Current Clinical Trials for Treating Elevated Lipoprotein(a)

Abstract

Purpose of Review

Numerous studies have established lipoprotein(a) [Lp(a)] as an independent and modifiable risk factor for atherosclerotic cardiovascular disease (ASCVD) and calcific aortic valve stenosis (CAVS). As such Lp(a) has become the focus of targeted drug therapy development with the goal of reducing Lp(a) serum concentrations and improving outcomes. This review aims to inform readers on the investigational agents currently in clinical trials and highlight key differences including dosing intervals and routes of administration that may facilitate uptake and retention of a particular potential medication in certain patient populations.

Recent Findings

Five investigational agents are currently undergoing various stages of clinical trials for the treatment of elevated Lp(a). Three potential therapies are small interfering RNA (siRNA) molecules and a fourth is an antisense oligonucleotide (ASO) all of which are subcutaneously injected. A fifth agent is a small molecule inhibitor that is orally administered. A sixth agent, a cholesteryl ester transfer protein (CETP) inhibitor that is primarily being studied for LDL-C reduction has shown promise for reducing Lp(a). A seventh agent based on gene-editing is currently in the developmental stage. Results have revealed notable reductions in Lp(a) with favorable tolerability and safety. Phase 3 trials will be crucial in determining the viability of lowering Lp(a) with such therapies and improving cardiovascular outcomes.

Summary

Promising results indicate the potential in the near future to have medications primarily for lowering Lp(a) which has thus far eluded targeted drug therapy. As such advances stand to benefit large segments of the population living with and at risk for ASCVD, future research is vital to validate safety and efficacy in the long-term as well to understand how to optimize uptake and retention among patients with diverse circumstances.

Introduction

Research to date implicates lipoprotein(a) [Lp(a)] as a likely modifiable risk factor involved in the pathogenesis of atherosclerotic cardiovascular disease (ASCVD) and calcific aortic valve stenosis (CAVS) [1]. Lp(a) levels circulating in the bloodstream are overwhelmingly genetically determined and are resistant to change via numerous established treatment methods such as statin regimens, which likely increase Lp(a) by about 10% and lifestyle changes. Although diet and exercise interventions have been proven to reduce low-density lipoprotein-cholesterol (LDL-C) and triglycerides or increase high-density lipoprotein cholesterol (HDL-C), this has not been the case with Lp(a) [2]. Since its discovery in 1963, research data have advanced our understanding of Lp(a) in the context of cardiovascular disease.

Earlier observational studies provided insight into the linkage between elevated Lp(a) levels and increased risk of myocardial infarction and stroke. Results of genetic studies and epidemiological studies have alluded to the causal role of Lp(a) in coronary artery disease [3]. More recent Mendelian randomization studies have alluded to Lp(a) as a causal agent for cardiovascular events. Although there are FDA approved lipid-lowering therapies such as inhibitors of proprotein convertase subtilisin-kexin type 9 (PCSK9) that reduce the incidence of cardiovascular events primarily by reducing LDL-C while providing a measure of benefit in lowering Lp(a), there are no approved medications specifically for lowering Lp(a) [4,5]. PCSK9 inhibitors reduce Lp(a) concentration by 20% to 25%, but they also reduce LDL-C, further complicating the task of apportioning the benefit of these drugs in reducing cardiovascular events to individual lipoprotein effects and leading to such medications not being FDA-approved for treating high Lp(a) in patients who may have indication for PCSK9 inhibitors to treat high LDL-C [6].

Approved in various countries worldwide, lipoprotein apheresis is FDA-approved in the United States for LDL-C and Lp(a) lowering and for treating patients with familial hypercholesterolemia (FH) [7,8]. Although this adjunctive nonpharmacological therapy may be of notable benefit in those who do not reach therapeutic goal with medications particularly in patients diagnosed with FH, it remains procedurally intensive. The National Lipid Association (NLA) in its focused update to the 2019 NLA Scientific Statement on Use of Lp(a) in Clinical Practice currently recommends measuring Lp(a) levels at least once in every adult as well as selected high-risk children for risk stratification [9]. The update stratifies risk according to Lp(a) levels with Lp(a) levels <75 nmol/L (30 mg/dL) considered to be low risk in individuals, Lp(a) levels ≥125 nmol/L (50 mg/dL) considered to be high risk, and individuals with Lp(a) levels between 75 and 125 nmol/L (30–50 mg/dL) considered to be at intermediate risk [9]. As such, there is a need to develop medications that specifically target and lower Lp(a) levels in circulation to a greater extent and provide therapeutic benefit in improving morbidity and mortality.

