Novel agents targeting Lp(a), triglycerides spearhead ‘profound change in therapies’
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Much research is being conducted on novel therapeutics to reduce residual lipid-related risks, a speaker said at the National Lipid Association Scientific Sessions.
“It has never been a more exciting time to be in the field of lipids, in terms of what we can do for our patients now and, in particular, what’s coming down the pipeline,” Christie M. Ballantyne, MD, FNLA, professor of medicine, molecular and human genetics and molecular physiology and biophysics; director of the Maria and Alando J. Ballantyne, M.D. Atherosclerosis Clinical Research Laboratory; director of the Center for Cardiometabolic Disease Prevention; co-director of the Lipid Metabolism and Atherosclerosis Clinic; the J. S. Abercrombie Chair in Atherosclerosis and Lipoprotein Research; and chief of cardiology and cardiovascular research at Baylor College of Medicine, said during a presentation.
The LDL hypothesis really should be thought of as the atherogenic lipoprotein hypothesis, Ballantyne said.
“It is actually the lipoprotein species interacting with the arterial wall that are driving the process of atherosclerosis, and we measure LDL cholesterol as a surrogate,” he said. “It turns out that, in addition to LDL particles, there are other atherogenic particles” that contribute to atherosclerosis, he said.
One atherogenic particle, lipoprotein(a), is known to cause CVD. Current treatments include aspirin, statins, PCSK9 inhibitors and apheresis, Ballantyne said, noting that high-intensity statins can raise Lp(a).
Ballantyne said there are two therapies targeting Lp(a) in phase 2 or 3 development: pelacarsen (Akcea/Ionis), an antisense therapy, and olpasiran (Amgen), a small interfering RNA (siRNA) therapy.
“We are now in a profound change in therapies,” he said. “You may be familiar with the approach of monoclonal antibodies, but now we are in the realm of messenger RNA therapeutics. We are finally using therapies using biotechnology approaches that have undergone major improvements in targeting delivery to the liver, which is derived from research in cell biology. This is moving very rapidly now in terms of antisense and siRNA. These therapies … allow a big reduction in dose, and side effects tend to be dose-related. We are seeing agents with very high efficacy and also very good tolerability. This is a great option for your patients with very high Lp(a).”
Pelacarsen is being tested in the phase 3 Lp(a) HORIZON study, and a phase 2 study of olpasiran is being planned, he said.
There is also a lot of activity with triglyceride-lowering agents, Ballantyne said.
“Maybe the biggest change over the last 20 years has been our focus shifting from HDL cholesterol as a target of therapy to triglyceride-rich lipoproteins and triglycerides as a target of therapy,” he said. “We always had the epidemiological data, but what ended up happening was when adjusted for HDL cholesterol, [triglycerides] would drop out. The genetics were pivotal. If a genetic variant is associated with a higher level of LDL, there is an increased risk for cardiovascular events, and with a lower level of LDL, there is reduced risk for cardiovascular events. The same thing is true in triglycerides but not HDL.”
He noted, however, that some CV benefit may derive from the effect triglycerides and other lipoproteins have on each other. “When you change the triglycerides profoundly, you change all of the lipoprotein particles, not just VLDL particles or remnant particles,” he said.
Fibrates, niacin, omega-3 fatty acids, statins and ezetimibe all decrease triglycerides between 5% and 50%, Ballantyne said.
Nonetheless, he said, there are many other triglyceride-lowering agents in development, including pemafibrate (Kowa), a selective peroxisome proliferator-activated receptor-alpha modulator; evinacumab (Regeneron), a human monoclonal antibody to ANGPTL3; vupanorsen (Ionis/Akcea), an antisense to ANGPTL3; ARO-ANG3 (Arrowhead), a siRNA to ANGPTL3; AKCEA-APOCIII-LRX (Akcea), an antisense to apolipoprotein C-III; ARO-APOC3 (Arrowhead), a siRNA to apo C-III; and BIO89-100 (89 Biopharma), a fibroblast growth factor 21 agonist.
“The newer biotech approaches with monoclonal antibodies, antisense and siRNA have come about because of the genetic associations of the importance of these genes in triglyceride metabolism,” he said. “They are all in the lipoprotein lipase pathway.”
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Ballantyne CM. 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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