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To describe lemborexant and daridorexant for insomnia treatment using number needed to treat (NNT), number needed to harm (NNH), and likelihood to be helped or harmed (LHH).
Dichotomous outcomes were identified from the two registrational daridorexant randomized controlled trials. Analogous data were then extracted for lemborexant from the two lemborexant registration studies.
Using pooled dosage data, lemborexant had a clinically relevant magnitude of therapeutic effect, as evidenced by NNT values versus placebo <10, and NNH values for lemborexant versus placebo were >10, suggesting that lemborexant is relatively tolerable. When comparing response versus discontinuation because of an adverse event (AE) for Month 3, the LHH ranges 5.2 to 10.4 for lemborexant pooled 5 mg and 10 mg doses (a favorable result). For daridorexant, the efficacy outcomes for pooled 25 mg and 50 mg doses generally result in NNT values versus placebo ≥10; in all instances, doses of 50 mg yield more robust NNT estimates than for the 25 mg dose. The rate of discontinuation because of an AE at Month 3 was higher for placebo than for daridorexant, rendering favorable LHH calculations for daridorexant despite the less robust NNT estimates, with an LHH in the range of 90.9 to 125 for Month 3 when comparing response versus discontinuation because of an AE (a favorable result).
Benefit-risk ratio for lemborexant and daridorexant is favorable as measured by NNT, NNH, and LHH. Indirect comparisons suggest an efficacy advantage for lemborexant and a tolerability advantage for daridorexant.
Lumateperone is an FDA-approved antipsychotic to treat schizophrenia and depressive episodes associated with bipolar I or bipolar II disorder as monotherapy and as adjunctive therapy with lithium or valproate. This post hoc analysis investigated the efficacy and tolerability of lumateperone in patients with schizophrenia via number needed to treat (NNT), number needed to harm (NNH), and likelihood to be helped or harmed (LHH).
Data were pooled from three late-phase 4–6 week placebo-controlled studies of lumateperone 42 mg/day in adults with schizophrenia and an acute exacerbation of psychosis (Study 005 [NCT01499563], Study 301 [NCT02282761], Study 302 [NCT02469155]). NNT and NNH were calculated vs placebo for several different Positive and Negative Syndrome Scale [PANSS] Total score response cutoffs (percent reduction from baseline) and for adverse events (AEs), respectively.
In the two informative studies (placebo, n=221; lumateperone, n=224), the NNT vs placebo for lumateperone was statistically significant for PANSS Total score reductions from baseline to 4 weeks/endpoint of ≥20% (NNT=9, 95% confidence interval [CI] 5–36) and ≥30% (NNT=8; 95%CI 5–21). In all studies pooled (placebo, n=412; lumateperone, n=406), study discontinuations due to AEs were uncommon and the NNH (389) was not statistically significant from placebo. The only AE with NNH vs placebo <10 was somnolence/sedation (NNH=8; 95%CI 6–12). With lumateperone treatment, weight gain ≥7% from baseline was similar to placebo (NNH=112) and fewer patients experienced akathisia than placebo. Lumateperone LHH ratios were >>1 for all AEs (range 13.6–48.6) except somnolence/sedation (LHH~1).
Lumateperone’s benefit-risk profile was favorable in late-phase schizophrenia trials.
HP-3070, a once-daily asenapine transdermal system, is FDA-approved for adults with schizophrenia. In a pivotal phase 3 randomized controlled study, patients with schizophrenia who were treated once daily with HP-3070 demonstrated significant improvement in Positive and Negative Syndrome Scale (PANSS) total scores compared with placebo. The PANSS score’s five-factor structure can also assess treatment efficacy across different domains. This post-hoc analysis of the pivotal study evaluated the efficacy of HP-3070 by examining these domains.
In the pivotal phase 3 study, adults with acute exacerbations of schizophrenia were randomized to 6 weeks of treatment with HP-3070 3.8mg/24h, 7.6mg/24h, or placebo. Factor analysis of PANSS scores was performed using five domains (negative symptoms, positive symptoms, disorganized thought, uncontrolled hostility/excitement, anxiety/depression). Mixed-model repeated-measures (MMRM) analysis included change from baseline in PANSS factor score as the repeated dependent variable, with country, treatment, visit, treatment by visit interaction, and baseline PANSS score as covariates.
The analysis included 607 patients. Least-squares mean estimates (standard error) of the difference from placebo in change from baseline to Week 6 for each factor were as follows: negative symptoms, 3.8mg/24h, -0.9 (0.43), P=0.045, and 7.6mg/24h, -0.4 (0.43), P=0.41; positive symptoms, 3.8mg/24h, -2.3 (0.57), P<0.001, and 7.6mg/24h, -2.0 (0.57), P<0.001; disorganized thought, 3.8mg/24h, -1.5 (0.38), P<0.001, and 7.6mg/24h, -0.9 (0.38), P=0.03; uncontrolled hostility/excitement: 3.8mg/24h, -1.1 (0.30), P<0.001, and 7.6mg/24h -0.9 (0.30), P=0.002; anxiety/depression, 3.8mg/24h, -0.5 (0.31), P=0.14, and 7.6mg/24h, -0.6 (0.31), P=0.07.
