Effect of Alirocumab 75 mg Subcutaneously Every 2 Weeks as Monotherapy Versus Ezetimibe Over 24 Weeks

Q2W: Every 2 weeks; q.d.: Every day; sc.: Subcutaneously.
Adapted with permission from [18].

Data are mean (standard deviation) baseline characteristics of all randomized patients, unless stated otherwise.
HDL-C: HDL-cholesterol; IQR: Interquartile range; LDL-C: LDL-cholesterol; SCORE: European Systematic Coronary Risk Estimation; TC: Total cholesterol; TG: Triglyceride.
Adapted with permission from [18].

^†See Table 4.
ALT: Alanine transaminase; AST: Aspartate aminotransferase; CK: Creatine kinase; d/c: Discontinuation; SAE: Serious adverse event; TEAE: Treatment-emergent adverse event; ULN: Upper limit of normal.
Adapted with permission from [18].

All six patients had abnormal fasting blood glucose (=100 mg/dl) or HbA1c =6.5% at screening or baseline.
DM: Diabetes mellitus.
Adapted with permission from [18].

ADA: Antidrug antibody; NA: Not applicable.

Authors and Disclosures

Eli M Roth*^,1 & James M McKenney²

¹University of Cincinnati & Sterling Research Group, 375 Glensprings Drive, 2nd Floor, Cincinnati, OH 45246, USA
²Virginia Commonwealth University & National Clinical Research, Inc., 2809 Emerywood Parkway, Suite 140, Richmond, VA 23294, USA

*Author for correspondence
Tel.: +1 513 671 8080; Fax: +1 513 671 8090; eroth@sterlingresearch.org

Financial & competing interests disclosure
EM Roth is an employee of a research company that receives grants from Sanofi, Regeneron, Pfizer, Esperion and Lilly (those currently developing lipid-modifying drugs) and is a consultant to Regeneron and Sanofi. JM McKenney is an employee of a research company that receives grants from Sanofi, Regeneron, Pfizer, Esperion and Lilly (those currently developing lipid-modifying drugs). The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.
No writing assistance was utilized in the production of this manuscript.

Sidebar

Executive Summary

Background

• Alirocumab (formerly SAR236553/REGN727) is a monoclonal antibody directed at PCSK9 that showed good efficacy in Phase II trials when added to background statin therapy.

• This is the first completed Phase III study in the ODYSSEY development program and is unique (compared with the Phase II studies) in the dose used (starting dose of 75 mg), the population (no background lipid-modifying therapies), the use of disposable autoinjectors for self-administration, the length of the study (24 weeks) and the alirocumab uptitration scheme (75–150 mg at week 12) for LDL-cholesterol (LDL-C) >100 mg/dl at week 8.

Study design

• This was a randomized, double-blind, active-controlled (ezetimibe), parallel-group, double-dummy study. General inclusion criteria were LDL-C between 100 and 190 mg/dL on no lipid-lowering medications in a moderate-risk population with a European Systematic Coronary Risk Estimation (SCORE) of 1–4%. In total, 103 patients were randomized into the study.

Data analysis

• The primary efficacy analysis population was the intent-to-treat (ITT) population, defined as the randomized population that actually received at least one dose or partial dose of investigational medicinal product and had both the baseline and at least one subsequent LDL-C value.

Results

• The primary end point – the percentage difference (least square mean) in LDL-C between the alirocumab arm and the ezetimibe arm at 24 weeks – was -31.6% for the ITT population (p < 0.0001). LDL-C lowering with alirocumab was 47.2% and with ezetimibe was 15.6%.

• Thirteen patients were uptitrated in error at week 12 from 75 to 150 mg subcutaneously every 2 weeks due to a programming error in the interactive voice responsive system (LDL-C ≥70 mg/dl instead of ≥100 mg/dl per protocol). Uptitration did not result in a significant decrease in LDL-C compared with the non-uptitrated group, and the primary end point excluding the 13 incorrectly uptitrated patients was not significantly different from the ITT population results.

Safety

• Safety parameters, adverse events and study discontinuation rates were similar between the two groups. No patterns of change in glucose or HbA1c were observed from screening to week 24. LDL-C values of <25 mg/dl were not associated with any particular safety finding. Low levels of antidrug antibodies were present in four of the alirocumab patients and these levels decreased or disappeared from week 12 to week 24, and then to week 34 (the follow-up visit).

Significance

• Alirocumab showed significantly better LDL-C lowering than ezetimibe, with a comparable safety profile to ezetimibe. Uptitrated patients did not show a significant reduction in their LDL-C compared with that achieved with alirocumab 75 mg subcutaneously every 2 weeks; this may have occurred because the PCSK9/LDL receptor system was already saturated in these patients.

Conclusion

• This new lower dose of alirocumab may be adequate to achieve substantial LDL-C lowering for many hypercholesterolemic patients at moderate cardiovascular risk who are not receiving other lipid-modifying therapies.