RNA-targeted therapeutics in cardiovascular disease: the time is now

Abstract

Ribonucleic acid (RNA)-targeted therapeutics, including antisense oligonucleotide technologies as well as small interfering RNAs (siRNAs), represent a new class of medications that may overcome several of the disadvantages of small molecule drugs or monoclonal antibodies. Specifically, upstream targeting at the messenger RNA (mRNA) level renders any disease-related protein a potential target, even those pathways previously deemed ‘undruggable’. Additional advantages include the comparably simple and cost-effective way of manufacturing and the long dosing intervals. A few agents are already approved and a wide array of cardiovascular drugs is in development, aimed at hypercholesterolaemia, hypertension, myocardial storage diseases, and the coagulation system. Here, we provide an update on the current status of RNA-targeted therapeutics in the cardiovascular arena.

RNA, SiRNA, Antisense oligonucleotides, Cardiovascular disease

Introduction

Most cardiovascular drugs are small molecules that can be taken orally and cross cell membranes to have their effects. In recent years, therapeutic antibodies have been approved for cardiovascular diseases (CVD), including those targeting proprotein convertase subtilisin/kexin type-9 (PCSK-9) and one targeting angiopoetin-like 3 (ANGPTL3) for selected patients with lipid disorders. However, costs and efforts associated with antibody development and production and the need for frequent parenteral application are barriers to widespread use. Nucleic acid-based therapies targeting ribonucleic acid (RNA) represent a new approach that might overcome several of the aforementioned barriers.¹ The family of RNA-targeted therapeutics includes antisense oligonucleotide (ASO) technologies as well as RNA interference with the use of small interfering RNA (siRNA), a concept recognized with the Nobel Prize in Physiology or Medicine in 2006. Within the last decade, owing to substantial advances in various fields including RNA biology, bioinformatics, and nanotechnology, several major hurdles in the development and delivery of such drugs have been overcome. Several advantages render this new class of pharmaceuticals disruptive, including the comparably simple and cost-effective way of manufacturing, longer dosing intervals, and the ability to target and regulate any disease-related protein including pathways previously deemed ‘undruggable’. This major new class of drugs has the potential to revolutionize our approach to the prevention and treatment of CVD.

With some agents already approved in the United States and Europe and a wide array of drugs targeting various therapeutic areas currently in development, we believe the time is now to provide an update on RNA therapeutics in cardiovascular medicine. In doing so, we have decided to focus on four therapeutic areas with agents in various stages of development—lipid-lowering, renin-angiotensin-aldosterone system (RAAS) inhibition, antithrombotic therapy, and myocardial storage disease modification (see Table 1 for an overview of strategies and agents).

Table 1

Overview of current ribonucleic acid therapeutics development in four cardiovascular treatment areas

Disease	Target	Drug	Mechanism	Developmental status	Effects on target	Dose	Clinical effects	Ref.
Hypercholesterolaemia; heterozygous familial hypercholesterolaemia; ASCVD secondary prevention	PCSK9	Inclisiran	siRNA against PCSK9	Approval, ongoing cardiovascular outcome trial	LDL-C reduction by 50%	284 mg day 0, day 90 followed by twice yearly	tbd	6
ASCVD secondary prevention with Lp(a) elevation	Apolipoprotein(a)	Pelacarsen	ASO against LPA mRNA	Ongoing Phase III trial (NCT04023552)	Dose-dependent up to 80% reduction in Lp(a)	80 mg once monthly	tbd	7
ASCVD secondary prevention with Lp(a) elevation	Apolipoprotein(a)	Olpasiran	GalNAc-conjugated siRNA against LPA	Phase I(NCT04987320) Phase II (NCT04270760)	71–97% reduction	tbd	tbd	8
ASCVD secondary prevention with Lp(a) elevation	Apolipoprotein(a)	SLN360	GalNAc-conjugated siRNA against LPA	Phase I	Dose-dependent reduction up to 98%	tbd	tbd	9
Therapeutic anticoagulation	Factor XI	IONIS-FXIRx	ASO against factor XI	Phase II, novel, refined agent in development (IONIS-FXLRx; Fesomersen	60–78% reduction in FXI activity	200–300 mg 2x/week followed by once a week	Reduction in post-operative deep vein thrombosis incidence	18
Therapeutic anticoagulation	Factor XI	Fesomersen (IONIS-FXI-LRx, FXI-LICA, BAY2976217)	GalNAc-conjugated ASO	Phase II in ESRD ongoing (NCT04534114)	ongoing	40–120mg	ongoing
TTR amyloidosis	TTR	Patisiran	siRNA against TTR	Approved, Phase III results available, specific TTR-CM trial ongoing (NCT04153149	80–90% reduction of serum TTR	0.3 mg/kgBW every 3 weeks	Reduced LV wall thickness, NT-proBNP, trend to MACE reduction	13
TTR amyloidosis	TTR	Vutrisiran	GalNAc-conjugated siRNA against TTR	Phase III trials ongoing (NCT04153149)	Dose depended TTR reduction up to > 95%	25 mg every 3 months	ongoing	14
TTR amyloidosis	TTR	Inotersen	2′-O-methoxyethyl-modified ASO inhibitor	Phase III in TTR neuropathy patients completed, phase II TTR-CM trial underway (NCT03702829)	Up to -80%	300 mg s.c./week	No effect on echocardiographic parameters	15
TTR amyloidosis	TTR	Eplontersen	GalNAc-ASO	Phase II (NCT04843020) and Phase III (NCT04136171) trials currently running	Dose depended reduction up to > 90% reduction of serum TTR	45 mg every 4 weeks	ongoing	16
Hypertension	Angiotensinogen	Zilebesiran	siRNA (s.c.) against angiotensinogen	Phase I completed, in Phase II (NCT05103332; NCT04936035)	>90% reduction in angiotensin at week 24.	Tbd every 3–6 months	SBP reduction > 20 mmHg over 24 weeks	20