HP-3070 demonstrated treatment effects on a PANSS five-factor model, with the results indicating impact on negative symptoms, positive symptoms, disorganized thought, uncontrolled hostility/excitement, and anxiety/depression. These findings suggest that HP-3070 may address a broad range of symptoms in schizophrenia.
Noven Pharmaceuticals, Inc., a wholly-owned subsidiary of Hisamitsu Pharmaceutical, Co.
Aripiprazole 2-month ready-to-use 960 mg (Ari 2MRTU 960) is a new long-acting injectable (LAI) antipsychotic formulation for gluteal administration every 2 months. This 32-week trial evaluated the safety, pharmacokinetics, and efficacy of multiple-dose administration of Ari 2MRTU 960 in clinically stable adults with schizophrenia or bipolar I disorder (BP-I), versus that of aripiprazole once-monthly 400 mg (AOM 400; an LAI indicated for the maintenance treatment of schizophrenia in adult patients stabilized with oral aripiprazole [indication varies by country]). Safety and efficacy outcomes in the subpopulation of patients with schizophrenia are reported here.
Patients with schizophrenia were randomized to receive Ari 2MRTU 960 every 56±2 days or AOM 400 every 28±2 days. Safety and tolerability assessments included adverse event (AE) reporting, Visual Analogue Scale [VAS] scores (scale range: 0–100) for patient-reported injection site pain, and extrapyramidal symptom (EPS) monitoring. Efficacy was evaluated at Week 32 using mean (standard deviation [SD]) Clinical Global Impression – Improvement (CGI-I) score, and mean (SD) change from baseline in Clinical Global Impression – Severity (CGI-S) score, Subjective Well-being under Neuroleptic Treatment – Short Form [SWN-S] Total score, and Positive and Negative Syndrome Scale (PANSS) Total score.
Study completion rate was 79.3% (73/92 patients) in the Ari 2MRTU 960 group and 67.7% (63/93 patients) in the AOM 400 group. Demographics and disease characteristics were well balanced between groups at baseline (mean [SD] PANSS Total score: Ari 2MRTU 960, 62.0 [13.5]; AOM 400, 61.8 [13.5]; mean (SD) CGI-S score: Ari 2MRTU 960, 3.3 [0.9]; AOM 400, 3.1 [0.9]). Treatment-emergent AE (TEAE) incidence was 66.3% with Ari 2MRTU 960 and 63.4% with AOM 400. The most frequent TEAEs were increased weight (Ari 2MRTU 960, 21.7%; AOM 400, 18.3%) and injection site pain (Ari 2MRTU 960, 15.2%; AOM 400, 9.7%). Mean (SD) VAS score for pain after last injection was 1.5 (4.58) with Ari 2MRTU 960 and 1.3 (2.79) with AOM 400. Minimal change was seen in EPS in either group. At Week 32, mean (SD) CGI-I score was similar between groups (Ari 2MRTU 960, 3.5 [1.0]; AOM 400, 3.6 [0.9]). Minimal change from baseline was seen at Week 32 in CGI-S score and SWN-S Total score. There was no clinically meaningful difference between the groups for PANSS Total score (difference of least squares mean change from baseline [95% confidence interval]: -0.9 [-3.5, 1.8]; p=0.5154).
In patients with schizophrenia, administration of Ari 2MRTU 960, as compared with AOM 400, was generally well tolerated, and clinical stability was maintained during the study.
Otsuka Pharmaceutical Development & Commercialization, Inc. (Princeton, NJ, USA) and H. Lundbeck A/S (Valby, Denmark).
Patients with schizophrenia may exhibit symptoms of hostility. HP-3070, a once-daily asenapine transdermal system, is the first antipsychotic patch approved by the FDA for use in adults with schizophrenia, and its efficacy in this indication has been demonstrated. This post hoc analysis of a phase 3 randomized study investigated the efficacy of HP-3070 in treating hostility in patients with schizophrenia.
In the pivotal phase 3 study, adults with schizophrenia were randomized 1:1:1 to once-daily treatment with HP-3070 3.8 mg/24 h, 7.6 mg/24 h, or placebo for 6 weeks. Least-squares mean (LSM) changes in the PANSS hostility item score (P7) and PANSS-Excited Component (PANSS-EC), the sum of items P4 (Excitement), P7 (Hostility), G4 (Tension), G8 (Uncooperativeness), and G14 (Poor impulse control), from baseline to week 6 were assessed post hoc. Efficacy was analyzed with a mixed-effects model for repeated measures (MMRM) adjusted for PANSS-positive symptoms, items P1 (Delusions), P2 (Conceptual disorganization), P3 (Hallucinatory behavior), P5 (Grandiosity), P6 (Suspiciousness/persecution), and G9 (Unusual thought content) and presence of somnolence (including hypersomnia, hypersomnolence, or sedation) or akathisia.
