 administration, asenapine concentrations increased gradually over approximately 12 hours and remained steady until the patch was removed 24 hours after application. Asenapine area under the curve values at HP-3070 3.8 and 7.6 mg/24 hours doses were similar to those for sublingual asenapine 5 and 10 mg twice-daily doses, respectively, whereas peak exposure (maximum observed plasma concentration) was significantly lower. During daily application of HP-3070, steady-state PK was reached within approximately 72 hours after initiating daily dosing and was characterized by peak-to-trough asenapine plasma concentration ratio of approximately 1.5. HP-3070 PK was dose proportional in the dose range studied, not affected by administration site, and similar across the studied ethnic groups. Application of external heat increased the rate of asenapine absorption (time to reach maximum observed plasma concentration) but did not significantly affect peak and total exposure. IMPLICATIONS/CONCLUSIONS: HP-3070 exhibited a dose-dependent PK profile unaffected by site of administration or ethnicity. HP-3070 showed a predictable absorption profile with limited variability, with an area under the curve similar to that of sublingual asenapine. Based on these PK metrics, HP-3070 steadily delivers asenapine with lower peaks and troughs than sublingual administration of asenapine.