Principles of RNA-targeted therapeutics

Small molecule drugs typically require a target receptor or enzyme to exhibit an effect on a certain pathway. Proteins or pathways lacking such a target, one example that will be elucidated in more detail later in this manuscript is Lipoprotein(a) [lp(a)],² were therefore deemed ‘undruggable’ by conventional small molecules. Targeted monoclonal antibody-based drugs can overcome some of the aforementioned limitations but are generally limited to secreted proteins or extracellular domains of cell surface receptors and abundant proteins can require large amounts of antibodies. In addition, manufacturing is complex and expensive.

Messenger RNAs (mRNA) are single-stranded RNA molecules, transcripted from the gene in question and used by ribosomes as a blueprint to assemble proteins. Synthesized mRNA can be used for vaccination (as for SARS-CoV-2) and potentially as a protein replacement therapy.¹ RNA-targeted therapies use ASOs or siRNAs to promote degradation of specific mRNAs and/or prevent their translation to the target protein. ASOs consist of a short single-stranded deoxyribonucleotide complementary to the target mRNA that binds to the target mRNA, leading to recognition by the endonuclease ribonuclease H (RNaseH) and cleavage and reduced protein translation.² SiRNAs are short double-stranded RNA pieces, consisting of a guide strand complementary to the target mRNA and a passenger strand. After dissociating from the passenger strand, the guide strand interacts with the RNA-induced silencing complex (RISC) leading to the cleavage of the target mRNA. As the guide strand remains in the RISC it can continue to degrade further mRNAs, as shown in Figure 1, in part explaining the long-lasting effects of therapeutic siRNAs.

Figure 1

Mechanisms of action of novel ribonucleic acid based therapeutics. Ribonucleic acid therapeutics based on small interfering RNA or antisense oligonucleotide technologies aim to prevent target protein translation by degrading messenger RNA after transcription from the target gene before protein translation. Several recent advancements facilitated target cell-specific entry. One example widely used for compounds in the cardiovascular arena shown here is N-Acetylgalactosamine -conjugation designed for hepatocyte-specific uptake via asialoglycoprotein receptor. Once within the cytoplasm, the double-stranded small interfering RNA disintegrates, the passenger strand is being dismantled. The guide strand is loaded on the RNA induced silencing complex and complementarily binds the target messenger RNA causing degradation of the messenger RNA thus hindering protein assembly. The RNA induced silencing complex-guide strand complex can continue binding and degrading target messenger RNA, which in part explains the long-lasting effects of therapeutic small interfering RNAs. Single-strand antisense oligonucleotides may bind to the messenger RNA in the nucleus causing ribonuclease H1 mediated messenger RNA degradation. Both mechanisms (small interfering RNA and antisense oligonucleotide) ultimately cause messenger RNA degradation which consequently prohibits target protein translation and assembly. RNA, ribonucleic acid; mRNA, messenger RNA; siRNA, small interfering RNA; ASO, antisense oligonucleotide; ASGPR, asialoglycoprotein receptor; GalNAc, N-Acetylgalactosamine; RISC, RNA induced silencing complex; RNASE H1, ribonuclease H1.

