PCSK9 Inhibitors: New Tools to Lower LDL Cholesterol

On the heels of the approval of alirocumab (Praluent), a first-in-class cholesterol-lowering medication marketed by Sanofi/Regeneron Pharmaceuticals, Amgen's evolocumab (Repatha) became the second treatment in its class to receive the green light from the FDA.

PCSK9 inhibitors

Praluent and Repatha both belong to a potent new class of low-density lipoprotein (LDL) cholesterol-lowering drugs known as proprotein convertase subtilisin kexin type 9 (PCSK9) inhibitors.

PCSK9 is a protein that inactivates receptors in the liver that remove LDL cholesterol from the blood. By inhibiting the activity of PCSK9, more receptors are available to rid the blood of LDL cholesterol, resulting in lower levels.

Who will receive PCSK9 inhibitors?

Let's face it; Praluent and Repatha are not going to replace atorvastatin and other statins anytime soon.

These new cholesterol-lowering drugs are not the answer for general hypercholesterolemia. Rather, they are intended for use in specific populations of patients with inherited conditions that elevate LDL cholesterol levels, those who cannot tolerate statins, and those with cardiovascular disease that require more than just statins. Patients will continue to be advised to quit smoking, exercise, and maintain a healthy diet.

Repatha, along with diet and maximally tolerated statin therapy, is approved for use in adult patients with inherited conditions that cause elevated LDL cholesterol levels: heterozygous familial hypercholesterolemia (HeFH) and homozygous familial hypercholesterolemia (HoFH). It is also approved for patients with clinical atherosclerotic cardiovascular disease, such as heart attacks or strokes, who require more than statin therapy to lower their LDL cholesterol.

Praluent was similarly approved for patients with cardiovascular disease and those with HeFH.

Both drugs are administered subcutaneously every 2 to 4 weeks. Although they are generally well-tolerated, reported side effects for both treatments include nasophyringitis, flu, itching, and injection site reactions. Serious allergic reactions have also been reported.

Repatha and Praluent do not appear to cause muscle-related adverse events that are associated with statin use. Ongoing studies will determine the drugs' long-term safety and cardiovascular outcomes.

HeFH and HoFH treatments are costly

For most patients, statins are effective at reducing cholesterol levels and cost just a few dollars a month. For about 1 in 5 patients, however, a statin doesn’t lower cholesterol enough.

For patients with HeFH or HoFH, statins and other potent drugs don't bring cholesterol levels down to optimum levels, even at maximum dosages. For some with HeFH or HoFH, the answer has been another treatment, known as apheresis, which requires the patient to go to a clinic and sit for hours while his or her blood flows into a machine that cleanses it of LDL cholesterol. Two weeks later, the LDL is back again, and the process must be repeated.

Apheresis isn't cheap. In fact, it costs about $8000 per month.

Praluent or Repatha may help these patients avoid these time-consuming trips to the clinic at a reduced price. But PCSK9 inhibitors aren't cheap, either.

Praluent is available in 2 doses, 75 mg and 150 mg. Both doses are available in a single 1 mL injection delivered in a single-dose prefilled pen or syringe that patients self-administer every 2 weeks. Both doses of the drug will be priced wholesale at $1120 for a 28-day supply, or roughly $14,560 a year.

Repatha injections are given as 140 mg every other week or as 420 mg once monthly. The wholesale cost of the drug will be $14,100 a year for the every other week injection.

While PCSK9 inhibitors are admittedly pricey, it is important to note that patients who have heart attacks or similar cardiovascular events run up costs estimated at $50,000 to $100,000 per year.

Will PCSK9 inhibitor therapy translate to fewer heart attacks, strokes, and deaths?

Despite many advances in treatment, cardiovascular disease remains the leading cause of death worldwide. Multiple clinical trials have demonstrated that statins lower the risk of heart attack or stroke.

While trials have shown that PCSK9 inhibitors are extremely powerful cholesterol-lowering agents—reducing LDL cholesterol by 50% to 70%, compared with 25% to 55% with statins—these studies haven't definitely proven that they prevent heart attacks or strokes.

Ongoing studies won't be completed for another 2 or 3 years, but early results provide evidence that heart attacks and strokes may be cut in half.

Pfizer is catching up

Phase 3 studies are currently underway for Pfizer's PCSK9 inhibitor bococizumab, with 22,000 patients enrolled globally. Bococizumab's FDA approval is not expected until sometime in 2017.