LEGACY: Phase 2a Trial to Evaluate the Safety, Pharmacokinetics, and Pharmacodynamic Effects of the Anti-EL (Endothelial Lipase) Antibody MEDI5884 in Patients With Stable Coronary Artery Disease.

OBJECTIVE: Functional HDL (high-density lipoprotein) particles that facilitate cholesterol efflux may be cardioprotective. EL (endothelial lipase) hydrolyzes phospholipids promoting catabolism of HDL and subsequent renal excretion. MEDI5884 is a selective, humanized, monoclonal, EL-neutralizing antibody. We sought to determine the safety, pharmacokinetics, and pharmacodynamic effects of multiple doses of MEDI5884 in patients with stable coronary artery disease. Approach and Results: LEGACY was a phase 2a, double-blind, placebo-controlled, parallel-design trial that randomized 132 patients with stable coronary artery disease receiving high-intensity statin therapy to 3 monthly doses of 1 of 5 dose levels of MEDI5884 (50, 100, 200, 350, or 500 mg SC) or matching placebo. The primary end point was the safety and tolerability of MEDI5884 through the end of the study (day 151). Additional end points included change in HDL cholesterol and cholesterol efflux from baseline to day 91, hepatic uptake of cholesterol at day 91, changes in various other lipid parameters. The incidence of adverse events was similar between the placebo and MEDI5884 groups. In a dose-dependent manner, MEDI5884 increased HDL cholesterol up to 51.4% (P<0.0001) and global cholesterol efflux up to 26.2% ([95% CI, 14.3-38.0] P<0.0001). MEDI5884 increased HDL particle number up to 14.4%. At the highest dose tested, an increase in LDL (low-density lipoprotein) cholesterol up to 28.7% (P<0.0001) and apoB (apolipoprotein B) up to 13.1% (P=0.04) was observed with MEDI5884. However, at the potential target doses for future studies, there was no meaningful increase in LDL cholesterol or apoB. CONCLUSIONS: Inhibition of EL by MEDI5884 increases the quantity and quality of functional HDL in patients with stable coronary artery disease on high-intensity statin therapy without an adverse safety signal at the likely dose to be used. These data support further clinical investigation. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT03351738.

Blocking endothelial lipase with monoclonal antibody MEDI5884 durably increases high density lipoprotein in nonhuman primates and in a phase 1 trial.

Cardiovascular disease (CVD) is the leading global cause of death, and treatments that further reduce CV risk remain an unmet medical need. Epidemiological studies have consistently identified low high-density lipoprotein cholesterol (HDL-C) as an independent risk factor for CVD, making HDL elevation a potential clinical target for improved CVD resolution. Endothelial lipase (EL) is a circulating enzyme that regulates HDL turnover by hydrolyzing HDL phospholipids and driving HDL particle clearance. Using MEDI5884, a first-in-class, EL-neutralizing, monoclonal antibody, we tested the hypothesis that pharmacological inhibition of EL would increase HDL-C by enhancing HDL stability. In nonhuman primates, MEDI5884 treatment resulted in lasting, dose-dependent elevations in HDL-C and circulating phospholipids, confirming the mechanism of EL action. We then showed that a favorable lipoprotein profile of elevated HDL-C and reduced low-density lipoprotein cholesterol (LDL-C) could be achieved by combining MEDI5884 with a PCSK9 inhibitor. Last, when tested in healthy human volunteers, MEDI5884 not only raised HDL-C but also increased HDL particle numbers and average HDL size while enhancing HDL functionality, reinforcing EL neutralization as a viable clinical approach aimed at reducing CV risk.

MEDI0382, a GLP-1 and glucagon receptor dual agonist, in obese or overweight patients with type 2 diabetes: a randomised, controlled, double-blind, ascending dose and phase 2a study.

