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The ODYSSEY COMBO I study (http://clinicaltrials.gov/show/NCT01644175) evaluated efficacy and safety of alirocumab as add-on therapy to stable maximally tolerated daily statin with or without other lipid-lowering therapy in high cardiovascular risk patients with suboptimally controlled hypercholesterolemia. This multicenter, phase 3, randomized (2:1 alirocumab vs placebo), double-blind, 52-week trial enrolled 316 patients with established coronary heart disease or coronary heart disease risk equivalents and hypercholesterolemia. Alirocumab (75 mg every 2 weeks [Q2W]) or placebo Q2W was self-administered subcutaneously via 1 mL prefilled pen. The alirocumab dose was increased to 150 mg Q2W (also 1 mL) at week 12 if week 8 low-density lipoprotein cholesterol (LDL-C) was ≥70 mg/dL. The primary efficacy end point was percent change in LDL-C from baseline to week 24 (intention-to-treat analysis). At week 24, estimated mean (95% CI) changes in LDL-C from baseline were −48.2% (−52.0% to −44.4%) and −2.3% (−7.6% to 3.1%) for alirocumab and placebo, respectively, an estimated mean (95% CI) difference of −45.9% (−52.5% to −39.3%) (P < .0001). Low-density lipoprotein cholesterol <70 mg/dL was achieved by 75% alirocumab versus 9% placebo patients at week 24. At week 12, 83.2% of evaluable alirocumab-treated patients remained on 75-mg Q2W. Treatment-emergent adverse events were comparable between groups. Alirocumab treatment achieved a significantly greater reduction in LDL-C and allowed a greater proportion of patients to achieve LDL-C goals, versus placebo after 24 weeks in high cardiovascular risk patients with suboptimally controlled hypercholesterolemia at baseline despite receiving maximally tolerated statin with or without other lipid-lowering therapy. The frequency of treatment-emergent adverse events and study medication discontinuations were generally comparable between treatment groups.

Inhibition of proprotein convertase subtilisin/kexin type 9 serine protease (PCSK9) resulted in large reductions of low-density lipoprotein cholesterol (LDL-C) in phase 1 trials. We assessed the efficacy and safety of various doses and dosing intervals of REGN727, a monoclonal antibody to PCSK9, added to statins, to further lower LDL-C in patients with heterozygous familial hypercholesterolaemia. This multicentre, randomised, placebo-controlled phase 2 trial was done at 16 lipid clinics in the USA and Canada. Between Jan 18, 2011, and Nov 7, 2011, we enrolled adults with heterozygous familial hypercholesterolaemia and LDL-C concentrations of 2·6 mmol/L or higher on stable diet and statin dose, with or without ezetimibe. Patients were randomly assigned to receive REGN727 150 mg, 200 mg, or 300 mg every 4 weeks, or 150 mg every 2 weeks, or placebo every 2 weeks (ratio 1:1:1:1:1). Randomisation was stratified by concomitant use of ezetimibe at baseline. Investigators, study staff, and patients were masked to treatment group. Blinding was maintained by administration of placebo alternating with REGN727 for the groups of 4 week dosing. The primary endpoint was mean percent reduction in LDL-C from baseline at week 12 and was analysed in the modified intention-to-treat population with an analysis of covariance (ANCOVA) model with treatment group. This trial is registered in ClinicalTrials.gov, number NCT 01266876. 77 patients were randomly assigned to study groups (15–16 patients per group) and all were analysed. Least-squares (LS) mean LDL-C reduction from baseline to week 12 was 28·9% (SE 5·08) for 150 mg every 4 weeks (p=0·0113), 31·54% (4·91) for 200 mg every 4 weeks (p=0·0035), 42·53% (5·09) for 300 mg every 4 weeks (p<0·0001), and 67·90% (4·85) for 150 mg every 2 weeks (p<0·0001), compared with 10·65% (5·04) with placebo. One serious adverse event was reported with placebo and none with REGN727. No increases of more than three times the upper limit of normal were reported for hepatic transaminases or creatinine kinase. The most common adverse event was injection-site reaction with one patient in the group of 300 mg REGN727 terminating treatment. REGN727 was well tolerated and achieved substantial further LDL-C reduction in patients with heterozygous familial hypercholesterolaemia and elevated LDL-C treated with high-dose statins, with or without ezetimibe. REGN727 has the potential to provide optimum control of LDL-C in patients with this disorder. Sanofi US and Regeneron Pharmaceuticals Incorporated.