Lp(a) is formed when apolipoprotein(a) [apo(a)] covalently binds to apolipoprotein B-100 (apoB) a low-density lipoprotein (LDL) particle [10,11]. The Lp(a) gene transcribes the messenger RNA (mRNA) that encodes the protein apo(a). With regard to the investigational agents in the pipeline, apo(a) production is targeted by the three small interfering RNA (siRNA) drugs and one antisense oligonucleotide (ASO) drug, and apo(a) binding is targeted by one small molecule inhibitor. There are currently five investigational agents in various phases of clinical trials with a primary intended indication for lowering Lp(a). Randomized studies with these pharmacological agents may provide further evidence that reducing Lp(a) levels moderates the risk of adverse cardiovascular events [3]. Four of these potential therapies are RNA-based with three of them being small interfering RNA agents (olpasiran, zerlasiran, and lepodisiran) that effectively silence specific genes. Small interfering RNA (siRNA) refers to double-stranded RNA molecules typically 20 to 24 base pairs in length that activate RNA-induced silencing complexes (RISC) which then cleave intended mRNA molecules preventing their expression [12,13].

The other RNA-based therapy is an antisense oligonucleotide (ASO) (pelacarsen) that is short, single-stranded, and acts by binding to the complementary target RNA, leading to RNAse-H activation and mRNA degradation [14]. An example of an approved siRNA medication is inclisiran which reduces low-density lipoprotein cholesterol (LDL-C) by inhibiting the synthesis of proprotein convertase subtilisin/kexin type-9 (PCSK9) that is responsible for internalizing and degrading hepatic LDL receptors [15]. Inclisiran is notable as the first siRNA therapeutic targeting PCSK9 as two other FDA approved medications alirocumab and evolocumab are monoclonal antibodies that inhibit binding of PCSK9 to LDL receptors [16,17]. The fifth investigational agent is a small molecule inhibitor (muvalaplin) and compared to the subcutaneously injected RNA-based agents, this is orally ingested. A sixth agent, a cholesteryl ester transfer protein (CETP) inhibitor (obicetrapib) that is primarily being studied for LDL-C reduction has shown promise for reducing Lp(a). A seventh agent that is as of yet to be named is based on gene-editing and is currently in the developmental stage. Figure 1 compares the six investigational agents that have data on Lp(a) lowering.

Figure 1.

Current and potential investigational agents for lowering Lp(a)

Pelacarsen

Pelacarsen (TQJ230) is an antisense oligonucleotide (ASO) investigational agent currently in phase 3 trials that inhibits apo(a) formation by binding to the mRNA transcript of the LPA gene. Similarly to the siRNA investigational agents, this potential therapeutic that is also RNA-based is conjugated to N-acetylgalactosamine (GalNAc) that enhances liver-specific targeting by binding to asialoglycoprotein receptors (ASGPR) on hepatocytes thereby limiting the potential for off-target side effects and increasing concentration at the intended site.

Pelacarsen had its start as an ASO that was not conjugated to GalNAc and lacked this specific hepatocyte-targeting feature that nevertheless showed promising phase 1 and 2 trial results in lowering Lp(a) levels in participants who had elevated Lp(a) and were otherwise healthy and who had elevated Lp(a) and established cardiovascular disease [18]. Dose-dependent mean percentage decreases in plasma Lp(a) concentration ranged from 39.6% to 77.8% [19]. GalNAc conjugation resulted in an increase in potency by a factor of 15 to 30 wherein a phase 2a trial revealed a dose-dependent circulating Lp(a) reduction of 66% to 92% in patients who had elevated Lp(a) levels [18,20]. A randomized, double-blind, placebo-controlled, dose-ranging phase 2 study (NCT03070782) was carried out with patients who had established cardiovascular disease and elevated Lp(a) levels of at least 150 nmol per liter or 60 mg per deciliter [18]. Subcutaneous doses of pelacarsen or APO(a)-L_RX as it was known then resulted in dose-dependent lowering of Lp(a) with a mean −80% change at the highest dose of 20 mg every week (Table 4). The most common adverse events were injection-site reactions occurring in 27% of patients who received APO(a)-L_RX and in 6% of those who received placebo. Most injections-site reactions were mild, although one participant who had reactions discontinued treatment.

The phase 3 trial (NCT04023552) for pelacarsen known as the Lp(a) HORIZON trial is ongoing to demonstrate the benefit of pelacarsen compared to placebo in reducing the risk of expanded MACE (cardiovascular death, non-fatal MI, non-fatal stroke, and urgent coronary revascularization requiring hospitalization) in the overall study population with established CVD and two elevated Lp(a) criteria with one being at least 70 mg/dL and the second being at least 90 mg/dL [21,22]. The dose regimen being used is 80 mg once monthly, the equivalent of the 20 mg weekly dose in the NCT03070782 phase 2 study that resulted in a mean 80% reduction of Lp(a) [21]. The trial is expected to read out in mid-2025.

Olpasiran

Olpasiran formerly known as AMG 890 is another siRNA investigational agent that is currently in a phase 3 trial, further along in development compared to lepodisiran. Similar to lepodisiran, olpasiran is directed at hepatic synthesis of the Lp(a) component apo(a), such that degradation of the apo(a) encoding mRNA prevents the production of Lp(a) [23]. Olpasiran is currently in phase 3 clinical trials for cardiovascular outcomes. It is also notable that current study results point to the dosing regimen for olpasiran to be every 12 weeks as compared to a possible longer interval of once or twice per year for lepodisiran.

