Effects of the active amyloid beta immunotherapy CAD106 on PET measurements of amyloid plaque deposition in cognitively unimpaired APOE ε4 homozygotes.

INTRODUCTION: Alzheimer's Prevention Initiative Generation Study 1 evaluated amyloid beta (Aß) active immunotherapy (vaccine) CAD106 and BACE-1 inhibitor umibecestat in cognitively unimpaired 60- to 75-year-old participants at genetic risk for Alzheimer's disease (AD). The study was reduced in size and terminated early. Results from the CAD106 cohort are presented. METHODS: Sixty-five apolipoprotein E ε4 homozygotes with/without amyloid deposition received intramuscular CAD106 450 µg (n = 42) or placebo (n = 23) at baseline; Weeks 1, 7, 13; and quarterly; 51 of them had follow-up Aß positron emission tomography (PET) scans at 18 to 24 months. RESULTS: CAD106 induced measurable serum Aß immunoglobulin G titers in 41/42 participants, slower rates of Aß plaque accumulation (mean [standard deviation] annualized change from baseline in amyloid PET Centiloid: -0.91[5.65] for CAD106 versus 8.36 [6.68] for placebo; P < 0.001), and three amyloid-related imaging abnormality cases (one symptomatic). DISCUSSION: Despite early termination, these findings support the potential value of conducting larger prevention trials of Aß active immunotherapies in individuals at risk for AD. HIGHLIGHTS: This was the first amyloid-lowering prevention trial in persons at genetic risk of late-onset Alzheimer's disease (AD). Active immunotherapy targeting amyloid (CAD106) was tested in this prevention trial. CAD106 significantly slowed down amyloid plaque deposition in apolipoprotein E homozygotes. CAD106 was generally safe and well tolerated, with only three amyloid-related imaging abnormality cases (one symptomatic). Such an approach deserves further evaluation in larger AD prevention trials.

Ceritinib plus Nivolumab in Patients with Advanced ALK-Rearranged Non-Small Cell Lung Cancer: Results of an Open-Label, Multicenter, Phase 1B Study.

INTRODUCTION: Induction of programmed death ligand 1 (PD-L1) expression due to constitutive oncogenic signaling has been reported in NSCLC models harboring echinoderm microtubule associated protein like 4 gene (EML4)-ALK receptor tyrosine kinase gene (ALK) rearrangements. We assessed the safety and activity of ceritinib plus nivolumab in these patients. METHODS: In this open-label, phase 1B, multicenter, dose escalation and expansion study, previously treated (with ALK receptor tyrosine kinase [ALK] inhibitor [ALKI]/chemotherapy) or treatment-naive patients with stage IIIB or IV ALK-rearranged NSCLC received nivolumab, 3 mg/kg intravenously every 2 weeks, plus ceritinib, 450 mg/300 mg daily, with a low-fat meal. RESULTS: In total, 36 patients were treated (a 450-mg cohort [n=14] and a 300-mg cohort [n=22]). In the 450-mg cohort, four patients experienced dose-limiting toxicities. In the 300-mg cohort, two patients experienced dose-limiting toxicities. Among ALKI-naive patients, the overall response rate (ORR) was 83% (95% confidence interval [CI]: 35.9-99.6) in the 450-mg cohort and 60% (95% CI: 26.2-87.8) in the 300-mg cohort. Among ALKI-pretreated patients, the ORR was 50% (95% CI: 15.7-84.3) in the 450-mg cohort and 25% (95% CI: 5.5-57.2) in the 300-mg cohort. The ORR point estimate was observed to be greater in patients who were positive for PD-L1 than in those who were negative for PD-L1, with overlapping CIs (e.g., at a cutoff ≥1% PD-L1, 64% of patients [95% CI: 35.1-87.2] had confirmed responses as compared with those with negative PD-L1 staining (31% [95% CI: 11.0-58.7]). The most frequently reported grade 3 or 4 adverse events were increased alanine aminotransferase level (25%), increased gamma-glutamyl transferase level (22%), increased amylase level (14%), increased lipase level (11%), and maculopapular rash (11%). The incidence of all-grade rash (grouped term) was 64% in both cohorts; grade 3 rash was reported in 29% and 14% of patients in the 450-mg and 300-mg cohorts, respectively; no grade 4 rash was reported. CONCLUSION: Ceritinib plus nivolumab has activity; ORR appears to correlate with PD-L1 at baseline. Toxicity, especially rash, is more common than with either single agent.

