Future therapeutics may dramatically lower LDL
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LDL-lowering therapeutics have evolved since the introduction of bile acid sequestrants in 1973, and approaches in development may prove even more effective than those in the past and present, according to a speaker.
Today, research continues and PCSK9 inhibition via inclisiran (Novartis) and genetic editing may be on the horizon. During a presentation at the National Lipid Association Scientific Sessions, Mary P. McGowan, MD, FNLA, co-director of the lipid clinic at Dartmouth Hitchcock Medical Center and the chief medical officer of the FH Foundation, discussed the past, present and future LDL-lowering therapies.
“In 1987, statins came on the market with a huge splash and many people thought we would need nothing else ... they are the bedrock of how we treat people, but they're not everything,” McGowan said during the presentation. “We were grateful in 2002 when ezetimibe came on the market. Lipoprotein apheresis has been so important for patients with familial hypercholesterolemia or atherosclerotic CVD. Evolocumab and alirocumab coming on the market in 2015 had a slow start, but in my practice, we're using them more frequently and they're very important for people with difficult to treat dyslipidemia, familial hypercholesterolemia or ASCVD. Lomitapide and evinacumab offer therapies that don't require the LDL receptor for their efficacy and it's important for patients with the null receptors and homozygous FH. Bempedoic acid coming on the market in 2020 provides a new mechanism of action for LDL reduction.”
According to the presentation, the percentage of expected LDL lowering with these drugs are as follows:
- statin therapy (medium-to-high intensity), 35-55%;
- ezetimibe, 18-25%;
- bile acid sequestrant (Welchol, Daiichi Sankyo), 18-25%;
- PCSK9 inhibitors (evolocumab [Repatha, Amgen] and alirocumab [Praluent, Sanofi/Regeneron]), 40-65%;
- bempedoic acid (Nexletol, Esperion Therapeutics), 17-25%; and
- bempedoic acid plus ezetimibe (Nexlizet, Esperion Therapeutics), 38%.
Among patients with FH and ASCVD, lipoprotein apheresis can lower LDL by a time averaged 35% to 40%. In patients with homozygous FH, lomitapide (Juxtapid, Amryt) can lower LDL by 35% to 50% and evinacumab (Evkeeza, Regeneron) can lower LDL up to 49%, according to the presentation.
McGowan added that diet and exercise can also lower LDL by approximately 10% to 15% and is a good strategy to avoiding polypharmacy, as patients with elevated LDL may also be receiving therapies to improve other risk factors such as hypertension, diabetes, cigarette smoking and LP(a).
“When we think about statins, we tend to think about the high dose high-intensity statins, 40 or 80 mg of atorvastatin or 20 or 40 mg of rosuvastatin, and those are the doses we want to use in people with FH or ASCVD,” McGowan said. “But if somebody doesn't tolerate the highest dose, there is a role for the low intensity or the moderate intensity [statins]. You may need to add another agent, but almost all of the statins are generic at this point and very useful in our armamentarium, no matter what the dose.”
According to the presentation, “the future is bright for LDL reduction,” with inclisiran and CRISPR gene therapy for heterozygous FH currently in the pipeline.
According to McGowan, inclisiran is a PCSK9 inhibitor similar to alirocumab and evolocumab; however, it is a small interfering RNA that targets the production of PCSK9 protein. As a result of the “destruction” of the PCSK9 protein, there are more LDL receptors and LDL is more easily removed from the bloodstream, she said.
According to the presentation, CRISPR-CAS nucleases and CRISPR-based editors have the potential to permanently modify disease causing genes.
“This concept of a one-and-done infusion will take the gene for a particular protein, PCSK9 for example, and shut it off. Potentially, for life,” McGowan said.
In CRISPR version 1.0, the technology can go through an entire genome, like a GPS, according to McGowan, find the exact address for the gene and cut through it, thereby turning it off. According to the presentation, CRISPR version 2.0 uses base editing. It also locates the target gene, but replaces a single base letter, and turns it off.
In an animal study, published in Nature in May 2021, researchers described CRISPR base editing in non-human primates. According to the presentation, after a single infusion of lipid nanoparticles surrounded by PCSK9 messenger RNA, researchers observed a 90% reduction in PCSK9 and a 60% reduction in LDL.
Assuming regulatory approval, according to McGowan, the first-in-human studies of CRISPR base editing for PCSK9 and LDL reduction could begin in 2022. If that research is successful, it may benefit patients with homozygous FH, she said.
Reference:
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McGowan MP. Session I: Update on the Dyslipidemia Research Pipeline. Presented at: National Lipid Association Scientific Sessions; Sept. 24-26, 2021; Orlando, Fla. (hybrid meeting).
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