Efficacy and Safety of a Novel Oral Inducer of Apolipoprotein A-I Synthesis in Statin-Treated Patients With Stable Coronary Artery Disease A Randomized Controlled Trial

OBJECTIVES: The purpose of this study was to investigate the safety, tolerability, and efficacy of RVX-208, the first oral agent designed to enhance apolipoprotein A-I (apoA-I) synthesis. BACKGROUND: No agent that selectively induces synthesis of apoA-I has reached an advanced stage of clinical development. METHODS: A total of 299 statin-treated patients with coronary artery disease were treated with placebo, or RVX-208 at a dose of 50 mg, 100 mg, or 150 mg twice daily for 12 weeks. Changes in lipid-related biomarkers, in addition to safety and tolerability, of RVX-208 were investigated. RESULTS: For each dose of RVX-208, individual pairwise comparisons of apoA-I changes with placebo, the primary end point, did not achieve statistical significance. However, treatment with RVX-208 was associated with a dose-dependent increase in apoA-I levels by up to 5.6% (p = 0.035 for trend). Administration of RVX-208 resulted in significant increases in levels of high-density lipoprotein cholesterol (HDL-C) ranging from 3.2% to 8.3% (p = 0.02), and large HDL particles increased by 11.1% to 21.1% (p = 0.003). ApoA-I levels increased rapidly from 8 to 12 weeks, suggesting that peak pharmacological effect has not been achieved by the end of the 12-week study. Transient and reversible elevations in liver transaminases >3 times the upper limit of normal were observed in 18 patients treated with RVX-208, with no associated increase in bilirubin levels. CONCLUSIONS: Administration of RVX-208 for 12 weeks was associated with increases in apoA-I, HDL-C, and concentration of large HDL particles, consistent with facilitation of cholesterol mobilization. Maximal increases in apoA-I may require longer exposure. An increase in liver enzymes was observed with active treatment. (Clinical Trial for Dose Finding and Safety of RVX000222 in Subjects With Stable Coronary Artery Disease; NCT01058018

Effect of infusion of high-density lipoprotein mimetic containing recombinant apolipoprotein A-I Milano on coronary disease in patients with an acute coronary syndrome in the MILANO-PILOT trial: A randomized clinical trial

IMPORTANCE Infusing a high-density lipoprotein mimetic containing apolipoprotein A-I Milano demonstrated potential atheroma regression in patients following an acute coronary syndrome. To our knowledge, the effect of infusing a new mimetic preparation (MDCO-216) with contemporary statin therapy is unknown. OBJECTIVE To determine the effect of infusingMDCO-216 on coronary atherosclerosis progression. DESIGN, SETTING, AND PARTICIPANTS This double-blind, randomized clinical trial conducted in 22 hospitals in Canada and Europe compared the effects of 5 weekly intravenous infusions of MDCO-216 at a dose of 20mg/kg weekly (n = 59) with placebo (n = 67) in statin-treated patients with an acute coronary syndrome. MAIN OUTCOMES AND MEASURES The primary efficacy measurewas the nominal change in percent atheroma volume (PAV) from baseline to day 36 as measured by serial intravascular ultrasonography. The secondary efficacy measureswere the nominal changes in normalized total atheroma volume (TAV), atheroma volume in the most diseased 10-mm segment, and the percentage of patientswhodemonstrated plaque regression. Safety and tolerabilitywere also evaluated. RESULTS Among 122 randomized patients (mean [SD] age, 61.8 [10.4] years; 93men[76.2%]; 61 [50.0%] with prior statin use; and a mean [SD] low-density lipoprotein cholesterol [LDL-C] level of 87.6 [40.5]mg/dL [to convert to millimoles per liter, multiply by0.0259]), 113 (92.6%) had evaluable imaging results at follow-up. The receiving-treatment LDL-C levelswere comparable with the placebo andMDCO-216 (68.6 vs 70.5mg/dL; difference, -2.5mg/dL; 95%CI, -10.1 to 5.0; P = .51).Areduction in high-density lipoprotein cholesterol levelswas observed inMDCO, but not placebo patients (-3.3 vs 3.0mg/dL [to convert to millimoles per liter, multiply by0.0259]; difference, -6.3mg/dL; 95%CI, -8.5 to -4.1; P < .001). Percent atheroma volume, whichwas adjusted for baseline values, decreased0.94%with the placebo and0.21% withMDCO-216 (difference,0.73%; 95%CI, -0.07 to 1.52; P = .07). Normalized TAVdecreased 7.9mm3 with the placebo and 6.4mm3 withMDCO-216 (difference, 1.6mm3; 95%CI, -5.6 to 8.7; P = .67), and atheroma volume in the most diseased segment decreased 1.8mm3 with the placebo and 2.2mm3 with MDCO-216 (difference0.4mm3; 95%CI, -4.4 to 3.5; P = .83).Asimilar percentage of patients demonstrated a regression of PAV(67.2%vs 55.8%; P = .21) and TAV(68.9%vs 71.2%; P = .79) in the placebo andMDCO-216 groups, respectively. CONCLUSIONS AND RELEVANCE Among patients with an acute coronary syndrome, infusing MDCO-216 did not produce an incremental plaque regression in the setting of contemporary statin therapy

