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/m2. 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.

Introduction: Preclinical data suggest myostatin and activin A are important negative regulators of muscle mass. Trevogrumab (a monoclonal antibody [mAb]) binds and blocks myostatin signalling, while garetosmab (a mAb) binds and blocks activin A, AB and AC signalling. Here, the effects of administering trevogrumab and garetosmab, alone or in combination, on body composition in healthy participants was assessed. Methods: This Phase 1, double-blind, placebo-controlled study randomized healthy males and postmenopausal females to single-dose or multiple-dose parts of the study. For single-dose, females received: trevogrumab 6 mg/kg (n=6); garetosmab 10 mg/kg (n=6); combination trevogrumab 6 mg/kg and garetosmab (1 mg/kg, n=6; 3 mg/kg, n=6; 10 mg/kg, n=12); or placebo (PBO; n=12). For multiple‑dose, females received: garetosmab 10 mg/kg every 4 weeks (Q4W; n=6) or PBO (n=2); combination trevogrumab 6 mg/kg and garetosmab 10 mg/kg every 2 weeks (n=6) or PBO (n=4). In the multiple dose part, males received garetosmab 10 mg/kg Q4W (n=8) or PBO (n=8). Results: Thigh muscle volume (TMV) increased from baseline 7.7% with trevogrumab 6 mg/kg + garetosmab 10 mg/kg (nominal P<0.001 vs PBO) and 4.6% with trevogrumab 6 mg/kg (nominal P<0.05 vs PBO) 8 weeks after single-dose. Total fat mass and android fat mass (AFM) decreased from baseline with trevogrumab 6 mg/kg + garetosmab 10 mg/kg (-4.6% and -6.7%; both nominal P<0.05 vs PBO). After multiple-dose, TMV initially increased after 3 doses of trevogrumab 6 mg/kg + garetosmab 10 mg/kg but decreased to similar levels as PBO at Week 28; AFM and visceral fat mass decreased from baseline by 14.3% and 20.1%, respectively (both nominal P<0.05 vs PBO). No safety concerns were identified in any active treatment groups. Conclusion: Combined administration of trevogrumab and garetosmab led to dose-dependent, greater‑than‑additive increases in TMV and lean mass, while decreasing fat mass in healthy participants. Disclosure D. Gonzalez Trotter: Employee; Regeneron Pharmaceuticals Inc. Stock/Shareholder; Regeneron Pharmaceuticals Inc. S. Donahue: Employee; Regeneron Pharmaceuticals Inc. Stock/Shareholder; Regeneron Pharmaceuticals Inc. C. Wynne: Employee; NZCR. Stock/Shareholder; NZCR. S. Ali: Employee; Regeneron Pharmaceuticals Inc. Stock/Shareholder; Regeneron Pharmaceuticals Inc. P. Parasoglou: Employee; Regeneron Pharmaceuticals Inc. Stock/Shareholder; Regeneron Pharmaceuticals Inc. A. Boyapati: Employee; Regeneron Pharmaceuticals Inc. Stock/Shareholder; Regeneron Pharmaceuticals Inc. K. Mohammadi: Employee; Regeneron Pharmaceuticals Inc. Stock/Shareholder; Regeneron Pharmaceuticals Inc. B.J. Musser: Employee; Regeneron Pharmaceuticals Inc. Stock/Shareholder; Merck Sharp & Dohme Corp. P. Meier: Employee; Regeneron Pharmaceuticals Inc. Stock/Shareholder; Regeneron Pharmaceuticals Inc. J. Mastaitis: Employee; Regeneron Pharmaceuticals Inc. E. Gasparino: Employee; Regeneron Pharmaceuticals Inc. Stock/Shareholder; Regeneron Pharmaceuticals Inc. J. Trejos: Employee; Regeneron Pharmaceuticals Inc. Stock/Shareholder; Regeneron Pharmaceuticals Inc. J.D. Davis: Employee; Regeneron Pharmaceuticals Inc. Stock/Shareholder; Regeneron Pharmaceuticals Inc. G.A. Herman: Employee; Regeneron Pharmaceuticals Inc. Stock/Shareholder; Regeneron Pharmaceuticals Inc. R. Pordy: Employee; Regeneron Pharmaceuticals Inc. Funding Regeneron Pharmaceuticals, Inc.

