Updates in Small Interfering RNA for the Treatment of Dyslipidemias.

PURPOSE OF REVIEW: Atherosclerotic cardiovascular disease (ASCVD) is still the leading cause of death worldwide. Despite excellent pharmacological approaches, clinical registries consistently show that many people with dyslipidemia do not achieve optimal management, and many of them are treated with low-intensity lipid-lowering therapies. Beyond the well-known association between low-density lipoprotein cholesterol (LDL-C) and cardiovascular prevention, the atherogenicity of lipoprotein(a) and the impact of triglyceride (TG)-rich lipoproteins cannot be overlooked. Within this landscape, the use of RNA-based therapies can help the treatment of difficult to target lipid disorders. RECENT FINDINGS: The safety and efficacy of LDL-C lowering with the siRNA inclisiran has been documented in the open-label ORION-3 trial, with a follow-up of 4 years. While the outcome trial is pending, a pooled analysis of ORION-9, ORION-10, and ORION-11 has shown the potential of inclisiran to reduce composite major adverse cardiovascular events. Concerning lipoprotein(a), data of OCEAN(a)-DOSE trial with olpasiran show a dose-dependent drop in lipoprotein(a) levels with an optimal pharmacodynamic profile when administered every 12 weeks. Concerning TG lowering, although ARO-APOC3 and ARO-ANG3 are effective to lower apolipoprotein(apo)C-III and angiopoietin-like 3 (ANGPTL3) levels, these drugs are still in their infancy. In the era moving toward a personalized risk management, the use of siRNA represents a blossoming armamentarium to tackle dyslipidaemias for ASCVD risk reduction.

Novel Pharmacological Therapies for the Management of Hyperlipoproteinemia(a).

Lipoprotein(a) [Lp(a)] is a well-established risk factor for cardiovascular disease, predisposing to major cardiovascular events, including coronary heart disease, stroke, aortic valve calcification and abdominal aortic aneurysm. Lp(a) is differentiated from other lipoprotein molecules through apolipoprotein(a), which possesses atherogenic and antithrombolytic properties attributed to its structure. Lp(a) levels are mostly genetically predetermined and influenced by the size of LPA gene variants, with smaller isoforms resulting in a greater synthesis rate of apo(a) and, ultimately, elevated Lp(a) levels. As a result, serum Lp(a) levels may highly vary from extremely low to extremely high. Hyperlipoproteinemia(a) is defined as Lp(a) levels > 30 mg/dL in the US and >50 mg/dL in Europe. Because of its association with CVD, Lp(a) levels should be measured at least once a lifetime in adults. The ultimate goal is to identify individuals with increased risk of CVD and intervene accordingly. Traditional pharmacological interventions like niacin, statins, ezetimibe, aspirin, PCSK-9 inhibitors, mipomersen, estrogens and CETP inhibitors have not yet yielded satisfactory results. The mean Lp(a) reduction, if any, is barely 50% for all agents, with statins increasing Lp(a) levels, whereas a reduction of 80-90% appears to be required to achieve a significant decrease in major cardiovascular events. Novel RNA-interfering agents that specifically target hepatocytes are aimed in this direction. Pelacarsen is an antisense oligonucleotide, while olpasiran, LY3819469 and SLN360 are small interfering RNAs, all conjugated with a N-acetylgalactosamine molecule. Their ultimate objective is to genetically silence LPA, reduce apo(a) production and lower serum Lp(a) levels. Evidence thus so far demonstrates that monthly subcutaneous administration of a single dose yields optimal results with persisting substantial reductions in Lp(a) levels, potentially enhancing CVD risk reduction. The Lp(a) reduction achieved with novel RNA agents may exceed 95%. The results of ongoing and future clinical trials are eagerly anticipated, and it is hoped that guidelines for the tailored management of Lp(a) levels with these novel agents may not be far off.

Molecular Therapies in Cardiovascular Diseases: Small Interfering RNA in Atherosclerosis, Heart Failure, and Hypertension.