Previous individual trials of alirocumab (a PCSK9 monoclonal antibody) showed significant low-density lipoprotein cholesterol reductions with overall treatment-emergent adverse event (TEAE) rates comparable with controls. This analysis evaluated safety data from 14 trials (4 phase 2 and 10 phase 3, 8 to 104 weeks; n = 5,234), in 2 pools according to control (placebo/ezetimibe). Overall, 3,340 patients received alirocumab (4,029 patient-years' exposure), 1,276 received placebo, and 618 received ezetimibe. Incidence of deaths, serious TEAEs, discontinuations because of TEAEs, and overall TEAEs were similar between alirocumab and control groups. Alirocumab was associated with a higher incidence of local injection site reactions (7.4% vs 5.3% with placebo; 3.1% vs 2.3% with ezetimibe), pruritus (1.3% vs 0.4% placebo; 0.9% vs 0.5% ezetimibe), and upper respiratory tract infection signs and symptoms (2.1% vs 1.1% placebo; 1.3% vs 0.8% ezetimibe). Incidence of musculoskeletal, neurologic, neurocognitive, ophthalmologic, hepatic events, and TEAEs related to diabetes/diabetes complications was similar between alirocumab and control groups. In a prespecified analysis of phase 3 studies, adjudicated major adverse cardiovascular events (coronary heart disease death, nonfatal myocardial infarction, ischemic stroke, and unstable angina requiring hospitalization) occurred in 1.8% alirocumab versus 2.6% placebo patients (hazard ratio 0.69, 95% confidence interval 0.43 to 1.11) and 2.8% alirocumab versus 1.5% ezetimibe patients (hazard ratio 1.4, 95% confidence interval 0.65 to 3.02). In conclusion, pooled safety data from 14 trials demonstrate that alirocumab is generally well tolerated with a favorable safety profile.

Evinacumab, a monoclonal antibody that blocks ANGPTL3, was administered to nine adults with homozygous familial hypercholesterolemia. At 4 weeks, LDL cholesterol was reduced by a mean of 49%, with a mean absolute change from baseline of −157 mg per deciliter.

Homozygous familial hypercholesterolemia (HoFH) is a rare and serious genetic condition characterized by premature cardiovascular disease due to severely elevated low‐density lipoprotein cholesterol (LDL‐C). HoFH primarily results from loss‐of‐function (LOF) mutations in the LDL receptor (LDLR), reducing LDL‐C clearance such that patients experience severe hypercholesterolemia, exacerbating the risk of developing cardiovascular events. Treatment options such as statins, lomitapide, ezetimibe, proprotein convertase subtilisin/kexin type 9 inhibitors, and apheresis help lower LDL‐C; however, many patients with HoFH still fail to reach their target LDL‐C levels and many of these lipid‐lowering therapies are not indicated for pediatric use. Angiopoietin‐like protein 3 (ANGPTL3) has been identified as a target to treat elevated LDL‐C by acting as a natural inhibitor of lipoprotein lipase (LPL) and endothelial lipase (EL), enzymes involved in the hydrolysis of the triglyceride and phospholipid content of very low‐density lipoproteins. Persons heterozygous for LOF mutations in ANGPTL3 were reported to have lower LDL‐C than non‐carriers and lower risk of coronary artery disease. Evinacumab is a first‐in‐class human monoclonal antibody that specifically binds to ANGPTL3 to prevent its inhibition of LPL and EL. In clinical trials, a 15 mg/kg intravenous dose every 4 weeks has shown a mean percent change from baseline in LDL‐C of ~50% in adult, adolescent, and pediatric patients with HoFH. This mini review article describes the mechanism of action of evinacumab, evinacumab population PK and PD modeling, and clinical development history of evinacumab for the treatment of HoFH.