Similarly to the previously discussed phase 1 study for lepodisiran, the first phase 1 study (NCT03626662) of olpasiran was a randomized, double-blind, and placebo-controlled single ascending-dose trial where the primary outcomes of this study were safety and tolerability and the secondary outcomes were changes in Lp(a) levels and pharmacokinetics of olpasiran [24,25]. Olpasiran was found to be well tolerated with a dose-dependent 71 to 97% reduction of Lp(a) levels in participants. Of the subcutaneous doses 3 mg, 9 mg, 30 mg, 75 mg, and 225 mg, lowering of Lp(a) concentrations lasted for several months with 9 mg and above. Maximum Lp(a) suppression occurred between days 43 and 71, and while concentrations gradually increased toward baseline, at day 225 they remained below the levels achieved by placebo. Like lepodisiran there was a dose-dependent increase in serum concentration of this investigational agent. There were no serious adverse events in those receiving olpasiran. Within 7.5 hours after dosing, olpasiran reached mean maximum concentration, and most of what was dosed was cleared from the serum by 2 to 3 days. It is worth noting that another phase 1 trial was conducted to characterize the pharmacokinetic features of a single dose of olpasiran in Japanese and non-Japanese participants. As opposed to the NCT03626662 trial of olpasiran that was randomized, double-blind, and placebo-controlled, this trial was open-label and parallel-group. However, findings were similar in that there were also dose-dependent serum concentration increases, median time to maximum concentration ranged between 3.0 to 9.0 hours, clearance of most of the dose occurred by day 2 or 3, and olpasiran was well tolerated [26]. Similar to lepodisiran, in order to improve specific targeting and delivery to the liver, olpasiran was conjugated with GalNAc that binds to receptors on hepatocytes.

The phase 2 OCEAN(a)-DOSE trial (Olpasiran Trials of Cardiovascular Events and Lipoprotein(a) Reduction-Dose Finding Study) (NCT04270760) was carried to further evaluate the efficacy and safety of olpasiran as a randomized, double-blind, placebo-controlled, dose-finding trial in 281 enrolled participants with established atherosclerotic cardiovascular disease (ASCVD) [27]. ASCVD in the enrolled patients was defined by having at least 1 of the following 4 criteria: A history of coronary revascularization with percutaneous coronary intervention (PCI) or coronary artery bypass grafting (CABG), diagnosis of CAD with or without prior myocardial infarction (MI), diagnosis of ASCVD, or diagnosis of PAD. As opposed to the phase 1 trial where participants received a single dose of olpasiran, this phase 2 trial involved giving multiple doses in specific intervals to further evaluate safety and efficacy with repeated administration. In addition to having ASCVD, participants had a serum Lp(a) concentration above 150 nmol/L. The treatment period of the trial was 48 weeks after which a follow-up interval to assess safety occurred for a minimum of 24 weeks. Percent change in Lp(a) baseline concentration at week 36 served as the primary endpoint, with significant and dose-dependent reductions in Lp(a) levels noted at 36 weeks in those receiving olpasiran. Lp(a) concentration in the placebo group had increased by a mean of 3.6% resulting in some placebo-adjusted mean percent changes for those receiving olpasiran being greater than 100%. Placebo-adjusted mean percent changes were −70.5% for the 10-mg dose given every 12 weeks, −97.4% for the 75-mg dose given every 12 weeks, −101.1% for the 225-mg dose given every 12 weeks, and −100.5% for the 225-mg dose administered every 24 weeks.

Additionally, the percentage of patients with a Lp(a) concentration of less than 125 nmol/L at 36 weeks was 67% for those who received the 10 mg dose every 12 weeks, 100% for those who received the 75 mg dose every 12 weeks, 100% for those who received the 225 mg dose every 12 weeks, and 98% for those who received the 225 mg dose every 24 weeks. This is notable as consensus sets an abnormally elevated value of Lp(a) at above 125 nmol per liter, indicating that higher doses, which in this study were 75 mg and above are needed for substantial long-term Lp(a) reduction. Furthermore, a more frequent dosing schedule, which in this study would be 12 weeks rather than 24 weeks may be optimal as results indicate that the longer interval of dosing every 24 weeks has a reduced effect in curbing Lp(a) production.

In terms of safety and tolerability, the overall incidence of adverse events among those receiving placebo and those receiving olpasiran was fairly similar. Pain at the injection site was the most common adverse event in the individuals that received olpasiran. Patients in both the placebo and varying olpasiran dosing groups had similar hyperglycemia incidence or new-onset or worsening diabetes mellitus at 7% of patients overall. As in the phase 1 study (NCT03626662), notable reductions in Lp(a) concentrations were observed with doses of olpasiran, this time in persons with ASCVD.

