The FINANCIAL — Amgen on April 3 announced new detailed data from the Phase 3 GAUSS-3 (Goal Achievement After Utilizing an Anti-PCSK9 Antibody in Statin Intolerant Subjects-3) trial evaluating Repatha (evolocumab) in patients with high cholesterol who cannot tolerate statins.
The study showed that in patients with reproducible statin intolerance due to muscle-related side effects (MRSE), the use of Repatha compared to ezetimibe resulted in a significantly greater reduction in low-density lipoprotein cholesterol (LDL-C) after 24 weeks. These data were presented today at a Late-Breaking Clinical Trial session at the American College of Cardiology’s 65th Annual Scientific Session (ACC.16) and simultaneously published in the Journal of the American Medical Association.
Data from prespecified co-primary endpoints showed the mean LDL-C reduction from baseline at weeks 22 and 24 was 54.5 percent for Repatha compared to 16.7 percent for ezetimibe (p<0.001). At week 24, LDL-C reduction was 52.8 percent for Repatha compared to 16.7 percent for ezetimibe (p<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 percent of Repatha patients and 28.8 percent of ezetimibe patients. In patients treated with ezetimibe, active study drug was stopped for muscle symptoms in 6.8 percent of patients, compared to 0.7 percent of patients treated with Repatha, according to Amgen.
“Statin-associated muscle symptoms represent a major unresolved challenge in the care of patients with cardiovascular disease,” said Sean E. Harper, M.D., executive vice president of Research and Development at Amgen. “These findings are promising, demonstrating safety and efficacy results consistent with the other GAUSS studies.”
The GAUSS-3 study built upon knowledge gained from the GAUSS-1 and GAUSS-2 studies, which used patient-reported incidence of statin-related side effects. GAUSS-3 employed a rigorous active statin rechallenge in patients with history of intolerance to two or more statins to determine a patient population that experienced MRSE on statin therapy but not on placebo. Despite the short, 10-week rechallenge, more than 40 percent of patients rechallenged with atorvastatin developed intolerable muscle side effects to atorvastatin and not placebo.
“By employing a unique crossover design, these study results provide insights into our understanding of statin intolerance, which can be difficult to define from patient-reported symptoms alone,” said co-lead author Erik S.G. Stroes, M.D., Ph.D., chair and professor of the Department of Vascular Medicine at the Academic Medical Center (AMC), Amsterdam. “This rigorously-designed trial clearly shows that in carefully selected patients, statin intolerance withstands the placebo-controlled test. These often high-risk patients truly experience muscle-related side effects while on statin therapy and may therefore benefit from an alternative treatment like evolocumab to lower their LDL cholesterol.”
In the GAUSS-3 trial there were no new safety findings. The most common adverse events that occurred in greater than 5 percent of patients in the Repatha group were myalgia (13.8 percent Repatha; 21.9 percent ezetimibe), nasopharyngitis (9.7 percent Repatha; 2.7 percent ezetimibe), muscle spasms (9.0 percent Repatha; 6.8 percent ezetimibe), arthralgia (9.0 percent Repatha; 1.4 percent ezetimibe), pain in extremity (9.0 percent Repatha; 1.4 percent ezetimibe), fatigue (8.3 percent Repatha; 6.8 percent ezetimibe), headache (6.9 percent Repatha; 9.6 percent ezetimibe) and back pain (6.9 percent Repatha; 8.2 percent ezetimibe).
GAUSS-3 Study Design
GAUSS-3 (Goal Achievement After Utilizing an Anti-PCSK9 Antibody in Statin Intolerant Subjects-3) is a Phase 3, multicenter, randomized, double-blind, placebo-controlled statin rechallenge trial designed to evaluate the safety, tolerability and efficacy of Repatha in 491 patients with high cholesterol who could not tolerate statins due to MRSE.
The 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 >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 Repatha and ezetimibe in 218 patients. In Part B, patients were re-randomized 2:1 to receive either subcutaneous Repatha 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 Repatha 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 Repatha 140 mg every two weeks or 420 mg once monthly. Data from the open label extension may be subject of a future presentation or publication.
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 <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 (ApoA) ratio, lipoprotein(a), triglycerides, HDL-C and very low-density lipoprotein cholesterol (VLDL-C).
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