Sarcopenia, originally defined as age-related low muscle mass and function, has also been used to describe the loss of muscle mass and quality among certain populations, such as sarcopenic obesity (SO) . SO refers to loss of muscle and function in obese subjects; however, given age is not a factor in SO, we classified SO as obesity with low lean muscle mass (OLLMM) . Given the paucity of data in OLLMM, the purpose was to describe the prevalence of OLLMM in the US. Data from NHANES 2017-2018 were used to estimate the prevalence of OLLMM in adults ≥20 yrs of age. OLLMM was defined as DEXA-assessed low appendicular lean mass, adjusted for BMI (men <0.789, women <0.512) and obesity (body fat%: men >25%, women >35%) . Since DEXA was only measured in those aged 20-59 in NHANES 2017-2018, we utilized logistic regression models to predict OLLMM from NHANES 1999-20for those ≥60 yrs. The prevalence of OLLMM was estimated overall, by sex, age group, and diabetes status (prediabetes and T2DM) . We extrapolated results to the US using NHANES sampling weights. Of the 4174 adults (representing 181M US adults) , we identified 827 (28.8M, 15.9% of the US pop.) with OLLMM. Older adults had higher prevalence of OLLMM as did those with prediabetes and T2DM (Figure 1) . The prevalence of OLLMM in the US is high. While the prevalence of OLLMM was higher with age, its prevalence was also high in diabetics, regardless of age. Clinicians should monitor for OLLMM among obese T2DM patients. Disclosure D.J. Murdock: Employee; Regeneron Pharmaceuticals Inc. Stock/Shareholder; Regeneron Pharmaceuticals Inc. N. Wu: Employee; Regeneron Pharmaceuticals Inc. Stock/Shareholder; Regeneron Pharmaceuticals Inc. D.J. Glass: Employee; Regeneron Pharmaceuticals Inc. Stock/Shareholder; Regeneron Pharmaceuticals Inc. J.S. Grimsby: Employee; Regeneron Pharmaceuticals Inc. Stock/Shareholder; Regeneron Pharmaceuticals Inc. R.A. Calle: Employee; Regeneron Pharmaceuticals Inc. Stock/Shareholder; Regeneron Pharmaceuticals Inc. S. Donahue: Employee; Regeneron Pharmaceuticals Inc. Stock/Shareholder; Regeneron Pharmaceuticals Inc. M. Sleeman: Employee; Regeneron Pharmaceuticals Inc. Stock/Shareholder; Regeneron Pharmaceuticals Inc. R.J. Sanchez: Employee; Regeneron Pharmaceuticals Inc. Stock/Shareholder; Regeneron Pharmaceuticals Inc. Funding Supported by Regeneron Pharmaceuticals, Inc.

Background Sarcopenia is defined as age-related low muscle mass and function, and can also describe the loss of muscle mass in certain medical conditions, such as sarcopenic obesity. Sarcopenic obesity describes loss of muscle and function in obese individuals; however, as sarcopenia is an age-related condition and obesity can occur in any age group, a more accurate term is obesity with low lean muscle mass (OLLMM). Given limited data on OLLMM (particularly in those aged < 65 years), the purpose of this study was to estimate the prevalence of OLLMM in adults aged ≥ 20 years in the USA. Methods Data from the National Health and Nutrition Examination Survey (NHANES) 2017–2018 and 1999–2006 were used. OLLMM was defined as an appendicular lean mass, adjusted for body mass index (BMI), cut-off point < 0.789 for males and < 0.512 for females, measured by dual-energy X-ray absorptiometry (DXA). DXA was only measured in individuals 20–59 years old in NHANES 2017–2018; we therefore utilized logistic regression models to predict OLLMM from NHANES 1999–2006 for those aged ≥ 60 years. The prevalence of OLLMM was estimated overall, and by sex, age, race/ethnicity, and clinical subgroup (high BMI, prediabetes, type 2 diabetes mellitus [T2DM], non-alcoholic fatty liver disease [NAFLD] with fibrosis, or post-bariatric surgery). Prevalence estimates were extrapolated to the USA population using NHANES sampling weights. Results We estimated that, during 2017–2018, 28.7 million or 15.9% of the USA population had OLLMM. The prevalence of OLLMM was greater in older individuals (8.1%, aged 20–59 years vs 28.3%, aged ≥ 60 years), highest (66.6%) in Mexican-American females aged ≥ 60 years, and lowest (2.6%) in non-Hispanic Black males aged 20–59 years. There was a higher prevalence of OLLMM in adults with prediabetes (19.7%), T2DM (34.5%), NAFLD with fibrosis (25.4%), or post-bariatric surgery (21.8%), compared with those without each condition. Conclusions Overall, the burden of OLLMM in the USA is substantial, affecting almost 30 million adults. The prevalence of OLLMM increased with age, and among those with prediabetes, T2DM, NAFLD with fibrosis, or post-bariatric surgery. A unified definition of OLLMM will aid diagnosis and treatment strategies.

