Promising results with the daily oral small molecule lipoprotein(a) inhibitor, muvalaplin, in high-risk cardiovascular patients with elevated lipoprotein(a) levels

Lipoprotein(a) [Lp(a)] is a particle similar to the low-density lipoprotein (LDL) particle but also contains apoprotein(a) [apo(a)], which is linked to apolipoprotein B-100 on the particle surface (1). Moreover, sequence homology exists between apo(a) and plasminogen (2). The plasma levels of Lp(a) are largely genetically determined, so a single lifetime measurement can identify patients with elevated levels (3). Most importantly, elevated levels of Lp(a) are an independent causal risk factor for atherosclerotic cardiovascular disease (ASCVD) as well as for, and associations between elevated Lp(a) and ischemic stroke, peripheral arterial disease, or heart failure exist (4).

Lp(a) likely contributes to atherosclerosis via prothrombotic and proinflammatory mechanisms, and on an equimolar basis, Lp(a) is approximately 5 to 6 times more atherogenic than LDL-cholesterol (LDL-C) (5). Therefore, therapeutically decreasing Lp(a) levels would be expected to contribute to risk reduction of both ASCVD and CAVS. While long-term pharmacological follow-up studies are still ongoing, the German Lipoprotein Apheresis Registry follow-up study showed that reduction of Lp(a) in patients with elevated Lp(a) levels decreases ASCVD events (6). Of note, the PCSK-9 inhibitors lower Lp(a) levels by approximately 15–30% (7). In the recent post hoc analysis of the Odyssey Outcomes trial, the PCSK9 inhibitor alirocumab improved cardiovascular outcomes after an acute coronary syndrome (ACS) in both males and females and reduced major adverse cardiovascular events (MACE) (coronary heart disease death, non-fatal myocardial infarction, fatal/non-fatal ischemic stroke, unstable angina requiring hospitalization) to a greater degree among patients having a high baseline Lp(a) level (8). It, therefore, seems plausible that reducing Lp(a) levels in high-risk populations, even if only modestly, may be beneficial.

It has been estimated that approximately 10% to 20% of the general population have elevated Lp(a) levels over >50 mg/dL (>125 nmol/L) (9). However, many physicians are not aware of Lp(a) as an independent ASCVD risk factor, and the measurement of Lp(a) is rarely performed (9). In a recent population-based multicenter study in the USA, among adults aged 18 to 80 years with ASCVD, one-third of the participants had an Lp(a) level over 50 mg/dL (>125 nmol/L) (10). This study also showed that, compared to other ethnicities, the Lp(a) levels were highest in black participants. Yet, the impact of elevated Lp(a) levels may have a more significant influence on plaque burden or progression in whites than in blacks (11). As Lp(a) levels increase postmenopausally, there may also be age-related differences between men and women. In a recently published prospective long-term cohort study in the USA by Ridker and coworkers (12), the levels of high-sensitivity C-reactive protein (hs-CRP), LDL-C, and Lp(a) were measured at baseline in 27,939 initially healthy women who were then followed for 30 years. During the follow-up, 3,662 first major cardiovascular events occurred, and each of the above three baseline measurements predicted the 30-year risk of a major event.

The results of a phase 2 randomized, double-blind, placebo-controlled multinational and multiethnic study of 166 patients and 67 controls treated daily with the oral Lp(a) inhibitor muvalaplin for 12 weeks was published online in November 2024 (13). The participating patients were 40 years or older and at high cardiovascular risk, and they had Lp(a) levels of 175 nmol (70 mg/dL) or greater at study entry. Nearly all of the patients were on statin, and approximately half of them were also on ezetimibe. Additionally, over 80% of patients were on antithrombotic agents. Of the patients, 76% had coronary artery disease, 40% had suffered a previous acute myocardial infarction, 38% had type 2 diabetes (T2D), 11% had familial hypercholesterolemia, and 5% had suffered a cerebrovascular accident. The ethnic background of the patients was White in 65%, Black in 5%, and Asian in 27%, and 33% of the patients were women. At the 12-week endpoint, muvalaplin (10, 60, or 240 mg daily) showed respective placebo-adjusted percentage reductions from baseline in Lp(a) of 47.6%, 81.7%, and 85.8% when an intact Lp(a) assay was used, i.e., a method that determines apo(a) present in the Lp(a) particles, and reductions of 40.4%, 70.0% and 68.9% when the traditional apo(a) assay was used, i.e., a method that determines total circulating apo(a), i.e., both the particle-bound and freely circulating apo(a). Muvalaplin 10, 60, and 240 mg also decreased apolipoprotein B levels by 8.9%, 13.1%, and 16.1%, respectively. No significant changes in plasminogen levels were observed at the 12-week endpoint, and the levels of hs-CRP remained unchanged. Muvalaplin was well tolerated, and only one patient on the 240 mg daily dose demonstrated transient alanine aminotransferase concentrations 10 times the upper limit of normal.