Weight change and metabolic effects of asenapine in patients with schizophrenia and bipolar disorder.

OBJECTIVE: To describe weight changes and metabolic effects of asenapine compared with placebo and olanzapine in adults. METHOD: Post hoc analyses were performed using data from 17 asenapine trials (13 schizophrenia and 4 bipolar mania trials) with placebo (5-10 mg twice daily; n = 1,748; 1-6 weeks) and/or olanzapine (5-20 mg, once daily; n = 3,430; 3-100 weeks). Data were pooled based on treatment into placebo-controlled and olanzapine-controlled trials. For trials with placebo and olanzapine treatment groups, the asenapine population was included in both pools. Changes from baseline for weight, body mass index, and fasting lipid and glucose levels were determined. The Medical Dictionary for Regulatory Activities was used to define metabolic adverse events. RESULTS: Mean (standard error [SE]) weight change was greater with asenapine than with placebo (1.2 [0.2] vs 0.14 [0.2] kg; P < .0001) and similar in schizophrenia and bipolar disorder. Mean changes differed for asenapine versus placebo in triglycerides (1.8 [6.3] vs -12.2 [5.9] mg/dL; P < .01) and fasting glucose (1.9 [1.7] vs -1.6 [1.5] mg/dL; P < .05). In the olanzapine-controlled trials, weight change was significantly lower with asenapine than with olanzapine (0.9 [0.1] vs 3.1 [0.2] kg; P < .0001). Changes associated with asenapine were lower than those with olanzapine in fasting glucose (2.0 vs 3.3 mg/dL), total cholesterol (-0.4 [1.1] vs 6.2 [1.2] mg/dL; P < .0001), low-density lipoprotein cholesterol (-0.3 [1.1] vs 3.1 [1.2] mg/dL; P < .01), and triglycerides (-0.9 [5.4] vs 24.3 [5.8] mg/dL; P < .0001). CONCLUSIONS: Asenapine was associated with greater weight gain and glucose changes than placebo and not associated with a meaningful change in triglycerides or cholesterol levels. Asenapine was not significantly different from olanzapine in change in glucose levels and lower than olanzapine with respect to triglycerides, weight gain, and increased cholesterol.

Long-term effects of asenapine or olanzapine in patients with persistent negative symptoms of schizophrenia: a pooled analysis.

BACKGROUND: A Phase 2 efficacy study suggested that asenapine (ASE) was superior to risperidone in decreasing negative symptoms in schizophrenia at 6 weeks, prompting design of two negative symptom studies. Two 26-week core studies with 26-week extensions compared asenapine (ASE: 5-10mg twice-daily] and olanzapine (OLA: 5-20mg once-daily) as monotherapies in reducing persistent negative symptoms (PNS). While neither study met the primary endpoint of superiority of ASE over OLA, ASE was statistically superior to OLA in one extension study. This prompted a pooled analysis of the treatment effects of both drugs. METHODS: Data were pooled from two 26-week core studies and extensions. Efficacy endpoints: change in Negative Symptom Assessment scale-16 (NSA-16) total score at Week 26 (prespecified primary endpoint) and Week 52. Additional measures: change in Positive and Negative Syndrome Scale (PANSS)-total, Marder factors, negative subscale scores, Clinical Global Impression Severity of Illness score (CGI-S) assessments, NSA-16 factor domains, NSA global score, and individual items. RESULTS: Pooled data from the extension studies (n=502) showed no differences between ASE and OLA at Week 26. At Week 52, ASE showed superiority over OLA in NSA-16 total score, NSA global, PANSS Marder negative and PANSS negative subscales, some NSA-16 items, and four of five factor domains. In addition, pooled data for patients who entered the core trials (n=949) were analyzed over 52weeks (whether or not patients entered the extension). No significant differences between groups were observed in change in NSA-16 total score at 26-weeks. At Week 52, ASE was significantly superior over OLA in this measure, NSA global score and PANSS Marder negative factor. There were more early dropouts due to AEs, including worsening of the disease, in the ASE group. CONCLUSION: In this pooled analysis, ASE and OLA did not differ significantly over 26 weeks, but indicated a signal of superiority for ASE with continued treatment up to 52 weeks.