The phase 3 OCEAN(a)-Outcomes trial (NCT05581303) will evaluate olpasiran effects in patients with a higher Lp(a) of 200 nmol/L or greater with higher cardiovascular risk [28]. Elevated CVD risk will be defined as having had a history of MI, coronary revascularization with percutaneous coronary intervention (PCI), or both plus additional risk factors such as age greater than 65 years, diabetes mellitus, ischemic stroke, PAD, and multivessel PCI. In contrast the phase 2 trial had less stringent criteria such as allowing those who did not have a history of MI or coronary revascularization with PCI but had established ASCVD by other means. This double-blind, randomized, placebo-controlled phase 3 study may contribute to understanding how much Lp(a) needs to be reduced in order to have a meaningful risk reduction of cardiovascular events and as a larger and longer trial can help further evaluate long-term efficacy and safety. The primary objective involves comparing the effect of treatment with olpasiran versus placebo on the risk of cardiovascular outcomes such as urgent coronary revascularization, myocardial infarction (MI), or death from coronary heart disease (CHD).

Zerlasiran

Zerlasiran (SLN360) like lepodisiran and olpasiran is another subcutaneously injected siRNA aimed at reducing Lp(a) levels [2,29]. A phase 2 study (NCT05537571) has recently been completed with this investigational agent. As with lepodisiran and olpasiran the phase 1 study (NCT04606602) of zerlasiran was a randomized, double-blind, and placebo-controlled single ascending-dose trial involving patients not previously diagnosed with ASCVD but who had elevated Lp(a) serums levels of 150 nmol/L or greater where the primary outcomes were safety and tolerability and the secondary outcomes were changes in Lp(a) levels and pharmacokinetics of zerlasiran. Similarly to lepodisiran and olpasiran, zerlasiran reduces concentrations of Lp(a) by targeting the hepatic production of apo(a). As with lepodisiran and olpasiran, zerlasiran is GalNAc conjugated to enhance affinity for hepatocytes. Favorable pharmacodynamics were evidenced by the maximal median percentage change results in plasma Lp(a) from baseline over 150 days of −10%, −46%, −86%, −96%, and −98% for those receiving placebo and zerlasiran doses of 30 mg, 100 mg, 300 mg, and 600 mg respectively. Additionally, these results convey dose-dependent lowering of plasma Lp(a) levels. In addition to being dose dependent, the lowering of Lp(a) levels persisted through 150 days post injection with median Lp(a) concentrations on day 150 remaining more than 70% below baseline for the 300 mg dose group and more than 80% below baseline for the 600 mg dose group.

The follow up period was then extended to 1 year for these 2 highest dose groups such that they would be followed up to day 365 after their single dose of either 300 mg or 600 mg [2]. In addition, the study enrolled additional participants to receive 2 doses of either placebo, 200 mg at a 4-week interval, 300 mg at an 8-week interval, or 450 mg at an 8-week interval. These patients were followed up to day 201 from their initial administration [30]. Although criteria for Lp(a) levels were identical at 150 nmol/L or more, this second set of patients now have stable ASCVD as opposed to no history of ASCVD for the initial single dose group. Median changes in Lp(a) concentration at 365 days for those who received a single dose were 14%, −30%, and −29% for the placebo, 300 mg zerlasiran dose, and 600 mg dose groups respectively. Maximal median percent changes for those who received 2 doses were 7%, −97%, −98%, and −99% for the placebo, 200 mg, 300 mg, and 450 mg dose groups respectively. At the follow up day of 201, the percent changes were 0.3%, −60%, −90%, and −89%. Such data indicates that relatively infrequent dosing may be viable with this pharmacological agent in order to have sustained lowered levels of Lp(a).

Zerlasiran was well tolerated with 2 serious adverse events occurring in a single participant who received a single dose that were deemed to not be related to zerlasiran. This participant was admitted to the hospital at day 45 due to fever and severe headache occurring after receiving a SARS-CoV-2 vaccine on day 38 and had cholecystitis complications later in the study period, but these 2 events were established to be unrelated to the experimental agent. The most frequently occurring treatment-emergent adverse event was injection site reaction followed by headache, which were both generally mild.