Small interfering RNA (siRNA) represents a novel, fascinating therapeutic strategy that allows for selective reduction in the production of a specific protein through RNA interference. In the cardiovascular (CV) field, several siRNAs have been developed in the last decade. Inclisiran has been shown to significantly reduce low-density lipoprotein cholesterol (LDL-C) circulating levels with a reassuring safety profile, also in older patients, by hampering proprotein convertase subtilisin/kexin type 9 (PCSK9) production. Olpasiran, directed against apolipoprotein(a) mRNA, prevents the assembly of lipoprotein(a) [Lp(a)] particles, a lipoprotein linked to an increased risk of ischemic CV disease and heart valve damage. Patisiran, binding transthyretin (TTR) mRNA, has demonstrated an ability to improve heart failure and polyneuropathy in patients with TTR amyloidosis, even in older patients with wild-type form. Zilebesiran, designed to reduce angiotensinogen secretion, significantly decreases systolic and diastolic blood pressure (BP). Thanks to their effectiveness, safety, and tolerability profile, and with a very low number of administrations in a year, thus overcoming adherence issues, these novel drugs are the leaders of a new era in molecular therapies for CV diseases.

Lp(a) in the Pathogenesis of Aortic Stenosis and Approach to Therapy with Antisense Oligonucleotides or Short Interfering RNA.

To date, no medical therapy can slow the progression of aortic stenosis. Fibrocalcific stenosis is the most frequent form in the general population and affects about 6% of the elderly population. Over the years, diagnosis has evolved thanks to echocardiography and computed tomography assessments. The application of artificial intelligence to electrocardiography could further implement early diagnosis. Patients with severe aortic stenosis, especially symptomatic patients, have valve repair as their only therapeutic option by surgical or percutaneous technique (TAVI). The discovery that the pathogenetic mechanism of aortic stenosis is similar to the atherosclerosis process has made it possible to evaluate the hypothesis of medical therapy for aortic stenosis. Several drugs have been tested to reduce low-density lipoprotein (LDL) and lipoprotein(a) (Lp(a)) levels, inflammation, and calcification. The Proprotein Convertase Subtilisin/Kexin type 9 inhibitors (PCSK9-i) could decrease the progression of aortic stenosis and the requirement for valve implantation. Great interest is related to circulating Lp(a) levels as causally linked to degenerative aortic stenosis. New therapies with ASO (antisense oligonucleotides) and siRNA (small interfering RNA) are currently being tested. Olpasiran and pelacarsen reduce circulating Lp(a) levels by 85-90%. Phase 3 studies are underway to evaluate the effect of these drugs on cardiovascular events (cardiovascular death, non-fatal myocardial injury, and non-fatal stroke) in patients with elevated Lp(a) and CVD (cardiovascular diseases). For instance, if a reduction in Lp(a) levels is associated with aortic stenosis prevention or progression, further prospective clinical trials are warranted to confirm this observation in this high-risk population.

Expanding therapeutic options: overview of novel pharmacotherapies for dyslipidemia.

INTRODUCTION: Dyslipidemia plays a crucial role in the development of atherosclerotic cardiovascular diseases. AREAS COVERED: This article explores the emerging therapeutic targets for the treatment of dyslipidemia and provides novel insights into this field. Thus, it aims to contribute to the understanding and advancement of therapeutic options for managing dyslipidemia. EXPERT OPINION: Optimizing the use of available first- and second-line lipid-lowering drugs allows us to adequately control low-density lipoprotein cholesterol (LDL-C) levels, even in statin-intolerant individuals and in patients at high and very high risk of developing cardiovascular diseases who must reach more aggressive LDL-C targets. The drugs under development will further improve our ability to manage the overall lipid-related cardiovascular disease risk and target other dyslipidemia biomarkers.

Early health technology assessment of gene silencing therapies for lowering lipoprotein(a) in the secondary prevention of coronary heart disease.

