Results from the GAUSS-3 trial presented Sunday at the American College of Cardiology should be good news for Amgen, but an editorial in JAMA says the cost of evolocumab exceeds "willingness to pay" limits.
A leading cardiologist presented findings Sunday that show the PCSK9 inhibitor evolocumab (Repatha) is far better at lowering cholesterol than ezetimibe, and that it does so with fewer side effects in patients who have known statin intolerance.
Steven E. Nissen, MD, MACC, of the Cleveland Clinic, led a two-part study, which first confirmed a group of patients with uncontrolled low-density lipoprotein (LDL) cholesterol did indeed have statin intolerance. Then, the group was randomized to take either evolocumab or ezetimibe for 24 weeks; patients taking evolocumab showed a 52.8% reduction in LDL cholesterol, compared with a 16.7% reduction for those taking ezetimibe.1
The results of the trial, known as GAUSS-3, were presented Sunday at the American College of Cardiology 65th Scientific Session, being held in Chicago. The study was simultaneously published in JAMA.
However, the news isn’t all good for Amgen, the maker of evolocumab: an editorial in JAMA argues that PCSK9 inhibitors are priced so high they aren’t worth it, except for a tiny fraction of high-risk patients who are statin-intolerant.
The $14,000-a-year price tag for evolocumab (Repatha) far exceeds acceptable “willingness to pay” thresholds, according to the editorial led by David D. Waters, MD, former chief of cardiology at San Francisco General Hospital and professor emeritus at UC San Francisco.
Evolocumab, the editorial states, would need to cost $2600 a year to be “to be worthwhile for a statin-intolerant patient with cardiovascular disease and an LDL-level of 70mg/dL or greater.”2
“These findings provide unique insights into the challenging clinical problem of muscle symptoms in statin treated patients,” Nissen, who is chairman of Cardiovascular Medicine at Cleveland Clinic. “Evolocumab substantially lowered LDL cholesterol with few patients experiencing muscle symptoms. The study has important implications for both guidelines and regulatory policy, because it provides strong evidence that muscle-related statin intolerance is a real and reproducible phenomenon.”
The JAMA editorial doesn’t say Nissen’s findings have no bearing on prescribing evolocumab for those who experience muscle pains with statins; however, the writers say such uses should be limited. “A patient at very high risk for a cardiovascular event with intolerable muscle symptoms while taking even a low statin dose should be considered as a candidate for this treatment. Less than 1% of all ‘statin-intolerant’ patients might belong to this group at present. For other patients with statin intolerance, the appropriateness of these agents is less clear.”2
Such conclusions, however, do not obscure the findings: evolocumab continues to produce remarkable results in lowering cholesterol. Clinical trials that led to FDA approval in August 2015 showed evolocumab reduced LDL levels up to 60%.
Supporters of evolocumab and the other approved drug in the class, alirocumab (Praluent), also priced around $14,000, have hoped that long-term safety studies will eventually convince FDA to broaden the narrow approval granted last summer to other groups of patients, including those who are statin-intolerant. During his presentation, Nissen said between 5% and 10% of patients with high LDL cholesterol decline statins because of muscle-related effects.
But health plans and pharmacy benefit managers have kept tight reins on access to PCSK9 inhibitors, in light of the label as well as their cost.
In this trial, researchers sought first to confirm beyond a doubt that they had a group of patients that was indeed statin intolerant. These patients also had very high levels of LDL cholesterol, averaging more than 210 mg/dL. Researchers started with 511 patients enrolled in 53 centers. All had a history of statin intolerance due to muscle-related adverse effects. Of this group 491 were randomized to take part in a two-part crossover study: patients took either 20 mg of atorvastatin or placebo for 10 weeks, then the groups switched for another 10 weeks with a 2-week washout period in between. In this group, 82% had reported failing 3 or more statins. Twenty patients did not complete this phase of the study.
Of the 491 participants, 209, or 42.6%, reported muscle-related effects while taking atorvastatin but not while taking placebo. More than a quarter, 26.5%, reported muscle pain while taking placebo but not the statin, suggesting that while statin intolerance can be confirmed in many patients, some pain cannot be attributed to statins. This group, plus 19 participants from an earlier phase of GAUSS with confirmed muscle damage attributable to statins, were randomized 2:1 to take evolocumab (145 patients) or ezetimibe (73 patients).
Because evolocumab is an injectable and ezetimibe is a pill, those taking the injectable (420 mg) were given a placebo pill, and those taking the study pill (10 mg) were given a placebo injectable. In contrast with the statin therapy, only 5 patients (6.8%) of the patients on ezetimibe stopped taking therapy for muscle weakness, and only 1 (0.7%) stopped taking evolocumab for this reason.
Nissen acknowledged Sunday that issue of statin intolerance is both controversial and challenging due to a lack of biomarkers, but it is nonetheless an unmet need. With physicians confronted by patients who have very high LDL cholesterol but refuse to take statins, he said, “development of an appropriate alternative represents important medical priority.”
Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors work by binding to and inhibiting PCSK9, a protein that degrades LDL cholesterol receptors on the surface of the liver. These drugs are designed to increase the number of LDL receptors on the liver, thus allowing the liver to remove LDL cholesterol from the blood more effectively. Ezetimibe, a currently approved drug used as a control in the trial, lowers blood cholesterol by decreasing the absorption of cholesterol in the small intestine.
Besides the concerns about the cost of PCSK9 inhibitors, FDA awaits long-term safety studies. Also, Amgen and alirocumab’s sponsors, Sanofi and Regeneron, are in court in a patent dispute. Amgen won a jury trial that has the potential to take alirocumab off the market, although some believe the result will be royalty payments.
Frederick Masoudi, MD, chief science advisor at the National Cardiovascular Data Registry; and professor of medicine, University of Colorado, said the results were important given the controversy over statin intolerance and the lack of biomarkers.
He said it was noteworthy that despite the repeated failures of the patient group, 17.3% reported no symptoms in the first phase of the trial. “It pays to be patient,” he said. For cost and other reasons, “Statins remain the mainstay of prevention.”
Amgen funded the study.
1. Nissen SE, Stroes E, Dent-Acosta RE, et al. The GAUSS-3 randomized clinical trial [published online April 3, 2016]. JAMA. 2016; doi:10.1001/jama.2016.3608
2. Waters DD, Hsue PY, Bangalore S. PCSK9 inhibitors for statin intolerance? [published online April 3 2016]. JAMA. 2016.