olpasiran (AMG 890) / Amgen, Arrowhead, Royalty - LARVOL DELTA

AMGEN REPORTS FOURTH QUARTER AND FULL YEAR 2024 FINANCIAL RESULTS (PRNewswire) - "Olpasiran (AMG 890): A Phase 3 CV outcomes study in patients with elevated Lp(a) and at high risk for a CV event is expected to be initiated in H2 2025 / H1 2026.....VESALIUS-CV, a Phase 3 CV outcomes study of Repatha, is ongoing in patients at high CV risk without prior myocardial infarction or stroke. Data readout is event driven and anticipated in H2 2025....UPLIZNA: The FDA accepted the regulatory submission for the Phase 3 MITIGATE study under priority review with a Prescription Drug User Fee Act (PDUFA) action date of April 3, 2025."

FDA filing • New P3 trial • P3 data • PDUFA • Cardiovascular • Coronary Artery Disease • Immunology

A Study to Assess the Effect of Olpasiran on QT/QTc Intervals in Healthy Participants (clinicaltrials.gov) - P1 | N=32 | Completed | Sponsor: Amgen | Active, not recruiting ➔ Completed

Trial completion

Lp(a): A Rapidly Evolving Therapeutic Landscape. (PubMed, Curr Atheroscler Rep) - "Pelacarsen and olpasiran are two novel RNA-based injectable therapies which are being studied in ongoing phase 3 clinical trials, with the earliest of these to be concluded in 2025...Other candidate drugs, such as Lepodisiran, Zerlasiran, and Muvalaplin, are also in early-stage development. While there are presently no Lp(a)-lowering drugs available for routine clinical use, several promising candidates are currently under investigation. If these prove to be effective in randomized clinical trials, they will expand the cardiovascular care armamentarium and will allow clinicians to treat a presently unmitigated cardiovascular risk factor."

Clinical • Journal • Review • Atherosclerosis • Cardiovascular • Coronary Artery Disease • Dyslipidemia

Olpasiran lowering of lipoprotein(a) according to baseline levels: insights from the OCEAN(a)-DOSE study. (PubMed, Eur Heart J) - No abstract available

Journal • Atherosclerosis • Cardiovascular • Dyslipidemia

A Study to Assess the Effect of Olpasiran on QT/QTc Intervals in Healthy Participants (clinicaltrials.gov) - P1 | N=32 | Active, not recruiting | Sponsor: Amgen | Recruiting ➔ Active, not recruiting

Enrollment closed

Expanding drug targets for 112 chronic diseases using a machine learning-assisted genetic priority score. (PubMed, Nat Commun) - "ML-GPS increases coverage of drug targets, with the top 1% of all scores providing support for 15,077 gene-phecode pairs that previously had no support. ML-GPS can also identify well-known target-disease relationships, promising targets without indicated drugs, and targets for several drugs in clinical trials, including LRRK2 inhibitors for Parkinson's disease and olpasiran for cardiovascular disease."

Journal • Machine learning • Cardiovascular • CNS Disorders • Movement Disorders • Parkinson's Disease • LRRK2

A Study to Assess the Effect of Olpasiran on QT/QTc Intervals in Healthy Participants (clinicaltrials.gov) - P1 | N=32 | Recruiting | Sponsor: Amgen | Not yet recruiting ➔ Recruiting

Enrollment open

Early health technology assessment of gene silencing therapies for lowering lipoprotein(a) in the secondary prevention of coronary heart disease. (PubMed, J Clin Lipidol) - P3 | "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."

Journal • Cardiovascular • Coronary Artery Disease • Heart Failure

Expanding therapeutic options: overview of novel pharmacotherapies for dyslipidemia. (PubMed, Expert Opin Pharmacother) - "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."