BACKGROUND: Olpasiran and pelacarsen are gene-silencing therapies that lower lipoprotein(a). Cardiovascular outcome trials are ongoing. Mendelian randomisation studies estimated clinical benefits from lipoprotein(a) lowering. OBJECTIVE: Our study estimated prices at which olpasiran and pelacarsen, in addition to standard-of-care, would be deemed cost-effective in reducing risk of recurrent coronary heart disease (CHD) events in the Australian healthcare system. METHODS: We developed a decision tree and lifetime Markov model. For olpasiran, participants had CHD and lipoprotein(a) 260 nmol/L at baseline and three-monthly injections, profiled on OCEAN(a) Outcomes trial (NCT05581303). Baseline risks of CHD, costs and utilities were obtained from published sources. Clinical trial data were used to derive reductions in lipoprotein(a) from treatment. Mendelian randomisation study data were used to estimate downstream clinical benefits. Annual discounting was 5 %. For pelacarsen, participants had CHD and lipoprotein(a) 226 nmol/L at baseline and one- monthly injections, profiled on Lp(a) HORIZON (NCT04023552) trial. RESULTS: Olpasiran in addition to standard-of-care saved 0.87 discounted quality-adjusted life years (QALYs) per person. Olpasiran in addition to standard-of-care would be cost- effective at annual prices of AU$1867 (AU$467 per dose) at threshold AU$28,000 per QALY. Pelacarsen would be cost-effective at annual prices of AU$984 (AU$82 per dose). For ICER threshold AU$50,000 per QALY, olpasiran and pelacarsen would be cost-effective at annual prices AU$4207 and AU$2464 respectively. CONCLUSION: This early health technology assessment model used inclusion criteria from clinical trials. Olpasiran and pelacarsen would be cost-effective if annual treatment prices were AU$1867 and AU$984 respectively, from the Australian healthcare perspective.

Targeting Lipoprotein(a): Can RNA Therapeutics Provide the Next Step in the Prevention of Cardiovascular Disease?

Numerous genetic and epidemiologic studies have demonstrated an association between elevated levels of lipoprotein(a) (Lp[a]) and cardiovascular disease. As a result, lowering Lp(a) levels is widely recognized as a promising strategy for reducing the risk of new-onset coronary heart disease, stroke, and heart failure. Lp(a) consists of a low-density lipoprotein-like particle with covalently linked apolipoprotein A (apo[a]) and apolipoprotein B-100, which explains its pro-thrombotic, pro-inflammatory, and pro-atherogenic properties. Lp(a) serum concentrations are genetically determined by the apo(a) isoform, with shorter isoforms having a higher rate of particle synthesis. To date, there are no approved pharmacological therapies that effectively reduce Lp(a) levels. Promising treatment approaches targeting apo(a) expression include RNA-based drugs such as pelacarsen, olpasiran, SLN360, and lepodisiran, which are currently in clinical trials. In this comprehensive review, we provide a detailed overview of RNA-based therapeutic approaches and discuss the recent advances and challenges of RNA therapeutics specifically designed to reduce Lp(a) levels and thus the risk of cardiovascular disease.

Cardiovascular outcomes in patients with coronary artery disease and elevated lipoprotein(a): implications for the OCEAN(a)-outcomes trial population.

Aims: The ongoing Olpasiran Trials of Cardiovascular Events and Lipoprotein(a) Reduction [OCEAN(a)]-Outcomes trial is evaluating whether Lp(a) lowering can reduce the incidence of cardiovascular events among patients with prior myocardial infarction (MI) or percutaneous coronary intervention (PCI) and elevated Lp(a) (≥200 nmol/L). The purpose of this study is to evaluate the association of elevated Lp(a) with cardiovascular outcomes in an observational cohort resembling the OCEAN(a)-Outcomes trial main enrolment criteria. Methods and results: This study included patients aged 18-85 years with Lp(a) measured as part of their clinical care between 2000 and 2019. While patients were required to have a history of MI, or PCI, those with severe kidney dysfunction or a malignant neoplasm were excluded. Elevated Lp(a) was defined as ≥200 nmol/L consistent with the OCEAN(a)-Outcomes trial. The primary outcome was a composite of coronary heart disease death, MI, or coronary revascularization. Natural language processing algorithms, billing and ICD codes, and laboratory data were employed to identify outcomes and covariates. A total of 3142 patients met the eligibility criteria, the median age was 61 (IQR: 52-73) years, 28.6% were women, and 12.3% had elevated Lp(a). Over a median follow-up of 12.2 years (IQR: 6.2-14.3), the primary composite outcome occurred more frequently in patients with versus without elevated Lp(a) [46.0 vs. 38.0%, unadjHR = 1.30 (95% CI: 1.09-1.53), P = 0.003]. Following adjustment for measured confounders, elevated Lp(a) remained independently associated with the primary outcome [adjHR = 1.33 (95% CI: 1.12-1.58), P = 0.001]. Conclusion: In an observational cohort resembling the main OCEAN(a)-Outcomes Trial enrolment criteria, patients with an Lp(a) ≥200 nmol/L had a higher risk of cardiovascular outcomes.

Role of lipoprotein(a) in atherosclerotic cardiovascular disease: A review of current and emerging therapies.