Comparison of somnolence associated with asenapine, olanzapine, risperidone, and haloperidol relative to placebo in patients with schizophrenia or bipolar disorder.

BACKGROUND: Patients with schizophrenia or bipolar disorder (BPD) may be differentially sensitive to antipsychotics. This study assessed the median time to onset, duration, and rate of somnolence associated with asenapine and other antipsychotics in both indications. METHODS: Ten clinical trials (n = 4786) were analyzed as five cohorts pooled according to indication and study design. RESULTS: In the short-term schizophrenia cohort, the incidence of somnolence was 13.1%, 19.1%, 8.5% 5.2%, and 6.9% with asenapine, olanzapine, risperidone, haloperidol, and placebo, respectively. Median time to onset of somnolence was 2 days for asenapine and olanzapine, and 6, 3, and 7 days for risperidone, haloperidol, and placebo, respectively. Median duration was 15 days for asenapine and olanzapine, and 3, 22.5, and 4.5 days for risperidone, haloperidol, and placebo, respectively. In the long-term schizophrenia cohort, the incidence, time to onset, and duration of somnolence with asenapine and olanzapine were 18.4% versus 19.6%, 9.0 days versus 12 days, and 22 days versus 21 days, respectively. In schizophrenia with persistent negative symptoms, the incidence, median time to onset, and duration of somnolence with asenapine and olanzapine were 18.5% versus 21.1%, 9.0 days versus 7.5 days, and 25.0 days versus 41.5 days, respectively. In the monotherapy for BPD cohort, the incidence of somnolence with asenapine, olanzapine, and placebo was 23.8%, 26.4%, and 6.4%, respectively. Median time to onset and duration of somnolence with asenapine, olanzapine, and placebo were 1, 2, and 2 days, respectively, and 7, 8.5, and 5 days. In the adjunctive therapy for BPD cohort, the incidence, median time to onset, and duration of somnolence with asenapine and placebo were 24.0% versus 10.2%, 1.5 days versus 2 days, and 12.5 days versus 7 days, respectively. CONCLUSION: In the short-term schizophrenia cohort, time to onset and duration of somnolence with asenapine was similar to that with olanzapine and haloperidol. Only asenapine and olanzapine had significantly higher rates of somnolence relative to placebo. The time to onset, duration, and incidence of somnolence with asenapine and olanzapine was similar in patients with long-term schizophrenia and those with BPD. Patients with BPD were more sensitive than those with schizophrenia to asenapine and olanzapine.

Asenapine effects on individual Young Mania Rating Scale items in bipolar disorder patients with acute manic or mixed episodes: a pooled analysis.

BACKGROUND: An exploratory post hoc analysis was conducted to evaluate the potential differential effects over time of asenapine and olanzapine compared with placebo on the eleven individual items comprising the Young Mania Rating Scale (YMRS) in patients with manic or mixed episodes in bipolar I disorder. METHODS: Data were pooled from two 3-week randomized, controlled trials in which the eleven individual items comprising the YMRS were measured over 21 days. An analysis of covariance model adjusted by baseline value was used to test for differences in changes from baseline in YMRS scores between groups. RESULTS: Each of the eleven individual YMRS item scores was significantly reduced compared with placebo at day 21. After 2 days of treatment, asenapine and olanzapine were superior to placebo for six of the YMRS items: disruptive/aggressive behavior, content, irritability, elevated mood, sleep, and speech. CONCLUSION: Reduction in manic symptoms over 21 days was associated with a broad-based improvement across all symptom domains with no subset of symptoms predominating.