BACKGROUND: Weight loss is often key in the management of obese or overweight patients with type 2 diabetes, yet few treatments for diabetes achieve clinically meaningful weight loss. We aimed to assess the efficacy, tolerability, and safety of treatment with MEDI0382, a balanced glucagon-like peptide-1 and glucagon receptor dual agonist developed to provide glycaemic control and weight loss, in patients with type 2 diabetes. METHODS: This randomised, placebo-controlled, double-blind, combined multiple-ascending dose (MAD) and phase 2a study was done at 11 study sites (hospitals and contract research organisations) in Germany. We enrolled patients aged 18-65 years with controlled type 2 diabetes (glycated haemoglobin A1c [HbA1c] levels of 6·5-8·5% at screening) and a body-mass index between 27 kg/m2 and 40 kg/m2. An interactive web-response system was used to randomly assign patients to receive MEDI0382 or placebo. Patients were randomly assigned 2:1 in cohorts A-C and 3:1 in cohorts D and E in the MAD portion of the study, and 1:1 in the phase 2a portion. Randomisation was done by a contracted third-party operator who was not involved in the clinical operations of the study. The pharmacists, participants, and study site personnel involved in treating and assessing participants were masked to treatment allocation. Patients received once-daily subcutaneous injections of the study drug at doses of no more than 300 µg for 22 days or less in the MAD portion of the study, and a dose of no more than 200 µg for 41 days or less in the phase 2a portion. The two primary endpoints of the phase 2a portion were the change from baseline to day 41 in glucose area under the curve at 0-4 h (AUC0-4 h) after a mixed-meal tolerance test (MMTT), assessed in all participants who received at least one dose of study drug and whose measurements were taken at baseline and day 41, and change from baseline in bodyweight, assessed in the intention-to-treat (ITT) population. Safety analyses were done in all participants who received any study drug analysed according to the treatment they received. This study is registered with ClinicalTrials.gov, number NCT02548585. FINDINGS: Patients were recruited between Dec 9, 2015, and Feb 24, 2017. 61 patients were randomly assigned to the MAD part of the study (42 to MEDI0382 and 19 to placebo). 51 patients were randomly assigned to the phase 2a part, of whom 25 were randomly assigned to MEDI0382 and 26 to placebo. In the phase 2a study, three patients in the MEDI0382 group and one in the placebo group discontinued, all as a result of adverse events. 22 (88%) patients in the MEDI0382 group and 25 (96%) in the placebo group received at least one dose and had measurements taken at baseline and day 41. Glucose AUC0-4 h post MMTT decreased significantly with MEDI0382 versus placebo (least squares [LS] mean -32·78% [90% CI -36·98 to -28·57] vs -10·16% [-14·10 to -6·21], and the mean difference was -22·62% [-28·40 to -16·85]; p<0·0001). In the ITT population, reduction in bodyweight was significantly greater with MEDI0382 than with placebo (LS mean -3·84 kg [90% CI -4·55 to -3·12] vs -1·70 kg [-2·40 to -1·01] and mean difference of 2·14 kg [-3·13 to -1·31]; p=0·0008). The proportion of patients who had a treatment-emergent adverse event (TEAE) was similar between treatment groups (22 [88%] of 25 in the MEDI0382 group vs 23 [88%] of 26 in the placebo group); gastrointestinal disorders (18 [72%] vs 13 [40%]) and decreased appetite (five [20%] vs none) occurred more frequently with MEDI0382 than placebo. No participants in the MEDI0382 group had a grade 3 or worse TEAE (vs two [8%] in the placebo group). INTERPRETATION: MEDI0382 has the potential to deliver clinically meaningful reductions in blood glucose and bodyweight in obese or overweight individuals with type 2 diabetes. FUNDING: MedImmune.

Efficacy and safety of aripiprazole once-monthly in obese and nonobese patients with schizophrenia: a post hoc analysis.

PURPOSE: To assess the efficacy and safety of aripiprazole once-monthly 400 mg (AOM 400), an extended-release injectable suspension of aripiprazole, in obese and nonobese patients. PATIENTS AND METHODS: This post hoc analysis of a 38-week randomized, double-blind, active-controlled, noninferiority study (NCT00706654) compared the clinical profile of AOM 400 in obese (body mass index [BMI] ≥30 kg/m(2)) and nonobese (BMI <30 kg/m(2)) patients with schizophrenia for ≥3 years. Patients were randomized 2:2:1 to AOM 400, oral aripiprazole 10-30 mg/d, or aripiprazole once-monthly 50 mg (AOM 50 mg) (subtherapeutic dose). Within obese and nonobese patient subgroups, treatment-group differences in Kaplan-Meier estimated relapse rates at week 26 (z-test) and in observed rates of impending relapse through week 38 (chi-square test) were analyzed. Treatment-emergent adverse events (TEAEs) (>10% in any treatment group) were summarized. RESULTS: At baseline of the randomized phase, obesity rates were similar among patients randomized to AOM 400 (n=95/265, 36%), oral aripiprazole (n=95/266, 36%), and AOM 50 mg (n=43/131, 33%). In both obese and nonobese patients, relapse rates through week 38 for patients randomized to AOM 400 (obese, 7.4%; nonobese, 8.8%) were similar to those in patients on oral aripiprazole (obese, 8.4%; nonobese, 7.6%), whereas relapse rates were significantly lower with AOM 400 versus AOM 50 mg (obese, 27.9% [P=0.0012]; nonobese, 19.3% [P=0.0153]). The most common TEAEs with AOM 400 in obese and nonobese patients were insomnia (12.6% and 11.2%), headache (12.6% and 8.2%), injection site pain (11.6% and 5.3%), akathisia (10.5% and 10.6%), upper respiratory tract infection (10.5% and 4.7%), weight increase (10.5% and 8.2%), and weight decrease (6.3% and 11.8%). Within the AOM 400 group, 7.6% of patients who were nonobese at baseline became obese, and 17.9% of obese patients became nonobese during randomized treatment. CONCLUSION: The clinical profile of AOM 400 was similar in obese and nonobese patients.

