Many recent approvals, upcoming trials for lipid-lowering therapies
Click Here to Manage Email Alerts
In an update on FDA approvals and late-breaking trials in lipid therapies, a speaker reviewed the current and future landscapes of LDL- and triglyceride-lowering therapies.
During a presentation at the Cardiometabolic Health Congress, 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, shone a spotlight on the recent FDA approval and late-breaking clinical research in the area of lipids and atherosclerotic CVD prevention.
As Healio previously reported, in February, the FDA approved evinacumab (Evkeeza, Regeneron) for the treatment of patients aged 12 years or older with homozygous familial hypercholesterolemia as an adjunct to other lipid-lowering therapies.
According to the presentation, evinacumab neutralizes angiopoietin-like 3, an inhibitor of lipoprotein lipase, with the effect of reducing triglycerides and LDL.
The approval was based on the top-line results of the ELIPSE HoFH phase 3 trial, which showed that evinacumab reduced LDL by 49% in patients with HoFH who were also taking other medications.
“It was really surprising to me, the results of this trial,” Ballantyne said during the presentation. “It's really a novel mechanism of action. Although the FDA indication is for people with homozygous FH, it has also been shown to work in people who have refractory hypercholesterolemia. These are people with FH who were unable to be treated successfully, and it has a similar benefit in that population.”
According to data published in The New England Journal of Medicine, a once-monthly infusion of evinacumab reduced LDL by more than 50% compared with placebo in patients with refractory hypercholesterolemia.
Ballantyne also cited a phase 2 trial presented at the 2021 American College of Cardiology Scientific Sessions, in which researchers evaluated the effects of evinacumab in patients with severe hypertriglyceridemia, at least one hospitalization for acute pancreatitis and multifactorial chylomicronemia syndrome with heterozygous loss-of-function mutations in APOA5, APOC2, GPIHBP1, LMF1, or LPL and patients with no lipoprotein lipase pathway mutations.
As Healio previously reported, the median reduction in triglycerides from baseline to 12 weeks was 68.8%.
In addition, the European Medicines Agency approved the inclisiran (Novartis), a small interfering RNA inhibiting PCSK9, in June 2021 for LDL lowering; however, FDA approval is still pending.
According to the presentation, inclisiran is indicated for adults with primary hypercholesterolemia or mixed dyslipidemia, as an adjunct to diet, with a recommended dose of 284 mg administered as a single subcutaneous injection, initially, again at 3 months and subsequently every 6 months.
“First, we had the fully human monoclonals, that's what ANGPTL3 is, and now this is a small interfering RNA,” Ballantyne said during the presentation. “Everybody in this room have probably got the mRNA vaccines that work by overproduction, where here, you’re silencing ... you knocked down the levels of PCSK9. The unique thing here is you receive an initial injection, a 3-month injection and then an injection every 6 months, and it reduces LDL by 50%.”
Next, Ballantyne discussed alirocumab (Praluent, Sanofi/Regeneron), a PCSK9 inhibitor that is a monoclonal antibody, that gained an expanded indication in April 2021 as an add-on therapy for adult patients with HoFH.
Alirocumab is given by subcutaneous injection as frequently as every 2 weeks.
As Healio previously reported, alirocumab injection conferred an average relative LDL reduction of 35.6% at 12 weeks compared with placebo. The average absolute reduction in LDL was 62.8 mg/dL in the alirocumab group.
“Alirocumab is also approved for pediatric usage in homozygous FH and heterozygous FH in ages 10 and up,” Ballantyne said during the presentation. “We want to start treating earlier in children who have severe heterozygous and homozygous FH, and they've allowed the dosing to go up to 420 mg every 2 weeks, if needed.”
Ballantyne also mentioned the RESCUE trial that evaluated the effects of ziltivekimab (Novo Nordisk), a novel interleukin-6 ligand inhibitor, on inflammation in patients with moderate to severe chronic kidney disease and high sensitivity C-reactive protein of 2 mg/L or more.
As Healio previously reported, ziltivekimab improved multiple inflammatory and thrombotic biomarkers associated with atherosclerosis.
In addition, researchers have initiated the large-scale ZEUS trial that will evaluate the effects of ziltivekimab in patients with CVD, chronic kidney disease and inflammation compared with placebo, with a follow-up of approximately 4 years; the trial is scheduled to be completed in late 2025.
“There are a lot of outcomes trials in progress,” Ballantyne said. “We didn't have any big ones this year, but we're having some coming up soon.”
Ballantyne said the following in-progress outcomes trials of new lipid therapies are of interest:
- the PROMINENT trial of pemafibrate (Kowa);
- the VESALIUS-CV trial of evolocumab (Repatha, Amgen);
- the CLEAR Outcomes trial of bempedoic acid (Nexletol, Esperion Therapeutics);
- the ORION-4 trial of inclisiran; and
- the HORIZON trial of pelacarsen (Ionis/Akcea/Novartis).
References:
- FDA approves add-on therapy for patients with genetic form of severely high cholesterol. www.fda.gov/drugs/news-events-human-drugs/fda-approves-add-therapy-patients-genetic-form-severely-high-cholesterol. Published on Apr. 4, 2021. Accessed on Apr. 4, 2021.
- FDA Approves First-in-class Evkeeza (evinacumab-dgnb) for Patients with Ultra-rare Inherited Form of High Cholesterol. www.prnewswire.com/news-releases/fda-approves-first-in-class-evkeeza-evinacumab-dgnb-for-patients-with-ultra-rare-inherited-form-of-high-cholesterol-301227183.html. Published on Feb. 11, 2021. Accessed on Oct. 15, 2021.
- Ridker PM, et al. Lancet. 2021;doi:10.1016/S0140-6736(21)00520-1.
- Rosenson RS, et al. N Engl J Med. 2020;doi:10.1056/NEJMoa2031049.
- Rosenson RS, et al. Joint American College of Cardiology/Journal of the American Medical Association Late-Breaking Clinical Trials. Presented at: American College of Cardiology Scientific Session; May 15-17, 2021 (virtual meeting).
Collapse
Ballantyne CM. FDA Update and Keynote. Presented at: Cardiometabolic Health Congress; Oct. 14-17, 2021; National Harbor, Md. (hybrid meeting).
Read more about
Click Here to Manage Email Alerts