A translational approach to evaluate the efficacy and safety of the novel AMPA receptor positive allosteric modulator org 26576 in adult attention-deficit/hyperactivity disorder.

BACKGROUND: It has been posited that glutamate dysregulation contributes to the pathophysiology of attention-deficit/hyperactivity disorder (ADHD). Modulation of glutamate neurotransmission may provide alternative therapeutic options. The novel 2-amino-3-(5-methyl-3-oxo-1,2-oxazol-4-yl)propanoic acid receptor positive allosteric modulator Org 26576 was investigated with a translational approach including preclinical and clinical testing. METHODS: Neonatal rat 6-hydroxydopamine lesion-induced hyperactivity was used as preclinical model. Seventy-eight ADHD adults entered a multicenter, double-blind, placebo-controlled, two-period crossover trial. After 1 week placebo lead-in, 67 subjects were randomized into one of four treatment sequences: sequence A (n = 15) Org 26576 (100 mg b.i.d.) for 3 weeks, followed by a 2-week placebo crossover and 3 weeks placebo; sequence B (n = 16) 5 weeks placebo followed by 3 weeks Org 26576 (100 mg b.i.d.); sequence C (n = 18) Org 26576 flexible dose (100-300 mg b.i.d.) for 3 weeks, then 5 weeks placebo; sequence D (n = 18) 5 weeks placebo followed by 3 weeks Org 26576 (100-300 mg b.i.d.). The Adult ADHD Investigator Symptom Rating Scale was used to assess changes in ADHD symptomatology. RESULTS: Org 26576 (1, 3, 10 mg/kg intraperitoneal) produced dose-dependent inhibition of locomotor hyperactivity in 6-hydroxydopamine-lesioned rats. Org 26576 (100 mg b.i.d.) was superior to placebo in treating symptoms of adult ADHD subjects. The primary Adult ADHD Investigator Symptom Rating Scale results were supported by some secondary analyses. However, Org 26576 (100-300 mg b.i.d.) did not confirm these results. Most frequently reported adverse events were nausea, dizziness, and headache. CONCLUSIONS: These preclinical and clinical findings suggest that Org 25676 may have utility in the treatment of ADHD.

Safety and tolerability of switching to asenapine from other antipsychotic agents: pooled results from two randomized multicenter trials in stable patients with persistent negative symptoms in schizophrenia.

BACKGROUND: In clinical practice, clinicians often need to switch antipsychotic medications in patients with schizophrenia to optimize treatment outcomes. Here, we describe the safety and tolerability of switching existing antipsychotic treatments to asenapine or olanzapine monotherapy using various switching regimens. METHODS: Data were pooled from 949 patients in two 26-week randomized double-blind studies. Patients with persistent negative symptoms of schizophrenia, stable for at least 5 months prior to screening and 1 additional month before randomization, were randomized to and treated with either asenapine (n = 485) or olanzapine (n = 464), and were tapered off existing antipsychotic(s) at variable rates within 28 days. RESULTS: Prior to randomization, most patients were treated with second-generation antipsychotics (SGAs) (asenapine: 79.6%; olanzapine: 78.2%) and first-generation antipsychotics (FGAs) (31.1%; 29.7%), while depot formulations were used by 12.4% and 11.4%, respectively. Median time to taper off previous antipsychotics was 7 days, with approximately 40% of patients abruptly discontinuing their previous medication. Similar percentages of patients in each group reported at least one adverse event (AE) (asenapine: 76.9%; olanzapine: 75.2%). The majority of AEs occurred within the first 28 days. The most frequently reported AEs were somnolence, insomnia, and headache. The incidence of AEs in patients switching from SGAs, FGAs, or depot medications was similar between asenapine and olanzapine (77.5% vs 74.6%, 75.5% vs 79.7%, 85.0% vs 86.8%, respectively). AEs were more frequent in subjects previously treated with two antipsychotics (asenapine: 79.4%; olanzapine: 83.9%) versus one antipsychotic (asenapine: 76.3%; olanzapine: 72.2%) in the switch period. CONCLUSION: The presented data from post hoc pooled analyses may provide practical guidance for physicians switching partially stabilized patients with schizophrenia and persistent negative symptoms to asenapine or olanzapine.