The development of small-molecule prototype compounds with subnanomolar potency as Lp(a) inhibitors, ultimately leading to the discovery of muvalaplin, is fascinating (14). The mechanism of action of muvalaplin is unique, as it inhibits the first step of Lp(a) formation by small molecule interactions with apo(a). Lp(a) assembly in the liver is thought to be a two-step process: first apo(a) and apoB-100 associate non-covalently intracellularly, and then a disulfide bond is formed between apo(a) and apoB-100 at the cell surface (15). Diaz and coworkers (14) showed in transgenic mice and cynomolgus monkeys that the LSN3353871 prototype compound decreased Lp(a) levels by up to 78% and 40%, respectively. The next design was a trimeric molecule LY3473329 (now known as muvalaplin), which engaged more than one of the repeated K_IV8 domains in apo(a), and the respective Lp(a) decreases with this trimeric molecule were 92% in transgenic mice and 71% in cynomolgus monkeys. In addition, the potential undesired off-target effects of LY3473329 on plasminogen were studied, and it was found that the compound decreased plasminogen activity in rats. However, this finding was rat-specific, and in humans, LY3473329 was shown not to affect plasmin activity. Indeed, in the study by Nicholls and coworkers (13), no significant changes in plasminogen concentrations were observed during the 12-week follow-up.

Muvalaplin is the first small molecular oral drug for reducing Lp(a); yet, research into potential Lp(a) lowering therapies is progressing rapidly. To show potential clinical benefits in patients at high risk of cardiovascular events, large, longer-term clinical trials need to be conducted. The current commercial Lp(a) assays measure the level of total apo(a), including muvalaplin-bound apo(a), and, as shown in the study by (13), these assays underestimate the efficacy of muvalaplin. Thus, for the reliable measurement of Lp(a) levels during muvalaplin treatment, a novel insensitive immunoassay is required (16).

In addition to oral muvalaplin, several Lp(a) lowering antisense oligonucleotide small interfering RNA (siRNA) formulations (olpasiran, zerlasiran, lepodisiran) and an antisense oligonucleotide (pelacarsen) are currently being studied in clinical trials (17-21). In a very recent phase 2 study, olpasiran, a novel Lp(a)-targeting siRNA, led to a significant over 90% reduction in Lp(a) (22). Although olpasiran also reduced oxidized phospholipids (OxPL), it did not reduce the levels of hs-CRP or high-sensitivity interleukin 6. These findings imply that, to fully understand the effects of Lp(a)-lowering on inflammatory biomarkers, further research is required. Another potential concern is that many of the currently tested Lp(a)-lowering drugs are highly effective in reducing Lp(a) levels, i.e., by over 90%. Is there a risk of lowering Lp(a) too much, or, as with lowering LDL-C, is “lower better and lowest best”? Moreover, we still have open questions regarding the biological functions and metabolism of Lp(a). Interestingly, in a study based on Mendelian randomization analyses using data from the UK biobank, Yeung and coworkers (23) reported that very low Lp(a) levels (<3.8 nmol/L or <1.5 mg/dL) are associated with a higher risk of T2D and of non-alcoholic liver disease. Although this result was based on genetically determined low Lp(a) levels, it calls for careful detection and monitoring of these metabolic disturbances in any long-term Lp(a)-lowering studies.

Time will tell if Lp(a)-lowering therapies will have the same or even greater cardiovascular benefits, as have been conclusively demonstrated in large outcome trials with therapies that lower LDL-C (24). We believe that the first target group for Lp(a)-lowering therapies should be patients at a double lifelong heritable risk of premature atherosclerosis based on a combined high LDL-C and high Lp(a), i.e., patients with familial hypercholesterolemia and an elevated Lp(a) level (25).

Acknowledgments

None.

Footnote

Provenance and Peer Review: This article was commissioned by the editorial office, Annals of Translational Medicine. The article has undergone external peer review.

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Funding: None.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://atm.amegroups.com/article/view/10.21037/atm-25-40/coif). A.V. has received consultancy fees from Amgen and Novartis. P.T.K. has received consultancy fees, lecture honoraria, and/or travel fees from Amgen, Novartis, Raisio Group, Amarin and Sanofi. F.R. has received research grants, honoraria, or consulting fees for professional input and/or lectures from Sanofi, Regeneron, Amgen, Novartis and LIB Therapeutics. The authors have no other conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

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