The phase 2 trial (NCT05537571) that recently concluded builds upon the phase 1 trial similarly to the other siRNA investigational agents discussed in that it is larger, involved giving multiple doses in specific intervals to further evaluate safety and efficacy with repeated administration, and involves participants with higher risk ASCVD [31]. This placebo-controlled, randomized, double-blind study enrolled 178 patients with an elevated Lp(a) concentration of 125 nmol/L or greater and who are at high risk for ASCVD events defined as having a prior MI, stroke, CAD, PAD or computed tomography detected coronary calcium [32]. Participants who were randomized to receive placebo were given a subcutaneous placebo dose every 16 weeks for 3 doses or every 24 weeks for 2 doses. Those who were assigned to receive zerlasiran were given a subcutaneous dose of 450 mg every 24 weeks for 2 doses, 300 mg every 16 weeks for 3 doses, or 300 mg every 24 weeks for 2 doses. Rather than use maximal reduction in Lp(a) or lowering of Lp(a) by a specific time point, this study utilized time-averaged reduction in Lp(a) during 36 weeks of follow-up in an effort to more accurately report the effects of treatment over time that includes intervals between doses [32]. The least-squares mean placebo-adjusted time-averaged percent change in Lp(a) concentration from baseline to week 36 was greater than 80% for all groups (Table 2). Zerlasiran was found to be well-tolerated with the most common adverse events being mild injection site reactions, and none of the 20 serious adverse events in 17 patients were considered to be related to the investigational agent. The study provides evidence for a cumulative effect on Lp(a) reduction after several doses of an siRNA drug in that the 3 doses of 300 mg given every 16 weeks exhibited greater subsequent effects with 66% mean Lp(a) reduction 16 weeks after the first dose, which increased to 81% at 32 weeks or 16 weeks post second dose, and 83% at 48 weeks or 16 weeks post third dose. Such results may indicate that less frequent dosing may be reasonable in a long-term phase 3 trial [32].

Lepodisiran

The investigational agent lepodisiran (LY3819469) is a GalNAc-conjugated siRNA directed at hepatic synthesis of apo(a) [33]. Lepodisiran is being developed and studied with the aim of reducing the risk of major adverse cardiovascular events (MACE) in patients who have elevated risk of ASCVD and high Lp(a) levels [33]. In order to evaluate the primary outcomes of safety and tolerability and the secondary outcomes of pharmacokinetic effects after dose administration and pharmacodynamic effects of lepodisiran on Lp(a) levels, a single ascending-dose trial was conducted with the last follow-up visit occurring 336 days (48 weeks) after administration.

The phase 1 trial (NCT04914546) enrolled 48 adults across 5 clinical research sites in the US and Singapore who had elevated Lp(a) serum concentrations of either ≥75 nmol/L or or ≥30 mg/dL and who were not diagnosed with cardiovascular disease, but may have had dyslipidemia and well-controlled hypertension in the setting of clinical laboratory results within the normal reference range or with no clinical significance. Following randomization, participants received placebo or a single subcutaneous (SC) lepodisiran dose of either 4 mg, 12 mg, 32 mg, 96 mg, 304 mg, or 608 mg. With respect to the primary outcomes of safety and tolerability of these single ascending doses, lepodisiran was well tolerated with only 1 serious adverse event occurring that was a fall from a bicycle 141 days post injection resulting in a facial injury. Safety was assessed based on the occurrence of adverse events including injection site reactions, hypersensitivity reactions, hepatobiliary system reactions, and cytokine-release syndrome. Injection site reactions including pain at the injection site occurred for most patients in the various dosage groups including the placebo group. These were transient with most resolving prior to discharge from the clinical research unit. There were transient elevations of aminotransaminases greater than 3 times the upper limit of normal in two participants who received lepodisiran. There were transient elevations of creatine kinase levels greater than 5 times the upper limit of normal in three participants who were given lepodisiran. These abnormally increased values all normalized at the next follow up visit. Neither systemic hypersensitivity reactions or cytokine release syndrome events occurred.

The maximal median changes from baseline in serum Lp(a) concentrations for the single ascending lepodisiran doses appear in Table 1. Maximal median changes were greater than 90% for the 96 mg, 304 mg, and 608 mg doses. Reductions in serum Lp(a) concentrations were found to be long in duration, with a median change of −94% in Lp(a) at day 337 in the group that received a 608-mg dose, contributing favorably to the secondary outcome of pharmacodynamic effects of lepodisiran on plasma levels of fasting Lp(a) serum concentrations through a follow-up of 336 days (48 weeks).

Measurement of plasma levels of lepodisiran through 168 days constituted an additional secondary outcome of pharmacokinetic effects after dose administration. Lepodisiran plasma concentrations for all doses revealed dose-dependent increases, peaked within 10.5 hours, and were below the lower level of quantitation by 48 hours. Taken together, these two secondary outcomes point favorably to being able to dose lepodisiran once or twice per year and still achieve a high level of Lp(a) reduction while reducing potential side effects.

These favorable findings in a phase 1 trial support further study of this investigational agent. With a limitation of the aforementioned study being its relatively small sample-size, a larger phase 2 trial (NCT05565742) with an estimated recruitment of 216 participants is currently underway to further investigate the efficacy and safety of lepodisiran in adults with high levels of Lp(a) of at least 175 nmol/L [33,34]. ACCLAIM-Lp(a) is a phase 3 trial (NCT06292013) currently in recruitment will investigate the efficacy of lepodisiran in reducing MACE in adults with elevated Lp(a) [35]. Participants will have an elevated Lp(a) level of at least 175 nmol/L and must either be at least 18 years of age with established ASCVD with a prior event or revascularization or be at least 55 years old with risk factors for a first cardiovascular event such as familial hypercholesterolemia, coronary artery disease (CAD), peripheral artery disease (PAD), or other high-risk factors. With an enrollment goal of 12,500 the study is expected to follow participants over about 4.5 years with the primary outcome measure being that of time to first occurrence of a MACE-4 composite endpoint including cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, and urgent coronary revascularization [35].