Meta-analyses of the efficacy of asenapine for acute schizophrenia: comparisons with placebo and other antipsychotics.

CONTEXT: Asenapine is an approved treatment for schizophrenia in the United States. OBJECTIVE: Meta-analyses were conducted to evaluate the efficacy of asenapine in acute schizophrenia compared with placebo and other antipsychotics. DATA SOURCES: Four asenapine trials from the asenapine development program were pooled for the meta-analysis. To compare asenapine versus placebo treatment effect with other antipsychotics, we added integrated asenapine data to a previously published meta-analysis. For comparative efficacy of asenapine versus other second-generation antipsychotics (SGAs), data from a second published meta-analysis were combined with the 4 asenapine trials. DATA ANALYSES: To evaluate efficacy, mean change in Positive and Negative Syndrome Scale (PANSS) total score was examined in asenapine and other antipsychotics. To assess clinical relevance, PANSS response rates and associated odds ratios (ORs) for treatment response were assessed. To assess the relative efficacy of SGAs, a network meta-analysis with PANSS total score change was conducted by using data from the 2 published meta-analyses together with asenapine data. RESULTS: Asenapine was superior to placebo with regard to mean change in PANSS total score (last observation carried forward [LOCF]: -3.6, P = .002; mixed model for repeated measures [MMRM]: -4.1, P = .001), an effect comparable to active controls from the same trials (LOCF: -4.0, P = .002; MMRM: -4.8, P = .001). PANSS responder rates were significantly better with asenapine versus placebo (OR, 1.9; P < .001) and comparable to active controls (OR, 1.7; P = .002). Effect sizes for asenapine were somewhat lower than those reported in the literature for other SGAs. Network meta-analysis also demonstrated that the efficacy of asenapine was comparable to that of other SGAs; estimated differences between asenapine and other SGAs ranged from 3.9 points (95% CI, 0.3 to 7.4) greater than ziprasidone to 2.9 points (95% CI, -0.1 to 5.9) less than olanzapine. CONCLUSIONS: These meta-analyses indicate that the efficacy of asenapine for acute schizophrenia is superior to placebo and comparable to several other SGAs.

Asenapine versus olanzapine in people with persistent negative symptoms of schizophrenia.

Two randomized, double-blind, 26-week core studies (Eastern [EH] and Western Hemisphere [WH]) tested the hypothesis that asenapine is superior to olanzapine for persistent negative symptoms of schizophrenia; 26-week extension studies assessed the comparative long-term efficacy and safety of these agents. In the core studies, 949 people were randomized to asenapine (n = 241 and 244) or olanzapine (n = 240 and 224); 26-week completion rates with asenapine were 64.7% and 49.6% (olanzapine, 80.4% and 63.8%) in the EH and WH, respectively. In the EH and WH extensions, respectively (asenapine, n = 134 and 86; olanzapine, n = 172 and 110), 52-week completion rates were 84.3% and 66.3% with asenapine (olanzapine, 89.0% and 80.9%). Asenapine was not superior to olanzapine in change in the 16-item Negative Symptom Assessment Scale total score in either core study, but asenapine was superior to olanzapine at week 52 in the WH extension study. Olanzapine was associated with modest, but significantly greater, changes in PANSS positive subscale score at various assessment times in both core studies and the WH extension study. Incidence of treatment-emergent adverse events was comparable between treatments across studies. Weight gain was consistently lower with asenapine. Extrapyramidal symptom-related adverse event incidence was higher with asenapine (EH: 8.3%; 95% confidence interval [CI], 5.1%-12.5%; WH: 16.4%; 95% CI, 11.9%-21.6%) than olanzapine (EH: 3.3%; 95% CI, 1.4%-6.4%; WH: 12.1%; 95% CI, 8.1%-17.0%), but Extrapyramidal Symptom Rating Scale-Abbreviated total score changes did not significantly differ between treatments. In conclusion, asenapine superiority over olanzapine was not observed in the core studies. Both treatments improved persistent negative symptoms, but discontinuation rates were higher with asenapine.