Among the 369 patients with a baseline PANSS hostility item score >1 and hostility scores collected at both baseline and week 6 (126 HP-3070 7.6 mg/24 h; 123 3.8 mg/24 h; 120 placebo), the week 6 LSM (95% CI) change from baseline in PANSS hostility item score was significantly better with HP-3070 than placebo for 7.6 mg/24 h (−0.4 [−0.6, −0.2]; P < .001) and 3.8 mg/24 h (−0.3 [−0.6, −0.1]; P < .01). Similar results were observed after adjusting for covariates (P < .01 for both doses). The week 6 PANSS-EC LSM change from baseline was also greater for HP-3070 7.6 mg/24 h (−1.1 [−1.9, −0.4]; n = 164; P < .01) and 3.8 mg/24 h (−1.3 [−2.0, −0.6]; n = 168; P < .001) compared with placebo (n = 165).
In this post hoc analysis, HP-3070 was superior to placebo in reducing hostility in patients with schizophrenia, even after adjusting for covariates, suggesting that these effects are at least partially independent of general antipsychotic effects or of effects on sedation or akathisia. These findings suggest that HP-3070 may have a specific anti-hostility effect in patients with schizophrenia.
Noven Pharmaceuticals, Inc., a wholly-owned subsidiary of Hisamitsu Pharmaceutical, Co.
Episodes of acute agitation associated with psychiatric disorders are often managed in emergency and inpatient settings. These trials evaluated the efficacy, safety, and tolerability of dexmedetomidine orally dissolving film (ODF), an investigational treatment for acute agitation associated with schizophrenia (SERENITY I) or bipolar disorder (SERENITY II). Dexmedetomidine ODF is a highly selective agonist of alpha 2 adrenergic receptors that modulate norepinephrine release from the locus coeruleus. Two randomized, double-blind, placebo-controlled Phase 3 trials in 15 U.S. sites included participants aged 18 to 75 with acute agitation and a DSM-5 diagnosis of schizophrenia or schizoaffective disorder (Serenity I) or bipolar disorder I or II (Serenity II). Agitation was defined as ³14 on the Positive and Negative Syndrome Scale-Excited Component (PEC) at screening and baseline, and ³4 on at least 1 of the 5 PEC items (poor impulse control, tension, hostility, uncooperativeness, and excitement) at baseline. Randomization was 1:1:1 to dexmedetomidine ODF 120 or 180 mcg or matching placebo. All participants self-administered study drugs. For persistent or recurrent agitation after 2 hours, investigators could redose a half-dose. The primary endpoint was changed from baseline in PEC total at 2 hours. The secondary endpoint was the earliest time at which a statistically significant separation from placebo occurred.A total of 380 patients were randomized in each trial (N = 760). All doses of dexmedetomidine ODF met the primary endpoint of change from baseline in PEC at 2 hours vs placebo (P < .001). Statistically significant improvement in PEC occurred as early as 20 minutes with the 180 mcg dose in both trials. A second (half-strength) dose was given to 10 (4.0%) participants in the 180 mcg groups, 34 (13.3%) in the 120 mcg groups, and 58 (23.0%) in the placebo groups in Serenity 1 and Serenity 2. There were no drug-related serious or severe TEAEs in either trial. No participant was unarousable by the Agitation and Calmness Evaluation Scale. For dexmedetomidine 180 mcg, 120 mcg, and placebo, the incidence of TEAEs was 37.3%, 39.5%, and 15.1% in Serenity 1 and 35.7%, 34.9%, and 17.5% in Serenity 2. Somnolence was the most common TEAE in both trials (22% Serenity I; 21% Serenity 2). Of 110 somnolence reports, 75% were mild and 25% moderate. In 2 Phase 3 trials, the investigational treatment, dexmedetomidine ODF, effectively treated acute agitation associated with schizophrenia or bipolar disorder, with onset of action as early as 20 minutes at the 180 mcg dose. Both doses of dexmedetomidine ODF produced a calming effect without unarousable sedation. Mild or moderate somnolence was the most common AE. Dexmedetomidine ODF is a selective alpha-2 adrenergic receptor agonist that allows self-administration, making it a potential addition to noninvasive treatments for acute agitation associated with schizophrenia or bipolar disorder.
The endogenous opioid system affects metabolism, including weight regulation. Evidence from preclinical and clinical studies provides a rationale for targeting this system to mitigate weight-related side effects of antipsychotics. This review describes the role of the opioid system in regulating weight and metabolism, examines the effects of opioid receptor antagonism on those functions, and explores the use of opioid antagonists to mitigate antipsychotic-associated weight gain and/or metabolic effects.
A PubMed literature search was conducted to identify representative opioid antagonists and associated preclinical and clinical studies examining their potential for the regulation of weight and metabolism.
The mu opioid receptor (MOR), delta opioid receptor (DOR), and kappa opioid receptor (KOR) types have overlapping but distinct patterns of central and peripheral expression, and each contributes to the regulation of body weight and metabolism. Three representative opioid antagonists (eg, naltrexone, samidorphan, and LY255582) were identified for illustration. These opioid antagonists differed in their receptor binding and pharmacokinetic profiles, including oral bioavailability, systemic clearance, and half-life, and were associated with varying effects on food intake, energy utilization, and metabolic dysregulation.
