NEW CLASS OF DRUGS: THERAPEUTIC RNAi INHIBITION OF PCSK9 AS A SPECIFIC LDL-C LOWERING THERAPY.

Area of Science:

• Cardiovascular Pharmacology
• Genetic Medicine

Background:

• Hyperlipidemia is a significant risk factor for coronary heart disease (CHD), the leading cause of mortality.
• Existing lipid-lowering treatments have limitations in efficacy.
• Novel pharmacological interventions targeting LDL cholesterol (LDL-C) are under development.

Purpose of the Study:

• To present a new class of LDL-C lowering drugs.
• To discuss investigational drugs in Phase II or III clinical trials.
• To highlight the potential of RNA interference (RNAi) targeting PCSK9.

Main Methods:

• Review of current and emerging lipid-lowering therapies.
• Focus on proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors.
• Discussion of monoclonal antibodies (mAbs) and RNAi-based therapies.

Main Results:

• PCSK9 inhibition enhances LDL clearance from plasma, reducing LDL-C levels.
• Three PCSK9 inhibitor monoclonal antibodies are in clinical outcome trials.
• ALN-PCSsc, an RNAi therapeutic, inhibits PCSK9 synthesis in the liver.

Conclusions:

• ALN-PCSsc represents a first-in-class RNAi therapeutic for lowering LDL-C.
• ALN-PCSsc has potential advantages over existing anti-PCSK9 monoclonal antibodies.
• Further clinical evaluation, including the ORION-1 Phase II study, is ongoing.