Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors

By Ph. Yasmeen Rafique

 

A new class of lipid lowering agents to be used as an adjunct to statins

 

PCSK9 is primarily synthesized, secreted and expressed in the liver, where it binds to LDLRs in the hepatocellular membrane to form a complex. The PCSK9/LDLR complex then enters the endosomal system where it is eventually degraded in the lysosomes, hence, preventing the transportation of LDLR to the cell surface. Therefore, increased levels of PCSK9 can inhibit LDLR recycling to the cell surface which in turn increases the low-density lipoprotein-cholesterol (LDL-C) levels in the blood. PCSK9 inhibitors, such as human IgG2 monoclonal antibodies (mAbs), target PCSK9 to prevent it from binding to the LDLR and hence result in increased LDLR expression, which eventually lead to increased hepatic uptake of LDL-C, reducing LDL-C levels in the blood.

 

Patients with familial hypercholesterolemia (FH) are sometimes unable to achieve normal LDL-C levels, even when they are treated with the maximum dose of statins mainly due to an increase in the transcription of PCSK9 upon using statins in these patients. Therefore, PCSK9 inhibitors are promising therapeutic targets for the treatment of FH and might improve the efficacy of statins in such patients. Three mAbs against PCSK9 have been developed. These include Alirocumab (REGN727/SAR236553) developed by Sano /Regeneron and marketed under the brand name Praluent, Evolocumab (AMG 145), developed by Amgen and marketed under the brand name Repatha as well as Bococizumab (RN316) developed by Pfizer and undergoing phase III clinical trials.

 

Alirocumab (Praluent)

 

Description

The first human monoclonal antibody against PCSK9 to be approved by the food and drug administration (FDA).

Indication

It is approved for use as an adjunct to diet and maximally tolerated statin therapy in adult patients with heterozygous familial hypercholesterolemia (HeFH) or patients with clinical atherosclerotic cardiovascular disease such as heart attacks or strokes, who require additional lowering of LDL-C.

Dosage

It is available in the form of a subcutaneous(sc) injection in the strength of 75 mg/ml as well as 150 mg/ml. The recommended starting dose is 75 mg every two weeks. If the LDL-C lowering response is inadequate, the dose may be increased to 150 mg every two weeks, which is also the maximum dose that can be administered.

 

Evolocumab (Repantha)

 

Description

The second drug approved by FDA under the class of PCSK9 inhibitors

Indication

Evolocumab (Repantha) is approved by FDA for the same indications as Alirocumab (Praluent). However, unlike Alirocumab (Praluent), Evolocumab (Repantha) is also indicated for homozygous familial hypercholesterolemia (HoFH) in addition to HeFH.

Dosage

It is available in the form of a sc injection in the strength of 140 mg/ml in a single use prefilled syringe as well as 420 mg/3.5ml in a single use Pushtronix system (on-body infusor with prefilled cartlidge). The recommended dose for HeFH is 140 mg every 2 weeks or 420 mg once a month while the recommended dose for HoFH is 420 mg once a month.

Dosage adjustment in renal or hepatic impairment

Both Alirocumab (Praluent) and Evolocumab (Repantha) do not require dosage adjustment in either mild to moderate renal or hepatic impairment. However, their safety in severe renal or hepatic impairment has not been studied yet.

Adverse effects

The most common side effects of both drugs include injection site reactions, such as itching, swelling, pain, or bruising, nasopharyngitis, upper respiratory tract infection, flu and back pain. Allergic reactions, such as rash and hives, have been reported. Patients should stop using these drugs and get medical help if they experience symptoms of a serious allergic reaction.

 

References