Physicians' Academy for Cardiovascular Education

More evidence for durability of efficacy and safety of PCSK9 inhibition

Mar. 17, 2015 - news

Efficacy and Safety of Different Dosing Regimens of Alirocumab (Starting Doses of 75 mg Every Two Weeks and 150 mg Every Four Weeks) versus Placebo in Patients with Hypercholesterolemia Not Treated Using Statins: The ODYSSEY CHOICE II Study

Presented during the ACC Scientific Session by: Michel Farnier

Pooled Safety and Adverse Events in Nine Randomized, Placebo-Controlled, Phase 2 and 3 Clinical Trials of Alirocumab

Presented during the ACC Scientific Session by: Peter H. Jones

Adverse Events in Patients with Low-Density Lipoprotein Cholesterol Levels <25 or <15 mg/dL on at Least Two Consecutive Visits in Fourteen Randomized, Controlled, Clinical Trials of Alirocumab

Presented during the ACC Scientific Session by: Jennifer Robinson
Three presentations at the ACC conference discussed recent results with the monoclonal antibody alirocumab, directed at PCSK9, a promising strategy to reduce LDL-c levels. Previous studies have shown robust LDL-c lowering after inhibition of PCSK9, with a safety profile comparable to placebo.
Michel Farnier and colleagues examined in the CHOICE II study whether treatment with alirocumab (ALI) 150 mg once every four weeks (Q4W) yields sustained efficacy, as compared with 75 mg every two weeks (Q2W), in patients with hypercholesterolaemia who are not treated with statins.
Statins increase PCSK9 levels, which might lead to increased clearance of the PCSK9 antibodies. This possibly limits sustained efficacy of Q4W administration. In patients who do not take statins, this is not at stake, so in these patients efficacy may be sustained with a Q4W dosing regime.
In a comparison between placebo, ALI 75 mg Q2W and ALI 150 mg Q4W (with adjustment of the regime to 150 mg Q2W in week 12 if LDL-c targets were not met in week 8), patients randomised to ALI 150 mg Q4W showed a significantly larger LDL-c reduction in week 24 as compared with baseline than did the placebo group (LS mean difference [SE]: 56.4 [3.3]%; P<0.0001). About half of patients needed a dose regime adjustment. These people had higher average baseline LDL-c levels.
Treatment-emerging adverse events (TEAEs) occurred in 63.8% of placebo-treated and in 77.6% of ALI 150 mg Q4W-treated patients. Muscle –related symptoms occurred to a similar extent in both treatment groups.
Peter H. Jones presented the pooled safety data of nine randomised and placebo-controlled phase 2 and 3 (ODYSSEY programme) studies with alirocumab, in patients with hypercholesterolaemia, on statin background therapy. In total data of 2482 patients treated with ALI and of 1277 patients on placebo were analysed, with data for longer than a year study duration for over half of the patients.
Any TEAE was seen at similar frequencies in patients treated with ALI (75.8%) and placebo (76.4%), and also the number of serious TEAEs was comparable (ALI: 13.7%, placebo: 14.3%). Local injection site reactions occurred more often with ALI (7.2% vs. 5.1%, HR: 1.48, 1.12-19.97), and this was reason for discontinuation for 0.2% of patients on ALI and for 0.4% of patients on placebo. The number of adjudicated CV events was comparable in both treatment groups (3.6% with ALI and 3.5% with placebo). A Cox model analysis of time to first MACE yielded a HR: 0.65 (95%CI: 0.40-1.08, with a nominal P: 0.0985) for cumulative probability to an event for ALI vs. placebo, analysed over 84 weeks. No safety signals were observed for use of alirocumab on a background of statin therapy.
Jennifer Robinson finally revealed information on adverse events in patients who reached very low LDL-c levels (in two consecutive visits calculated LDL-c<25 or 15 mg/dL) with alirocumab treatment. Pooled data of 5234 patients, tested in 14 phase 2 and 3 (ODYSSEY programme) studies were therefore analysed (ALI: n=3340, placebo: n=1894), including data from ODYSSEY LONG TERM.
796 patients on ALI (23.8% had LDL-c<25 mg/dL at two consecutive visits, and 288 patients (8.6%) even reached LDL-c<15 mg/dL. In general, TEAEs were seen at similar frequencies between ALI-treated patients with very low LDL-c levels, all ALI-treated patients and the placebo group. No safety signals were observed for patients with very low LDL-c levels.
In ODYSSEY LONG TERM additional laboratory measurements were performed into parameters that might be related to very low LDL-c levels. This did not yield clinically relevant observations with regard to cortisol levels and fat soluble vitamins.
Robinson et al, simultaneously published an article about ODYSSEY LONG TERM in New England Journal of Medicine.
The poster of Michel Farnier and the presentation of Peter Jones were published on the website of Regeneron.