Physicians' Academy for Cardiovascular Education

Sustained LDL-c reduction upon dose adjustment of PCSK9 inhibitor

Individualized low-density lipoprotein cholesterol reduction with alirocumab titration strategy in heterozygous familial hypercholesterolemia: Results from an open-label extension of the ODYSSEY LONG TERM trial

Literature - Dufour R, Hovingh GK, Guyton JR et al., - J Clin Lipidol. 2019; 13 : 138-147.

Introduction and methods

A recent EAS/ESC Consensus statement and a few guidelines state that treatment with PCSK9-directed antibodies should be considered for patients with heterozygous familial hypercholesterolemia (HeFH) at very high CV risk, with a family history of coronary artery disease at a very young age, or an LDL-c level far from goal despite being on other maximally tolerated lipid-lowering therapy [1-5].

The PCSK9 inhibitor alirocumab can be administered at doses of 75 or 150 mg every 2 weeks (Q2W). Both dosing regimens have demonstrated consistent LDL-c reductions of between 44% and 61% in the ODYSSEY clinical trial program [6-11]. In most studies, the reduction was not dependent on LDL-c levels at baseline [6-8,10].

The ODYSSEY LONG TERM trial assessed the long-term safety and efficacy of alirocumab 150 mg Q2W [12]. For some patients, however, the lower dose may be sufficient to achieve their CV-risk-based LDL-c goals. HeFH patients receiving 150 mg Q2W in ODYSSEY LONG TERM could opt to enroll in the open-label extension (OLE) study, and receive alirocumab 75 mg Q2W at entry in ODYSSEY OLE. ODYSSEY OLE studied the effects of both approved doses of alirocumab in the same HeFH patient cohort, with relatively high LDL-c levels despite maximally tolerated statin therapy.

214 Patients enrolled in ODYSSEY OLE. From week 12, physicians were allowed to adjust the alirocumab dose from 75 to 150 Q2W and back, depending on their clinical judgment and the patient’s LDL-c level. Background statin and other lipid-lowering therapy were to be kept stable during OLE, if possible. The primary objective of ODYSSEY OLE was to assess long-term safety of alirocumab added to background therapy in HeFH, and the secondary objective was evaluation of long-term efficacy and immunogenicity.

Main results


Long-term efficacy



Both the 75 mg and the 150 mg Q2W doses of alirocumab yielded substantial LDL-c reductions over the treatment duration of up to four years. The difference in percentage reduction in LDL-c between the two doses of alirocumab (15.8%) is as expected based on simulation models used for design of the ODYSSEY phase 3 clinical trial program, and consistent with what was seen in double-blind trials. Both patients who remained on 75 mg Q2W and those with a dose increase to 150 mg Q2W showed a sustained reduction in LDL-c. These findings allow for an individualized approach to LDL-c lowering with PCSK9 inhibition in patients with HeFH.


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