Preclinical and clinical data suggest that antagonism of the endogenous opioid system is a mechanism to address antipsychotic-associated weight gain and metabolic dysregulation. However, evidence suggests that the differing roles of MOR, DOR, and KOR in metabolism, together with the differences in receptor binding, pharmacokinetic, and functional activity profiles of the opioid receptor antagonists discussed in this review, likely contribute to their differential pharmacodynamic effects and clinical outcomes observed regarding antipsychotic-associated weight gain.
Four medications are FDA approved for bipolar depression: lurasidone (LUR), cariprazine (CAR), quetiapine IR & XR (QUE), and olanzapine-fluoxetine combination (OFC). Indirect comparisons for efficacy using Number Needed to Treat (NNT) and for tolerability using Number Needed to Harm (NNH) can be useful clinical benchmarks to aid treatment decisions. Benefit and risk may also be examined using the Likelihood to be Helped or Harmed (LHH). In this post-hoc analysis, we examined the benefit-risk ratio of the four treatments using LHH.
Individual and pooled monotherapy data from short-term clinical registration trials of patients with bipolar depression were assessed for LUR, CAR, pooled QUE (300 and 600 mg), and pooled OFC (considered as monotherapy for this study at fixed doses of 6/25, 6/50, 12/50 mg) data. NNT estimates were calculated using the proportions of MADRS responders (defined as ≥ 50% improvement at study endpoint) and MADRS remitters (defined as a score of ≤ 10 [for LUR and CAR] and ≤ 12 [for QUE and OFC]) at study endpoint. NNH data were calculated for the proportions of patients who discontinued due to an adverse event (AE) and for individual AEs commonly associated with each treatment. LHH was calculated as the ratio of NNH/NNT to determine the benefit-risk ratio.
The NNT estimates for response vs. placebo were: 5 for both LUR 20–60 mg and 80–120 mg; 10 for both CAR 1.5 mg and 3.0 mg; 6 for QUE; and 4 for OFC. The NNTs for remission vs placebo were: 7 for LUR 20–60 mg and 9 for LUR 80–120 mg; 10 for CAR 1.5 mg and 13 for CAR 3.0 mg; 6 for QUE; and 5 for OFC. The NNH estimates for discontinuations due to AEs were: 642 for LUR 20–60 mg and −151 for LUR 80–120 mg; 298 for CAR 1.5 mg and 31 for CAR 3.0 mg; 10 for QUE; and −37 for OFC. NNH values that were negative were assigned a value of 1000 to permit LHH to be calculated. The LHHs for response vs discontinuation due to an AE were: 128.4 for LUR 20–60 mg and 200 for LUR 80–120 mg; 29.8 for CAR 1.5 mg and 3.1 for CAR 3.0 mg; 1.7 for QUE; and 250 for OFC. The LHHs for response vs akathisia were: 3.6 for LUR 20–60 mg and 2.4 for LUR 80–120 mg; 3.6 for CAR 1.5 mg and 1.3 for CAR 3.0 mg; 34 for QUE; and not available (NA) for OFC. The LHHs for response vs EPS were: 8 for LUR 20–60 mg and 3.2 for LUR 80–120 mg; 5 for CAR 1.5 mg and 2.5 for CAR 3.0 mg; NA for QUE; and NA for OFC. The LHH for response vs weight gain was 5.8 for LUR 20–60 mg and 1110 for LUR 80–120 mg; 5 for both doses of CAR; 2.7 for QUE; and 1.5 for OFC.
LHH can illustrate the trade-offs regarding potential benefits versus potential harms. Across a variety of measures, the lower-dose groups for both LUR and CAR generally evidenced a better benefit-risk profile than the higher-dose groups. While quetiapine and OFC demonstrated robust efficacy, their reduced tolerability resulted in a more marginal benefit-risk ratio for some of the outcomes.
The Abnormal Involuntary Movement Scale (AIMS) total score (sum of items 1–7) is usually the primary efficacy measure in tardive dyskinesia (TD) clinical trials. However, item 8 of the AIMS (clinician’s global impression of severity) might also be an appropriate assessment in real-life healthcare settings. To explore the potential of item 8 as a clinical measure, post hoc analyses were conducted using data from a long-term study of valbenazine, an approved TD medication.
In KINECT 4 (NCT02405091), adults with TD received once-daily valbenazine (40 or 80 mg) for 48 weeks. Analyses included two sets of AIMS item 8 scores: based on investigators ratings of item 8 using protocol-defined descriptors; and based on investigators highest scores from items 1–7 (analyzed post hoc). Shift analyses included an improvement from score =3 at baseline (moderate or severe) to score =2 at Week 48 (none to mild).
At baseline in all participants (N=163), AIMS item 8 mean scores were 3.2 (protocol) and 3.3 (post hoc). In participants with a score =3 at baseline per investigators ratings using protocol-defined descriptors, 95.9% [94/98] shifted to a score =2 by Week 48. A similar result (93.9% [93/99]) was found when item 8 was based on investigators highest scores from items 1–7.
