The Phase III GLAGOV trial showed Repatha (evolocumab; Amgen/Astellas) treatment to reduce atherosclerotic plaque burden in an apparently dose-dependent manner, even at very small low-density lipoprotein-cholesterol (LDL-C) levels. This trial is highly significant as it is the first to show the beneficial impact of a non-statin therapy on atherosclerotic plaque regression.
Positive results from Amgen’s Phase III GLAGOV trial were released at the American Heart Association conference in New Orleans on 16 November 2016, with findings simultaneously published in the Journal of the American Medical Association. The Phase III GLAGOV trial is an intravascular ultrasound study (IVUS) which investigated the impact of monthly Repatha on top of background statin therapy compared with statin therapy alone, in 968 patients undergoing coronary catheterization. The primary outcome of the study was change in percent atheroma volume (PAV) from baseline at 78 weeks, and secondary outcomes included change in total atheroma volume and percentage of patients experiencing plaque regression.
The Phase III trial met both primary and secondary endpoints, and raised no significant safety concerns. Patients treated with Repatha plus statin therapy experienced a statistically significant reduction in PAV of 0.95%, compared to an increase of 0.05% in those treated with statin alone. Additionally, 67% of the Repatha-treated group experienced a reduction in PAV, versus 47% of the statin monotherapy group. Participants in the study had a baseline LDL of 92.5mg/dl across both treatment arms, which reduced to 29.0mg/dl in the Repatha-treated group (representing a 68% reduction) compared to 90.1mg/dl in the placebo arm. Furthermore, the trial raised no significant safety concerns over the 78-week period.
Pushing LDL-C down to very low levels with Repatha treatment caused a continuous reduction in atherosclerotic plaque burden. In the Phase III trial, Repatha treatment was shown to cause a continuous reduction in PAV in an almost linear fashion, down to LDL-C levels of 20mg/dl. This is a highly important finding as it demonstrates the beneficial impact of lowering LDL-C to much lower levels than previously achieved, and provides solid support for the “lower is better” hypothesis. While it was frequently assumed that the impact of LDL-C lowering on atherosclerotic plaques would diminish after pushing LDL-C down to a certain level, there was no tailing-off effect with Repatha treatment at very low levels. Physicians had expressed concerns over the impact of reducing LDL-C to such low levels, however, these findings provide significant support for extreme LDL-C lowering to provide further cardiovascular (CV) benefits in a range of high-risk dyslipidemia patients.
The GLAGOV results are unlikely to have an immediate impact on Repatha’s uptake, but provide encouragement for the drugs’ ongoing cardiovascular outcomes trial (CVOT). While Repatha’s observed beneficial impact on the regression of atherosclerotic plaques is encouraging, it is not fully known how PAV translates in CV outcomes. Using IVUS as a surrogate has a fairly good record of prediction for CV risk, however, these results will need to be confirmed in long-term CV outcomes. Interestingly, the incidence of adverse CV events in the GLAGOV trial was shown to be lower in the Repatha-treated group than the placebo group, but this trial was not powered to assess clinical endpoints. The Phase III FOURIER trial has been designed to investigate the long-term impact of Repatha treatment on CV outcomes, and full results of this trial will be required to confirm the suspected beneficial impact of Repatha treatment on clinical events.
Positive CVOT results may help to ease reimbursement restrictions which are currently limiting the uptake of proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors. Since launching in 2015, Repatha and its major competitor, Praluent (alirocumab; Sanofi/Regeneron), have struggled to penetrate the dyslipidemia market, predominantly due to payers’ strict reimbursement protocols over the high annual costs of the drugs. At a US list price of around $14,000 per patient per year, and without the availability of CV outcomes data, payers across the US and Europe have severely restricted access to PCSK9 inhibitors for the most high-risk dyslipidemia patients. While Phase III data demonstrating the drugs’ impressive lipid-lowering abilities, along with the recent data from Repatha’s GLAGOV trial, are encouraging, these positive findings will need to be replicated in the drugs’ CVOTs in order for physicians and payers to fully accept the drugs’ clinical benefits. If the PCSK9 inhibitors demonstrate significant improvements in CV outcomes in comparison to current lipid-lowering therapies, then reimbursement restrictions are likely to ease across the US and Europe, and uptake will likely increase.