Impact of PCSK9 inhibition on coronary atheroma progression: Rationale and design of Global Assessment of Plaque Regression with a PCSK9 Antibody as Measured by Intravascular Ultrasound (GLAGOV)

Statin-mediated low-density lipoprotein cholesterol (LDL-C) lowering fails to prevent more than half of cardiovascular events in clinical trials. Serial plaque imaging studies have highlighted the benefits of aggressive LDL-C lowering, with plaque regression evident in up to two-thirds of patients with achieved LDL-C levels <70 mg/dL. Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors permit LDL-C-lowering by a further 54% to 75% in statin-treated patients. The impact of achieving very low LDL-C levels with PCSK9 inhibitors on coronary atherosclerosis has not been investigated. To test the hypothesis that incremental LDL-C lowering with the PCSK9 inhibitor, evolocumab, will result in a significantly greater change from baseline in coronary atheroma volume than placebo in subjects receiving maximally tolerated statin therapy. A phase 3, multicenter, double-blind, randomized, placebo-controlled trial evaluating the impact of evolocumab on coronary atheroma volume as assessed by serial coronary intravascular ultrasound at baseline in patients undergoing a clinically indicated coronary angiogram with angiographic evidence of coronary atheroma, and after 78 weeks of treatment. Subjects (n = 968) were randomized 1:1 into 2 groups to receive monthly either evolocumab 420 mg or placebo subcutaneous injections. The GLAGOV trial will explore whether greater degrees of plaque regression are achievable with ultrahigh-intensity LDL-C lowering after combination statin-PCSK9 inhibitor therapy. GLAGOV will provide important mechanistic, safety, and efficacy data prior to the eagerly anticipated clinical outcomes trials testing the PCSK9 inhibitor hypothesis (www.clinicaltrials.gov identifier NCT01813422

Effect of Evolocumab on Coronary Plaque Composition

Background: Incremental low-density lipoprotein (LDL) cholesterol lowering with the proprotein convertase subtilisin kexin type 9 inhibitor evolocumab regresses coronary atherosclerosis in statin-treated patients. Objectives: The purpose of this study was to evaluate the effect of adding evolocumab to statin therapy on coronary plaque composition. Methods: A total of 968 statin-treated coronary artery disease patients underwent serial coronary intravascular ultrasound imaging at baseline and following 76 weeks of treatment with placebo or evolocumab 420 mg monthly. Plaque composition changes were determined in 331 patients with evaluable radiofrequency analysis of the ultrasound backscatter signal. Results: Compared with statin monotherapy, evolocumab further reduced LDL cholesterol (33.5 mg/dl vs. 89.9 mg/dl; p < 0.0001) and induced regression of percent atheroma volume (−1.2% vs. +0.17%; p < 0.0001) and total atheroma volume (−3.6 mm3 vs. −0.8 mm3; p = 0.04). No difference was observed between the evolocumab and placebo groups in changes in calcium (1.0 ± 0.3 mm3 vs. 0.6 ± 0.3 mm3; p = 0.49), fibrous (−3.0 ± 0.6 mm3 vs. −2.4 ± 0.6 mm3; p = 0.49), fibrofatty (−5.0 ± 1.0 mm3 vs. −3.0 ± 1.0 mm3; p = 0.49), and necrotic (−0.6 ± 0.5 mm3 vs. −0.1 ± 0.5 mm3; p = 0.49) volumes. An inverse correlation was observed between changes in LDL cholesterol and plaque calcification (r = −0.15; p < 0.001). Conclusions: The addition of evolocumab to a statin did not produce differential changes in plaque composition compared with statin monotherapy. This suggests that evaluation of plaque morphology using virtual histology imaging may provide no incremental information about the plaque effects of evolocumab beyond measurement of plaque burden. (GLobal Assessment of Plaque reGression With a PCSK9 antibOdy as Measured by intraVascular Ultrasound [GLAGOV]; NCT01813422

