Novel therapies to know for ASCVD prevention in 2021 and beyond
Significant therapeutic advancements have been achieved in the management of dyslipidemia. The ability to decrease LDL to previously unattainable levels, owing largely to the development of PCSK9 monoclonal antibodies, has illuminated two important lessons.
No. 1, when it comes to LDL, data support a “lower is better” paradigm, with outcomes from FOURIER and ODYSSEY OUTCOMES showing progressive atherosclerotic CVD event reduction even at LDL levels well below 30 mg/dL. To that end, guidelines continue to encourage greater LDL reduction. For very high-risk patients, the 2018 Guideline on the Management of Blood Cholesterol from the American College of Cardiology, the American Heart Association and other societies recommends LDL less than 70 mg/dL, whereas the European Society of Cardiology advocates for less than 55 mg/dL and even less than 40 mg/dL in select patients.
No. 2, since residual ASCVD risk persists even at such low LDL levels, this highlights the need for earlier prevention, as well as the role played by other atherogenic culprits, such as triglycerides and lipoprotein(a), and the inflammatory cascade mediating plaque formation.
The need to meet lower LDL goals and address residual risk drive the demand for additional therapeutics. Here, we review novel agents entering the field of primary and secondary prevention addressing the following pathways: LDL, triglycerides, Lp(a), inflammation and obesity (Figure). For each, we review the mechanisms, trial data, safety profiles and current availability for clinical use. We conclude with a brief glimpse into the future of biotech therapies.
The first oral nonstatin to be approved for LDL reduction since 2002, bempedoic acid (Nexletol, Esperion Therapeutics) is a once-daily medication that impairs cholesterol synthesis upstream of 3-hydroxy-3-methyl-glutaryl-coenzyme A (HMG-CoA) reductase by inhibiting ATP citrate lyase. As bempedoic acid is a prodrug requiring activation by an enzyme exclusively found in hepatocytes, it is not active in skeletal muscle, and thus circumvents side effects causing statin-associated muscle symptoms.
Bempedoic acid has demonstrated safety and efficacy across several populations through the CLEAR trials: as monotherapy and combination therapy with ezetimibe among patients with statin-associated muscle symptoms (CLEAR Serenity: 21% LDL reduction with bempedoic acid; CLEAR Tranquility: 24% LDL reduction with bempedoic acid/ezetimibe), and as an add-on to guideline-directed statin therapy (CLEAR Harmony: 17% LDL reduction). These trials support the flexibility of bempedoic acid as an adjunct or alternative to front-line, oral LDL-reducing agents. Interestingly, a significant 25% reduction in high-sensitivity C-reactive protein was also observed with bempedoic acid use.
At least when studied in conjunction to statin therapy, bempedoic acid was associated with modest elevations in uric acid and incidence of gout as well as increased incidence of tendon rupture (0.5% of patients).
Bempedoic acid has been FDA-approved since February 2020 for patients with familial hypercholesterolemia (FH) or ASCVD already on statin therapy requiring additional LDL reduction. Approval as a stand-alone therapy will hinge on results from an ongoing outcomes study among patients with statin intolerance. In the interim, a combination bempedoic acid/ezetimibe pill (Nexlizet, Esperion Therapeutics) has been approved, offering an appealing option for patients needing additional LDL lowering with mean reductions of 40%. Although still a small market player, bempedoic acid experienced a 500% growth in prescriptions in its third quarter. In Europe, bempedoic acid is approved more broadly for management of dyslipidemia and as monotherapy in patients with statin-associated muscle symptoms
Inclisiran (Novartis) adds another item to the tally of small interfering RNA (siRNA) therapeutics that employ interfering RNA fragments to inhibit the production of proteins. Namely, inclisiran inhibits production of PCSK9 and, thus, operates upstream of PCSK9 inhibitors. One promising advantage is its appealing dosing regimen of just twice-yearly injections.
In the recently published ORION randomized trials evaluating the safety and efficacy of inclisiran, LDL reductions of 50% occurred among patients with and without ASCVD and on maximally tolerated statin therapy. Inclisiran use also achieved significant reductions in non-HDL, apolipoprotein B and Lp(a) on the order of 25%, comparable to reductions seen with PCSK9 inhibitors. The ongoing ORION-4 trial will investigate effects on clinical outcomes.
With respect to safety profile, only injection-related adverse events were more frequent in the inclisiran group and overall were mild and not persistent.
Inclisiran was approved in December for use in Europe. Approval in the U.S. has been delayed due to a pending manufacturing site inspection, with regulators citing inability to visit the factory due to COVID-19 travel restrictions. After inspection, inclisiran should be on track for FDA approval during the second quarter of 2021.
A monoclonal antibody to angiopoietin-like protein 3 (ANGPTL3), evinacumab-dgnb (Evkeeza, Regeneron) neutralizes ANGPTL3 to activate both lipoprotein and endothelial lipase, with the net effect being significant reductions in triglycerides and LDL.