In their basic form, ASOs and siRNAs are prone to nuclease degradation and are not target-cell specific. One solution is to complex the oligonucleotides with nanoparticles of polymer or lipid-based formulations. Another approach is to conjugate the nucleic acid agents with ligands facilitating cell-specific entry. One example is N-acetylgalactosamine (GalNAc)-conjugation that ensures a strictly hepatocyte-specific uptake via the hepatocyte asialoglycoprotein receptor (ASGPR). This has become a standard approach and is now being used in most nucleic acid therapeutics targeted to the liver, allowing for lower doses with same efficacy and potentially fewer side effects. The long-lasting effects of siRNAs that result in mRNA knockdown sustained for several months may be a limitation. Novel developments such as reverse siRNA silencing using short, synthetic, high-affinity oligonucleotides complementary to the siRNA guide strand may enable better modulation of the effects of siRNA drugs.³ Further, we aim to summarize current developments with RNA-targeted therapeutics in four distinct cardiovascular areas.

Lipid disorders

Homozygous familial hypercholesterolaemia causes very severely elevated low-density lipoprotein-cholesterol (LDL-C) and markedly premature atherosclerotic CVD (ASCVD). Apolipoprotien B1-100 (ApoB-100) is the primary protein in LDL and is produced by the liver. Mipomersen, an ASO targeting hepatic apolipoprotein-B-100 mRNA, reduces apoB-100 secretion translating into LDL-C reduction of around 25%. Adverse effects on the liver include increased transaminases and hepatic fat. Mipomersen was approved by the Food and Drug Administration (FDA) in 2013 for the orphan indication of familiar hypercholesterolaemia.⁴ It was the first nucleic acid therapy approved for systemic administration and was an important addition to the armamentarium for the treatment of homozygous familiar hypercholesterolaemia.

Current European guidelines suggest a target LDL-C goal of < 55 mg/dL and at least a 50% reduction from baseline levels in patients with atherosclerotic disease. A portion of patients will need additional treatments besides high-intensity statin and ezetimibe to reach their target goal. Antibody-based inhibitors of PCSK9, a serine protease involved in LDL-receptor degradation, have been shown to achieve a strong LDL-C reduction of ∼60% and a significant reduction in cardiovascular events. While effective medications, these antibodies require subcutaneous injection twice monthly. Inclisiran is a GalNAc-conjugated therapeutic siRNA targeting PCSK9, with pharmacodynamics that supports twice-yearly dosing. Within the phase III ORION program, inclisiran was tested in patients with heterozygous familial hypercholesterolaemia⁵ and with ASCVD or high risk for ASCVD.⁶ Treatment with inclisiran lowered LDL-C levels by ∼50% and no serious hepatic toxicity or other serious adverse events were noted.

Inclisiran was recently approved by both the European Medicines Agency (EMA) and the FDA based on LDL-lowering effects. The phase III cardiovascular outcomes trials are ongoing. ORION-4 is testing inclisiran vs. placebo in 15 000 patients with established ASCVD (NCT03705234). Inclusion criteria comprise an age of 55 years or older and history of a prior myocardial infarction, a prior ischemic stroke, or established peripheral artery disease with prior revascularization or aneurysm surgery. No LDL-C threshold is necessary for inclusion, contrary to the two PCSK9 antibody trials. The primary outcome that will be evaluated after a follow-up time of around 5 years is a composite of coronary heart disease death, myocardial infarction, fatal or nonfatal ischemic stroke, or urgent coronary revascularization. The VICTORION-2 PREVENT plans to randomize 15 000 patients with established ASCVD and a fasting LDL-C of above 70 mg/dL on stable lipid lowering therapy that must include a high intensity statin therapy (NCT05030428). Patients will be randomized to placebo or inclisiran therapy, the primary outcome is time to a composite 3-point major adverse cardiovascular event (MACE). Based on every six-month dosing, and especially if the cardiovascular outcome trials (CVOTs) prove efficacy in reducing CV events with adequate safety, inclisiran has the potential to transform LDL-lowering treatment for prevention of CV events.