Effect of Evolocumab on Progression of Coronary Disease in Statin-Treated Patients : the GLAGOV Randomized Clinical Trial

Reducing levels of low-density lipoprotein cholesterol (LDL-C) with intensive statin therapy reduces progression of coronary atherosclerosis in proportion to achieved LDL-C levels. Proprotein convertase subtilisin kexin type 9 (PCSK9) inhibitors produce incremental LDL-C lowering in statin-treated patients; however, the effects of these drugs on coronary atherosclerosis have not been evaluated. To determine the effects of PCSK9 inhibition with evolocumab on progression of coronary atherosclerosis in statin-treated patients. The GLAGOV multicenter, double-blind, placebo-controlled, randomized clinical trial (enrollment May 3, 2013, to January 12, 2015) conducted at 197 academic and community hospitals in North America, Europe, South America, Asia, Australia, and South Africa and enrolling 968 patients presenting for coronary angiography. Participants with angiographic coronary disease were randomized to receive monthly evolocumab (420 mg) (n = 484) or placebo (n = 484) via subcutaneous injection for 76 weeks, in addition to statins. The primary efficacy measure was the nominal change in percent atheroma volume (PAV) from baseline to week 78, measured by serial intravascular ultrasonography (IVUS) imaging. Secondary efficacy measures were nominal change in normalized total atheroma volume (TAV) and percentage of patients demonstrating plaque regression. Safety and tolerability were also evaluated. Among the 968 treated patients (mean age, 59.8 years [SD, 9.2]; 269 [27.8%] women; mean LDL-C level, 92.5 mg/dL [SD, 27.2]), 846 had evaluable imaging at follow-up. Compared with placebo, the evolocumab group achieved lower mean, time-weighted LDL-C levels (93.0 vs 36.6 mg/dL; difference, -56.5 mg/dL [95% CI, -59.7 to -53.4]; P  < .001). The primary efficacy parameter, PAV, increased 0.05% with placebo and decreased 0.95% with evolocumab (difference, -1.0% [95% CI, -1.8% to -0.64%]; P  < .001). The secondary efficacy parameter, normalized TAV, decreased 0.9 mm3 with placebo and 5.8 mm3 with evolocumab (difference, -4.9 mm3 [95% CI, -7.3 to -2.5]; P  < .001). Evolocumab induced plaque regression in a greater percentage of patients than placebo (64.3% vs 47.3%; difference, 17.0% [95% CI, 10.4% to 23.6%]; P  < .001 for PAV and 61.5% vs 48.9%; difference, 12.5% [95% CI, 5.9% to 19.2%]; P  < .001 for TAV). Among patients with angiographic coronary disease treated with statins, addition of evolocumab, compared with placebo, resulted in a greater decrease in PAV after 76 weeks of treatment. Further studies are needed to assess the effects of PCSK9 inhibition on clinical outcomes. clinicaltrials.gov Identifier: NCT0181342

Effect of the REG1 anticoagulation system versus bivalirudin on outcomes after percutaneous coronary intervention (REGULATE-PCI): a randomised clinical trial.