Because it reduces LDL in a receptor-independent fashion, evinacumab-dgnb was first validated in the homozygous FH population, achieving a nearly 50% reduction in both LDL and triglycerides with once-monthly subcutaneous injections. Similar reductions occurred when evinacumab-dgnb was applied more broadly to patients with refractory hypercholesterolemia already on advanced agents. Evinacumab-dgnb was generally well tolerated with slightly higher incidence of injection site reactions, arthralgia/myalgia and urinary tract infections compared with placebo.
After a priority review, the FDA approved evinacumab-dgnb on Feb. 11 for use in patients with homozygous FH.
Evidence supporting the role for triglyceride reduction in CVD has been reinforced by the recent REDUCE-IT trial, demonstrating reduction in the composite outcome of death, nonfatal MI and stroke with icosapent ethyl (Vascepa, Amarin). Results from the EVAPORATE trial also illustrated very small but statistically significant reductions in low-attenuation plaque with use of icosapent ethyl. However, the benefits of icosapent ethyl appear to be greater than can be attributed to triglyceride-lowering alone.
Moreover, other omega-3 fatty acid therapies have failed, most notably a carboxylic acid formulation of omega-3 fatty acids (eicosapentaenoic acid and docosahexaenoic acid; Epanova, AstraZeneca) in the STRENGTH trial. Additional agents are in development offering further promise for potent triglyceride reduction.
Volanesorsen (Waylivra, Akcea) is an antisense oligonucleotide therapy interfering with translation of messenger RNA to protein, namely ApoC-III, which inhibits lipoprotein lipase. Volanesorsen has been most extensively studied in patients with familial chylomicronemia syndrome (FCS) who, due to defects or absence of lipoprotein lipase, have severely elevated triglycerides.
In the randomized APPROACH trial, volanesorsen administered every 1 to 2 weeks led to a 77% reduction in triglyceride levels among patients with FCS, with an absolute reduction of more than 1,700 mg/dL. Thrombocytopenia was observed more frequently with use of volanesorsen (33% of recipients), leading to withdrawal of some patients.
Volanesorsen was approved for use in Europe in May 2019 for patients with FCS. It was not approved by the FDA in 2018 due to concerns for aforementioned adverse events. However, with new safety data from the 2019 APPROACH trial, the manufacturer continues to work with the FDA to reconsider approval.
Historically, use of fibrates has been limited by occasional off-target effects causing hepatic and renal injury. Pemafibrate (Kowa) has emerged as a more selective and potent agonist of the peroxisome proliferator-activated receptor (PPAR)-alpha receptor, promising more significant triglyceride reduction and fewer off-target effects.
In a multicenter, randomized, placebo-controlled trial, twice-daily regimens of pemafibrate demonstrated superiority in triglyceride reduction compared with fenofibrate 100 mg daily and noninferiority to fenofibrate 200 mg daily, but better tolerated with fewer adverse events. Unlike fenofibrate, there was no worsening of liver or renal function with pemafibrate.
The PROMINENT trial investigating clinical outcomes, which will determine approval in Europe and the U.S., is currently underway and is projected to end in early 2022.
At present, few agents have been shown to meaningfully reduce Lp(a), which is increasingly appreciated as a risk factor for ASCVD and aortic stenosis. Biologic therapies are actively being developed that promise to reduce Lp(a) robustly.
In a phase 2 trial, AKCEA-APO(a)-LRx (Akcea/Ionis/Novartis), an antisense oligonucleotide therapy inhibiting production of ApoA, demonstrated Lp(a) reductions of 70% to 80% with monthly injections that were well tolerated and free of thrombocytopenia seen with other antisense oligonucleotide therapies. AMG 890 (Amgen) is another Lp(a) drug in development using a siRNA approach. Like inclisiran, the more stable siRNA configuration allows spacing of the dosing frequency to two to four times per year. A phase 3 clinical outcome trial is underway for AKCEA-APO(a)-LRx ending in 2024, and a phase 2 efficacy trial for AMG 890 is ending in 2023.
In addition to new lipid-lowering agents, the coming decade will see new applications of old anti-inflammatory therapies for primary and secondary prevention to temper the inflammatory process driving plaque formation.
The CANTOS trial applying canakinumab (Ilaris, Novartis), an interleukin-1-beta inhibitor, to patients with recent MI was the first to prove that anti-inflammatory therapies could reduce ASCVD events. Canakinumab produced a small but significant increase in fatal infections counterbalanced by a reduction in cancer deaths. The manufacturer is not pursuing marketing this agent for CV indications.
Colchicine has garnered increasing attention after the 2019 COLCOT trial demonstrated efficacy in patients who had MI less than 30 days before enrollment. Colchicine 0.5 mg daily was associated with a 22% relative reduction in ischemic events, driven primarily by reduction in stroke and hospitalizations for angina. Pneumonia was noted more frequently with colchicine, although the absolute difference (0.5%) was modest.
Recent data have also supported use of colchicine beyond the acute period in the management of chronic coronary disease, demonstrating a 30% relative risk reduction in CV events (composite of CV death, nonfatal MI, stroke or revascularization) among patients randomly assigned to colchicine 0.5 mg daily. A trend toward increased mortality from non-CV causes was observed with colchicine, but it was not significant. A widely available drug already used in clinical practice, colchicine’s role in ASCVD prevention is still unfolding.
