Efficacy and safety of alirocumab in high cardiovascular risk patients with inadequately controlled hypercholesterolaemia on maximally tolerated daily statin: results from the ODYSSEY COMBO II study
By Christopher Paul Cannon, FESC (Boston, United States of America)
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List of Authors:
Christopher P. Cannon,1 Bertrand Cariou,2 Dirk Blom,3 James M. McKenney,4 Christelle Lorenzato,5 Robert Pordy,6 Umesh Chaudhari,7 Helen M. Colhoun,8
1-Harvard Clinical Research Institute, Boston, MA, USA;
2-L’Institut du Thorax, CHU de Nantes, Nantes, France;
3-Division of Lipidology, Department of Medicine, University of Cape Town and MRC Cape Heart Group, Cape Town, South Africa;
4-Virginia Commonwealth University and National Clinical Research, Inc., Richmond, VA, USA;
5-Sanofi, Paris, France;
6-Regeneron Pharmaceuticals, Inc., Tarrytown, NY, USA; 7-Sanofi, Bridgewater, NJ, USA;
8-University of Dundee, Dundee, Scotland, UK
Alirocumab, a fully human monoclonal antibody to proprotein convertase subtilisin/kexin type 9 (PCSK9), is currently being investigated for the treatment of hypercholesterolaemia and for the reduction of cardiovascular (CV) events.
ODYSSEY COMBO II (NCT01644188) is a Phase 3, randomised, double-blind, multicentre, 104week study in patients with history of CVD and low-density lipoprotein cholesterol (LDL-C) ≥1.81 mmol/L (≥70 mg/dL), or no history of CVD but with other risk factors and LDL-C ≥2.59 mmol/L (≥100 mg/dL), and who were receiving a maximally tolerated daily statin dose (stable for at least 4 weeks prior to screening); other lipid-lowering therapies were not permitted. Patients were randomised 2:1 to either alirocumab 75 mg subcutaneously (SC) every 2 weeks (Q2W) or ezetimibe 10 mg daily. At Week 12, the dose of alirocumab was increased to 150 mg Q2W if Week 8 LDL-C was ≥1.81 mmol/L. Alirocumab (75/150 mg) and placebo injections were administered as a single 1 mL using a prefilled pen. This prespecified analysis includes the primary endpoint (% change in LDL-C from baseline to Week 24, intent-to-treat analysis), efficacy up to Week 52, and safety analysis up to Week 52-102, including all data collected after the last patient completed Week 52 visit.
Mean (SD) baseline LDL-C levels were 2.8 (0.9) mmol/L [108.6 (36.5) mg/dL] in the alirocumab arm (N=479) and 2.7 (0.9) mmol/L [104.6 (34.1) mg/dL] in the ezetimibe arm (N=241). Only 18.4% of alirocumab patients required a dose increase to 150 mg Q2W at Week 12. At Week 24, LS mean (SE) reductions from baseline were 50.6 (1.4)% and 20.7 (1.9)% for alirocumab and ezetimibe, respectively (both on a background of maximally tolerated statin), for a difference of -29.8 (2.3)% (p<0.0001); 77% of alirocumab and 46% of ezetimibe patients achieved LDL-C <1.81 mmol/L (<70 mg/dL) (p<0.0001). Achieved LS mean (SE) LDL-C levels at Week 24 were 1.34 (0.04) mmol/L [51.6 (1.4) mg/dL] with alirocumab and 2.14 (0.05) mmol/L [82.5 (2.0) mg/dL] with ezetimibe. These differences were maintained to Week 52. At 52 weeks, 84.8% and 85.5% of patients in the alirocumab and ezetimibe groups, respectively, were continuing study treatments. Treatment-emergent adverse events (TEAEs) occurred in 71.2% (N=341) of alirocumab patients and 67.2% (N=162) of ezetimibe patients. TEAEs led to discontinuation in 7.5% (N=36) of alirocumab and 5.4% (N=13) of ezetimibe patients. The most common TEAEs (occurring in ≥5% of patients from either treatment arm) were upper respiratory tract infection, accidental overdose, dizziness and myalgia.