Evolutionary pressures to protect against food scarcity likely resulted in highly-conserved pathways designed to minimize energy expenditure, one of which involves the minimization of muscle mass; these mechanisms may be counter-productive in a modern world suffering from obesity and sarcopenia. Growth differentiation factor 8 (GDF8)/myostatin, acting via ActRIIA/B receptors, is the best-characterized negative regulator of muscle mass, leading to therapeutic efforts to augment muscle growth by blocking GDF8 or ActRIIA/B. ActRIIA/B blockade approximately doubles the muscle increase of GDF8 blockade, and as ActRIIA/B responds to multiple other TGFβ-family members, this implies other ligands might also regulate muscle mass. Previously, we suggested that activin A (ActA) is the key second negative regulator acting via ActRIIA/B, as blockade of both GDF8 and ActA in mice/monkeys matches the muscle growth of ActRIIA/B blockade. Here, we extend these observations to humans in a two-part, randomized, placebo-controlled Phase 1 trial ( www.clinicaltrials.gov , NCT02943239) conducted at two sites in New Zealand. Eligible subjects included healthy postmenopausal females aged 45–70 years and males aged 35–60 years not intending to father children, with a body mass index of 18–32 kg/m 2 . Part I tested single-dose administration of anti-GDF8 alone, anti-ActA alone, several dose combinations of anti-GDF8 + anti-ActA, or placebo in healthy postmenopausal females; part II tested multiple-dose administration of anti-ActA alone or placebo in healthy postmenopausal females, combination anti-GDF8 + anti-ActA or placebo in healthy postmenopausal females, and anti-ActA alone or placebo in healthy males. The primary outcome measure was the incidence and severity of treatment-emergent adverse events through week 16 for the single-dose part of the study and through week 40 for the multiple-dose part of the study. Secondary endpoints included percent and absolute change in thigh muscle volume, percent and absolute change in total and regional body composition, pharmacokinetic profiles of the GDF8 and ActA mAbs in serum over time, changes in serum total GDF8 and total ActA levels over time, and the presence of anti-drug antibodies against the GDF8 mAb or the ActA mAb. Magnetic resonance imaging was used to quantitate changes in thigh muscle volume and dual x-ray absorptiometry was used to quantitate changes in regional body composition (total lean mass, appendicular lean body mass, android fat mass, and total fat mass). A total of 82 subjects were enrolled (48 in the single-dose part and 34 in the multiple-dose part of the study). Baseline demographic and clinical characteristics were generally balanced across the single- and multiple-dose parts of the study. Combining GDF8 and ActA blocking antibodies led to greater muscle growth than either antibody alone; increases in muscle were accompanied by reductions in fat. The observed clinical effects on muscle and fat paralleled mAb exposure in serum. The combination was generally well tolerated, and no subjects tested positive for anti-drug antibodies post-treatment. These results suggest that GDF8 and ActA are the dominant negative regulators of muscle mass in humans, and that combined blockade may be a promising therapeutic approach in muscle atrophy and obesity settings. GDF8 and activin A are the dominant negative regulators of muscle mass in animal models. This two-part, randomized, placebo-controlled Phase 1 trial suggests that GDF8 and activin A are also the dominant negative regulators of muscle mass in humans.