Shift analyses using AIMS item 8 scores indicated that most participants in KINECT 4 had a clinically meaningful improvement after 48 weeks of once-daily treatment with valbenazine. AIMS item 8 may be an appropriate clinical measure for assessing changes in TD severity.
Olanzapine effectively treats schizophrenia and bipolar I disorder (BD-I); however, its use is hindered by significant weight gain. A combination of olanzapine and samidorphan (OLZ/SAM) is in development to provide the efficacy of olanzapine while mitigating olanzapine-associated weight gain through opioid-receptor blockade. Here, we summarize OLZ/SAM clinical data.
The OLZ/SAM development program consists of 18 phase 1–3 clinical studies evaluating antipsychotic and weight mitigation efficacy of OLZ/SAM, along with pharmacokinetics, safety, and tolerability. Safety evaluation also included metabolic laboratory assessments.
OLZ/SAM significantly improved psychotic symptoms (measured by Positive and Negative Syndrome Scale); improvements were similar to that observed with olanzapine vs placebo. OLZ/SAM resulted in significantly less weight gain than olanzapine. Additionally, 2 long-term phase 3 extension studies confirmed the durability of antipsychotic effect, as well as stabilization of weight and metabolic parameters in those continuing treatment. Supporting the potential use of OLZ/SAM in BD-I, OLZ/SAM or olanzapine resulted in bioequivalent olanzapine plasma concentrations, and OLZ/SAM did not affect lithium or valproate pharmacokinetics. OLZ/SAM treatment had no clinically relevant effects on ECG parameters (including QTc interval). OLZ/SAM and olanzapine safety were similar, except for reduced weight gain with OLZ/SAM; no additional safety risks were identified.
Data across 18 OLZ/SAM studies in >1600 subjects support an antipsychotic efficacy and safety profile for OLZ/SAM that is similar to olanzapine, with significantly less weight gain than olanzapine. OLZ/SAM is a potential new treatment for schizophrenia and BD-I patients needing efficacious long-term treatment with reduced risk of weight gain.
Current guidelines for the treatment of patients with schizophrenia advocate that patients receive treatment with a long-acting injectable (LAI) antipsychotic medication if they prefer such treatment or if they have a history of poor or uncertain adherence. Available LAI formulations in the United States include first-generation antipsychotics (fluphenazine decanoate and haloperidol decanoate), risperidone/paliperidone containing products (risperidone microspheres, paliperidone palmitate, and risperidone subcutaneous), aripiprazole containing products (aripiprazole monohydrate and aripiprazole lauroxil), and olanzapine pamoate. LAI antipsychotics can address the guesswork about adherence status and patients may prefer them if they are offered this as a choice, including individuals early in their disease course. Additional approved indications in the United States for LAI antipsychotics include bipolar I disorder maintenance treatment for risperidone microspheres and aripiprazole monohydrate, and schizoaffective disorder for paliperidone palmitate once monthly. Differences and similarities among the different products are discussed, including guidance regarding optimal treatment selection. Tips are provided to enhance effective patient communication to maximize the likelihood of acceptance of this treatment modality.
Objective: Compare burden of disease among patients with dementia-related psychosis (DRP), dementia without psychosis (dementia only), and dementia-related agitation/aggression (DAA) in long-term care (LTC) facilities.
Background: Patients with dementia often experience neuropsychiatric symptoms (NPS), including psychosis and agitation/aggression. Real-world data on the comorbidity profile of DRP and DAA patients are limited.
Design/Methods: Dementia patients were identified from a US LTC database based on ?2 dementia diagnosis codes or 1 dementia diagnosis code and antidementia therapy prescription during 1 Jan 2013 to 30 May 2017. Patients were categorized into DRP (?2 psychosis or 1 psychosis diagnosis code and prescription of antipsychotic therapy and no history of agitation/aggression diagnosis), dementia only (no psychosis or agitation/aggression diagnosis and no history of antipsychotic therapy [dementia only]), and DAA (?2 diagnosis codes of agitation/aggression and no history of psychosis diagnosis or antipsychotic therapy) groups (index date). Comorbidities and concomitant therapies were defined during 12 months prior to index date.
Results: There were 26,002 dementia residents: DRP (n=11,921; 46%); dementia only (n=11,432; 44%); DAA (n=2649; 10%). DRP patients were younger (mean age 80.8 years) than dementia only (84.3 years) or DAA (83.8 years). DRP patients were sicker overall versus dementia only: anemia (32% vs 29%); anxiety (55% vs 33%); bladder disorders (19% vs 13%); depression (75% vs 58%); hypertension (43% vs 33%); diabetes (43% vs 38%); insomnia disorders (32% vs 19%); (all P<0.05). More DAA patients had anxiety (43%), depression (66%), hypertension (43%), and insomnia disorders (26%) than dementia only (all P<0.05). Most DRP patients (94.3%) received off-label treatment for DRP; approximately one third (31.6%) of DAA patients received off-label treatment for DRP.
Conclusions: This study, the first of its type to use a US LTC database, demonstrated a significant comorbidity burden associated with DRP or DAA compared with dementia only, which should be considered when using off-label treatments. These data highlight the need for safe and effective treatments for dementia NPS.