Training for assessment of negative symptoms of schizophrenia across languages and cultures: comparison of the NSA-16 with the PANSS Negative Subscale and Negative Symptom factor.

BACKGROUND: The 16-item Negative Symptom Assessment scale (NSA-16) has been validated in English-speaking raters. We analyzed the level of agreement achieved among raters of different nationalities using the NSA-16 and the Positive and Negative Syndrome Scale (PANSS) negative subscale and Marder negative factor. METHODS: Raters participating in two international trials were trained in the use of each instrument through lectures and feedback on their ratings of at least one videotaped interview of a schizophrenic patient. Overall and regional (North America, Western Europe, Eastern Europe, South/Central America, and Australia and South Africa combined) kappa values were calculated and mean total scores were compared (1-way analysis of variance) by region for each instrument. In addition, within-scales variance was calculated by item to help identify negative symptoms that were particularly challenging to obtain agreement on across cultures. RESULTS: In the combined group of international raters, the kappa values for ratings of the NSA-16, PANSS negative subscale, and Marder negative factors were 0.89, 0.84, and 0.82, respectively. Kappa values calculated by geographic region ranged from 0.87 to 0.94 for the NSA-16 compared with 0.82 to 0.86 for the PANSS negative subscale and 0.79 to 0.87 for the PANSS Marder negative factor. CONCLUSIONS: Despite cultural and linguistic differences among raters, standardizing measurement of negative symptoms in international clinical trials is possible using available rating scales: NSA-16, PANSS negative subscale, and Marder negative subscale. Agreement among raters was at least as high using the NSA-16 as using the PANSS instruments.

Validation of a 4-item Negative Symptom Assessment (NSA-4): a short, practical clinical tool for the assessment of negative symptoms in schizophrenia.

The 16-item Negative Symptom Assessment (NSA-16) scale is a validated tool for evaluating negative symptoms of schizophrenia. The psychometric properties and predictive power of a four-item version (NSA-4) were compared with the NSA-16. Baseline data from 561 patients with predominant negative symptoms of schizophrenia who participated in two identically designed clinical trials were evaluated. Ordered logistic regression analysis of ratings using NSA-4 and NSA-16 were compared with ratings using several other standard tools to determine predictive validity and construct validity. Internal consistency and test--retest reliability were also analyzed. NSA-16 and NSA-4 scores were both predictive of scores on the NSA global rating (odds ratio = 0.83-0.86) and the Clinical Global Impressions--Severity scale (odds ratio = 0.91-0.93). NSA-16 and NSA-4 showed high correlation with each other (Pearson r = 0.85), similar high correlation with other measures of negative symptoms (demonstrating convergent validity), and lesser correlations with measures of other forms of psychopathology (demonstrating divergent validity). NSA-16 and NSA-4 both showed acceptable internal consistency (Cronbach α, 0.85 and 0.64, respectively) and test--retest reliability (intraclass correlation coefficient, 0.87 and 0.82). This study demonstrates that NSA-4 offers accuracy comparable to the NSA-16 in rating negative symptoms in patients with schizophrenia.