Elevated lipoprotein(a) Lp(a) is independently associated with increased cardiovascular risk. However, treatment options for elevated Lp(a) are limited. Alirocumab, a monoclonal antibody to ...proprotein convertase subtilisin/kexin type 9, reduced low-density lipoprotein cholesterol (LDL-C) by up to 62% from baseline in phase 3 studies, with adverse event rates similar between alirocumab and controls. We evaluated the effect of alirocumab on serum Lp(a) using pooled data from the phase 3 ODYSSEY program: 4,915 patients with hypercholesterolemia from 10 phase 3 studies were included. Eight studies evaluated alirocumab 75 mg every 2 weeks (Q2W), with possible increase to 150 mg Q2W at week 12 depending on LDL-C at week 8 (75/150 mg Q2W); the other 2 studies evaluated alirocumab 150-mg Q2W from the outset. Comparators were placebo or ezetimibe. Eight studies were conducted on a background of statins, and 2 studies were carried out with no statins. Alirocumab was associated with significant reductions in Lp(a), regardless of starting dose and use of concomitant statins. At week 24, reductions from baseline were 23% to 27% with alirocumab 75/150-mg Q2W and 29% with alirocumab 150-mg Q2W (all comparisons p <0.0001 vs controls). Reductions were sustained over 78 to 104 weeks. Lp(a) reductions with alirocumab were independent of race, gender, presence of familial hypercholesterolemia, baseline Lp(a), and LDL-C concentrations, or use of statins. In conclusion, in addition to marked reduction in LDL-C, alirocumab leads to a significant and sustained lowering of Lp(a).
Summary Background Patients with homozygous familial hypercholesterolaemia respond inadequately to existing drugs. We aimed to assess the efficacy and safety of the microsomal triglyceride transfer ...protein inhibitor lomitapide in adults with this disease. Methods We did a single-arm, open-label, phase 3 study of lomitapide for treatment of patients with homozygous familial hypercholesterolemia. Current lipid lowering therapy was maintained from 6 weeks before baseline through to at least week 26. Lomitapide dose was escalated on the basis of safety and tolerability from 5 mg to a maximum of 60 mg a day. The primary endpoint was mean percent change in levels of LDL cholesterol from baseline to week 26, after which patients remained on lomitapide through to week 78 for safety assessment. Percent change from baseline to week 26 was assessed with a mixed linear model. Findings 29 men and women with homozygous familial hypercholesterolaemia, aged 18 years or older, were recruited from 11 centres in four countries (USA, Canada, South Africa, and Italy). 23 of 29 enrolled patients completed both the efficacy phase (26 weeks) and the full study (78 weeks). The median dose of lomitapide was 40 mg a day. LDL cholesterol was reduced by 50% (95% CI −62 to −39) from baseline (mean 8·7 mmol/L SD 2·9) to week 26 (4·3 mmol/L 2·5; p<0·0001). Levels of LDL cholesterol were lower than 2·6 mmol/L in eight patients at 26 weeks. Concentrations of LDL cholesterol remained reduced by 44% (95% CI −57 to −31; p<0·0001) at week 56 and 38% (–52 to −24; p<0·0001) at week 78. Gastrointestinal symptoms were the most common adverse event. Four patients had aminotransaminase levels of more than five times the upper limit of normal, which resolved after dose reduction or temporary interruption of lomitapide. No patient permanently discontinued treatment because of liver abnormalities. Interpretation Our study suggests that treatment with lomitapide could be a valuable drug in the management of homozygous familial hypercholesterolaemia. Funding FDA Office of the Orphan Product Development, Aegerion Pharmaceuticals.
Background Following acute coronary syndrome (ACS), the risk for future cardiovascular events is high and is related to levels of low-density lipoprotein cholesterol (LDL-C) even within the setting ...of intensive statin treatment. Proprotein convertase subtilisin/kexin type 9 (PCSK9) regulates LDL receptor expression and circulating levels of LDL-C. Antibodies to PCSK9 can produce substantial and sustained reductions of LDL-C. The ODYSSEY Outcomes trial tests the hypothesis that treatment with alirocumab, a fully human monoclonal antibody to PCSK9, improves cardiovascular outcomes after ACS. Design This Phase 3 study will randomize approximately 18,000 patients to receive biweekly injections of alirocumab (75-150 mg) or matching placebo beginning 1 to 12 months after an index hospitalization for acute myocardial infarction or unstable angina. Qualifying patients are treated with atorvastatin 40 or 80 mg daily, rosuvastatin 20 or 40 mg daily, or the maximum tolerated and approved dose of one of these agents and fulfill one of the following criteria: LDL-C ≥ 70 mg/dL, non–high-density lipoprotein cholesterol ≥ 100 mg/dL, or apolipoprotein B ≥ 80 mg/dL. The primary efficacy measure is time to first occurrence of coronary heart disease death, acute myocardial infarction, hospitalization for unstable angina, or ischemic stroke. The trial is expected to continue until 1613 primary end point events have occurred with minimum follow-up of at least 2 years, providing 90% power to detect a 15% hazard reduction. Adverse events of special interest include allergic events and injection site reactions. Interim analyses are planned when approximately 50% and 75% of the targeted number of primary end points have occurred. Summary ODYSSEY Outcomes will determine whether the addition of the PCSK9 antibody alirocumab to intensive statin therapy reduces cardiovascular morbidity and mortality after ACS.