BACKGROUND: The 24-week randomized, double-blind ODYSSEY ALTERNATIVE trial (NCT01709513) demonstrated significant low-density lipoprotein cholesterol (LDL-C) reductions with the PCSK9 inhibitor alirocumab vs ezetimibe in statin-intolerant patients, with significantly fewer skeletal muscle events (SMEs; 32.5%) vs atorvastatin (46.0%; hazard ratio: 0.61, 95% confidence interval: 0.38 to 0.99, P = .042). OBJECTIVE: ALTERNATIVE participants could enter an open-label treatment period (OLTP) for assessment of long-term safety. METHODS: Two hundred and eighty one patients entered the OLTP; 93.7%, 84.0%, and 92.9% of patients who received atorvastatin, ezetimibe, and alirocumab, respectively, during double-blind treatment, including 216 patients (76.9%) who completed double-blind treatment, as well as patients who either prematurely discontinued treatment due to SME (n = 51 [18.1%]) or other reasons (n = 14 [5.0%]) but completed week 24 assessments. All patients in the OLTP received alirocumab (75 or 150 mg every 2 weeks based on investigator decision) for similar to 3 years or until commercial availability, whichever came first. RESULTS: SMEs were reported by 38.4% of patients in the OLTP. Safety results from the OLTP were similar to those of the alirocumab group in the double-blind period, except for a lower rate of discontinuations due to SMEs observed with alirocumab in the OLTP (3.2% vs 15.9% in the doubleblind period). At OLTP week 8, mean LDL-C reduction from baseline (=week 0 of double-blind period) was 52.0%, with reductions sustained through to the end-of-treatment visits (55.4% and 53.7% reduction at weeks 100 and 148, respectively). CONCLUSIONS: In this population of statin-intolerant patients, alirocumab was well tolerated and produced durable LDL-C reductions over 3 years. (C) 2020 National Lipid Association. Published by Elsevier Inc.

BACKGROUND Homozygous familial hypercholesterolemia (HoFH) is characterized by extremely elevated low-density lipoprotein-cholesterol (LDL-C) levels and early onset atherosclerotic cardiovascular disease despite treatment with conventional lipid-lowering treatment. OBJECTIVES This study was designed to assess LDL-C reduction with the proprotein convertase subtilisin/kexin type 9 inhibitor alirocumab in adult patients with HoFH. METHODS This randomized, double-blind, placebo-controlled, parallel-group, phase 3 study evaluated efficacy and safety of alirocumab 150 mg every 2 weeks. The primary endpoint was percent reduction from baseline in LDL-C versus placebo after 12 weeks of treatment. RESULTS Patients (N = 69) were randomized 2:1 to alirocumab or placebo. At baseline, background lipid-lowering treatment included 67 patients receiving statin (59 patients on high-intensity statin); 50 patients on ezetimibe; 10 patients on lomitapide; and 10 patients undergoing apheresis. Mean baseline LDL-C was 259.6 mg/dl in the placebo group and 295.0 mg/dl in the alirocumab group. At week 12, the least squares mean difference in LDL-C percent change from baseline was -35.6% (alirocumab [-26.9%] vs. placebo [8.6%]; p < 0.0001). Reductions (least squares mean difference) in other atherogenic lipids at week 12 were: apolipoprotein B, -29.8%; non-high-density lipoprotein cholesterol, -32.9%; total cholesterol, -26.5%; and lipoprotein(a), -28.4% (all p < 0.0001). No serious adverse events, permanent treatment discontinuations, or deaths due to treatment-emergent adverse events were reported during the double-blind treatment period. CONCLUSIONS In the largest randomized controlled interventional trial in HoFH patients to date, alirocumab resulted in significant and clinically meaningful reductions in LDL-C at week 12. Alirocumab was generally well tolerated, with a safety profile comparable to that of placebo. (c) 2020 The Authors. Published by Elsevier on behalf of the American College of Cardiology Foundation. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