Study Sponsored By: ACADIA Pharmaceuticals Inc.
NR, SA, VA are employees of ACADIA Pharmaceuticals
LC has served as a consultant, speaker, holds stock in, or receives royalties from: Acadia, Alkermes, Allergan, Avanir, BioXcel, Eisai, Impel, Indivior, Intra -Cellular Therapies, Janssen, Lundbeck, Luye, Merck, Neurocrine, Noven, Osmotica, Otsuka, Pfizer, Sage, Shire, Sunovion, Takeda, Teva, Vanda, Bristol-Myers Squibb, Eli Lilly, J & J; Wiley (Editor-in-Chief, International Journal of Clinical Practice), UpToDate (reviewer), Springer Healthcare (book)
This submission is an encore of a poster abstract originally presented at ISPOR 2019, New Orleans, LA, USA, May 18–22, 2019; original presentation under the same title.
Binge-eating disorder (BED) is associated with obesity (BMI ≥30) in approximately 40-45% of patients. Dasotraline is a long-acting dopamine/norepinephrine reuptake inhibitor with a PK profile characterized by slow absorption and an elimination half-life of 47-77 hours, permitting once-daily dosing. In a recent placebo-controlled, flexible-dose study, dasotraline demonstrated significant efficacy in patients with BED. We now report an analysis from this study of the effect of dasotraline on body weight.
Patients with moderate-to-severe BED, based on DSM-5 criteria, were randomized to 12 weeks of double-blind flexible-dose treatment with dasotraline (4-8 mg/d) vs. placebo. The primary efficacy outcome was number of binge-eating days/week. Mean change in body weight at Week 12 (assessed as a safety outcome) was analyzed by baseline body mass index (BMI, kg/m2) category. Inferential statistics were not performed.
The safety population consisted of 317 patients (female, 84%; mean age, 38.2 years; mean weight, 97.3 kg). At baseline, the proportions of patients in each BMI category were as follows: normal (<25 kg/m2: 5.7%), overweight (25 to <30 kg/m2: 18.3%), obesity class I (30 to <35 kg/m2: 24.9%), class II (35 to <40 kg/m2: 29.3%), and class III (≥40 kg/m2: 21.8%). For the overall patient sample, treatment with dasotraline significantly reduced the number of binge-eating days per week vs. placebo (-3.74 vs. -2.75; P<0.0001; effect size = 0.74). Mean changes at Week 12 in weight (kg) for completers treated with dasotraline vs. placebo, by baseline BMI category, were as follows: normal weight (-4.6 vs. -0.2), overweight (-5.8 vs. +1.3), and combined obesity classes I-III (-6.2 vs. +0.3). Among obese patients (Class I-III, combined) treated with dasotraline, weight reduction (≥5%) was observed in 45.3% of patients (vs. 4.1% on placebo); and weight reduction ≥10% in approximately 13.7% of patients (vs. none on placebo). Weight-related adverse events, for dasotraline vs. placebo, consisted of decreased appetite (19.7% vs. 6.9%), decreased weight (12.1% vs. 0%), and increased weight (0.6% vs. 1.3%).
Among patients completing 12 weeks of treatment with dasotraline, weight reduction ≥5% was observed in 45% of obese patients with a BMI ≥30. The most frequent weight-related adverse event was decreased appetite, reported in approximately one in five patients treated with dasotraline.
Clinicaltrials.gov number: NCT02564588
Supported by funding from Sunovion Pharmaceuticals Inc.
Targeting of glutamate receptors is a novel approach for the treatment of major depressive disorder (MDD). This study aimed to review the usefulness for esketamine nasal spray for the management of treatment-resistant depression (TRD) using the tools of evidence-based medicine: number needed to treat (NNT), number needed to harm (NNH), and likelihood to be helped or harmed (LHH).
Data sources were four completed Phase 3 randomized, double-blind, placebo-controlled, studies, including two pivotal registration studies of esketamine nasal spray in TRD in non-elderly adults (acute flexible-dose study NCT02418585, maintenance study NCT02493868) Efficacy outcomes included acute response (≥50% decrease from baseline on Montgomery-Asberg Depression Rating Scale [MADRS] total score), acute remission (MADRS scores ≤12; and other thresholds using the MADRS and Clinical Global Impressions-Severity [CGI-S] scales), categorical shifts in MADRS and CGI-S scores, and avoidance of relapse/recurrence (observed relapse rates). NNT, NNH and LLH are calculated for combination of esketamine nasal spray and oral antidepressant (esketamine+AD) vs AD+placebo in patients with TRD.