Journal • Review • Atherosclerosis • Cardiovascular • Dyslipidemia • Metabolic Disorders

RNA interference therapy in cardiology: will new targets improve therapeutic goals? (PubMed, Drugs Context) - "Patisiran, the first FDA-approved siRNA medication, targets hereditary transthyretin amyloidosis with polyneuropathy. Givosiran, lumasiran and nedosiran further expand siRNA applications in treating rare genetic diseases, demonstrating positive outcomes. In cardiology, inclisiran, approved for hypercholesterolaemia, showcases sustained reductions in LDL cholesterol levels...Lipoprotein(a), an independent risk factor for atherosclerotic cardiovascular disease, has become a focus of siRNA therapies, precipitating the development of specific siRNA drugs like olpasiran, zerlasiran and lepodisiran, with promising reductions in lipoprotein(a) levels...Zodasiran and plozasiran address potential risk factors for cardiovascular diseases, targeting triglyceride-rich lipoproteins. Zilebesiran, which targets hepatic angiotensinogen mRNA, has demonstrated a dose-related reduction in serum angiotensinogen levels, thereby lowering blood pressure in patients with systemic arterial..."

Journal • Review • Amyloidosis • Atherosclerosis • Cardiac Amyloidosis • Cardiovascular • Dyslipidemia • Genetic Disorders • Hypertension • Pain • Pulmonary Arterial Hypertension

Olpasiran Pharmacodynamic Study: Ensuring We Go a Mile Deep But More Than an Inch Wide. (PubMed, J Am Coll Cardiol) - No abstract available

Journal • PK/PD data • Atherosclerosis • Cardiovascular • Dyslipidemia

The Off-Treatment Effects of Olpasiran on Lipoprotein(a) Lowering: OCEAN(a)-DOSE Extension Period Results. (PubMed, J Am Coll Cardiol) - P2 | "Olpasiran is a potent siRNA with prolonged effects on Lp(a) lowering. Participants receiving doses ≥75 mg Q12W sustained a ∼40% to 50% reduction in Lp(a) levels close to 1 year after the last dose. (Olpasiran Trials of Cardiovascular Events And LipoproteiN[a] Reduction-DOSE Finding Study [OCEAN(a)-DOSE]; NCT04270760)."

Clinical • Journal • Atherosclerosis • Cardiovascular • Dyslipidemia

Current and future outlook on the manufacturing of multi-modality synthetic drug substances (ACS-Fall 2024) - "Other themes visited will include clinical development constraints, process mass intensity, cost of goods, process safety, and readiness for process validation. Examples will be included for the development of processes to manufacture olpasiran, omecamtiv mecarbil, and sotorasib."

Lipoprotein (a) and cerebrovascular disease. (PubMed, J Int Med Res) - "Lp(a) seems to play a significant role in the pathogenesis of arterial ischemic stroke in children because environmental thrombotic and atherogenic factors are generally not present.Phase 3 trials of novel Lp(a) targeting agents, such as pelacarsen and olpasiran, are anticipated to demonstrate their efficacy in reducing the incidence of stroke. Given the richness of the literature, new guidelines regarding Lp(a) screening and management in targeted populations are warranted to provide more effective primary and secondary prevention."

Journal • Review • Atherosclerosis • Cardiovascular • CNS Disorders • Dyslipidemia • Ischemic stroke • Pediatrics • Vascular Neurology

Lipoprotein (a) and lipid-lowering treatment from the perspective of a cardiac surgeon. An impact on the prognosis in patients with aortic valve replacement and after heart transplantation. (PubMed, Int J Cardiol Cardiovasc Risk Prev) - "There is still no targeted therapy for Lp(a), however, drugs such as pelacarsen, olpasiran, zerlasiran, lepodisiran and muvalaplin are in clinical trials and have been shown to be effective in significantly reducing Lp(a) levels. Therefore, the assessment of Lp(a) concentration in these patients will allow for a more accurate stratification of their cardiovascular risk, and the possibility of lowering Lp(a) will allow for the optimization of this risk. In this article, we summarized the most important information regarding the role of Lp(a) and lipid-lowering treatment in patients after AVR and HTx."

Journal • Cardiovascular • Transplantation

Therapeutic Potential of Lipoprotein(a) Inhibitors. (PubMed, Drugs) - "Early studies of antisense oligonucleotides (e.g., mipomersen, pelacarsen), RNA interference (e.g., olpasiran, zerlasiran, lepodisiran) and small molecule inhibitors (e.g., muvalaplin) have demonstrated effective Lp(a) lowering and good tolerability. These agents are moving forward in clinical development, in order to determine whether Lp(a) lowering reduces cardiovascular risk. The results of these studies have the potential to transform our approach to the prevention of cardiovascular disease."