BACKGROUND:Familial hypercholesterolemia is characterized by high levels of low-density lipoprotein cholesterol (LDL-C), and causes of familial hypercholesterolemia include apolipoprotein B (APOB) loss-of-function mutations (LOFm) and proprotein convertase subtilisin/kexin type 9 (PCSK9) gain-of-function mutations (GOFm). OBJECTIVE:The aim of this study was to compare the pharmacokinetics and pharmacodynamics of alirocumab between patients with APOB LOFm vs PCSK9 GOFm. METHODS:Patients (6 APOB LOFm and 17 PCSK9 GOFm carriers) with LDL-C ≥70 mg/dL on maximally tolerated lipid-lowering therapies received alirocumab 150 mg at Weeks 0, 2, 4, and 6, placebo at Week 8, alirocumab at Week 10, placebo at Weeks 12 and 14, then completed a follow-up period at Week 22. RESULTS:At Week 8, mean ± standard error (SE) alirocumab concentration was lower in APOB LOFm carriers compared with PCSK9 GOFm carriers (12.12 ± 1.81 vs 16.74 ± 2.53 mg/L). APOB LOFm carriers had higher mean ± SE total PCSK9 (6.56 ± 0.73 mg/L) and lower mean ± SE free PCSK9 (0.025 ± 0.016 mg/L) at Week 8 compared with PCSK9 GOFm carriers (4.21 ± 0.35 and 0.11 ± 0.035 mg/L for total and free PCSK9, respectively). Despite this observed greater PCSK9 suppression, mean ± SE percent LDL-C reduction was lower in APOB LOFm (55.3 ± 1.0%) compared with PCSK9 GOFm carriers (73.1 ± 0.9%). Treatment-emergent adverse events occurred in 16 patients (94.1%) in the PCSK9 GOFm group and 5 patients (83.3%) in the APOB LOFm group. CONCLUSIONS:Overall, PCSK9 inhibition with alirocumab results in clinically meaningful reductions in LDL-C in both APOB LOFm and PCSK9 GOFm carriers, although reductions were greater in the PCSK9 GOFm carriers. The results indicate a possible underlying contributor to hypercholesterolemia other than PCSK9 in patients with APOB LOFm. CLINICAL TRIAL REGISTRATION:NCT01604824; clinicaltrials.gov.

Autosomal dominant hypercholesterolemia results from mutations affecting the low-density lipoprotein receptor pathway, including proprotein convertase subtilisin/kexin type 9 (PCSK9) gain-of-function mutations (GoFm) and apolipoprotein B (APOB) loss-of-function mutations (LoFm). This study examined the long-term efficacy and safety of alirocumab in patients with PCSK9 GoFm and APOB LoFm who participated in the open-label extension to a Phase 2 double-blind study (NCT01604824). Of the 23 patients who completed the 14-week double-blind period and 8-week follow-up, 21 opted to continue in the open-label extension (PCSK9 GoFm, n = 15; APOB LoFm, n = 6). Patients received alirocumab 150 mg every 2 weeks from week 32 up to 3 years for PCSK9 GoFm and 2 years for APOB LoFm. Mean duration of alirocumab exposure was 129 weeks (median: 144 weeks). After initiation of alirocumab treatment, low-density lipoprotein cholesterol (LDL-C) decreased in both groups. At week 80, mean percent reduction in LDL-C from baseline was 58.0% and 47.1% for PCSK9 GoFm and APOB LoFm groups, respectively. Treatment-emergent adverse events were reported in 19 patients (90.5%); no patients discontinued treatment due to treatment-emergent adverse events. In patients with autosomal dominant hypercholesterolemia and elevated LDL-C levels despite receiving maximally tolerated lipid-lowering therapies, alirocumab 150 mg every 2 weeks resulted in clinically meaningful reductions in LDL-C, sustained through to 3 years and 2 years for patients with PCSK9 GoFm and APOB LoFm, respectively. Alirocumab was generally well tolerated with no unexpected safety concerns.