Lp(a) is a lipoprotein related to LDL that is an independent causal risk factor for the development of ASCVD and aortic stenosis. Lp(a) is produced by the liver where apolipoprotein(a) is covalently bound to apolipoprotein-B-100 of an LDL-C particle. Levels of Lp(a) are highly genetically determined. Epidemiological studies have consistently shown that elevated Lp(a) is associated with ASCVD and aortic stenosis, and genetic causal inference strongly indicates that this association is causal. No specific Lp(a)-lowering treatments are currently available.² PCSK9 inhibition reduces Lp(a) levels modestly, while apheresis reduces Lp(a) substantially, but transiently. Lack of a known physiologic role for apolipoprotein(a) and specific inhibition of apolipoprotein(a) protein synthesis in the liver without affecting LDL-C assembly represents an ideal strategy. Pelacarsen is a GalNAc-conjugated ASO that was recently tested in a dose-finding study in patients with established cardiovascular disease and Lp(a) levels > 60 mg/dL (150 nmol/L).⁷ Treatment appeared to be safe and inhibition of apolipoprotein(a) translation was associated with a Lp(a)-reduction of up to 80%. The phase III Lp(a) HORIZON trial tests the effects of pelacarsen treatment (80 mg once a month) in nearly 8,000 patients with established ASCVD on the occurrence of a 4-point MACE endpoint (NCT04023552). Follow-up will be conducted for 4 years and first results are expected in 2024. Olpasiran is a GalNAc-conjugated siRNA targeted at LPA mRNA translation in hepatocytes. In a phase I study, treatment with olpasiran reduced Lp(a) levels by 71–97% with effects persisting for several months.⁸ A phase II dose-finding study including 290 patients is currently underway (NCT04270760). SLN360, yet another GalNAc-conjugated siRNA targeting LPA mRNA, was well tolerated in a phase I study and dose-dependently lowered plasma Lp(a) concentrations by up to 98%, an effect that persisted for at least 150 days after administration.⁹

ANGPTL3, synthesized and secreted by the liver, is an inhibitor of lipoprotein lipase (LPL) and endothelial lipase (EL) and genetic reduction in ANGPTL3 in humans reduces triglycerides (TGs), LDL-C, and high-density lipoprotein-cholesterol (HDL-C). An antibody to ANGPTL3, evinacumab, is approved for LDL-lowering in patients with homozygous familial hypercholesterolaemia. ANGPTL3 is also a target for nucleic acid-based therapeutics. Vupanorsen, an ASO targeting ANGPTL2, dose-dependently reduced non-high-density lipoprotein levels in patients with dyslipidemia in phase II TRANSLATE-TIMI-70 trial.¹⁰ However, there were observed increases in liver transaminases and liver fat, leading to a pause in development and raising questions about this approach. A siRNA targeted to ANGPTL3 is also in clinical development and these studies will help to address whether the liver observations with vupanorsen are related to ANGPTL3 targeting or is somehow off-target.

Apolipoprotein CIII represents an important regulator of TG metabolism which also inhibits lipoprotein lipase. Importantly, loss-of-function mutations were associated with lower TG levels and a lower risk of atherosclerotic disease. Volanesorsen and its GalNAc-conjugated successor olezarsen are ASOs, and ARO-APOC3 is a siRNA targeting apolipoprotein CIII that has been shown to reduce plasma TG levels. For a more detailed overview of the rapidly expanding field of RNA-targeted therapeutics for lowering TG-rich lipoproteins, we refer the readers to the review by Rosenson et al.¹¹

Transthyretin-mediated cardiac amyloidosis

In hereditary transthyretin-mediated (hATTR) amyloidosis, a variant in the TTR gene causes misfolding of the circulating TTR protein and generation of monomeric TTR which then accumulates as amyloid fibrils in several tissues, including the nervous system, the kidneys, the gastrointestinal system, and the heart. Cardiac accumulation causes amyloid cardiomyopathy characterized by left ventricular wall thickening, ventricular stiffening as well as diastolic and systolic dysfunction.¹² One therapeutic approach is tafamidis, a small molecule drug that stabilizes the TTR protein and has been shown to reduce heart failure hospitalizations and mortality and improve quality of life. Because TTR is made and secreted by the liver, nucleic acid therapeutics targeting the TTR mRNA are highly attractive.¹²