In this population of high CV risk patients unable to achieve targets with maximal statin use, a "treat to target" approach with alirocumab, in which approximately 80% did not require an increase in dose to 150 mg Q2W, achieved significantly greater (~30% absolute) reductions in LDL-C vs. ezetimibe after 24 and 52 weeks of treatment. At Week 24, >75% of alirocumab-treated patients achieved LDL-C <1.81 mmol/L (<70 mg/dL). The frequency of TEAEs was similar between the alirocumab and ezetimibe groups.
Efficacy and safety of alirocumab in patients with heterozygous familial hypercholesterolaemia not adequately controlled with current lipid-lowering therapy: results of ODYSSEY FH I and FH II studies
By Michel Farnier (Dijon, France)
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List of Authors:
John J.P. Kastelein,1 Henry N. Ginsberg,2 Gisle Langslet,3 G. Kees Hovingh,1 Richard Ceska,4 Robert Dufour,5 Dirk Blom,6 Fernando Civeira,7 Michel Krempf,8 Michel Farnier,9
1-Department of Vascular Medicine, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands;
2-Columbia University, New York, NY, USA;
3-Lipid Clinic, Oslo University Hospital, Oslo, Norway;
4-Center of Preventive Cardiology, 1st School of Medicine and University Hospital, Charles University, Prague, Czech Republic;
5-Institut de Recherches Cliniques de Montreal, Montreal, Canada;
6-Division of Lipidology, Department of Medicine, University of Cape Town and MRC Cape Heart Group, Cape Town, South Africa;
7-Lipid Unit, Hospital Universitario Miguel Servet, Zaragoza, Spain;
8-CHU de Nantes - Hopital Nord Laennec, Saint-Herblain, France;
9-Point Médical, Dijon, France
FH I and FH II (NCT01623115; NCT01709500) are Phase 3 studies in the ODYSSEY programme evaluating long-term efficacy and safety of alirocumab, a proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor, exclusively in patients with heterozygous familial hypercholesterolaemia (heFH) inadequately controlled on their current statin and other lipid-lowering therapy (LLT).
ODYSSEY FH I and FH II are ongoing randomised, 78-week, double-blind, placebo-controlled trials being conducted in North America, Europe and South Africa. Patients with heFH inadequately controlled on maximally tolerated stable statin therapy with or without other LLT were randomised in a 2:1 ratio to receive alirocumab 75 mg or placebo every 2 weeks (Q2W) for 78 weeks via 1-mL subcutaneous injection using a prefilled pen. If LDL-C at Week 8 was ≥1.81 mmol/L (70 mg/dL), the alirocumab dose was increased to 150 mg Q2W (also 1 mL volume) at Week 12. In this prespecified analysis we report the primary efficacy endpoint (the % change in LDL-C from baseline to Week 24, by intent-to-treat [ITT] analysis), efficacy to Week 52, and safety data to Week 52-78 (including all data collected after last patient completed Week 52 visit).
Alirocumab produced significant reductions in LDL-C at Week 24 in both studies vs. placebo (Table), which were maintained to Week 52. Treatment-emergent adverse events (TEAEs) across both studies occurred in a similar proportion of patients on alirocumab (74.8% [N=366]) and placebo (75.4% [N=184]), leading to study discontinuation in 3.1% [N=15] and 3.7% [N=9] of patients, respectively. Most common TEAEs (occurring in ≥5% of patients from either treatment arm) included injection site reactions, nasopharyngitis, influenza and headache.
Alirocumab demonstrated significantly greater LDL-C lowering vs. placebo after 24 weeks treatment in a large cohort of heFH patients with poorly controlled LDL-C despite maximally-tolerated statin therapy and other LLT. A majority of patients treated with alirocumab reached prespecified lipid goals at Week 24. AEs were generally comparable between groups.