Evinacumab, an angiopoietin‐like 3 (ANGPTL3) inhibitor, significantly reduces low‐density lipoprotein cholesterol (LDL‐C), independent of low‐density lipoprotein receptor, in patients with homozygous familial hypercholesterolemia (HoFH). A population pharmacokinetic (PK)/pharmacodynamic (PD) model was previously developed to characterize evinacumab exposure and LDL‐C response in adolescents and adults. In this analysis, the PK/PD model was refined to include children aged 5 to < 12 years and to characterize the lipoprotein apheresis effect on LDL‐C reduction. The PK of evinacumab was characterized by a two‐compartment model with parallel linear and non‐linear elimination. Linear disposition parameters were allometrically scaled by body weight. Baseline ANGPTL3 concentrations and disease status (non‐HoFH vs. HoFH) influenced the maximum target‐mediated rate of elimination but had a minimal effect on evinacumab exposures at 15 mg/kg intravenous doses every 4 weeks across weight/age groups. In patients with HoFH, the LDL‐C reduction was adequately described by an indirect response model in which evinacumab inhibits the formation of LDL‐C and that includes a secondary elimination process quantifying the lipoprotein apheresis effect. Older age was associated with a decrease in baseline LDL‐C. An increase in body weight was associated with a reduction in the maximum inhibitory effect of evinacumab. Model‐based simulations showed that while evinacumab exposure is reduced with decreasing age/body weight, younger patients are predicted to have a comparable or greater magnitude of LDL‐C reduction than older patients at a dose of 15 mg/kg. Overall, the model adequately predicted the evinacumab exposure and LDL‐C reduction in children, adolescents, and adults with HoFH, aligning with clinically relevant observations.

Background Some data suggest that low levels of low-density lipoprotein cholesterol (LDL-C) are associated with risk of cataracts. Proprotein convertase subtilisin–kexin type 9 (PCSK9) inhibitors reduce LDL-C below levels achieved with statins alone. We determined whether the incidence of cataracts was influenced by treatment with the PCSK9 inhibitor alirocumab versus placebo, and whether that incidence was affected by achieved LDL-C levels. Methods The ODYSSEY OUTCOMES trial (NCT01663402) compared alirocumab with placebo in 18,924 patients with recent acute coronary syndrome receiving high-intensity or maximum-tolerated statin. Incident cataracts were pre-specified events of interest. In multivariable analysis using propensity score-matching on characteristics including cataract risk factors, incident cataracts were compared in the alirocumab and placebo groups according to LDL-C levels achieved with alirocumab. Results Over median follow-up of 2.8 years (interquartile range 2.3 − 3.4), the incidence of cataracts was similar with alirocumab (127/9462 [1.3%]) versus placebo (134/9462 [1.4%]); hazard ratio [HR] 0.94, 95% confidence interval [CI] 0.74 − 1.20). In patients treated with alirocumab with ≥ 2 LDL-C values < 25 mg/dL (0.65 mmol/L), the incidence of cataracts was 71/4305 (1.6%), versus 60/4305 (1.4%) in propensity score-matched patients from the placebo group (HR 1.10, CI 95% 0.78 − 1.55). In patients treated with alirocumab with ≥ 2 LDL-C values < 15 mg/dL (0.39 mmol/L), the incidence of cataracts was 13/782 (1.7%), versus 36/2346 (1.5%) in matched patients from the placebo group (HR 1.03, CI 95% 0.54 − 1.94). Conclusion Treatment with alirocumab versus placebo, added to statin, did not influence the incidence of cataracts, even when achieved LDL-C levels on alirocumab were very low. Longer follow-up studies might be necessary to exclude the long-term effects on the incidence or progression of cataracts. Trial registration ClinicalTrials.gov Identifier: NCT01663402 .

