Amgen (AMGN) Announces Significant Data for Repatha in Regressing CAD-Related Atherosclerosis

November 15, 2016 12:46 PM EST

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Amgen (Nasdaq: AMGN) announced that adding Repatha (evolocumab) to optimized statin therapy resulted in statistically significant regression of atherosclerosis in patients with coronary artery disease (CAD). The detailed results from the GLAGOV Phase 3 coronary intravascular ultrasound imaging trial were presented at a Late-Breaking Clinical Trials Session of the American Heart Association (AHA) Scientific Sessions 2016 and simultaneously published in the Journal of the American Medical Association.

The GLAGOV study evaluated whether Repatha, a proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor for the treatment of certain patients with elevated low-density lipoprotein cholesterol (LDL-C), would modify atherosclerotic plaque build-up in the coronary arteries of patients already treated with optimized statin therapy, as measured by intravascular ultrasound (IVUS) at baseline and week 78.

"The cardiovascular community began conducting imaging studies with LDL-C therapies to measure slowing of atherosclerotic disease progression. This study shows that maximal LDL-C reduction with Repatha can actually regress coronary atherosclerotic disease compared to statins alone," said Sean E. Harper, M.D., executive vice president of Research and Development at Amgen. "In fact, nearly two-thirds of patients on Repatha in this trial, the vast majority of whom were already on high to moderate intensity statin therapy at baseline, experienced a reduction in plaque burden."

The study met its primary objective showing that treatment with Repatha resulted in a statistically significant regression from baseline in percent atheroma volume (PAV), which is the proportion of arterial lumen occupied by plaque. Patients in the Repatha arm experienced a 0.95 percent decrease versus baseline in PAV compared with an increase of 0.05 percent versus baseline in patients receiving optimized statin therapy plus placebo (Repatha arm p<0.0001; placebo arm p=0.78). The difference between the two comparators was statistically significant (p<0.0001). In addition, adding Repatha yielded plaque regression in PAV for a greater percentage of patients than for those receiving placebo (64.3 percent versus 47.3 percent, respectively, p<0.0001). At baseline, 98 percent of patients in both arms were on high to moderate intensity statin therapy.

Patients in the Repatha arm experienced a mean decrease in normalized total atheroma volume (TAV), which is a measure of plaque volume, of 5.8mm³ compared with 0.9mm³ seen in the placebo arm (Repatha arm p<0.0001; placebo arm p=0.45). The difference between the two comparators was statistically significant (p<0.0001). Additionally, adding Repatha yielded plaque regression in TAV for a greater percentage of patients than placebo (61.5 percent versus 48.9 percent, respectively, p=0.0002).

"Based on previous studies, we did not know if GLAGOV would show additional plaque regression at LDL-C levels below 60 mg/dL," said Stephen J. Nicholls, M.D., Ph.D., professor of Cardiology and deputy director, South Australian Health & Medical Research Institute, Adelaide, Australia. "One of the most compelling results from GLAGOV is the continued reduction of plaque at LDL-C levels well below commonly accepted thresholds."

At baseline, patients had a mean LDL-C of 92.5 mg/dL across both treatment arms. During 78 weeks of treatment, the time-weighted mean LDL-C level was 36.6 mg/dL in the Repatha arm, which represents a reduction of 59.8 percent, compared with 93.0 mg/dL in the placebo arm. At week 78, the mean LDL-C in the Repatha arm was 29 mg/dL, which represents a 68.0 percent decrease from baseline, and in the placebo arm was 90 mg/dL.

An exploratory analysis evaluated the level of plaque reduction achieved in the 144 patients with baseline LDL-C levels below 70 mg/dL (the lowest treatment target among the current global guidelines). In this analysis, these patients experienced the greatest decrease in plaque burden from baseline (change in PAV) with Repatha compared with placebo (-1.97 percent versus -0.35 percent, respectively, p<0.0001). In addition, more than 80 percent of patients in this subset experienced plaque regression (by change in PAV) with Repatha (81.2 percent Repatha; 48.0 percent placebo, p<0.0001).

No new safety concerns were identified in the GLAGOV trial. The incidence of treatment-emergent adverse events was comparable among both groups (67.9 percent Repatha; 79.8 percent placebo). Adverse events of clinical importance reviewed in this study included myalgia (7.0 percent Repatha; 5.8 percent placebo), new diagnosis of diabetes mellitus (3.6 percent Repatha; 3.7 percent placebo), neurocognitive events (1.4 percent Repatha; 1.2 percent placebo) and injection site reactions (0.4 percent Repatha; 0.0 percent placebo). In the GLAGOV study, binding antibodies were rarely observed (0.2 percent [1 patient] in the Repatha-treated arm) and no patients tested positively for neutralizing antibodies.

Although the study was not powered to assess effects on cardiovascular events, an exploratory analysis revealed that positively-adjudicated major cardiovascular events occurred in 12.2 percent of patients receiving Repatha and 15.3 percent in those receiving placebo. The majority of adjudicated events were coronary revascularizations (10.3 percent Repatha; 13.6 percent placebo), followed by myocardial infarction (2.1 percent Repatha; 2.9 percent placebo). All other adjudicated cardiovascular events occurred in ≤0.8 percent of patients in each treatment group.

Harper continued, "The compelling data from GLAGOV remove any scientific doubt about the ability of Repatha to lower LDL-C and the impact it has on the critical underlying disease process. We remain concerned that many patients are experiencing barriers to accessing Repatha, despite their physician's treatment recommendations. We look forward to our outcomes study, FOURIER, and will continue to work with payers to improve access for patients who need additional LDL-C lowering."

GLAGOV Study Design

GLAGOV (GLobal Assessment of Plaque ReGression with a PCSK9 AntibOdy as Measured by IntraVascular Ultrasound) is a Phase 3, multicenter, double-blind, randomized, placebo-controlled trial designed to evaluate the effect of Repatha on the change in burden of CAD in 968 patients undergoing clinically indicated coronary angiogram and on optimized background statin therapy.

Patients were required to have been treated with a stable statin dose for at least four weeks and to have a LDL-C ≥80 mg/dL or between 60 and 80 mg/dL with one major cardiovascular risk factor (defined as non-coronary atherosclerotic vascular disease, myocardial infarction or hospitalization for unstable angina in the preceding two years or type 2 diabetes mellitus) or three minor cardiovascular risk factors (defined as current cigarette smoking, hypertension, low levels of HDL cholesterol, family history of premature coronary heart disease, high sensitivity C-reactive protein (hs-CRP) ≥2 mg/L or age ≥50 years in men and 55 years in women).

Patients were randomized 1:1 into two treatment groups to either receive monthly Repatha 420 mg or placebo subcutaneous injections. Optimized statin therapy was defined as at least atorvastatin 20 mg daily or equivalent, titrated to achieve LDL-C reduction per regional guidelines. Highly effective statin therapy (equivalent to atorvastatin 40 mg daily or higher) was recommended for all patients. Those patients with LDL-C >100 mg/dL (2.6 mmol/L) not taking highly effective statin therapy, required investigators' attestation as to why such doses were not appropriate. The primary endpoint was change in PAV from baseline to week 78 compared to placebo, as determined by IVUS. IVUS is a high-resolution imaging tool that allows for the quantification of coronary atheroma in the coronary arteries.

Secondary endpoints included PAV regression (any reduction from baseline); change in TAV from baseline to week 78; and regression (any reduction from baseline) in TAV.

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