Muvalaplin

Muvalaplin (LY3473329) is a small oral molecule inhibitor that targets the assembly of Lp(a) by disrupting the initial noncovalent interaction between apo(a) and apoB-100 thereby decreasing Lp(a) production and levels [1]. A phase 2 trial has recently been completed (NCT05563246) to further understand the efficacy and safety this oral investigational agent taken once per day in individuals with elevated Lp(a) of at least 175 nmol/L who are at high risk for cardiovascular events [36]. The unique role of muvalaplin as an orally administered agent may serve as a therapeutic alternative leading to wider reach in the intended population [1]. An orally administered drug may be feasible in certain patients for instance who are deterred by such issues as injection site reactions or who experience more intense injection site reactions, although findings in the aforementioned studies with siRNA agents have shown that injections site reactions have been mild.

The phase 1 (NCT04472676) randomized, double-blind, parallel-design study included both a single ascending dose group and a multiple ascending dose group. The participants in the single ascending dose group were administered either 1 mg, 10 mg, 30 mg, 100 mg, 200 mg, 400 mg, or 800 mg of muvalaplin. Those in the multiple ascending dose group were assigned to either receive 30 mg, 100 mg, 300 mg, 500 mg, or 800 mg of the investigational drug in which they orally ingested it once daily for 14 days [1]. These concentrations for the multiple ascending dose group were based on data from the single ascending dose group regarding safety and pharmacokinetics. Whereas the patients in the single ascending dose group were otherwise healthy with normal Lp(a) levels, patients who took muvalaplin daily for 14 days differed by having elevated Lp(a) levels equal to or greater than 30 mg/dL or 75 nmol/L [1,37].

No clinically significant adverse effects occurred. In the multiple ascending dose group, one adverse event acne was considered by the investigator to be related to the investigational agent. In terms of overall occurrences of adverse events for this group, the most common were headache (31%), diarrhea (20%), abdominal pain (15%), nausea (10%), and fatigue (10%). These were mostly mild in severity and transient.

In the multiple ascending dose group, reductions in Lp(a) levels from baseline occurred as early as day 2 [1]. The maximum placebo-adjusted reduction in Lp(a) levels was 63% to 65% following once per day administration of muvalaplin for 14 days. This percent reduction was seen with doses 100 mg and greater, and occurred on days 14 and 15. The time period for which Lp(a) levels returned to baseline ranged from day 29 for the 30 mg dose to day 64 for the 300 mg to 800 mg doses.

A comparison can be drawn with the aforementioned subcutaneously injected siRNA investigational agents that lower Lp(a) by more than 90% in many of the trialed doses. The orally administered muvalaplin lowers Lp(a) to a lesser degree at 63% to 65% [1]. However, the level of Lp(a) reduction for a therapeutic agent to be significant in lowering cardiovascular has yet to be established. Moreover, the 63% to 65% reduction stands as a notably greater reduction in Lp(a) than PCSK9 inhibitors approved for lowering LDL-C but also have an effect of lowering Lp(a) by about 20% to 25% [38].

The phase 2 trial (NCT05563246) as a placebo-controlled, randomized, double-blind study enrolled 233 participants with an elevated Lp(a) concentration of 175 nmol/L or greater and who are at high risk for cardiovascular events defined as having documented CAD, stroke, PAD, or ASCVD risk equivalents such as FH or type 2 diabetes [39]. Participants were assigned to receive once daily muvalaplin doses of either 10 mg, 60 mg, or 240 mg or placebo for 12 weeks. Placebo-adjusted percent changes from baseline in Lp(a) molar concentration were assessed using an assay to measure intact Lp(a) and a traditional apolipoprotein(a)-based assay. As muvalaplin inhibits the assembly of Lp(a) by disrupting the initial noncovalent interaction between apo(a) and apoB-100 the traditional apolipoprotein(a)-based assay that will effectively measure apolipoprotein(a) in intact Lp(a) particles, free apolipoprotein(a), and apolipoprotein(a) bound to muvalaplin may overestimate serum Lp(a) concentrations [39]. The utilization of an assay that measures intact Lp(a) effectively controlling for apolipoprotein(a) particles that are not in Lp(a) provides further support for the efficacy of muvalaplin. Placebo-adjusted reductions in Lp(a) were 47.6%, 81.7%, and 85.8% for the 10 mg/d, 60mg/d, and 240 mg/d dosages respectively using the novel intact Lp(a) assay. Using the traditional apolipoprotein(a)-based assay, the decreases in Lp(a) were 40.4%, 70.0%, and 68.9% for the muvalaplin doses of 10mg/d, 60mg/d, and 240 mg/d respectively (Table 3). Doses were well tolerated with no safety concerns noted.