Patisiran is a siRNA to TTR formulated as a lipid nanoparticle and administered intravenously to ensure efficient delivery to the liver, where it blocks the production of both wild-type and mutant TTR protein and dose-dependently reduces TTR protein in circulation.¹³ Patisiran was the first siRNA-based drug that was approved by the FDA. Within the phase III APOLLO trial, 225 patients with hereditary TTR amyloidosis were randomized in a 2:1 fashion to treatment with patisiran or placebo. Treatment with patisiran significantly improved hTTR-amyloidotic neuropathy. In a prespecified subpopulation with evidence of cardiac amyloidosis, treatment with patisiran over 18 months reduced NT-proBNP levels and decreased left ventricular wall thickness and global longitudinal strain.¹³ Exposure-adjusted rates of cardiac hospitalizations and all-cause death were numerically reduced by 46% (HT 0.54 95% CI 0.28–1.01). These results suggest that Patisiran treatment may not only stop disease progression but partly reverse the cardiac phenotype. The phase III APOLLO-B trial is evaluating the effect of patisiran in 360 patients with TTR-cardiomyopathy (TTR-CM). Another siRNA targeting TTR, vutrisiran, is conjugated to GalNAc and thus administered subcutaneously.¹⁴ The HELIOS study program of vutrisiran consists of two-phase III trials including patients with TTR-neuropathy and TTR-CM. Specifically, HELIOS-B tests the effects of vutrisiran treatment on major adverse cardiovascular events in 655 patients with TTR-CM (NCT04153149). Enrolment is completed and results are awaited for early 2024.

Inotersen is an unconjugated ASO to TTR that effectively reduces circulating TTR. It was approved in 2018 by the FDA and the EMA for the treatment of TTR-neuropathy at a dose of 248 mg subcutaneously once a week, based on the results of the NEURO-TTR trial.¹⁵ In a subanalysis, no difference in global longitudinal strain and other echocardiographic variables was observed in patients with TTR-CM. An ongoing phase II trial evaluates the tolerability and efficacy of inotersen in TTR-CM patients (NCT03702829). Eplontersen is an ASO with a similar sequence as inotersen, but is conjugated to GalNAc to facilitate liver-specific uptake. This specific formulation makes eplontersen approximately 50-fold more potent in reducing TTR expression.¹⁶ A small phase II trial in patients with TTR-CM (NCT04843020) that have completed 2 years in another inotersen trial (NCT037028289) for TTR-CM is underway. In addition, a phase III trial planning to include 750 patients with TTR-CM (CARDIO-TTRansform, NCT04136171) is currently in the recruitment stage. Treatment with eplontersen will be compared with a placebo, with a composite of cardiovascular mortality and recurrent cardiovascular events as the primary outcome assessed. Importantly, no hepatic safety issues associated with RNA therapeutics targeting TTR have been reported thus far.

Therapeutic anticoagulation

Direct-acting oral anticoagulants are now the dominant form of oral anticoagulation, related to safety, efficacy, and ease of use. Still, further reduction in bleeding risk while maintaining effective anticoagulation remains an important objective, especially in high-risk populations. The coagulation factor XI has a dual role by inhibiting fibrinolysis and participating in thrombin generation. Patients with severe factor XI deficiency are characterized by a reduced incidence of thrombotic events and only rare spontaneous bleeding events.¹⁷ Experimental models of factor XI inhibition suggest beneficial anti-thrombotic effects with minimal increase in bleeding. FXI-ASO (ISIS 416858, BAY2306001, IONIS-FXI_Rx) is a second-generation antisense ASO specifically targeting factor XI mRNA in the liver. In a phase II trial, 300 patients undergoing knee arthroplasty were randomized to FXI ASO at one of two doses or enoxaparin 40 mg once daily.¹⁸ Treatment with the two doses of FXI ASO effectively reduced factor XI levels and was superior (300 mg) or non-inferior (200 mg) to enoxaparin with respect to the incidence of the primary outcome of venous thromboembolism. Importantly, treatment with FXI ASO appeared to be safe and did not increase bleeding events. Patients with end-stage renal disease (ESRD) are at heightened risk for both ischemic and bleeding events and most anticoagulants are not approved for this patient cohort. In a phase II study, IONIS-FXI_Rx reduced factor XI activity and reduced clotting in the dialyzer in patients on haemodialysis without increasing bleeding events.¹⁹ Another, larger (n = 213) trial evaluating three different doses of IONIS-FXI_Rx in patients on haemodialysis is completed (EMERALD; NCT03358030). Fesomersen (IONIS-FXI-L_Rx, FXI-LICA, BAY2976217) is a second-generation GalNAc-conjugated chimeric antisense oligonucleotide facilitating effective and specific hepatic uptake. The RE-THINc ESRD trial is a phase II trial aiming to randomize 305 patients with end-stage renal disease on haemodialysis to one of three doses of fesomersen or placebo (NCT04534114), with the primary outcome measure of major and clinically-relevant non-major bleeding. If successful, RNA therapeutics could fill an important gap in this high-risk population.