Lipoprotein(a), or Lp(a), is structurally like low-density lipoprotein (LDL) but differs in that it contains glycoprotein apolipoprotein(a) [apo(a)]. Due to its prothrombotic and proinflammatory properties, Lp(a) is an independent risk factor for atherosclerotic cardiovascular disease (ASCVD) and aortic valve stenosis. Lp(a) levels are genetically determined, and it is estimated that 20%-25% of the global population has an Lp(a) level ≥50 mg/dL (or ≥125 nmol/L). Diet and lifestyle interventions have little to no effect on Lp(a) levels. Lipoprotein apheresis is the only approved treatment for elevated Lp(a) but is time-intensive for the patient and only modestly effective. Pharmacological approaches to reduce Lp(a) levels and its associated risks are of significant interest; however, currently available lipid-lowering therapies have limited effectiveness in reducing Lp(a) levels. Although statins are first-line agents to reduce LDL cholesterol levels, they modestly increase Lp(a) levels and have not been shown to change Lp(a)-mediated ASCVD risk. Alirocumab, evolocumab, and inclisiran reduce Lp(a) levels by 20-25%, yet the clinical implications of this reduction for Lp(a)-mediated ASCVD risk are uncertain. Niacin also lowers Lp(a) levels; however, its effectiveness in mitigating Lp(a)-mediated ASCVD risk remains unclear, and its side effects have limited its utilization. Recommendations for when to screen and how to manage individuals with elevated Lp(a) vary widely between national and international guidelines and scientific statements. Three investigational compounds targeting Lp(a), including small interfering RNA (siRNA) agents (olpasiran, SLN360) and an antisense oligonucleotide (pelacarsen), are in various stages of development. These compounds block the translation of messenger RNA (mRNA) into apo(a), a key structural component of Lp(a), thereby substantially reducing Lp(a) synthesis in the liver. The purpose of this review is to describe current recommendations for screening and managing elevated Lp(a), describe the effects of currently available lipid-lowering therapies on Lp(a) levels, and provide insight into emerging therapies targeting Lp(a).

Clinical Trial Design for Lipoprotein(a)-Lowering Therapies: JACC Focus Seminar 2/3.

Lipoprotein(a) [Lp(a)] is a source of residual risk in patients with atherosclerotic cardiovascular disease (ASCVD). Clinical trials of fully human monoclonal antibodies targeting proprotein convertase subtilisin kexin 9 have shown that reductions in Lp(a) concentrations may be a predictor of event reduction with this class of cholesterol-lowering therapy. With the advent of selective therapies targeting Lp(a) such as antisense oligonucleotides, small-interfering RNA-based therapies, and gene editing, lowering of Lp(a) may lead to reduction in ASCVD. The phase 3 Lp(a)HORIZON (Assessing the Impact of Lipoprotein(a) Lowering with TQJ230 on Major Cardiovascular Events in Patients With CVD) outcomes trial is currently testing the effect of pelacarsen, an antisense oligonucleotide, on ASCVD risk. Olpasiran is a small-interfering RNA that is in a phase 3 clinical trial. As these therapies enter clinical trials, challenges in trial design will have to be addressed to optimize patient selection and outcomes.

Lipoprotein(a): Its Association with Calcific Aortic Valve Stenosis, the Emerging RNA-Related Treatments and the Hope for a New Era in "Treating" Aortic Valve Calcification.

The treatment of patients with aortic valve calcification (AVC) and calcific aortic valve stenosis (CAVS) remains challenging as, until today, all non-invasive interventions have proven fruitless in preventing the disease's onset and progression. Despite the similarities in the pathogenesis of AVC and atherosclerosis, statins failed to show a favorable effect in preventing AVC progression. The recognition of lipoprotein(a) [Lp(a)] as a strong and potentially modifiable risk factor for the development and, perhaps, the progression of AVC and CAVS and the evolution of novel agents leading in a robust Lp(a) reduction, have rekindled hope for a promising future in the treatment of those patients. Lp(a) seems to promote AVC via a 'three hit' mechanism including lipid deposition, inflammation and autotaxin transportation. All of these lead to valve interstitial cells transition into osteoblast-like cells and, thus, to parenchymal calcification. Currently available lipid-lowering therapies have shown a neutral or mild effect on Lp(a), which was proven insufficient to contribute to clinical benefits. The short-term safety and the efficacy of the emerging agents in reducing Lp(a) have been proven; nevertheless, their effect on cardiovascular risk is currently under investigation in phase 3 clinical trials. A positive result of these trials will probably be the spark to test the hypothesis of the modification of AVC's natural history with the novel Lp(a)-lowering agents.