Introduction: Causes of autosomal dominant hypercholesterolemia include apolipoprotein B (ApoB) loss-of-function mutations (LoFm) and PCSK9 gain-of-function mutations (GoFm; very rare). Alirocumab ...

Objective: To compare lipid-lowering efficacy of adding alirocumab to rosuvastatin versus other treatment strategies (NCT01730053).Methods: Patients receiving baseline rosuvastatin regimens (10 or 20 mg) were randomized to: add-on alirocumab 75 mg every-2-weeks (Q2W) (1-mL subcutaneous injection via pre-filled pen); add-on ezetimibe 10 mg/day; or double-dose rosuvastatin. Patients had cardiovascular disease (CVD) and low-density lipoprotein cholesterol (LDLeC) >= 70 mg/dL (1.8 mmol/L) or CVD risk factors and LDLeC >= 100 mg/dL (2.6 mmol/L). In the alirocumab group, dose was blindly increased at Week 12 to 150 mg Q2W (also 1-mL volume) in patients not achieving their LDLeC target. Primary endpoint was percent change in calculated LDLeC from baseline to 24 weeks (intent-to-treat).Results: 305 patients were randomized. In the baseline rosuvastatin 10 mg group, significantly greater LDLeC reductions were observed with add-on alirocumab (-50.6%) versus ezetimibe (-14.4%; p < 0.0001) and double-dose rosuvastatin (-16.3%; p < 0.0001). In the baseline rosuvastatin 20 mg group, LDLeC reduction with add-on alirocumab was -36.3% compared with -11.0% with ezetimibe and -15.9% with double-dose rosuvastatin (p = 0.0136 and 0.0453, respectively; pre-specified threshold for significance p < 0.0125). Overall, similar to 80% alirocumab patients were maintained on 75 mg Q2W. Of alirocumab-treated patients, 84.9% and 66.7% in the baseline rosuvastatin 10 and 20 mg groups, respectively, achieved risk-based LDLeC targets. Treatment-emergent adverse events occurred in 56.3% of alirocumab patients versus 53.5% ezetimibe and 67.3% double-dose rosuvastatin (pooled data).Conclusions: The addition of alirocumab to rosuvastatin provided incremental LDLeC lowering versus adding ezetimibe or doubling the rosuvastatin dose. (C) 2015 Regeneron Pharmaceuticals, Inc. Published by Elsevier Ireland Ltd.

CONTEXT:Despite current standard of care, many patients at high risk of cardiovascular disease (CVD) still have elevated low-density lipoprotein cholesterol (LDL-C) levels. Alirocumab is a fully human monoclonal antibody inhibitor of proprotein convertase subtilisin/kexin type 9.OBJECTIVE:The objective of the study was to compare the LDL-C-lowering efficacy of adding alirocumab vs other common lipid-lowering strategies.DESIGN, PATIENTS, AND INTERVENTIONS:Patients (n = 355) with very high CVD risk and LDL-C levels of 70 mg/dL or greater or high CVD risk and LDL-C of 100 mg/dL or greater on baseline atorvastatin 20 or 40 mg were randomized to one of the following: 1) add-on alirocumab 75 mg every 2 weeks (Q2W) sc; 2) add-on ezetimibe 10 mg/d; 3) double atorvastatin dose; or 4) for atorvastatin 40 mg regimen only, switch to rosuvastatin 40 mg. For patients not achieving protocol-defined LDL-C goals, the alirocumab dose was increased (blinded) at week 12 to 150 mg Q2W.MAIN OUTCOME MEASURE:The primary end point was percentage change in calculated LDL-C from baseline to 24 weeks (intent to treat).RESULTS:Among atorvastatin 20 and 40 mg regimens, respectively, add-on alirocumab reduced LDL-C levels by 44.1% and 54.0% (P < .001 vs all comparators); add-on ezetimibe, 20.5% and 22.6%; doubling of atorvastatin dose, 5.0% and 4.8%; and switching atorvastatin 40 mg to rosuvastatin 40 mg, 21.4%. Most alirocumab-treated patients (87.2% and 84.6%) achieved their LDL-C goals. Most alirocumab-treated patients (86%) maintained their 75-mg Q2W regimen. Treatment-emergent adverse events occurred in 65.4% of alirocumab patients vs 64.4% ezetimibe and 63.8% double atorvastatin/switch to rosuvastatin (data were pooled).CONCLUSIONS:Adding alirocumab to atorvastatin provided significantly greater LDL-C reductions vs adding ezetimibe, doubling atorvastatin dose, or switching to rosuvastatin and enabled greater LDL-C goal achievement.