Patient-Centered Outcomes with Aripiprazole Once-Monthly for Maintenance Treatment in Patients with Schizophrenia: Results From Two Multicenter, Randomized, Double-Blind Studies.

OBJECTIVES: To further characterize the clinical profile of long-term treatment with aripiprazole once-monthly 400 mg (AOM 400) by examining patient-centered outcomes in adults with schizophrenia. METHODS: Data are from 2 separate studies: a 52-week, multicenter, randomized, double-blind, placebo-controlled study and a 38-week, multicenter, randomized, double-blind, active-controlled study that evaluated the clinical profile of AOM 400 as maintenance treatment in patients with schizophrenia. The studies were conducted from July 2008 through February 2011 and from September 2008 through August 2012, respectively. Both studies included the Drug Attitude Inventory (DAI), the Medication Adherence Questionnaire (MAQ), the Patient Satisfaction with Medication Questionnaire, and a resource utilization and hospitalization form as prespecified patient-centered endpoints. RESULTS: A total of 710 patients entered the oral stabilization phase in the 52-week study, and 403 patients were randomized to double-blind treatment. The corresponding sample sizes in the 38-week study were 842 and 662, respectively. In both studies, mean DAI and MAQ scores remained stable across all treatment phases; mean changes from baseline during the double-blind phase were not significantly different between treatment arms. Treatment satisfaction remained high throughout both studies, and most patients reported no or fewer side effects with AOM 400 relative to their prior medication. Most patients did not have unscheduled outpatient visits or hospitalizations throughout the studies. CONCLUSIONS: Data from 2 randomized, double-blind studies indicated that patient perceptions about treatment satisfaction, side effects, and medication adherence were maintained in patients with schizophrenia receiving maintenance treatment with AOM 400. TRIAL REGISTRATION: ClinicalTrials.gov: NCT00705783, NCT00706654.

Effects of aripiprazole once-monthly on domains of personal and social performance: results from 2 multicenter, randomized, double-blind studies.

OBJECTIVE: To assess the effects of maintenance therapy with aripiprazole once-monthly 400mg on personal and social functioning. METHODS: Data were analyzed from 2 randomized, double-blind trials of patients with schizophrenia requiring chronic antipsychotic treatment. One study was a 52-week trial of aripiprazole once-monthly 400mg versus placebo; the other was a 38-week trial of aripiprazole once-monthly 400mg, oral aripiprazole (10-30 mg daily), and aripiprazole once-monthly 50mg (subtherapeutic dose to test assay sensitivity). Functioning was assessed using the Personal and Social Performance (PSP) scale, comprising 4 domain subscales. RESULTS: In the 52-week study, 403 patients stabilized on aripiprazole once-monthly 400mg were randomized to receive aripiprazole once-monthly 400mg (n=269) or placebo (n=134). In the 38-week study, 662 patients stabilized on oral aripiprazole were randomized to receive aripiprazole once-monthly 400mg (n=265), oral aripiprazole (n=266), or aripiprazole once-monthly 50mg (subtherapeutic dose; n=131). In the 52-week study, mean changes from baseline were significantly worsened with placebo compared with aripiprazole once-monthly 400mg for PSP total score (P<0.001) and domain scores for Personal and Social Relationships (P<0.001), Self-Care (P<0.01), and Disturbing and Aggressive Behavior (P<0.0001). In the 38-week study, mean changes from baseline were significantly worsened with aripiprazole once-monthly 50mg compared with aripiprazole once-monthly 400mg for PSP total score (P<0.05) and the Personal and Social Relationships domain score (P<0.05). CONCLUSION: Patient functioning, assessed using the PSP scale, was maintained in stabilized patients treated with aripiprazole once-monthly in 2 pivotal relapse studies.