Targeted Treatment against Lipoprotein (a): The Coming Breakthrough in Lipid Lowering Therapy.

Atherosclerotic cardiovascular diseases (ASCVD) are a very important cause of premature death. The most important risk factor for ASCVD is lipid disorders. The incidence of lipid disorders and ASCVD is constantly increasing, which means that new methods of prevention and treatment of these diseases are still being searched for. In the management of patients with lipid disorders, the primary goal of therapy is to lower the serum LDL-C concentration. Despite the available effective lipid-lowering therapies, the risk of ASCVD is still increased in some patients. A high level of serum lipoprotein (a) (Lp(a)) is a risk factor for ASCVD independent of serum LDL-C concentration. About 20% of Europeans have elevated serum Lp(a) levels, requiring treatment to reduce serum Lp(a) concentrations in addition to LDL-C. Currently available lipid lowering drugs do not sufficiently reduce serum Lp(a) levels. Hence, drugs based on RNA technology, such as pelacarsen, olpasiran, SLN360 and LY3819469, are undergoing clinical trials. These drugs are very effective in lowering the serum Lp(a) concentration and have a satisfactory safety profile, which means that in the near future they will fill an important gap in the armamentarium of lipid-lowering drugs.

Pharmacokinetics, Pharmacodynamics, and Tolerability of Olpasiran in Healthy Japanese and Non-Japanese Participants: Results from a Phase I, Single-dose, Open-label Study.

PURPOSE: Olpasiran, an N-acetyl galactosamine-conjugated, hepatocyte-targeted, small interfering RNA, is being developed to reduce plasma lipoprotein (Lp)-(a) concentration by directly targeting the LPA gene. This study evaluated the pharmacokinetics, pharmacodynamics, and tolerability of a single SC injection of olpasiran in healthy, Japanese and non-Japanese participants. METHODS: In this Phase I, open-label, parallel-design study, Japanese participants were randomized in a 1:1:1:1 ratio to receive a single 3, 9, 75, or 225 mg dose of olpasiran. Non-Japanese participants received a single 75 mg dose of olpasiran. The primary end points were pharmacokinetic parameters, including Cmax, AUCinf, tmax, and t1/2. Tolerability and change in Lp(a) concentration were also assessed. FINDINGS: A total of 27 enrolled participants had a mean (SD) age of 48.0 (12.5) years. Olpasiran Cmax and AUCinf were increased in an approximately dose-proportional manner in the Japanese groups. Mean (SD) Cmax values were 242 (121.0) and 144 (71.3) ng/mL, and mean (SD) AUCinf values were 3550 (592.0) and 2620 (917.0) h·ng/mL, in the Japanese and non-Japanese groups, respectively, given 75 mg of olpasiran. Median tmax ranged from 3.0 to 9.0 hours and mean (SD) t1/2 ranged from 4.0 (0.3) to 6.9 (1.6) hours across all groups. The maximal Lp(a) reduction occurred at day 57, with mean (SD) Lp(a) percentage reductions from baseline ranging from 56.0% (21.0%) to 99.0% (0.2%). A reductions in Lp(a) was observed as early as day 4. All adverse events were mild in severity, with no serious or fatal adverse events. No clinically important changes in tolerability-related laboratory analytes or vital signs were observed. IMPLICATIONS: In this population of healthy Japanese participants, dose-proportional increases in exposure and reduced Lp(a) in a dose-dependent manner were found with single 3, 9, 75, and 225 mg doses of olpasiran. The magnitude and durability of Lp(a) reductions were similar between the Japanese and non-Japanese groups. Olpasiran was well tolerated, with no clinically important adverse events or laboratory or vital sign abnormalities.

American Heart Association (AHA) Scientific Sessions 2020 (November 13-17, 2020 - Virtual Meeting).

Participants from industry and academia attended the American Heart Association Scientific Sessions 2020 (AHA 2020) Annual Meeting held over November 13-17, 2020. AHA 2020 was originally scheduled to be held in Dallas, Texas, but due to public health concerns surrounding the SARS-CoV-2 (COVID-19) crisis, it was instead presented as a virtual summit. The virtual online program included oral, poster and poster discussion presentations, as well as track-based clinical science symposia throughout the conference.