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Aims To assess long-term (78 weeks) alirocumab treatment in patients with heterozygous familial hypercholesterolaemia (HeFH) and inadequate LDL-C control on maximally tolerated lipid-lowering therapy (LLT). Methods and results In two randomized, double-blind studies (ODYSSEY FH I, n = 486; FH II, n = 249), patients were randomized 2: 1 to alirocumab 75 mg or placebo every 2 weeks (Q2W). Alirocumab dose was increased at Week 12 to 150 mg Q2W if Week 8 LDL-C was ≥1.8 mmol/L (70 mg/dLS). Primary endpoint (both studies) was percentage change in calculated LDL-C from baseline to Week 24. Mean LDL-C levels decreased from 3.7 mmol/L (144.7 mg/dL) at baseline to 1.8 mmol/L (71.3 mg/dL; 257.9% vs. placebo) at Week 24 in patients randomized to alirocumab in FH I and from 3.5 mmol/L (134.6 mg/dL) to 1.8 mmol/L (67.7 mg/dL; 251.4% vs. placebo) in FH II (P < 0.0001). These reductions were maintained through Week 78. LDL-C <1.8 mmol/L (regardless of cardiovascular risk) was achieved at Week 24 by 59.8 and 68.2% of alirocumab-treated patients in FH I and FH II, respectively. Adverse events resulted in discontinuation in 3.4% of alirocumab-treated patients in FH I (vs. 6.1% placebo) and 3.6% (vs. 1.2%) in FH II. Rate of injection site reactions in alirocumab-treated patients was 12.4% in FH I and 11.4% in FH II (vs. 11.0 and 7.4% with placebo). Conclusion In patients with HeFH and inadequate LDL-C control at baseline despite maximally tolerated statin+other LLT, alirocumab treatment resulted in significant LDL-C lowering and greater achievement of LDL-C target levels and was well tolerated. [ABSTRACT FROM AUTHOR]

Background Statin intolerance has been a major limitation in the use of statins, especially at higher doses. New effective treatments are needed for lowering low-density lipoprotein cholesterol (LDL-C) in patients who cannot tolerate daily statin doses. Objective ODYSSEY ALTERNATIVE ( NCT01709513 ) evaluates efficacy and safety of alirocumab, a fully human proprotein convertase subtilisin/kexin type 9 monoclonal antibody, in patients with well-documented statin intolerance and moderate to very high cardiovascular risk. Methods This is a phase 3, multicenter, randomized, double-blind, double-dummy study in statin-intolerant patients. Intolerance was defined as inability to take at least 2 different statins because of muscle-related adverse events (AEs), 1 at the lowest approved starting dose. Patients first received single-blind subcutaneous and oral placebo for 4 weeks, and were withdrawn if they developed muscle-related AEs after the placebo treatment. Continuing patients were randomized (2:2:1 ratio) to alirocumab 75 mg self-administered via single 1 mL prefilled pen every 2 weeks or ezetimibe 10 mg/day or atorvastatin 20 mg/day (statin rechallenge), for 24 weeks. Alirocumab dose was increased to 150 mg every 2 weeks (also 1 mL) at week 12 depending on week 8 LDL-C level. The primary endpoint is percent change in LDL-C from baseline to week 24 by intent-to-treat analysis. Muscle-related AEs were assessed by spontaneous patient reports and clinic queries. Results A total of 314 patients have been randomized. Conclusions This is the first and only study of a new class of LDL-C–lowering agents in patients selected with a rigorously documented intolerance to statins, using a placebo run-in and statin control arm. [ABSTRACT FROM AUTHOR]

Background Patients with heterozygous familial hypercholesterolemia (HeFH) are characterized by elevated low-density lipoprotein cholesterol (LDL-C) levels. Long-term effects of proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibition have not been thoroughly investigated in these patients. Objective We evaluated efficacy and safety of alirocumab, a PCSK9 inhibitor, vs placebo in patients with HeFH. Methods In total, 1257 patients with HeFH on maximally tolerated statin ± other lipid-lowering therapies from four 78-week ODYSSEY trials were analyzed. In FH I and II, patients with baseline LDL-C levels ≥70/100 mg/dL ( n = 735), depending on documented cardiovascular disease history, received placebo or alirocumab 75 mg every 2 weeks (Q2W; with dose increase to 150 mg Q2W at week 12 if week 8 LDL-C was ≥70 mg/dL). Separately, data were pooled from HIGH FH (baseline LDL-C ≥160 mg/dL) and patients with HeFH from LONG TERM (baseline LDL-C ≥70 mg/dL), where patients received placebo or alirocumab 150 mg Q2W ( n = 522). Results At week 24, alirocumab reduced LDL-C levels by −48.8% (75/150 mg Q2W; placebo: +7.1%) and −55.0% (alirocumab 150 mg Q2W; placebo: +1.3%) (both P < .0001 vs placebo; intention-to-treat analysis). Least-squares mean LDL-C levels of 69.1 to 75.6 mg/dL (alirocumab 75/150 mg/dL Q2W; baseline: 141.3 mg/dL) and 72.2 to 82.3 mg/dL (alirocumab 150 mg Q2W; baseline: 168.4 mg/dL) were achieved at weeks 24 to 78 (on-treatment analysis). Additional beneficial effects were observed in other lipids. Treatment-emergent adverse event rates were similar in the alirocumab (80.5%) and placebo groups (83.0%). Conclusions In this large cohort of patients with HeFH, alirocumab significantly reduced LDL-C levels. Alirocumab was generally well tolerated. [ABSTRACT FROM AUTHOR]