Obicetrapib

Obicetrapib is a next-generation, oral, once-daily, low dose cholesteryl ester transfer protein (CETP) inhibitor currently in phase 3 cardiovascular outcomes trials that has demonstrated favorable safety and tolerability [45]. A pooled analysis on two phase 2 trials revealed that 10 mg of obicetrapib on top of high-intensity statin lowered Lp(a) by 57% vs placebo [46,47]. This is greater than PCSK9 inhibitors that reduce Lp(a) concentration by 20% to 25%, but as with PCSK9 inhibitors CETP inhibitors also reduce LDL-C, which may further compound the task of apportioning the benefit of this class of agents in reducing cardiovascular events to individual lipoprotein effects [6]. CETP is a hepatically secreted plasma glycoprotein involved in the bidirectional transfer of cholesteryl esters and triglycerides between HDL, very low-density lipoprotein (VLDL), and LDL particles, resulting in a net mass transfer of cholesteryl esters from HDL to VLDL and LDL and a net mass transfer of triglycerides from VLDL to LDL and HDL [45,48]. Although trials involving earlier generation CETP inhibitors did not demonstrate reduced risk of ASCVD, several next-generation CETP inhibitors have shown promising results for ASCVD risk reduction. The ROSE1 and ROSE2 phase 2 trials examined the effects of obicetrapib on top of high-intensity statins in patients with LDL greater than 70 mg/dL and without CVD [46,47]. Participants in ROSE1 received 5 or 10 mg of obicetrapib or placebo for 8 weeks. Those in ROSE2 received 10 mg of obicetrapib, 10 mg of obicetrapib and 10 mg ezetimibe, or placebo for 12 weeks. Median percent changes in LDL-C from baseline for 10 mg monotherapy were 50.8% in ROSE1 and 43.5% in ROSE2 [45]. Median percent changes in Lp(a) from baseline for 10 mg monotherapy were 56.5% in ROSE1 and 47.2 in ROSE2.

Gene-editing therapy

Medications based on gene-editing technology have the potential to precisely and permanently modify genes involved in disease processes, providing lasting therapeutic effects [49]. Rather than regular repeating doses, gene-editing medications in altering DNA sequences permanently are administered as a one-time treatment. The first gene-editing medication exagamglogene autotemcel was approved in 2023 and is indicated for sickle cell disease and beta thalassemia. Research and clinical trials are underway for gene-editing investigational agents to treat dyslipidemia including VERVE-102 that is being evaluated in the Heart-2 open-label phase 1b clinical. VERVE-102 is an investigational gene editing agent consisting of mRNA expressing an adenine base editor, guide RNA targeting the PCSK9 gene, and a GalNAc liver-targeting ligand, designed to permanently inactivate the PCSK9 gene in the liver and reduce LDL-C [50]. The earlier VERVE-101 agent demonstrated time-averaged reductions in LDL-C based on at least 28 days of follow up of 42% for a 0.45 mg/kg dose and 57% for a 0.6 mg/kg dose. Enrollment in the clinical trial for VERVE-101 has since been paused due to a grade 3 drug-induced transient elevation of serum alanine aminotransferase and grade 3 drug-induced thrombocytopenia [51]. VERVE-102 utilizes a different lipid nanoparticle delivery system that may reduce the potential for such side effects [50]. Research is underway to develop a single-course in vivo gene editing therapy to permanently lower Lp(a) using a novel editor [52]. Gene-editing therapy for treating dyslipidemia is promising with the potential for medications that may be given as a one-time dose with target-specific uptake. With the first gene-editing medication having been approved in 2023, concerns surrounding this relatively new therapy include the risk of germline editing and off-target gene edits. Gene-based therapies are among the most expensive medications, with list prices over 4 million US dollars for one patient [53].

Discussion

Common patterns and themes emerge with the various trial phases of these investigational agents. Safety and tolerability are established, with no serious adverse events attributed to any of the agents under investigation thus far. Common adverse events that have been mostly mild include injection site reactions for the 4 potential therapies with a subcutaneous route of administration. Trials of these agents reveal significant lowering of Lp(a) that is dose-dependent and long-lasting. As compared to inhibitors of PCSK9 that primarily treat dyslipidemia by lowering LDL-C in addition to some measured benefit in lowering Lp(a) by 20% to 25%, these 5 potential therapies specifically targeting Lp(a) have been shown to reduce Lp(a) by 63% to 65% for the orally administered small molecule inhibitor muvalaplin, 80% for the subcutaneously injected ASO pelacarsen, and over 90% for the siRNAs lepodisiran, olpasiran, and zerlasiran. Following successful phase 1 results for pharmacodynamic and safety profiles, phase 2 trials are needed with longer exposure and repeat dosing to further elucidate the duration of Lp(a) reduction and safety of the potential therapeutic.

