Heart disease, linked to elevated levels of low-density lipoprotein cholesterol (LDL), is the leading cause of death worldwide, according to the World Health Organization. LDL-lowering statins haven’t been able to stem this tide. Now, a bevy of new drugs that target a protein called PCSK9 are being developed that promise to do what statins couldn’t, according to a feature article in Chemical & Engineering News, an independent news outlet of the American Chemical Society.
People with naturally occurring PCSK9 mutations have extremely low levels of LDL and a correspondingly low incidence of heart disease, writes freelance contributor Alla Katsnelson. Normally, this protein regulates degradation of LDL receptors on cells, so inhibiting it leaves more receptors available to clear LDL from the blood — and unlike statins, without obvious side effects. The first PCSK9 inhibitors, monoclonal antibodies called Repatha and Praluent, were approved by the U.S. Food and Drug Administration (FDA) back in 2015, but they weren’t embraced by patients because of their high cost and requirement for self-injection every 2 weeks. Now, PCSK9 inhibitors based on many types of biomolecules, from small interfering RNAs to peptides to gene therapies, are being developed that could cost less, act longer and, in some cases, be taken orally.
Some of these therapies are now reaching, or getting closer, to the market. On December 22, 2021, FDA approved Novartis’ Leqvio, a small interfering RNA therapy that blocks translation of the PCSK9 gene. Although the medication must be injected, it only needs to be given twice per year, and it reduces LDL levels by about 52%. Merck & Co.’s MK-0616, a peptide currently in phase 1 clinical trials, can be taken orally, and preliminary data shows that it lowers LDL by 65%. Even more ambitious is Verve Therapeutics’ Verve-101, a gene therapy that could, in principle, permanently lower LDL with just a single dose. In preclinical trials, one dose reduced LDL levels in monkeys by 60% for at least 8 months. The company plans to begin testing the therapy in humans later this year.
The article is freely available here.
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