When it comes to the reduction of both atherogenic lipids and inflammation, few interventions are as potent as weight loss. GLP-1 receptor agonists have demonstrated significant CV benefits for both primary and secondary prevention for patients with and without diabetes.
In a randomized trial recently published in The New England Journal of Medicine, once-weekly injection of semaglutide (Ozempic, Novo Nordisk) in those with BMI greater than 30 kg/m2 and without diabetes led to a 15% weight reduction (absolute loss of 34 lb) after 68 weeks. Those randomly assigned to lifestyle intervention alone experienced weight reductions of only 2% (absolute loss of 6 lb). Notably, more than 85% of participants assigned semaglutide achieved a weight reduction of 5% or more, the recognized threshold for clinically relevant reduction in body weight, compared with only 31% in the placebo group. Moreover, beneficial reductions were seen in waist circumference, lipid profile, HbA1c and hsCRP, emphasizing the diverse CV benefits of weight loss.
Semaglutide was generally well tolerated outside of nausea and diarrhea, with cases overall being mild and attenuated over time. Given these promising results, a priority review was submitted to the FDA in December for a weight-loss indication, with the decision expected by May 2021.
The next frontier: Biotechnology
In addition to biologic therapies, biotechnology offers promise to address refractory dyslipidemias. Here, we present two such promising therapies within the biotechnology space.
Reverse cholesterol transport: Pre-beta HDL
Pre-beta HDL is a lipid-depleted form of HDL with high efficacy in clearing cholesterol from lipid-laden macrophages. Although pre-beta HDL naturally exists at very low serum concentrations, a technology approved by the FDA in December, the plasma delipidation system (PDS-2, HDL Therapeutics), converts an individual’s native HDL into pre-beta HDL. Autologous transfusion of highly concentrated pre-beta HDL then mediates clearance of cholesterol from existing plaques.
The efficacy of this therapy was demonstrated in individuals with homozygous FH. A regimen of seven weekly transfusions significantly reduced the volume of plaques on coronary CTA by approximately 20%. Importantly, the change was driven primarily by reductions in low-density and necrotic plaques, which are most associated with future fatal and nonfatal MI.
CRISPR-Cas9 gene editing
CRISPR-Cas9 technology may fundamentally shift the treatment paradigm for inherited dyslipidemias such as FH. By correcting genetic errors within hepatocytes, CRISPR-Cas9 therapies would provide definitive “one and done” treatment, overcoming adherence issues that plague even the most convenient oral and injectable therapies.
CRISPR-Cas9 restores function in the LDL receptor among mice with a common FH mutation. Significant reductions occurred in plasma lipid levels with concomitant reductions in atheromatous plaque on gross specimens.
CRISPR technology can be used not only to rectify genetic errors, but to induce them. Verve Therapeutics has demonstrated safety and efficacy of CRISPR technology in macaques to cause defects in PCSK9 and ANGPTL3, leading to reductions in LDL and triglycerides of 60% to 90%.
The future of CRISPR therapies is subject to ongoing clinical trials examining their safety in humans. Trials will need to demonstrate limited off-target effects; the potential for CRISPR to cause unintended mutations is a significant concern for regulatory authorities. Clinical trials examining CRISPR knockout of PCSK9 and ANGPTL3 are planned to begin in 2023.
Advancements in CV health to come
2021 and the years ahead will see the arrival of a new suite of therapeutics employing a variety of mechanisms to address residual risk via reduction of LDL, triglycerides and Lp(a), inflammation and excess weight. We outlined the mechanisms, trial data, safety profiles and current clinical statuses of these novel agents, summarized in the Table. These agents promise to fuel advancements in CV health in the decades to come.
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For more information:
Michael Chilazi, MD, is an internal medicine resident at Johns Hopkins Medicine. Twitter: @mchilazi.
Garima Sharma, MD, is assistant professor of medicine at Johns Hopkins University School of Medicine. Twitter: @garimasharma.
Marios Arvanitis, MD, is a cardiovascular disease fellow at Johns Hopkins Medicine.
Thorsten Leucker, MD, PhD, is associate director of the cardiology fellowship program and assistant professor of medicine at Johns Hopkins University School of Medicine. Twitter: @tleucker.
Roger S. Blumenthal, MD, is director of the Johns Hopkins Ciccarone Center for the Prevention of Cardiovascular Disease and professor of medicine at Johns Hopkins University School of Medicine. He is also the editor of the Prevention section of the Cardiology Today Editorial Board. Twitter: @rblument1.
Seth S. Martin, MD, MHS, is director of the Johns Hopkins Ciccarone Center’s Advanced Lipid Disorders Program and associate professor of medicine at Johns Hopkins University School of Medicine. He is also a member of the Cardiology Today Editorial Board. Twitter: @sethshaymartin. The authors can be reached at Johns Hopkins Ciccarone Center for the Prevention of Cardiovascular Disease, Division of Cardiology, Johns Hopkins University School of Medicine, 600 N. Wolfe St., Halsted 560, Baltimore, MD 21827.