Journal • Atherosclerosis • Cardiovascular • Dyslipidemia

New insights into the therapeutic options to lower lipoprotein(a). (PubMed, Eur J Clin Invest) - "If the results from the cardiovascular outcome trials, designed to demonstrate whether the reduction of Lp(a) of more than 80% as observed with pelacarsen, olpasiran or lepodisiran translates into the decrease of cardiovascular mortality and major adverse cardiovascular events, will be positive, lowering Lp(a) will become a new additional target in the management of patients with elevated cardiovascular risk."

Journal • Review • Atherosclerosis • Cardiovascular • Dyslipidemia • Myocardial Infarction

A Study to Assess the Effect of Olpasiran on QT/QTc Intervals in Healthy Participants (clinicaltrials.gov) - P1 | N=32 | Not yet recruiting | Sponsor: Amgen

New P1 trial

Elevated Lipoprotein(a) Levels: A Crucial Determinant of Cardiovascular Disease Risk and Target for Emerging Therapies. (PubMed, Curr Probl Cardiol) - "Newly emerging therapies, including pelacarsen, zerlasiran, olpasiran, muvalaplin, and lepodisiran, show promise in significantly lowering Lp(a) levels, potentially transforming the management of cardiovascular disease. However, further research is essential to assess these novel therapies' long-term efficacy and safety, heralding a new era in cardiovascular disease prevention and treatment and providing hope for at-risk patients."

Journal • Review • Atherosclerosis • Cardiovascular • Dyslipidemia • Hematological Disorders • Inflammation • Thrombosis

SMALL INTERFERING RNA (SIRNA) IMPACT ON LIPOPROTEIN(A) LEVELS: A SYSTEMATIC REVIEW (ACC 2024) - "Our methodology adhered to the PRISMA guidelines, with the Cochrane ROB2 tool used to assess study quality. Out of 19 RCTs (with 11 ongoing), the primary interventions were Inclisiran, Olpasiran, and SNL 360. siRNA therapy does not result in serious or fatal adverse events. It is a potential therapy in lowering Lp(a) levels in patients with hyperlipidemia. The effect of siRNA on Lp(a) appears promising, underscoring the need for more studies."

Review • Dyslipidemia • Hematological Disorders • Thrombocytopenia

Olpasiran Trials of Cardiovascular Events and Lipoprotein(a) Reduction (OCEAN(a)) - Outcomes Trial (clinicaltrials.gov) - P3 | N=7297 | Active, not recruiting | Sponsor: Amgen | Recruiting ➔ Active, not recruiting

Enrollment closed • Atherosclerosis • Cardiovascular • Dyslipidemia

Targeting Lipoprotein(a): Can RNA Therapeutics Provide the Next Step in the Prevention of Cardiovascular Disease? (PubMed, Cardiol Ther) - "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."

Journal • Review • Cardiovascular • Congestive Heart Failure • Coronary Artery Disease • Dyslipidemia • Heart Failure • APOB

Molecular Therapies in Cardiovascular Diseases: Small Interfering RNA in Atherosclerosis, Heart Failure, and Hypertension. (PubMed, Int J Mol Sci) - "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..."

Journal • Review • Amyloidosis • Atherosclerosis • Cardiovascular • Congestive Heart Failure • Dyslipidemia • Heart Failure • Hypertension • Pain

A Study to Evaluate the Pharmacokinetics, Safety, and Pharmacodynamics of Olpasiran in Participants With Normal Renal Function and Participants With Various Degrees of Renal Impairment (clinicaltrials.gov) - P1 | N=33 | Completed | Sponsor: Amgen | Active, not recruiting ➔ Completed

Trial completion • Renal Disease

Intraindividual Variability in Serial Lipoprotein(a) Concentration Among Placebo-Treated Patients in the OCEAN(a)-DOSE Trial (AHA 2023) - " OCEAN(a)-DOSE, a phase 2, randomized trial of the Lp(a)-lowering siRNA therapy olpasiran, enrolled 281 patients with atherosclerotic cardiovascular disease (ASCVD) and Lp(a) >150 nmol/L... Among patients with ASCVD and elevated baseline Lp(a) concentration, there was notable intra-individual variability in Lp(a) concentration over 72 weeks of follow-up. These findings suggest that Lp(a) may need to be measured more than once in a lifetime."

Clinical • Atherosclerosis • Cardiovascular • Dyslipidemia