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An RNAi Therapeutic Inhibitor of PCSK9

N Engl J Med; 2017 Jan 5; Fitzgerald, et al

Publish date:

Doses of 300 mg or more of inclisiran significantly reduced levels of PCSK9 and low-density lipoprotein cholesterol (LDL-C) for at least 6 months with no serious adverse events, a recent study found. Healthy volunteers with an LDL-C level of at least 100 mg/dL were randomly assigned in a 3:1 ratio a subcutaneous injection of inclisiran or placebo in either a single-ascending dose phase, or a multiple-dose phase. Researchers found:

  • In the single-dose phase, inclisiran doses of 300 mg or more reduced the PCSK9 levels and doses of 100 mg or more reduced the LDL-C level.
  • Reductions in the levels of PCSK9 and LDL-C were maintained at day 180 for doses of 300 mg or more.
  • All multiple-dose regimens reduced the levels of PCSK9 and LDL-C.
  • There were no serious adverse events or discontinuations.

Citation:

Fitzgerald K, White S, Borodovsky A, et al. A highly durable RNAi therapeutic inhibitor of PCSK9. N Engl J Med. 2017;376:41-51. doi:10.1056/NEJMoa1609243.

Commentary:

Inclisiran represents a new class of cholesterol lowering medications that work by inhibiting PCSK9. PCSK9 is the enzyme that clears the LDL-C receptor from the liver. When PCSK9 is inhibited, the LDL-C receptor is cleared more slowly so there are more LDL-C receptors available to clear LDL-C from the circulation, and serum LDL-C decreases. This is the mechanism for inclisiran as well as for the recently approved PCSK9 inhibitors alirocumab (Praluent) and evolocumab (Repatha), which are monoclonal antibodies that target PCSK9. The difference is that inclisiran is not a monoclonal antibody, but rather from a new class of medication that targets RNA directly to silence the RNA of the target and stop the production of the PCSK9 enzyme before it is built. This class of medication has a long duration of action, 6-12 months, and is apparently much easier to manufacture than monoclonal antibodies.1 They are still far from prime time, but we can be certain that we will be hearing more about this new class of agents. —Neil Skolnik, MD

  1. Khvorava A. Oligonucleotide Therapeutics—A new class of cholesterol-lowering drugs. N Engl J Med. 2107; 376:4-6. doi:10.1056/NEJMp1614154.

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