FDA approves PCSK9 inhibitor for lowering of LDL in certain patients

This decision goes along with the general approach to dealing with what otherwise is a pretty clear log-linear relationship between LDL cholesterol levels and coronary risk — that essentially establishes that lower is better. I was part of the National Cholesterol Education Program Coordinating Committee, but the last update out of that organization was in 2004. In that guideline, we noted that in very high-risk individuals with established coronary disease, in diabetic patients with additional risk factors or in metabolic syndrome patients with additional risk factors, an LDL less than 70 mg/dL was desirable. It’s hard to get to less than 70 mg/dL in all of these patients on statins alone, so combination therapy looks increasingly viable. On preliminary readout, PCSK9 inhibitors appear to be fairly safe; on the other hand, patients with very high-risk coronary disease are not at all safe. So this is a situation where you have a risk–benefit calculator and you can point to a provable benefit.

The FDA’s and advisory committee’s decisions are appropriate for high-risk patients or for patients with inherited cholesterol disorders who either can’t take statins or have optimized their cholesterol-lowering traditional medications. Having these two therapies available sooner rather than later is probably appropriate. The committee exercised reasonable caution with regard to lower-risk patients, wanting to wait until the outcomes studies were completed before they offered broader approval, which would translate to broader use of these medications.

This is a first step. Just because the FDA approves a medication with an indication doesn’t necessarily mean that everyone will get that drug, because payers and health care systems will invariably start to put up a series of algorithms that people will be required to go through to gain access to these drugs. Cost is going to be an issue any time a new therapy comes about. But for high-risk patients, patients with lifetime elevations in cholesterol or patients who have had recurrent CV events and can’t get to their targeted LDL cholesterol levels, having these drugs available sooner rather than later is good. I thought the committee’s deliberations were reasonable and appropriate.

I applaud the FDA for following the recommendation of its advisory panel recognizing the need that patients at high risk for cardiovascular disease have in improving the control of lipids as one of the most important causes of CVD and approving Praluent (alirocumab, Sanofi/Regeneron) for patients with HeFH and clinical atherosclerosis cardiovascular disease. The European Commission recently approved Repatha (evolocumab, Amgen,) another PCSK9 inhibitor, for CVD high-risk patients with uncontrolled cholesterol; specifically for patients with HeFH, HoFH (ages 12 and older) on statin and other lipid-lowering therapies unable to reach LDL-C goals or in combination with other lipid-lowering therapies in patients who are statin intolerant. I do anticipate that the FDA will soon approve Repatha, as well, signaling a new era in the management of lipid disorders in high-risk patients. For many years, the mainstays of lipid management were the statins, and indeed, we have witnessed a significant improvement in CVD with intensive lipid treatment with statins. However, at the same time, we recognize that statins typically are effective in just about one-quarter to one-third of patients prescribed the medications. Also, there are high-risk patients, like people with familial hypercholesterolemia, those on maximum appropriate amounts of statins who continue to have CV events and those who cannot tolerate statins, who need further management that has the potential to significantly reduce their risk. Until recently, available alternatives were limited primarily to bile acid sequestrants (BAS) and to Zetia (ezetimibe, Merck), both of which further reduce LDL by about 15% to 20%. Ezetimibe has recently been shown, in the IMPROVE-IT trial, to significantly improve CV outcomes by further modestly reducing LDL. However, there are practically no outcomes data to show the effectiveness of BAS in combination therapies.

The PCSK9 inhibitors represent a revolutionary approach in both drug development and in managing people with high cholesterol and very high risk for CVD. The physiology of PCSK9 and its relevance in human disease was first identified by gene mutations in humans only in 2003. Within a mere 3 years, PCSK9 was already a target of medication, and just about 8 years from drug development there was a submission to the FDA. This truly defines the future of drug development, which is what makes PCSK9 inhibitors so exciting. That the drugs are monoclonal antibodies makes them “ultimate medications” as they affect specifically only the target — PCSK9. Thus, the side-effect profile is exceedingly small, and indeed so far the drugs, based on published data, appear to be very safe and effective. From the available trial results and from what was presented to the advisory board, efficacy of these drugs ranges from 40% to 70% reduction of LDL cholesterol to levels never imaginable before. These drugs clearly are going to offer new opportunities for patients, particularly those mentioned above with familial hypercholesterolemia and those at higher risk for recurrent events despite treatment. Once outcomes trials are available, these drugs may introduce a paradigm shift in the management of people with high LDL and high risk for CVD.