New results from ODYSSEY trials show continued benefit of alirocumab

CHICAGO — Results of several studies from the ODYSSEY program presented at the American Heart Association Scientific Sessions indicate that the investigational PCSK9 inhibitor alirocumab continues to show LDL-lowering efficacy in a variety of patient populations.

Jennifer G. Robinson, MD, and colleagues conducted a post-hoc analysis of pooled results from five phase 3, placebo-controlled trials (n=3,459) with at least 52 weeks of data available. In this population, first adjudicated major CV events, defined as cardiac death, MI, stroke and unstable angina requiring hospitalization, occurred less frequently in patients assigned alirocumab (Sanofi/Regeneron) compared with patients assigned placebo (HR=0.65; 95% CI, 0.4-1.08).

Across those studies, patients assigned alirocumab had LDL lowered by 48.6% to 60.4% vs. 4.3% to 0.5% for those assigned placebo, and had a mean on-treatment difference in LDL of 70.5 mg/dL to 72.6 mg/dL compared with controls, according to Robinson, professor of epidemiology in the College of Public Health and professor of internal medicine at University of Iowa Carver College of Medicine.

The difference in outcomes “occurs starting at the beginning of follow-up and continues through up to 78 weeks of follow-up,” she said. “If you look at the context in which this is occurring, the people have high LDL in the 120s and 130s in the placebo groups compared with the 40s and 50s in the alirocumab groups. This is quite reassuring that this mechanism is on track, when we look across the program as a whole, in different populations of patients.”

The ODYSSEY OUTCOMES trial will provide the definitive evidence as to whether alirocumab is associated with lower CV event rates, Robinson said.

ODYSSEY OPTIONS I and II

The ODYSSEY OPTIONS I and II trials evaluated patients not at LDL goal (prior CVD, LDL ≥70 mg/dL; CVD risk factors, LDL ≥100 mg/dL). Patients then underwent practical lipid treatment strategies which included adding ezetimibe (Zetia, Merck), doubling of their statin dose, switching to a different statin or administration of alirocumab added to their ongoing statin therapy.

“At 24 weeks, the alirocumab groups experienced greater cholesterol reductions compared with other treatment options; safety and tolerability measures were comparable across all groups,” Harold Bays, MD, medical director and president of the Louisville Metabolic and Atherosclerosis Research Center, said.

In OPTIONS I, when added to atorvastatin 20 mg/day, those administered alirocumab 75 mg every 2 weeks (with option to increase to 150 mg every 2 weeks at 12 weeks) had a –23.6 mg/dL reduction in LDL compared with ezetimibe 10 mg/day added to atorvastatin 20 mg/day (P=.0004), and a –39.1 mg/dL reduction in LDL compared with those who had atorvastatin dose doubled to 40 mg/day (P<.0001). Likewise, when added to atorvastatin 40 mg/day, those assigned alirocumab 75 mg every 2 weeks (with option to increase to 150 mg every 2 weeks at 12 weeks) had a –31.4 mg/dL reduction in LDL compared with those who had ezetimibe 10 mg/day added to atorvastatin 40 mg/day, a –49.2 mg/dL LDL reduction compared with those who had their atorvastatin dose doubled to 80 mg/day, and a –32.6 mg/dL LDL reduction compared with those who switched to rosuvastatin (Crestor, AstraZeneca) 40 mg/day (P<.0001 for all).

In OPTIONS II, when added to rosuvastatin 10 mg/day, those administered alirocumab 75 mg every 2 weeks (with option to increase to 150 mg every 2 weeks at 12 weeks) plus rosuvastatin 10 mg/day had a –36.1 mg/dL LDL reduction compared with those who had ezetimibe 10 mg/day added to rosuvastatin 10 mg/day and a –34.2% LDL reduction compared with those who had rosuvastatin doubled to 20 mg/day (P<.0001 for both). When added to rosuvastatin 20 mg/day, those administered alirocumab 75 mg every 2 weeks (with option to increase to 150 mg every 2 weeks at 12 weeks) had a –25.3 mg/dL reduction in LDL compared with those who had ezetimibe 10 mg/day added to rosuvastatin 20 mg/day (P=.0136) and a –20.3 mg/dL reduction in LDL compared with those who had rosuvastatin dose doubled to 40 mg/day (P=.0453).

ODYSSEY HIGH FH

New data from the ODYSSEY HIGH FH study demonstrated significant reductions in LDL at 24 weeks among patients with severe heterozygous familial hypercholesterolemia who were assigned alirocumab compared with placebo.

Henry N. Ginsberg, MD, from the Columbia University College of Physicians and Surgeons, reported that investigators had enrolled 107 patients with heterozygous familial hypercholesterolemia and LDL ≥160 mg/dL despite being on maximally tolerated statin therapy and, in some cases, other lipid-lowering therapies.

The least squared mean change in LDL from baseline to week 24 was –45.7% in patients assigned alirocumab vs. –6.6% in those assigned placebo (difference, –39.1%; P<.0001). Exclusion of two sites with Good Clinical Practice noncompliance yielded similar results (difference, –48%; P<.0001), Ginsberg said.

Results were sustained to 52 weeks, and safety and tolerability issues were similar between the groups, he said.

ODYSSEY COMBO I

In high-risk patients with suboptimally controlled hypercholesterolemia on maximally tolerated doses of statins, alirocumab was associated with a significant reduction in LDL compared with placebo, Dean J. Kereiakes, MD, FACC, FSCAI, medical director of the Lindner Research Center at The Christ Hospital, Cincinnati, said during a presentation.

At 24 weeks, patients assigned alirocumab had a greater least squared mean percentage change in LDL compared with those assigned placebo (–48.2% vs. –2.3%; difference, –45.9%; P<.0001). In addition, treatment-emergent adverse events were comparable between the groups, according to Kereiakes, a member of the Cardiology Today’s Intervention Editorial Board. – by Erik Swain

For more information:

Bays H, Ginsberg HN, Kereiakes DJ and Robinson JG. CS.05: Results of ODYSSEY. All presented at: American Heart Association Scientific Sessions; Nov. 15-19, 2014; Chicago.

Disclosure: The studies were funded by Regeneron and Sanofi. Bays reports financial ties with Alere, Amarin, Amgen, Ardea, AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, California Raisin Board, Catabasis, Cymabay, Eisai, Eli Lilly, Esperion, Forest, Gilead, Given, GlaxoSmithKline, Isis Pharmaceuticals, Merck, Novartis, Omthera, Vivus and WPU. Ginsberg reports financial ties with Regeneron and Sanofi. Kereiakes reports financial ties with Abbott Vascular, Ablative Solutions Inc., Boston Scientific and Reva Medical. Robinson reports financial ties with Amarin, Amgen, AstraZeneca, Daiichi Sankyo, GlaxoSmithKline, Merck, Pfizer, Regeneron/Sanofi and Zinfandel/Takeda.