List of Authors:
Jennifer G. Robinson 1, Michel Farnier 2, Michel Krempf 3, Jean Bergeron 4, Gérald Luc 5, Maurizio Averna 6, Erik Stroes 7, Gisle Langslet 8, Frederick J. Raal 9, Mahfouz El Shahawy 10, Michael J. Koren 11, Norman Lepor 12, Christelle Lorenzato 13, Robert Pordy 14, Umesh Chaudhari 15, John J.P. Kastelein 7
1-University of Iowa, Iowa City, IA, USA;
2-Point Médical, Dijon, France;
3-CHU de Nantes - Hopital Nord Laennec, Saint-Herblain, France;
4-Clinique des Maladies Lipidique de Quebec Inc., Quebec, Canada;
5-University Hospital of Lille, Lille, France;
6-Università di Palermo – Policlinico “P.Giaccone”, Palermo, Italy;
7-Department of Vascular Medicine, Academic Medical Center, Amsterdam, The Netherlands;
8-Lipid Clinic, Oslo University Hospital, Oslo, Norway;
9-University of Witwatersrand, Johannesburg, South Africa;
10-Cardiovascular Center of Sarasota, Sarasota, FL, USA;
11-Jacksonville Center For Clinical Research, Jacksonville, FL;
12-Westside Medical Associates of Los Angeles, Beverly Hills, CA, USA;
13-Sanofi, Chilly-Mazarin, France;
14-Regeneron Pharmaceuticals, Inc., Tarrytown, NY, USA;
15-Sanofi, Bridgewater, NJ, USA
Monoclonal antibodies to proprotein convertase subtilisin/kexin type 9 (PCSK9) represent a new class of drug with potential for lipid lowering and CV risk reduction. As for any new class, extensive long-term evaluation of efficacy and safety in a large patient population is required. ODYSSEY LONG TERM (NCT01507831) assessed safety, tolerability and efficacy of alirocumab in 2,341 patients at high CV risk (including 17.7% of patients with heFH) for 18 months.
This phase 3, randomised, double-blind, placebo-controlled, parallel-group, multinational study enrolled patients with either (1) heterozygous familial hypercholesterolaemia (determined by genotyping or clinical criteria) or (2) coronary heart disease (CHD) or CHD risk equivalent. All patients had LDL-C ≥1.81 mmol/L (70 mg/dL) and were receiving a maximally tolerated stable statin dose with/without other lipid-lowering therapy (LLT) for ≥4 weeks prior to screening. Patients were randomised 2:1 to either alirocumab 150 mg or placebo subcutaneously every two weeks for 78 weeks. This prespecified analysis includes the primary efficacy endpoint (% change in LDL-C from baseline to Week 24, intent-to-treat analysis), efficacy to Week 52, and safety results to 52-78 weeks (52 weeks for all patients continuing treatment, and 817 patients exposed for at least 76 weeks [543 on alirocumab, 274 on placebo]).
Treatment-emergent adverse events (TEAEs) occurred in 78.6% (1,218 of 1,550) alirocumab and 80.6% (635 of 788) of placebo patients. TEAEs led to discontinuation in 6.2% and 5.5% of alirocumab and placebo patients, respectively. No marked imbalance was observed in the frequency of TEAEs. Treatment-emergent cardiovascular (CV) events were positively adjudicated in 4.0% and 4.4% of the alirocumab and placebo patients, respectively. In a post-hoc analysis, the rate of adjudicated major CV events (cardiac death, myocardial infarction, ischemic stroke, and unstable angina requiring hospitalization) was 1.4% for alirocumab vs. 3.0% for placebo (nominal P=0.0089), HR=0.46 (95% CI: 0.26 to 0.82). Mean [SD] baseline LDL-C levels were 3.2 [1.1] mmol/L (122.7 [42.6] mg/dL) in the alirocumab group and 3.2 [1.1] mmol/L (121.9 [41.4] mg/dL) in the placebo group. At Week 24, LS mean [SE] changes from baseline were -61.0 [0.7]% and +0.8 [1.0]% for alirocumab and placebo, respectively, for a difference in LDL-C % change from baseline to Week 24 of -61.9 [1.3]%, alirocumab vs. placebo (P<0.0001); 81% of the alirocumab-treated patients reached prespecified LDL-C treatment levels according to their level of CVD risk. Achieved LS mean [SE] LDL-C levels at Week 24 were 1.25 [0.02] mmol/L (48.3 [0.9] mg/dL) with alirocumab and 3.08 [0.03] mmol/L (118.9 [1.2] mg/dL) with placebo. LDL-C reduction with alirocumab was maintained to Week 52.
In the largest double-blind phase 3 study of a PCSK9 inhibitor with the longest follow-up to date, alirocumab demonstrated safety generally comparable with maximally tolerated statin therapy with/without other LLT and produced significant reductions in LDL-C, with a majority of alirocumab-treated patients reaching prespecified LDL-C treatment levels at Week 24.