Phase 3 trials are needed to establish therapeutic benefit of these agents in reducing risk of cardiovascular outcomes in those with elevated levels of Lp(a). Perhaps the promising results with regard to safety as well as efficiency can be partially explained through the use of a familiar method of organ-specific targeting in siRNA agents including those that have already been FDA approved such as the siRNA medication inclisiran that lowers LDL-C through inhibition of PCSK9 production. With therapies having a long duration of action, there is a theoretical concern over the likelihood for adverse events that may be irreversible [4]. Conjugation of the drug with GalNAc provides targeting to the asialoglycoprotein receptors highly and almost exclusively expressed on the surface of hepatocytes. This specificity allows for efficiency in being able to utilize a lower dose as well as safety in limiting systemic exposure [4]. Indeed, with pelacarsen, we see that GalNAc conjugation resulted in an increase in potency by a factor of 15 to 30 with a dose-dependent Lp(a) reduction of 66% to 92% in patients with elevated Lp(a) levels compared to 39.6% to 77.8% for the non-GalNAc conjugated predecessor [18–20].

Longer intervals between dosing may increase the number of patients who achieve and maintain therapeutic goals, as many patients may find it challenging to comply with more frequent medication administration. Low patient adherence may be attributed to several factors such as more frequent dosing recommendations as well as factors related to social determinants of health, including limited accessibility, and higher cost [16]. As a comparison the siRNA drug inclisiran that inhibits PCSK9 production and lowers LDL-C is dosed in longer intervals of once or twice yearly compared to the more frequently dosed monoclonal antibodies that are given at twice per week or once per month schedules [4,16]. RNA therapies based in interference as siRNA drugs tend to need less frequent dosing that other medications including other RNA-based ones such as antisense oligonucleotide based (ASO) [4,40]. This may be attributed to unique aspects of their degradation mechanisms. ASOs as single strands bind to their complementary target mRNA in cells leading to RNAse-H activation and mRNA degradation [41]. The antisense strand of double-stranded siRNAs binds to the RISC that then cleaves target mRNA. As siRNAs remain bound to the RISC, they can target multiple mRNA copies extending their effect further [41]. However, ASOs do have certain possible advantages. The single strand structure of ASOs may help to simplify and lower costs of production compared to double-stranded siRNAs [42]. As they are double-stranded, siRNAs face more challenging delivery to their target tissue compared to single-stranded ASOs [43]. However, siRNAs do have notable advantages as well. It is relatively easier and simpler to identify active and potent siRNAs, and siRNAs are more robust and stable whereas ASOs necessitate chemical modifications to be active inside cells [42]. In addition, continued research and development has facilitated the improvement of both ASOs and siRNAs with regard to modifications that increase their stability and efficacy as well as specific targeting to limit systemic exposure and improve potency [41].

Conclusion

Additional work will be needed to elucidate the level of Lp(a) reduction needed for clinical benefit. Notably, the orally administered muvalaplin lowers Lp(a) to a lesser degree than the aforementioned subcutaneously injected siRNA agents [1]. Without an established level of Lp(a) reduction for a medication to be therapeutically advantageous in lowering cardiovascular risk, it will be vital to see the results of phase 2 and 3 clinical trials in order to understand the viability of each of these potential medications with their differing levels of effect on lowering Lp(a). It is estimated that 1.4 billion of the global population have elevated Lp(a) above 50 mg/dL or 125 nmol/L [21,44]. As clinical trials for potential Lp(a) lowering drugs advance, the clinical practice recommendation by the National Lipid Association (NLA) to measure Lp(a) levels at least once in every adult for risk stratification has practical use in that health care professionals currently can perhaps more aggressively treat those patients with elevated Lp(a) results that deem them at higher risk for adverse cardiovascular outcomes.

Just as race and ethnicity have been studied in terms of Lp(a) levels and differences in cardiovascular disease risk, these social determinants of health should continue to be considered for future studies involving these potential therapies [54]. In the phase 2 trial of Olpasiran for example, only 2% of the patients identified as Hispanic, yet it has been noted that higher Lp(a) levels have been found in Black and Hispanic populations. Future studies should plan specifically to recruit sufficient numbers from these populations.

Although steps such as improved diet, increased exercise, and medications to lower LDL do not necessarily reduce Lp(a) concentration, they nevertheless may reduce ASCVD risk and improve outcomes. Furthermore, the use of PCSK9 inhibitors may be a more viable option to lower LDL in those with elevated Lp(a) given that these medications reduce Lp(a) albeit to a lower degree than the previously discussed investigational agents currently in clinical trials. Should phase 3 trials establish a benefit in lowering Lp(a) and reducing CVD risk, the need for a variety of medication options that may be differentiated by routes of administration, dosing schedules, and costs cannot be understated. The time, effort, and financial resources spent on targeting what many understand is one of the remaining untreatable ASCVD risk factors may prove to be a significant stride in improving outcomes as research continues to indicate a major role for Lp(a) in cardiac-related disease.