Yunling Du

Effect of a monoclonal antibody to PCSK9 on LDL cholesterol.

BACKGROUND Proprotein convertase subtilisin/kexin 9 (PCSK9), one of the serine proteases, binds to low-density lipoprotein (LDL) receptors, leading to their accelerated degradation and to increased LDL cholesterol levels. We report three phase 1 studies of a monoclonal antibody to PCSK9 designated as REGN727/SAR236553 (REGN727). METHODS In healthy volunteers, we performed two randomized, single ascending-dose studies of REGN727 administered either intravenously (40 subjects) or subcutaneously (32 subjects), as compared with placebo. These studies were followed by a randomized, placebo-controlled, multiple-dose trial in adults with heterozygous familial hypercholesterolemia who were receiving atorvastatin (21 subjects) and those with nonfamilial hypercholesterolemia who were receiving treatment with atorvastatin (30 subjects) (baseline LDL cholesterol, >100 mg per deciliter [2.6 mmol per liter]) or a modified diet alone (10 subjects) (baseline LDL cholesterol, >130 mg per deciliter [3.4 mmol per liter]). REGN727 doses of 50, 100, or 150 mg were administered subcutaneously on days 1, 29, and 43. The primary outcome for all studies was the occurrence of adverse events. The principal secondary outcome was the effect of REGN727 on the lipid profile. RESULTS Among subjects receiving REGN727, there were no discontinuations because of adverse events. REGN727 significantly lowered LDL cholesterol levels in all the studies. In the multiple-dose study, REGN727 doses of 50, 100, and 150 mg reduced measured LDL cholesterol levels in the combined atorvastatin-treated populations to 77.5 mg per deciliter (2.00 mmol per liter), 61.3 mg per deciliter (1.59 mmol per liter), and 53.8 mg per deciliter (1.39 mmol per liter), for a difference in the change from baseline of -39.2, -53.7, and -61.0 percentage points, respectively, as compared with placebo (P<0.001 for all comparisons). CONCLUSIONS In three phase 1 trials, a monoclonal antibody to PCSK9 significantly reduced LDL cholesterol levels in healthy volunteers and in subjects with familial or nonfamilial hypercholesterolemia. (Funded by Regeneron Pharmaceuticals and Sanofi; ClinicalTrials.gov numbers, NCT01026597, NCT01074372, and NCT01161082.).

Efficacy and safety of alirocumab vs ezetimibe in statin-intolerant patients, with a statin rechallenge arm: The ODYSSEY ALTERNATIVE randomized trial

BACKGROUND Statin intolerance limits many patients from achieving optimal low-density lipoprotein cholesterol (LDL-C) concentrations. Current options for such patients include using a lower but tolerated dose of a statin and adding or switching to ezetimibe or other non-statin therapies. METHODS ODYSSEY ALTERNATIVE (NCT01709513) compared alirocumab with ezetimibe in patients at moderate to high cardiovascular risk with statin intolerance (unable to tolerate ≥2 statins, including one at the lowest approved starting dose) due to muscle symptoms. A placebo run-in and statin rechallenge arm were included in an attempt to confirm intolerance. Patients (n = 361) received single-blind subcutaneous (SC) and oral placebo for 4 weeks during placebo run-in. Patients reporting muscle-related symptoms during the run-in were to be withdrawn. Continuing patients were randomized (2:2:1) to double-blind alirocumab 75 mg SC every 2 weeks (Q2W; plus oral placebo), ezetimibe 10 mg/d (plus SC placebo Q2W), or atorvastatin 20 mg/d (rechallenge; plus SC placebo Q2W) for 24 weeks. Alirocumab dose was increased to 150 mg Q2W at week 12 depending on week 8 LDL-C values. Primary end point was percent change in LDL-C from baseline to week 24 (intent-to-treat) for alirocumab vs ezetimibe. RESULTS Baseline mean (standard deviation) LDL-C was 191.3 (69.3) mg/dL (5.0 [1.8] mmol/L). Alirocumab reduced mean (standard error) LDL-C by 45.0% (2.2%) vs 14.6% (2.2%) with ezetimibe (mean difference 30.4% [3.1%], P < .0001). Skeletal muscle-related events were less frequent with alirocumab vs atorvastatin (hazard ratio 0.61, 95% confidence interval 0.38-0.99, P = .042). CONCLUSIONS Alirocumab produced greater LDL-C reductions than ezetimibe in statin-intolerant patients, with fewer skeletal-muscle adverse events vs atorvastatin.

Efficacy and safety of adding alirocumab to rosuvastatin versus adding ezetimibe or doubling the rosuvastatin dose in high cardiovascular-risk patients: The ODYSSEY OPTIONS II randomized trial

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 (LDL-C) ≥70 mg/dL (1.8 mmol/L) or CVD risk factors and LDL-C ≥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 LDL-C target. Primary endpoint was percent change in calculated LDL-C from baseline to 24 weeks (intent-to-treat). RESULTS 305 patients were randomized. In the baseline rosuvastatin 10 mg group, significantly greater LDL-C 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, LDL-C 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, ∼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 LDL-C 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 LDL-C lowering versus adding ezetimibe or doubling the rosuvastatin dose.

