WASHINGTON – Evolocumab, an investigational fully human monoclonal antibody, was associated with markedly greater LDL cholesterol reductions than ezetimibe in a phase III clinical trial of statin-intolerant patients.
"Robust LDL lowering and good tolerability make evolocumab a promising therapy for addressing the large unmet clinical need in high-risk hypercholesterolemic patients with statin intolerance," Dr. Erik S.G. Stroes said in presenting results of the phase III trial, known as GAUSS-2, at the annual meeting of the American College of Cardiology.
Evolocumab is an injected product that inhibits PCSK9 (proprotein convertase subtilisin/kexin type 9). Ezetimibe is the only well-tolerated and approved alternative available for LDL cholesterol lowering in patients who can’t take a statin.
Frontline Medical News
Dr. Jennifer G. Robinson
Recent real-world patient surveys suggest the rate of statin intolerance is 10%-20%, much more common than was initially apparent from the highly selective landmark statin clinical trials, observed Dr. Stroes, professor and chair of the department of vascular medicine at the Academic Medical Center, Amsterdam.
GAUSS-2 (the second study of Goal Achievement After Utilizing an Anti-PCSK9 Antibody in Statin-Intolerant Subjects) was a 12-week, double-blind, phase III clinical trial that included 307 participants. All had a history of intolerance to at least two statins. The majority of GAUSS-2 participants had previously discontinued three or more statins, nearly always because of muscle aches and pains, and almost one-quarter had unsuccessfully tried four or more statins.
The mean baseline LDL cholesterol level was 193 mg/dL. Subjects were randomized 2:2:1:1 to one of four treatment arms: subcutaneously injected evolocumab at 140 mg, given biweekly plus an oral placebo; evolocumab 420 mg, given monthly plus placebo; or 10 mg/day of oral ezetimibe plus a placebo injection given either biweekly or monthly.
The primary endpoint was the percentage change in LDL cholesterol levels from baseline through week 12. The two evolocumab dosing regimens proved clinically equivalent, with mean LDL cholesterol reductions of 53% and 56%, in contrast to the 15% and 18% reductions in the two ezetimibe arms.
As in the other four phase III evolocumab trials presented at ACC 14, the PCSK9 inhibitor was well tolerated with 96% of patients randomized to evolocumab in GAUSS-2 completing the 12-week study. Given that 100% of GAUSS-2 participants had a history of intolerable muscle-related side effects during multiple prior rounds of statin therapy, it’s noteworthy that the incidence of myalgia in the evolocumab group was 8%, even lower than the 18% rate in the ezetimibe group, Dr. Stroes commented.
Frontline Medical News
Dr. Erik Stroes
At the same late-breaking clinical trials session at which Dr. Stroes presented GAUSS-2, Dr. Jennifer G. Robinson presented the results of LAPLACE-2, a randomized, double-blind, 12-week, phase III trial in which investigators looked at the lipid-lowering effects of evolocumab in conjunction with various doses of atorvastatin, rosuvastatin, and simvastatin. LAPLACE-2 (LDL-C Assessment With PCSK9 Monoclonal Antibody Inhibition Combined With Statin Therapy) featured a complex study design in which roughly 1,900 patients with elevated LDL cholesterol levels were randomized to 1 of 24 treatment arms.
At week 12, the percent reduction in LDL cholesterol from baseline in the various evolocumab arms ranged from 55% to 76%. An LDL cholesterol level of less than 70 mg/dL was achieved in 86%-94% of patients on evolocumab and moderate-intensity statin therapy, such as atorvastatin at 10 mg/day and in 3%-95% of those on evolocumab and high-intensity statin therapy, such as atorvastatin at 80 mg/day or simvastatin at 40 mg/day.
At week 12, the mean LDL cholesterol level in patients on evolocumab plus high-intensity statin therapy was 35-38 mg/dL. In those on a moderate-intensity statin regimen, the mean LDL cholesterol level was 38-45 mg/dL, reported Dr. Robinson, professor of epidemiology and of medicine and director of the prevention intervention center at the University of Iowa, Iowa City.
With five evolocumab phase III clinical trials presented at ACC 14 showing a consistent pattern of large-scale LDL cholesterol lowering and a side effect profile essentially that of placebo, the crucial question now becomes whether achieving LDL cholesterol levels in the 35-45 mg/dL range will translate into a large reduction in cardiovascular events. All eyes have turned to the ongoing FOURIER (Further Cardiovascular Outcomes Research With PCSK9 Inhibition in Subjects With Elevated Risk) trial, in which 22,500 patients with clinical atherosclerotic cardiovascular disease are being randomized to evolocumab or placebo in combination with moderate- or high-intensity statin therapy with cardiovascular event rates as the key endpoints. Results are expected in 2018.
In the meantime, Dr. Robinson said, it’s possible that prior to the FOURIER results, the Food and Drug Administration will approve evolocumab with an indication for LDL cholesterol lowering. After all, ezetimibe was approved on the strength of far more modest lipid lowering, and in the absence of supporting outcome data. But if evolocumab were to receive marketing approval in advance of the event rate data, she added, the proper way for physicians to use it would be only in the patient groups with significant clinical unmet needs who were the focus of the phase III trials: those with statin intolerance (GAUSS-2), familial hypercholesterolemia and other genetic dyslipidemias (RUTHERFORD-2), or people whose cardiovascular risk status warrants high-intensity statin therapy but who can only tolerate moderate-intensity therapy (LAPLACE-2).