Background Nonadherence to cardiovascular medications, including daily, oral statin therapy, negatively impacts outcomes in patients requiring low-density lipoprotein cholesterol (LDL-C)-lowering ...therapy. The proprotein convertase subtilisin/kexin type 9 inhibitor alirocumab also reduces LDL-C, but has a different mode of administration (subcutaneous injection). Objective The objective of the study was to assess long-term adherence to alirocumab 75 or 150 mg, given every 2 weeks, in phase III trials of patients with sub-optimally controlled hypercholesterolemia. Methods Data were pooled from 6 ODYSSEY trials (n = 4212) with double-blind treatment durations of 52 to 104 weeks. Adherence was reported as percent of days receiving injections according to dosing schedule and categorized into 100% adherence, below-planned dosing, above-planned dosing, and both below- and above-planned dosing. Overall adherence was calculated as 100 (percent of days with below-planned dosing + percent of days with above-planned dosing). Safety of alirocumab and effect on LDL-C levels were also evaluated. Results Adherence was analyzed for 4197 patients (n = 2786 alirocumab; n = 1411 control). Mean overall adherence was high (alirocumab 98.0%; control 97.8%). Among patients receiving alirocumab, 45.7% were 100% adherent, 20.4% had below-planned dosing, 2.9% had above-planned dosing, and 31.1% had both below- and above-planned dosing. Mean percent reduction in LDL-C (baseline to Week 52) was 45.8% to 61.9%, depending on alirocumab dose, and was comparable across adherence categories. Treatment-emergent adverse events leading to alirocumab discontinuation were infrequent and included myalgia and injection-site reactions (<1% each). Conclusions Alirocumab injections were associated with a high level of adherence over ≥1 year. Infrequent below- or above-planned dosing had minimal impact on LDL-C reductions.
Abstract Background Proprotein convertase subtilisin/kexin type 9 monoclonal antibodies can reduce low-density lipoprotein cholesterol (LDL-C) to very low levels when added to background ...lipid-lowering therapy. Objectives The safety of alirocumab was evaluated in patients with at least 2 consecutive LDL-C values <25 or <15 mg/dl in the ODYSSEY program, with follow-up as long as 104 weeks. Methods Pooled data from 14 trials were analyzed (double-blind treatment 8 to 104 weeks; n = 3,340 alirocumab, n = 1,894 control placebo or ezetimibe; representing 4,029 alirocumab and 2,114 control double-blind patient-years’ exposure). Results In alirocumab-treated patients, 839 (25.1%) achieved 2 consecutive LDL-C values <25 mg/dl, and 314 (9.4%) achieved <15 mg/dl. Baseline LDL-C was lower (mean 100.3 vs. 134.3 mg/dl) in patients with LDL-C <25 versus ≥25 mg/dl. Similar rates of adverse events occurred in patients achieving LDL-C <25 and <15 mg/dl (72.7% and 71.7%, respectively), compared with 76.6% in those who did not achieve LDL-C <25 mg/dl. Neurological and neurocognitive events were similar among the 3 groups. In a propensity score analysis, the rate of cataracts was higher in patients with LDL-C <25 mg/dl (2.6%) versus ≥25 mg/dl (0.8%; hazard ratio: 3.40; 95% confidence interval: 1.58 to 7.35). However, no difference in cataract incidence was observed between pooled alirocumab and control groups. Conclusions LDL-C levels <25 or <15 mg/dl on alirocumab were not associated with an increase in overall treatment-emergent adverse event rates or neurocognitive events, although cataract incidence appeared to be increased in the group achieving LDL-C levels <25 mg/dl. (Pooled analyses of already reported trials; NCT01288443 , NCT01288469 , NCT01266876 , NCT01812707 , NCT01507831 , NCT01617655 , NCT01623115 , NCT01709500 , NCT01644175 , NCT01644188 , NCT01730040 , NCT01730053 , NCT01644474 , and NCT01709513 )
Proprotein convertase subtilisin kexin type-9 (PCSK9) inhibition using monoclonal antibodies (mAbs) lowers low-density lipoprotein cholesterol (LDL-C) by >50% in heterozygous familial ...hypercholesterolemia (HeFH) and non-FH dyslipidemic individuals (1). Because PCSK9 is a circulating inhibitor of the LDL receptor (LDLR), PCSK9 inhibition using mAbs should not lower plasma LDL-C in homozygous FH (HoFH) patients who completely lack the receptor (receptor-negative). Human dermal fibroblasts (HDF) isolated from 9 receptor-defective and 4 receptor-negative HoFH patients were grown in 0.5% serum and 40 g/ml mevastatin to maximally up-regulate LDLR, and subsequently incubated with recombinant PCSK9 (either wild-type or the gain of function mutant D374Y) (3), with or without increasing concentrations of alirocumab.
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