In the acute flexible-dose study of esketamine nasal spray (56-84 mg twice-weekly for 4 weeks), MADRS response with esketamine+AD vs AD+placebo at endpoint (rates 63.4% vs 49.5%, respectively) yielded an NNT value of 8, and MADRS remission at endpoint (48.2% vs 30.3%) resulted in a NNT vs AD+placebo of 6. NNH values vs AD+placebo were <10 for the adverse events (AE) of dissociation (26.1% vs 3.7%), vertigo (26.1% vs 2.8%), nausea (26.1% vs 6.4%), dizziness (20.9% vs 4.6%), and dysgeusia (24.3% vs 11.9%), the NNH values were 5, 5, 6, 7, and 9, respectively. Discontinuation rates due to AE (7.0% vs 0.9%) yielded a NNH of 17. LHH comparing MADRS remission vs discontinuation was 17/6, or approximately 3. The pattern of results was similar for the other acute studies and for the pooled data combining all 3 acute studies. Maintenance use of esketamine (dose 56-84 mg once-weekly or once-every-other-week) plus an oral AD demonstrated NNT values <10 for relapse and/or maintenance of remission in favor of esketamine+AD vs AD+placebo, a NNT of 4 was observed for outcome of relapse in patients with stable response at the time of randomization (relapse rates were 25.8% vs 57.6%, respectively). In the maintenance study, discontinuation rates due to an AE (2.6% vs 2.1%) yielded a non-significant NNH value of 178.
The low NNT values <10 for efficacy outcomes suggest potential benefits of esketamine+AD for both acute and maintenance use. LHH was favorable: esketamine+AD was 3 times more likely to result in acute remission vs discontinuation due to an AE.
Akathisia and restlessness are common adverse events associated with atypical antipsychotic use; in severe cases, symptoms may lead to treatment discontinuation. Cariprazine, a dopamine D3/D2 receptor partial agonist with preferential binding to D3 receptors, is approved for the treatment of schizophrenia (1.5–6 mg/d), and manic or mixed (3–6 mg/d) and depressive episodes (1.5–3 mg/d) associated with bipolar I disorder. Pooled post hoc analyses were conducted to characterize the incidence and severity of cariprazine-related akathisia and restlessness in patients who participated in bipolar disorder studies.
All studies were Phase II/III multicenter, randomized, double-blind, placebo-controlled, parallel-group studies in patients with bipolar I disorder who were currently experiencing a manic/mixed (NCT00488618, NCT01058096, NCT01058668) or depressive (NCT01396447, NCT02670538, NCT02670551) mood episode. Patients received flexibly dosed cariprazine 3-12 mg/d (day 1: 1.5 mg; day 2: 3 mg; subsequent up-titration in 3-mg increments if needed) or placebo in the bipolar mania studies and fixed-dose cariprazine 1.5 mg/d, 3 mg/d (slow titration to 1.5 mg [day 8] and 3 mg [day 15] or initiation at 1.5 mg with escalation to 3 mg on day 15), or placebo in the bipolar depression studies. The incidence, severity, and timing of treatment-emergent adverse events (TEAEs) of akathisia and restlessness were evaluated in this analysis.
In the bipolar mania studies (N=1065), TEAEs of akathisia occurred in 20.2% of cariprazine-treated patients and 4.8% of placebo-treated patients; 2.4% of cariprazine-treated patients discontinued due to akathisia. TEAEs of restlessness occurred in 6.7% and 2.3% of cariprazine- and placebo-treated patients, respectively, and caused discontinuation of 0.3% of cariprazine-treated patients. In the bipolar depression studies (N=1407), akathisia occurred in 2.1%, 5.5%, and 9.6% of patients in the placebo, cariprazine 1.5 mg/d, and cariprazine 3 mg/d groups, respectively; <2% of patients in each group discontinued due to akathisia. Restlessness occurred in 3.2% of placebo-treated patients and 2.1% and 6.6% of patients in the 1.5 and 3 mg/d groups, respectively; discontinuations due to restlessness occurred in 0.2% and 1.1% of patients in the 1.5 and 3 mg/d groups. Akathisia and restlessness in cariprazine-treated patients was generally mild or moderate in severity (>92% in both populations). Most akathisia events in the bipolar mania studies were reported for the first time within the first 2-3 weeks of treatment.
In these post hoc analyses, the incidence of akathisia and restlessness were generally higher with cariprazine than with placebo. However, most incidences were mild or moderate in severity, and infrequently led to discontinuation. Akathisia appears to be dose related in both mania and depression, suggesting lower doses and slower titration may reduce occurrence.
Binge-eating disorder (BED), the most common eating disorder in the US, is frequently associated with impairment in quality of life and functioning. Dasotraline, a long-acting dopamine/norepinephrine reuptake inhibitor, has a PK profile characterized by slow absorption and an elimination half-life of 47-77 hours, and is dosed once-daily. In a recent placebo-controlled, flexible-dose study, dasotraline demonstrated significant efficacy in patients with BED. We now report an analysis from this study of the effect of dasotraline on binge-related obsessions and compulsions.
Patients with moderate-to-severe BED, based on DSM-5 criteria, were randomized to 12 weeks of double-blind, placebo controlled, treatment with flexible doses of dasotraline (4, 6, and 8 mg/d). The primary efficacy measure was number of binge-eating days/week; secondary measures included the Binge Eating Clinical Global Impression of Severity (BE-CGI-S) score and the Yale-Brown Obsessive-Compulsive Scale Modified for Binge-Eating (Y-BOCS-BE), a validated, 10-item interviewer-administered measure designed to assess the severity of obsessional thoughts and compulsive behaviors related to binge eating. Change from baseline in efficacy measures in the Intent-to-treat (ITT) population were analyzed using a mixed model for repeated measures (MMRM) analysis.