Introduction: Not all patients at high cardiovascular (CV) risk achieve sufficient reduction in LDL-C levels by commonly used statin doses. Among patients treated with atorvastatin (ATV) 20 or 40 mg who did not achieve specified LDL-C treatment levels, ODYSSEY OPTIONS I compared: (1) adding the PCSK9 antibody, alirocumab; (2) adding ezetimibe (EZE); (3) doubling ATV dose, or (4) switching to rosuvastatin 40 mg. Methods: A Phase 3, randomized, double-blind, active-comparator and parallel-group study ([NCT01730040][1]) in high CV risk patients with CVD and LDL-C ≥70 mg/dL or without CVD but with CVD risk factors and LDL-C ≥100 mg/dL. Patients had stable ATV 20 or 40 mg/day for ≥4 weeks prior to study entry. Within each baseline ATV dose regimen, randomization included (Figure): (1) add-on alirocumab 75 mg administered subcutaneously (SC) every 2 weeks (Q2W) using a 1-mL autoinjector; (2) add-on EZE orally (PO) 10 mg/day; (3) doubling of ATV dose; or (4) switch from ATV 40 mg to rosuvastatin 40 mg (for ATV cohort 40 mg). Alirocumab dose was up-titrated at Week 12 in a blinded manner to 150 mg Q2W (using a 1-mL autoinjector) in patients not achieving their predetermined LDL-C level. The primary endpoint was the % change in calculated LDL-C from baseline to 24 weeks in the intent-to-treat population, and with prespecified on-treatment analysis. Results: In total, 355 patients were randomized: 231 (65.1%) were male, mean (SD) age was 62.9 (10.2) years, 211 (59.4%) had CHD, 178 (50.1%) had diabetes, and mean (SD) baseline LDL-C was 105.1 (34.1) mg/dL. Primary efficacy and safety analyses will be available for AHA. Conclusions: OPTIONS I is the only clinical trial of a PCSK9 inhibitor to compare alirocumab as add-on therapy to ATV to commonly used lipid treatment strategies: (1) addition of EZE, (2) doubling statin dose, or (3) a switch to more potent statin, in high CV-risk patients. ![][2] [1]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT01730040&atom=%2Fcirculationaha%2F130%2FSuppl_2%2FA16194.atom [2]: /embed/graphic-1.gif

The phase 3 ODYSSEY OPTIONS studies (OPTIONS I, NCT01730040; OPTIONS II, NCT01730053) are multicenter, multinational, randomized, double‐blind, active‐comparator, 24‐week studies evaluating the efficacy and safety of alirocumab, a fully human monoclonal antibody targeting proprotein convertase subtilisin/kexin type 9, as add‐on therapy in ∼ 650 high‐cardiovascular (CV)‐risk patients whose low‐density lipoprotein cholesterol (LDL‐C) levels are ≥100 mg/dL or ≥70 mg/dL according to the CV‐risk category, high and very high CV risk, respectively, with atorvastatin (20–40 mg/d) or rosuvastatin (10–20 mg/d). Patients are randomized to receive alirocumab 75 mg via a single, subcutaneous, 1‐mL injection by prefilled pen every 2 weeks (Q2W) as add‐on therapy to atorvastatin (20–40 mg) or rosuvastatin (10–20 mg); or to receive ezetimibe 10 mg/d as add‐on therapy to statin; or to receive statin up‐titration; or to switch from atorvastatin to rosuvastatin (OPTIONS I only). At week 12, based on week 8 LDL‐C levels, the alirocumab dose may be increased from 75 mg to 150 mg Q2W if LDL‐C levels remain ≥100 mg/dL or ≥70 mg/dL in patients with high or very high CV risk, respectively. The primary efficacy endpoint in both studies is difference in percent change in calculated LDL‐C from baseline to week 24 in the alirocumab vs control arms. The studies may provide guidance to inform clinical decision‐making when patients with CV risk require additional lipid‐lowering therapy to further reduce LDL‐C levels. The flexibility of the alirocumab dosing regimen allows for individualized therapy based on the degree of LDL‐C reduction required to achieve the desired LDL‐C level.