Hypertension

Hypertension is a major risk factor for cardiovascular diseases and is the number one modifiable cause of preventable death in the world. Despite the ready availability of various types of inexpensive antihypertensive drugs, many patients, even in the context of established cardiovascular disease, do not achieve normotension. Patient adherence to once or twice daily intake drugs remains a challenge, thus, novel approaches to blood pressure lowering are warranted high priority to improve world health. Several potent antihypertensive drugs interfere with the renin-angiotensin-aldosteron system (RAAS) as a mechanism of action. Zilebesiran (ALN-AGT) is a subcutaneously applied siRNA therapeutic targeted at hepatic angiotensinogen synthesis, the most upstream precursor in the RAAS. Interim findings from the ongoing phase I study in hypertensive patients testing seven different doses vs. placebo are encouraging. A single dose of zilebesiran lowered serum angiotensin levels by >90%, an effect that was sustained for 24 weeks in the highest dose. The higher dose resulted in a >20 mmHg reduction in 24-hour systolic blood pressure. Importantly, the achieved reduction in angiotensin levels correlated with blood pressure reductions.²⁰ Treatment was well tolerated and co-administration with irbesartan, an angiotensin-receptor blocker, appeared safe. The KARDIA-1 trial is a randomized double-blind dose-ranging phase II study evaluating the efficacy and safety of zilebesiran in patients with mild to moderate hypertension (NCT04936035). The study will recruit 375 participants, the primary endpoint is blood pressure change from baseline after three months of treatment (one dose of zilebesiran). In KARDIA-2, the efficacy and safety of zilebesiran on blood pressure in combination with the conventional antihypertensive medications olmesartan, amlodipine, or indapamide will be studied (NCT05103332). If successful, zilebesiran would provide a strongly needed alternative or add-on in the antihypertensive drug armamentarium, requiring only 2–4 injections a year. Large cardiovascular outcome trials are needed to rigorously assess the adverse effect profile, and the risk-benefit balance, especially in situations in which long-term RAAS-inhibition may be unfavorable, such as hypovolemia or hemodynamic impact of acute bleeding.

Conclusion and outlook

RNA-targeted nucleic acid therapeutics (ASOs, siRNAs) have the potential to disrupt the traditional approach to developing and applying drug treatments. Targeting mRNA renders nearly all disease targets druggable, novel techniques to RNA-based drug development are making it more affordable, targeting to the liver with high target and organ specificity has been enhanced by GalNac conjugation, and the ability to administer the treatment every few months may improve adherence, all of which address unmet needs. Other promising developments in the field of RNA-based therapeutics include the use or RNA aptamers or mRNA-based drugs or vaccines, the latter successfully applied in vaccinations against SARS-CoV-2. While this review address therapeutics targeting single genes, novel and broader understandings of the physiologic and pathophysiologic role of non-coding RNAs such as microRNAs will allow targeting of transcriptional networks in the future. Ultimately, gene therapy based on RNA interference and clustered regularly interspaced short palindromic repeats – cas 9 (CRISPR-Cas-9) genome editing with a broad array of potential therapeutic applications provides even greater potential.

The first RNA-targeted therapeutics in the cardiovascular field have been approved by regulatory agencies in Europe and the United States, which may be harbingers of a major shift in treating cardiovascular disease. Owing to advances in stability and delivery, more and more agents are currently being tested in clinical outcome trials. The results of these trials are eagerly awaited as the next step towards a potential revolution in cardiovascular therapeutics.

Funding

Austrian Academy of Sciences/Max Kade Foundation for Konstantin A. Krychtiuk.

Conflicts of interest: Konstantin A. Krychtiuk: advisory board activity for Novartis (2021).

Daniel J. Rader: serves on the Scientific Advisory Board for Alnylam, which makes small interfering RNA therapeutics, and for Novartis, which has licensed AKCEA-APO(a)-LRx. Consulting fees from Alnylam, Novartis, Verve, and Pfizer.

Chistopher B. Granger: Consulting fees Novartis, Alnylam and Bayer.

Data availability

As a review article, no new data were generated or analysed in support of this research.