$23 Billion Blockbuster?

The PCSK9 inhibitor buzz keeps rolling, especially since sitting before the FDA Advisory Committee earlier this month.  Amgen’s (Thousand Oaks, CA) Repatha and Sanofi’s (Paris, France) Praluent are a new class of cholesterol lowing drug looking to win final approvals by late summer. Both companies are pioneers in the realm of biologics (monoclonal antibodies) aimed at the heart.

Early use restrictions may limit prescriptions to patients with familial hypercholesterolemia—an inherited form of high cholesterol that can be resistant to current treatments. Doctor surveys suggest an interest in increasing access to a wider group of patients, leading some analysts to predict a $23 billion market for the drugs.

In this WEEKLY, we will suss out how PCSK9 inhibitors differ from their predecessor and what might be next in line for managing cholesterol.


The current standard of care for treating high cholesterol are small molecule drugs, called statins—think Lipitor (Pfizer, New York, NY) or Crestor (AstraZeneca, London, UK). These drugs work by inhibiting a liver enzyme called HMG-CoA reductase inhibitor, which plays a key role in the synthesis of cholesterol. Less enzyme, less cholesterol produced.

About 70% of the cholesterol in a typical person’s body is produced in the liver—which is why diet and exercise may not always control high cholesterol. While statins are easy to swallow and work well for many patients, they sometimes come with unwanted side effects, including muscle problems and an increased risk of diabetes.


Lipoproteins are divided into two categories: high-density lipoproteins (HDL) and low-density lipoproteins (LDL). A lipoprotein is a protein with fat molecules attached for use as a transport system. HDL is called good cholesterol because it transports the lipid component in a compact fashion without losing or dropping the fat molecule when traveling in the arteries. HDL can even scoop up and expunge the LDL, or bad cholesterol. LDL is more fluffy and detaches easily, wreaking havoc by oxidizing or subsequently attaching to arterial walls.

Mechanism Of Action: PCSK9

The body naturally keeps bad cholesterol in check with low-density lipoprotein (LDL) receptors. These receptors bind to excess LDL, which the liver cell absorbs. The liver breaks down the cholesterol and recycles the receptor back to the cell surface, where the LDL receptor can bind to and remove more LDL.

PCSK9 is a protein that also binds to the LDL receptor, which also triggers the liver cell to absorb the pair. However, the entire complex is degraded and the receptor is not recycled—sort of like a murder-suicide. This results in fewer LDL receptors, impeding the process of LDL removal.

Repatha and Praluent work by attaching to PCSK9, which prevents the protein’s interaction with low-density lipoprotein receptors on the surface of liver cells. By preventing the degradation of these critical receptors, PCSK9 inhibitors lower LDL levels and lessen the risk of a cardiovascular event. Clinical results report lowering of LDL levels by as much as 60%. One key advantage of the new PCSK9 inhibitors is their safety profile—in clinical trials, the adverse events observed were equivalent to that of the placebo.

On The Horizon

Therapeutic antibodies have a great track record for safety and efficacy and PCSK9 is a proven biologic target in the cholesterol-lowering landscape. On the flip side, antibodies have the liability of a very expensive production process which leads to higher prices for patients. Oh… and therapeutic antibodies are delivered via injection—which is not convenient when compared to swallowing a statin pill.

The development of a small molecule inhibitor of PCSK9 is a tantalizing proposition—and earlier this year, Pfizer announced they are doing just that, with clinical trials expected to begin in late 2015. Pfizer also has plans to develop a PCSK9 vaccine—essentially an annual injection that would stimulate the patient’s immune system to develop its own naturally occurring antibodies against PCSK9.

The outlook for treating high cholesterol is a little brighter. We at WEEKLY enjoy how the world of drug development always manages to have something else up it’s sleeve—in the form of a pill, an injection and even a potential vaccine.

Share This