BACKGROUND REG1 is a novel anticoagulation system consisting of pegnivacogin, an RNA aptamer inhibitor of coagulation factor IXa, and anivamersen, a complementary sequence reversal oligonucleotide. We tested the hypothesis that near complete inhibition of factor IXa with pegnivacogin during percutaneous coronary intervention, followed by partial reversal with anivamersen, would reduce ischaemic events compared with bivalirudin, without increasing bleeding. METHODS We did a randomised, open-label, active-controlled, multicentre, superiority trial to compare REG1 with bivalirudin at 225 hospitals in North America and Europe. We planned to randomly allocate 13,200 patients undergoing percutaneous coronary intervention in a 1:1 ratio to either REG1 (pegnivacogin 1 mg/kg bolus [>99% factor IXa inhibition] followed by 80% reversal with anivamersen after percutaneous coronary intervention) or bivalirudin. Exclusion criteria included ST segment elevation myocardial infarction within 48 h. The primary efficacy endpoint was the composite of all-cause death, myocardial infarction, stroke, and unplanned target lesion revascularisation by day 3 after randomisation. The principal safety endpoint was major bleeding. Analysis was by intention to treat. This trial is registered at ClinicalTrials.gov, identifier NCT01848106. The trial was terminated early after enrolment of 3232 patients due to severe allergic reactions. FINDINGS 1616 patients were allocated REG1 and 1616 were assigned bivalirudin, of whom 1605 and 1601 patients, respectively, received the assigned treatment. Severe allergic reactions were reported in ten (1%) of 1605 patients receiving REG1 versus one (<1%) of 1601 patients treated with bivalirudin. The composite primary endpoint did not differ between groups, with 108 (7%) of 1616 patients assigned REG1 and 103 (6%) of 1616 allocated bivalirudin reporting a primary endpoint event (odds ratio [OR] 1·05, 95% CI 0·80-1·39; p=0·72). Major bleeding was similar between treatment groups (seven [<1%] of 1605 receiving REG1 vs two [<1%] of 1601 treated with bivalirudin; OR 3·49, 95% CI 0·73-16·82; p=0·10), but major or minor bleeding was increased with REG1 (104 [6%] vs 65 [4%]; 1·64, 1·19-2·25; p=0·002). INTERPRETATION The reversible factor IXa inhibitor REG1, as currently formulated, is associated with severe allergic reactions. Although statistical power was limited because of early termination, there was no evidence that REG1 reduced ischaemic events or bleeding compared with bivalirudin. FUNDING Regado Biosciences Inc

Effect of the BET Protein Inhibitor, RVX-208, on Progression of Coronary Atherosclerosis: Results of the Phase 2b, Randomized, Double-Blind, Multicenter, ASSURE Trial.

BACKGROUND: Bromodomain and extra-terminal (BET) proteins regulate transcription of lipoprotein and inflammatory factors implicated in atherosclerosis. The impact of BET inhibition on atherosclerosis progression is unknown. METHODS: ASSURE was a double-blind, randomized, multicenter trial in which 323 patients with angiographic coronary disease and low high-density lipoprotein cholesterol (HDL-C) levels were randomized in a 3:1 fashion to treatment with the BET protein inhibitor RVX-208 200 mg or placebo for 26 weeks. Plaque progression was measured with serial intravascular ultrasound imaging. Lipid levels, safety, and tolerability were also assessed. RESULTS: During treatment, apolipoprotein (apo)A-I increased by 10.6 % with placebo (P < 0.001 compared with baseline) and 12.8 % with RVX-208 (P < 0.001 compared with baseline), between groups P = 0.18. HDL-C increased by 9.1 % with placebo (P < 0.001 compared with baseline) and 11.1 % with RVX-208 (P < 0.001 compared with baseline), between groups P = 0.24. Low-density lipoprotein cholesterol (LDL-C) decreased by 17.9 % with placebo (P < 0.001 compared with baseline) and 15.8 % with RVX-208 (P < 0.001 compared with baseline), between groups P = 0.55. The primary endpoint, the change in percent atheroma volume, decreased 0.30 % in placebo-treated patients (P = 0.23 compared with baseline) and 0.40 % in the RVX-208 group (P = 0.08 compared with baseline), between groups P = 0.81. Total atheroma volume decreased 3.8 mm3 in the placebo group (P = 0.01 compared with baseline) and 4.2 mm3 in the RVX-208 group (P < 0.001 compared with baseline), P = 0.86 between groups. A greater incidence of elevated liver enzymes was observed in RVX-208-treated patients (7.1 vs. 0 %, P = 0.009). CONCLUSION: Administration of the BET protein inhibitor RVX-208 showed no greater increase in apoA-I or HDL-C or incremental regression of atherosclerosis than administration of placebo. TRIAL REGISTRATION: ClinicalTrials.gov identifier-NCT01067820