New detailed data from the phase 3 GAUSS-3 ( Goal Achievement After Utilizing an Anti-PCSK9 Antibody in Statin Intolerant Subjects-3 ) trial evaluating Evolocumab ( Repatha ) in patients with high cholesterol who cannot tolerate statins were presented at the American College of Cardiology's 65th Annual Scientific Session ( ACC.16 ) and simultaneously published in the Journal of the American Medical Association ( JAMA ).
The study showed that in patients with reproducible statin intolerance due to muscle-related side effects ( MRSE ), the use of Evolocumab compared to Ezetimibe ( Zetia ) resulted in a significantly greater reduction in low-density lipoprotein cholesterol ( LDL-C ) after 24 weeks.
Data from prespecified co-primary endpoints showed the mean LDL-C reduction from baseline at weeks 22 and 24 was 54.5% for Evolocumab compared to 16.7% for Ezetimibe ( p less than 0.001 ).
At week 24, LDL-C reduction was 52.8% for Evolocumab compared to 16.7% for Ezetimibe ( p less than 0.001 ).
At baseline, the mean LDL-C level was 219.9 mg/dL for all patients entering the active-controlled part of the trial.
Muscle-related side effects were reported in 20.7% of Evolocumab patients and 28.8% of Ezetimibe patients.
In patients treated with Ezetimibe, active study drug was stopped for muscle symptoms in 6.8% of patients, compared to 0.7% of patients treated with Evolocumab.
GAUSS-3 study was divided into three parts ( A, B, C ):
Part A was a two-period, double-blind, placebo-controlled, 24-week cross-over rechallenge of Atorvastatin 20 mg in 491 patients with a history of statin intolerance to confirm the presence of statin-related MRSE.
In Part A, patients were randomized in a 1:1 ratio to receive either Atorvastatin 20 mg daily or oral placebo daily for 10 weeks ( period one ) before undergoing a two-week washout procedure and crossing over to the alternate therapy for a second 10 weeks ( period two ).
Upon completion of both periods one and two in Part A, patients who reported MRSE on Atorvastatin and absence of MRSE on placebo entered into another two-week washout period and advanced to Part B. Patients who did not develop MRSE on Atorvastatin or developed MRSE on placebo were removed from the study.
During Part A, patients who experienced a creatine kinase ( CK ) elevation more than 10x upper limit of normal ( ULN ) accompanied by muscle symptoms, with resolution of both CK elevation and muscle symptoms upon discontinuation of statin therapy, were considered the equivalent of intolerable MRSE and also advanced to Part B.
Part B was a 24-week double-blind, double-dummy, active-controlled comparison of Evolocumab and Ezetimibe in 218 patients.
In Part B, patients were re-randomized 2:1 to receive either subcutaneous Evolocumab 420 mg once monthly and daily oral placebo or oral Ezetimibe 10 mg daily and subcutaneous placebo monthly through week 48.
Part C is an ongoing, two-year, open-label extension, during which all patients who completed Part B receive Evolocumab to evaluate its long-term safety and efficacy in patients with objectively-documented statin intolerance.
All patients in the open-label extension portion receive subcutaneous Evolocumab 140 mg every two weeks or 420 mg once monthly.
The co-primary endpoints were the mean percent reductions from baseline in LDL-C at weeks 22 and 24 and the percent reduction from baseline in LDL-C at week 24 in Part B.
Secondary efficacy endpoints included means at weeks 22 and 24 and at week 24 for the following: change from baseline in LDL-C; LDL-C response less than 70 mg/dL; change from baseline in total cholesterol ( TC ); change from baseline in non-high-density lipoprotein cholesterol ( non-HDL-C ), apolipoprotein B ( ApoB ), TC/HDL-C ratio, ApoB/apolipoprotein A1 ( ApoA1 ) ratio, lipoprotein(a), triglycerides, HDL-C and very low-density lipoprotein cholesterol ( VLDL-C ).
Evolocumab is a human monoclonal antibody that inhibits proprotein convertase subtilisin/kexin type 9 ( PCSK9 ). Evolocumab binds to PCSK9 and inhibits circulating PCSK9 from binding to the low-density lipoprotein receptor ( LDLR ), preventing PCSK9-mediated LDLR degradation and permitting LDLR to recycle back to the liver cell surface. By inhibiting the binding of PCSK9 to LDLR, Evolocumab increases the number of LDLRs available to clear LDL from the blood, thereby lowering LDL-C levels. ( Xagena )
Source: Amgen, 2016