Lp(a) Therapeutics: A New Addition to the Armamentarium for ASCVD?

Elevated lipoprotein(a) [Lp(a)] is an established risk factor for atherosclerotic cardiovascular disease (ASCVD), which has been demonstrated in several epidemiological, genome-wide association, and Mendelian randomization studies.^1-3 However, no available therapies that lead to a substantial reduction in Lp(a) exist, and no clinical trial data support that lowering Lp(a) reduces adverse cardiovascular events.

Dr. Ron Blankstein discussed the Lp(a) therapeutics currently in development at the recent American Society of Preventive Cardiology 2023 Congress on CVD Prevention.

Novel Lp(a)-lowering therapies target apolipoprotein(a) [apo(a)], a key component of Lp(a). Several therapies are currently in various phases of clinical trials. Pelacarsen, a ligand-conjugated antisense oligonucleotide that binds to messenger RNA (mRNA), subsequently causing mRNA degradation and blocking the production of the apo(a) protein, has demonstrated the ability to reduce Lp(a) levels in a dose-dependent manner in patients with established cardiovascular disease.⁴ At the highest cumulative dose of pelacarsen (20 mg weekly), there was a mean 80% reduction in Lp(a).⁴ Pelacarsen 80 mg given subcutaneously monthly is currently being investigated in a phase 3 outcomes trial, HORIZON (NCT04023552), which recently completed enrollment of approximately 8300 patients.

Another therapeutic option for lowering Lp(a), olpasiran, is a small interfering RNA (siRNA) that leads to the degradation of the apo(a) mRNA, thereby preventing protein translation. The ability of olpasiran to significantly reduce Lp(a) concentrations in patients with established ASCVD was recently shown in the OCEAN(a)-DOSE trial.⁵ A Lp(a) reduction of more than 95% was seen when the drug was administered every 12 weeks at a 75-mg or 225-mg dose.⁵ Olpasiran subcutaneously every 12 weeks is being investigated in a phase 3 clinical trial, OCEAN(a)-Outcomes. Enrollment for that trial began in December 2022 (NCT05581303).

Dr. Blankstein called attention to the notable differences in the design of the 2 phase 3 clinical trials investigating Lp(a)-lowering therapies, HORIZON and OCEAN(a)-Outcomes. To be included in the HORIZON trial, patients needed an Lp(a) ≥70 mg/dL, while the threshold for enrollment in the OCEAN(a)-Outcomes trial is Lp(a) >200 nmol/L. Both trials include a secondary prevention population. HORIZON defines prior cardiovascular disease as myocardial infarction (MI), ischemic stroke, or symptomatic peripheral arterial disease, while OCEAN(a)-Outcomes is including patients with either MI or coronary revascularization with percutaneous coronary intervention and at least 1 additional risk factor. The primary end point of both trials is cardiovascular death, MI, and urgent coronary revascularization. The HORIZAN trial’s primary end point also includes nonfatal stroke.

The results of these trials are eagerly awaited, as they will provide important insight into whether lowering Lp(a) improves cardiovascular outcomes.

A few additional compounds are also currently in the early stages of development, including the siRNA compounds zerlasiran, also known as SLN360 (NCT05537571), and LY3819469 (NCT04914546), as well as the oral Lp(a) inhibitor muvalapin (NCT04472676).

Dr. Gurleen Kaur is a resident at Brigham and Women’s Hospital and served as a CardioNerds Conference Scholar during the American Society of Preventive Cardiology 2023 Congress on CVD Prevention.

References

1. Erqou S, Kaptoge S, Perry PL, et al; Emerging Risk Factors Collaboration. Lipoprotein(a) concentration and the risk of coronary heart disease, stroke, and nonvascular mortality. JAMA. 2009;302(4):412-423. doi:10.1001/jama.2009.1063
2. Kamstrup PR, Tybjærg-Hansen A, Nordestgaard BG. Extreme lipoprotein(a) levels and improved cardiovascular risk prediction. J Am Coll Cardiol. 2013;61(11):1146-1156. doi:10.1016/j.jacc.2012.12.023
3. Clarke R, Peden JF, Hopewell JC et al. Genetic variants associated with Lp(a) lipoprotein level and coronary disease. N Engl J Med. 2009;361(26):2518-2528. doi:10.1056/NEJMoa0902604
4. Tsimikas S, Karwatowska-Projopczuk E, Gouni-Berthold I, et al. Lipoprotein(a) reduction in persons with cardiovascular disease. N Eng J Med. 2020;382:244-255. doi:10.1056/NEJMoa1905239
5. O’Donoghue M, Rosenson R, Gencer B, et al. Small interfering RNA to reduce lipoprotein(a) in cardiovascular disease. N Eng J Med. 2022;387:1855-1864. doi:10.1056/NEJMoa2211023