Author: Dr Maryam Barkhordarian

Expert: Dr Steven Nissen

Reviewer: Dr Daniel Ambinder

“Elevation of lipoprotein(a) is an important risk factor responsible for considerable cardiovascular morbidity and mortality with no current pharmacological therapies approved by regulatory authorities. Nucleic acid therapeutics offer a highly promising approach to treat this previously untreatable disorder. Cardiovascular outcomes trials will determine whether these therapies can reduce the incidence of MACE.” mentioned by Dr. Steven Nissen at AHA 2023 scientific sessions, chief of academic officer at the Cleveland Clinic Heart, Vascular, and Thoracic institute. Dr. Nissen is the primary investigator of a phase 1 clinical trial on Lepodisiran: a short interfering RNA agent targeting Lipoprotein(a). 

This trial had a sample size of 48 participants without known cardiovascular disease, aged 18-65 with a lipoprotein entry level of 75 nmol/L. Each participant in each arm received one single dose of Lopedisiran with varying doses, (4, 12, 32, 96, 304 and 608 mg including placebo). Primary safety outcomes included adverse events, laboratory parameters and Lepodisiran plasma level within the first 48 hours of administration. The serum concentration of lipoprotein(a) was also measured through the subsequent 48 weeks. This trial showed a significant reduction in lipoprotein(a) levels following a single subcutaneous injection of 604 mg, with no reported major adverse events. Small sample size and the inability to conduct comprehensive safety assessment were mentioned as the limitations of this clinical trial(1). 

Dr. Michele O’Donoghue, chief of cardiology at Bringham and Women Hospital supported Dr. Nissen’s findings and provided an overview of recent trials addressing Lipoprotein(a). While the relationship between elevated Lipoprotein(a) and cardiovascular disease incidence is known (2), the extent of reduction in Lipoprotein(a) for a meaningful benefit in cardiovascular disease is unclear. She also highlighted evolution of RNA based therapies aimed to lower Lipoprotein(a) such as Pelacarsen-an antisense oligonucleotide- and small interfering RNAs like Olpasiran, Zerlasiran and Lepodisiran. A phase 2 trial on Pelacarsen showed dose-dependent effects of up to 80% reduction in lowering lipoprotein(a) in patients with elevated levels (3). She added, complete suppression of Lipoprotein(a) regardless of baseline level can be achieved with high dose of Olpasiran (4). A new gene editing method introduced by Dr. David Morrow at AHA scientific sessions 2023, potentially holding the most durable effects on lipoprotein(a) level reduction was also mentioned. 

While the association of cardiovascular disease with lipoprotein(a) is established, additional trials are essential to uncover the efficacy, durability, and potential side effects of the new RNA- based therapies to affect lipoprotein(a) level. 

Dr. Maryam Barkhordarian is a PGY2 resident at the Palisades Medical Center and served as a CardioNerds Conference Scholar for the American Heart Association 2023 Scientific Sessions.

1. Nissen SE, Linnebjerg H, Shen X, Wolski K, Ma X, Lim S, Michael LF, Ruotolo G, Gribble G, Navar AM, Nicholls SJ. Lepodisiran, an Extended-Duration Short Interfering RNA Targeting Lipoprotein(a): A Randomized Dose-Ascending Clinical Trial. JAMA. 2023 Nov 12. doi: 10.1001/jama.2023.21835. Epub ahead of print. PMID: 37952254.
2. Rader DJ, Bajaj A. Lipoprotein(a) and Oxidized Phospholipids: Partners in Crime or Individual Perpetrators in Cardiovascular Disease? J Am Coll Cardiol. 2023 May 9;81(18):1793-1796. doi: 10.1016/j.jacc.2023.02.051. PMID: 37137589.
3. Tsimikas S, Karwatowska-Prokopczuk E, Gouni-Berthold I, Tardif JC, Baum SJ, Steinhagen-Thiessen E, Shapiro MD, Stroes ES, Moriarty PM, Nordestgaard BG, Xia S, Guerriero J, Viney NJ, O'Dea L, Witztum JL; AKCEA-APO(a)-LRx Study Investigators. Lipoprotein(a) Reduction in Persons with Cardiovascular Disease. N Engl J Med. 2020 Jan 16;382(3):244-255. doi: 10.1056/NEJMoa1905239. Epub 2020 Jan 1. PMID: 31893580.
4. O'Donoghue ML, Rosenson RS, Gencer B, López JAG, Lepor NE, Baum SJ, Stout E, Gaudet D, Knusel B, Kuder JF, Ran X, Murphy SA, Wang H, Wu Y, Kassahun H, Sabatine MS; OCEAN(a)-DOSE Trial Investigators. Small Interfering RNA to Reduce Lipoprotein(a) in Cardiovascular Disease. N Engl J Med. 2022 Nov 17;387(20):1855-1864. doi: 10.1056/NEJMoa2211023. Epub 2022 Nov 6. PMID: 36342163.