Drug products: Repatha
ATC code: C10AX13
Published controlled studies have not shown any differences between men and women concerning a reduction of LDL-levels, cardiovascular morbidity or mortality.
Pharmacokinetics and dosing
After a s.c. dose of 140 mg every two weeks, women had 48% higher median unbound evolocumab trough serum concentrations at week 12 than men. For evolocumab 420 mg s.c. once monthly the difference was 18%. Women overall had lower body weight and higher trough concentrations were therefore expected .Population pharmacokinetic studies conducted by the manufacturer found no effect of sex on evolocumab pharmacokinetics after adjusting for body weight .
Several studies have shown similar efficacy of evolocumab on reductions in LDL levels in men and women. The dose-ranging phase 2 study LAPLACE-TIMI 57 evaluated the efficacy of evolocumab on LDL concentrations in adult patients with hypercholesterolemia already receiving a statin (311 men, 320 women). Evolocumab lowered LDL concentrations by 66% at 12 weeks and to similar extent in men and women . This study was also included in a pooled analysis of data from four phase 2 studies (in all 595 men, 764 women), showing that evolocumab treatment for 12 weeks reduced lipoprotein Lp(a) levels (-29.5%) independent of age and sex . No sex differences in LDL reductions were seen in the large phase 3 study RUTHERFORD-2, where patients with heterozygous familial hypercholesterolemia received s.c. evolocumab 140 mg every 2 weeks or 420 mg monthly, or matching placebo . A phase 3 study was performed in Japanese patients with hyperlipidemia or mixed dyslipidemia and high cardiovascular risk (in all 244 men, 160 women). LDL concentrations were reduced by >67% after treatment with atorvastatin and evolocumab for 12 weeks and reductions were comparable between men and women .The effect of evolocumab on progression of coronary atherosclerosis in statin-treated patients were undertaken in a double-blind, placebo-controlled RCT (699 men, 269 women). Follow up at 78 weeks showed greater decrease in percent atheroma volume in patients treated with addition of evolocumab, and similarly in men and women .In the Fourier-study persons (20,795 men, 6,769 women) with atherosclerotic cardiovascular disease, LDL >1.8 mmol/L, and receiving statin therapy were randomized to s.c. injections of either evolocumab 140 mg every 2 weeks, 420 mg monthly, or placebo and followed for a median time of 2.2 years. Both men and women had better effect on the primary outcome cardiovascular morbidity with an event rate of 8.1% in the treatment group vs 9.9% in the placebo group for women and a 10.3% event rate in the treatment group vs 11.8% in the placebo group for men. Total mortality in the entire treatment group was 1.5% lower than in the placebo group but sex-divided data was missing .
No published studies with a clinically relevant sex-analysis regarding adverse effects of evolocumab have been found.
Reproductive health issues
Regarding teratogenic aspects, please consult Janusmed Drugs and Birth Defects (in Swedish, Janusmed fosterpåverkan).
Date of litterature search: 2017-03-21
- Food and Drug Administration (FDA) . Clinical Pharmacology and Biopharmaceutics Review - REPATHA (evolocumab). US Food and Drug Administration [www]. [updated 2015-10-01, cited 2017-03-21]. länk
- Giugliano RP, Desai NR, Kohli P, Rogers WJ, Somaratne R, Huang F et al. Efficacy, safety, and tolerability of a monoclonal antibody to proprotein convertase subtilisin/kexin type 9 in combination with a statin in patients with hypercholesterolaemia (LAPLACE-TIMI 57): a randomised, placebo-controlled, dose-ranging, phase 2 study. Lancet. 2012;380:2007-17. PubMed
- Raal FJ, Giugliano RP, Sabatine MS, Koren MJ, Langslet G, Bays H et al. Reduction in lipoprotein(a) with PCSK9 monoclonal antibody evolocumab (AMG 145): a pooled analysis of more than 1,300 patients in 4 phase II trials. J Am Coll Cardiol. 2014;63:1278-88. PubMed
- Raal FJ, Stein EA, Dufour R, Turner T, Civeira F, Burgess L et al. PCSK9 inhibition with evolocumab (AMG 145) in heterozygous familial hypercholesterolaemia (RUTHERFORD-2): a randomised, double-blind, placebo-controlled trial. Lancet. 2015;385:331-40. PubMed
- Kiyosue A, Honarpour N, Kurtz C, Xue A, Wasserman SM, Hirayama A. A Phase 3 Study of Evolocumab (AMG 145) in Statin-Treated Japanese Patients at High Cardiovascular Risk. Am J Cardiol. 2016;117:40-7. PubMed
- Nicholls SJ, Puri R, Anderson T, Ballantyne CM, Cho L, Kastelein JJ et al. Effect of Evolocumab on Progression of Coronary Disease in Statin-Treated Patients: The GLAGOV Randomized Clinical Trial. JAMA. 2016;316:2373-2384. PubMed
- Sabatine MS, Giugliano RP, Keech AC, Honarpour N, Wiviott SD, Murphy SA et al. Evolocumab and Clinical Outcomes in Patients with Cardiovascular Disease. N Engl J Med. 2017. doi: 10.1056/NEJMoa1615664. [Epub ahead of print] PubMed
- Läkemedelsstatistik. Stockholm: Socialstyrelsen. 2016 [cited 2017-03-23.] länk
Reviewed by: Mia von Euler
Approved by: Karin Schenck-Gustafsson