The ITT population consisted of 317 patients (female, 84%; mean age, 38.2 years). LS mean reduction from baseline in number of Binge Eating (BE) days per week was significantly greater for dasotraline vs. placebo at week 12 (-3.74 vs. -2.75; P<0.0001; effect size [ES] = 0.74; primary endpoint); week 12 change was significantly greater for dasotraline vs. placebo on the Y-BOCS-BE total score (-17.05 vs. -9.88; P<0.0001; ES, 0.96), the obsession subscale score (-8.32 vs. -4.58; P<0.0001; ES, 0.95), and the compulsion subscale score (-8.69 vs. -5.35; P<0.0001; ES, 0.87). All 10 YBOCS-BE items were significantly improved on dasotraline vs. placebo at week 12 (P<0.001 for all comparisons; with effect sizes ranging from 0.54 to 0.90). At Week 12 (LOCF), for dasotraline and placebo, 52.3% and 18.4% of patients, respectively, had a BE-CGI-S score of 1 (“normal; not at all ill”; NNT=3). At endpoint, for patients with a global illness severity score of 1, the corresponding mean Y-BOCS-BE total scores were 0.5 and 0.7 for dasotraline and placebo, respectively, indicating that when BED illness severity approaches “normal, not at all ill”, binge-related obsessions and compulsions demonstrate comparably low levels of severity.
In this placebo-controlled, 12-week study of patients with moderate-to-severe binge eating disorder, treatment with dasotraline (4-8 mg/d) was associated with significant and clinically meaningful reduction in binge-related obsessional thoughts and compulsive behaviors.
Clinicaltrials.gov number: NCT02564588
Supported by funding from Sunovion Pharmaceuticals Inc.
Asenapine is a 2nd-generation antipsychotic currently marketed as a sublingual (SL) tablet in the US for the treatment of schizophrenia. HP-3070, asenapine transdermal system, is a patch for treatment of schizophrenia in adults. Low- and high- HP-3070 doses deliver asenapine concentrations that are similar to SL asenapine 5 mg BID and 10 mg BID, respectively, but with fewer peak and trough fluctuations.
In this Phase 3, randomized, double-blind, placebo (PBO)-controlled, 6-week inpatient study, adults with schizophrenia having baseline Positive and Negative Syndrome Scale (PANSS) total score ≥80 and Clinical Global Impression–Severity of Illness Scale (CGI-S) score ≥4 were randomized 1:1:1 to HP 3070 high-dose, HP-3070 low-dose, or PBO.
The primary efficacy objective was Week 6 PANSS score change from baseline (CFB) vs PBO.
The key secondary objective was Week 6 CGI-S CFB vs PBO. Safety assessments included treatment-emergent adverse events (TEAEs), laboratory results, vital signs, dermal safety, and extrapyramidal symptoms (EPS) assessments.
A total of 616 patients were randomized, with 486 patients completing the study. Discontinuation rates were 23.3%, 18.6%, and 21.4% for HP-3070 high-dose, HP-3070 low-dose, and PBO, respectively; withdrawal of consent and AEs were the most common reasons for discontinuation. Demographics and baseline characteristics were well-balanced among treatment groups.
For PANSS total score, least squares mean (LSM) (standard error [SE]) estimates of the treatment comparison (HP-3070 vs PBO) for CFB at Week 6 were -4.8 (1.634; 95% CI: -8.06, -1.64; p=0.003) and -6.6 (1.630; 95% CI: 9.81, 3.40; p<0.001) for HP-3070 high- and low-dose, respectively. For CGI-S CFB at Week 6, LSM (SE) for the treatment comparison were 0.4 (0.100; 95% CI: 0.55, 0.16; p<0.001) for HP 3070 high-dose and 0.4 (0.099; 95% CI: 0.64, 0.25; p<0.001) for low-dose.
No deaths or serious TEAEs related to study treatment occurred. The HP-3070 safety profile was consistent with SL asenapine. Incidence of TEAEs at the patch application site was higher for HP-3070 (14.2% high-dose, 15.2% low-dose) than for PBO (4.4%); most of these events were mild or moderate in severity. PBO patients had higher rates of psychiatric disorders (24.3% vs 15.7% and 17.6% for HP-3070 high- and low-dose, respectively), with insomnia and anxiety as most common. Study treatment discontinuations due to application site reactions or skin disorders were low (≤0.5%) across treatment groups. There was no marked mean CFB for vital signs or electrocardiogram parameters, nor treatment differences observed on EPS assessments.
In this study, HP-3070 was efficacious, safe, and well-tolerated for treating schizophrenia in adults; both doses met primary and key secondary endpoints. As the first transdermal antipsychotic patch in the US, HP-3070 will provide patients a novel treatment option.
Funded by Noven Pharmaceuticals, Inc., a wholly-owned subsidiary of Hisamitsu Pharmaceutical Co.