Alirocumab in patients with heterozygous familial hypercholesterolaemia undergoing lipoprotein apheresis: the ODYSSEY ESCAPE trial

Aim To evaluate the effect of alirocumab on frequency of standard apheresis treatments [weekly or every 2 weeks (Q2W)] in heterozygous familial hypercholesterolaemia (HeFH). Methods and results ODYSSEY ESCAPE (NCT02326220) was a double-blind study in 62 HeFH patients undergoing regular weekly or Q2W lipoprotein apheresis. Patients were randomly assigned (2:1, respectively) to receive alirocumab 150 mg (n = 41) or placebo (n = 21) Q2W subcutaneously for 18 weeks. From day 1 to week 6, apheresis rate was fixed according to the patient’s established schedule; from weeks 7 to 18, apheresis rate was adjusted based on the patient’s low-density lipoprotein cholesterol (LDL-C) response in a blinded fashion. Apheresis was not performed when the LDL-C value was ≥30% lower than the baseline (pre-apheresis) value. The primary efficacy endpoint was the rate of apheresis treatments over 12 weeks (weeks 7–18), standardized to number of planned treatments. In the alirocumab group the least square (LS) mean ± SE (95% confidence interval [CI]) per cent change in pre-apheresis LDL-C from baseline at week 6 was −53.7 ± 2.3 (−58.2 to − 49.2) compared with 1.6 ± 3.1 (–4.7 to 7.9) in the placebo group. The primary efficacy endpoint showed statistically significant benefit in favour of alirocumab (Hodges–Lehmann median estimate of treatment difference: 0.75; 95% CI 0.67–0.83; P < 0.0001). Therefore, alirocumab-treated patients had a 0.75 (75%) additional reduction in the standardized rate of apheresis treatments vs. placebo-treated patients. During this period, 63.4% of patients on alirocumab avoided all and 92.7% avoided at least half of the apheresis treatments. Adverse event rates were similar (75.6% of patients on alirocumab vs. 76.2% on placebo). Conclusions Lipoprotein apheresis was discontinued in 63.4% of patients on alirocumab who were previously undergoing regular apheresis, and the rate was at least halved in 92.7% of patients. Alirocumab was generally safe and well tolerated.

Characterization of Autosomal Dominant Hypercholesterolemia Caused by PCSK9 Gain of Function Mutations and its Specific Treatment with Alirocumab, a PCSK9 Monoclonal Antibody

Background—Patients with PCSK9 gene gain of function (GOF) mutations have a rare form of autosomal dominant hypercholesterolemia. However, data examining their clinical characteristics and geographic distribution are lacking. Furthermore, no randomized treatment study in this population has been reported. Methods and Results—We compiled clinical characteristics of PCSK9 GOF mutation carriers in a multinational retrospective, cross-sectional, observational study. We then performed a randomized placebo-phase, double-blind study of alirocumab 150 mg administered subcutaneously every 2 weeks to 13 patients representing 4 different PCSK9 GOF mutations with low-density lipoprotein cholesterol (LDL-C) ≥70 mg/dL on their current lipid-lowering therapies at baseline. Observational study: among 164 patients, 16 different PCSK9 GOF mutations distributed throughout the gene were associated with varying severity of untreated LDL-C levels. Coronary artery disease was common (33%; average age of onset, 49.4 years), and untreated LDL-C concentrations were higher compared with matched carriers of mutations in the LDLR (n=2126) or apolipoprotein B (n=470) genes. Intervention study: in PCSK9 GOF mutation patients randomly assigned to receive alirocumab, mean percent reduction in LDL-C at 2 weeks was 62.5% (P<0.0001) from baseline, 53.7% compared with placebo-treated PCSK9 GOF mutation patients (P=0.0009; primary end point). After all subjects received 8 weeks of alirocumab treatment, LDL-C was reduced by 73% from baseline (P<0.0001). Conclusions—PCSK9 GOF mutation carriers have elevated LDL-C levels and are at high risk of premature cardiovascular disease. Alirocumab, a PCSK9 antibody, markedly lowers LDL-C levels and seems to be well tolerated in these patients. Clinical Trial Registration—URL: http://www.clinicaltrials.gov. Unique Identifier: NCT01604824.

Efficacy and safety of alirocumab as add-on therapy in high-cardiovascular-risk patients with hypercholesterolemia not adequately controlled with atorvastatin (20 or 40 mg) or rosuvastatin (10 or 20 mg): design and rationale of the ODYSSEY OPTIONS Studies

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.