Background PCSK9 inhibition with alirocumab significantly reduced LDL-C levels in trials of up to 78 weeks' duration in patients with heterozygous familial hypercholesterolemia (HeFH). We report results from 3 years of an ongoing open-label treatment extension ( NCT01576484 ) to a 12-week double-blind trial in HeFH patients ( NCT01266876 ). Methods Patients who completed the parent study and were receiving stable daily statin ± ezetimibe could enter the open-label extension, where they received alirocumab 150 mg every 2 weeks (Q2W) subcutaneously (n = 58). The primary endpoint was safety (treatment-emergent adverse events, TEAEs). Efficacy endpoints included the percentage change in LDL-C from baseline at Week 24. Safety and efficacy data were available up to Weeks 156 and 148, respectively. Results Mean baseline LDL-C was 150.7 mg/dL (3.9 mmol/L), despite all patients being on a statin (76% on high-intensity statin; 72% also receiving ezetimibe). Over 156 weeks, 54 (93.1%) patients experienced a TEAE, 12 (20.7%) experienced a serious TEAE, and two (3.4%) discontinued due to a TEAE. Injection site reactions occurred in 21 (36.2%) patients. Mean (SD) reduction in LDL-C from baseline to Week 24 was 65.4 (21.1)%, with reductions maintained through 148 weeks (Week 148 reduction: 56.0 [23.8]%). Mean apolipoprotein B reduction was 50.9% and median lipoprotein (a) reduction was 22.5% at Week 24 (46.1% and 25.6% at Week 148, respectively). Conclusions Open-label treatment for 3 years with alirocumab 150 mg Q2W, administered with background statin ± ezetimibe, was generally well-tolerated and had a safety profile comparable with that seen in the overall alirocumab clinical trial program. Alirocumab provided significant, sustained LDL-C reductions. [ABSTRACT FROM AUTHOR]

Background: The 24-week randomized, double-blind (DB) ODYSSEY ALTERNATIVE (NCT01709513) trial demonstrated significant LDL-C reductions with the PCSK9 inhibitor alirocumab versus ezetimibe in statin-intolerant patients, with significantly fewer skeletal muscle events (SMEs; 32.5%) versus atorvastatin (ATV; 46.0%; hazard ratio: 0.61, 95% confidence interval: 0.38 to 0.99, P=0.042). SMEs led to discontinuation in 15.9% and 22.2% of patients treated with alirocumab and ATV, respectively. Objective: The objective of this open-label extension trial (OLE) was to gain long-term safety experience with alirocumab. Methods: Regardless of previous treatment allocation in the DB treatment period, 281 patients were eligible for inclusion in OLE. Patients completed the DB treatment period (n=216 [76.9%]) or prematurely discontinued treatment either due to SME (n=51 [18.1%]) or other reasons (n=14 [5.0%]), and completed Week 24 assessments. Patients received alirocumab for approximately 3 years or until it became commercially available, whichever came first. Results: At Week 32, mean LDL-C was reduced from baseline of parent study by 52.0% with reductions sustained through the end of treatment visits (approximately 3 years; 51.9%, 55.4% and 53.7% reduction at Weeks 36, 100 and 148, respectively). Mean duration of exposure was 113 weeks (Table 1). Treatment-emergent events during OLE are shown in Table 1. Overall, SMEs were reported by 38.4% of patients, but only led to alirocumab discontinuation in 9 patients (3.2%; pain in extremity: 2.1%; myalgia: 1.1%). Creatine kinase above upper limit of normal occurred in one patient. Conclusions: In this population of statin-intolerant patients, alirocumab produced durable LDL-C reductions over 3 years and was well tolerated. Safety results from the OLE were similar to the DB treatment period, except for a much lower rate of discontinuations due to muscle side effects observed with alirocumab (3.2% and 15.9%, respectively). [ABSTRACT FROM AUTHOR]

Background: Statin intolerance (SI) limits many patients (pts) from taking statins and achieving LDL-C goals. Ezetimibe (EZE) is a recommended option for SI pts. ODYSSEY ALTERNATIVE (NCT01709513) compared alirocumab (ALI) vs. EZE in pts with history of SI due to muscle symptoms (inability to tolerate ≥2 statins, 1 at lowest approved starting dose). The novel study design included a placebo (PBO) run-in period and statin rechallenge arm to document SI. Methods: SI pts (with CHD/other CV risk factors) first received single-blind subcutaneous and oral PBO for 4 weeks (W), and were excluded if muscle-related adverse events (AEs) were reported with PBOs. Continuing pts were randomized (2:2:1 ratio) to ALI 75 mg self-administered via 1-mL pre-filled pen every 2 weeks (Q2W) or EZE 10 mg/day or atorvastatin (ATV) 20 mg/day for 24 W. ALI dose was increased to 150 mg Q2W (also 1-mL) at W12 depending on CV risk and W8 LDL-C level. Primary endpoint was % change in LDL-C from baseline to W24 (intent-to-treat analysis). Pts could enter an open-label extension (OLE) and receive ALI 75/150 mg Q2W. Results: PBO run-in was completed by 87.0% (314/361) pts, 6.9% (25) discontinued due to muscle AE. Baseline mean LDL-C levels were 191-194 mg/dL (Table), 15% of pts had HeFH. ALI produced significant LDL-C reductions vs. EZE at W24 (Table). Although treatment-emergent adverse events (TEAEs) were generally comparable between groups, the rate of skeletal muscle related TEAEs was significantly lower for AU vs. ATV (P<0.05) (Table). Myalgia was the most common TEAE in all groups (Table). In total, 89.5% of randomized pts entered the OLE (Table).Conclusions: ALI demonstrated significantly greater LDL-C lowering vs. EZE after 24 W in an SI population with very high baseline LDL-C levels and was well-tolerated, with significantly lower rates of musculoskeletal TEAEs than ATV. ALI may be considered a good alternative therapy in patients with a history of SI. [ABSTRACT FROM AUTHOR]