Evinacumab, an angiopoietin‐like 3 inhibitor, significantly reduces low‐density lipoprotein cholesterol (LDL‐C) in patients with homozygous familial hypercholesterolemia (HoFH). Herein, we report pharmacokinetic and efficacy analyses of evinacumab in < 5‐year‐old patients with HoFH. Population pharmacometric models characterizing evinacumab exposure and LDL‐C response accounting for lipoprotein apheresis effect in ≥ 5‐year‐old patients were adapted for growth and maturation to predict and compare evinacumab and LDL‐C concentrations across age/weight groups in virtual ≥ 6‐month‐old patients receiving 15 mg/kg evinacumab intravenous (iv) infusions every 4 weeks (q4w). As expected from allometric theory, weight‐based dosing resulted in decreasing evinacumab exposures with declining body weight. Consistent with trends observed in > 5‐year‐old patients, the predicted percent change from LDL‐C baseline (%∆LDL‐C) was generally comparable or even higher in < 5‐year‐old patients (63.0%–68.5%) than in 5‐ to < 18‐year‐old patients (61.3%–67.8%) or adults (51.7%), with the predicted percentages of patients achieving %∆LDL‐C > 50% also higher in < 5‐year‐old patients (82.0%–86.9%) versus 5‐ to < 18‐year‐old patients (72.0%–84.5%) and adults (54.8%). Through a managed access program, six 1‐ to < 5‐year‐old patients received between 5 and 23 iv infusions of 15 mg/kg evinacumab q4w. Rapid and clinically meaningful LDL‐C reductions were observed, with %∆LDL‐C at the last reported dose ranging from 41.3% to 77.3%. Based on the actual patient dosing and plasmapheresis history, model‐predicted evinacumab and LDL‐C concentrations were comparable to the observed data collected in the managed access program. Overall, this analysis provides evidence for the use of evinacumab 15 mg/kg iv q4w dosing regimen in 6‐month‐old to 5‐year‐old patients.

Objective Assess the risk of new and worsening cancer events among participants who received the lipid‐lowering therapy alirocumab, a proprotein convertase subtilisin/kexin type 9 inhibitor. Design Pooled post hoc analysis. Setting Six phase 3 or phase 4 placebo‐controlled randomised trials with alirocumab. Participants A total of 24,070 patients from the safety population with complete dosing data (alirocumab, n = 12,533; placebo, n = 11,537). Intervention Alirocumab 75 mg, alirocumab 150 mg, alirocumab 75 mg increasing to 150 mg if low‐density lipoprotein cholesterol <50 mg/dL not achieved, or placebo, all every 2 weeks. All participants received background high‐intensity or maximum‐tolerated statin therapy. Outcomes and Measures The first new or worsening incident cancer events were assessed during the treatment‐emergent adverse event period. Four outcomes were evaluated: any‐neoplasm, malignant neoplasms, broad definition of hormone‐sensitive cancers, and stricter definition of hormone‐sensitive cancers. Sub‐distribution hazard ratios and 95% confidence intervals (CIs) were estimated using a competing risk framework, with death as a competing risk. Results Considering both treatment arms in aggregate, 969 (4.03%), 779 (3.24%), 178 (0.74%) and 167 (0.69%) patients developed any neoplasm, malignant neoplasms, broad definition of hormone‐sensitive cancer and strict definition of hormone‐sensitive cancer events, respectively. There was no significant difference in the risk of having any neoplasm in the alirocumab versus the placebo group (sub‐distribution hazards ratio [95% CI], 0.93 [0.82–1.1]; p = 0.28). A nominally lower risk of having any neoplasms with alirocumab was observed among subjects aged ≥64 years (sub‐distribution hazards ratio 0.83; 95% CI, 0.70–0.99). Conclusions Intensive low‐density lipoprotein cholesterol lowering with a proprotein convertase subtilisin/kexin type 9 inhibitor combined with statin does not appear to increase the risk of new or worsening cancer events. The risk of new and worsening cancer events was assessed among participants who received the proprotein convertase subtilisin/kexin type 9 inhibitor alirocumab combined with a statin. Our results demonstrated that intensive low‐density lipoprotein cholesterol lowering does not appear to increase the risk of new or worsening cancer events.