Potential of muvalaplin as a lipoprotein(a) inhibitor

KEYWORDS:

• ApoB
• LDL
• LDL-cholesterol
• Lp(a)
• Lp(a) inhibitor
• muvalaplin

1. Introduction

Discovered 60 years ago, lipoprotein(a) [Lp(a)] is a unique lipoprotein class found only in hedgehogs and primates, and whose physiological function is unknown [1]. Lp(a) is assembled in the liver and consists of a low density lipoprotein (LDL)-like particle, with the apoB-100 of LDL attached by a disulfide bond to apo(a), a large polymorphic hydrophilic glycoprotein (M_r 300–800 kDa), with structural homology to plasminogen, which is encoded by the LPA gene [2]. Circulating Lp(a) levels exhibit a strong genetic component (estimated to be ~90%) related to variation at the LPA locus, primarily due to a variable number of repeat copies of the kringle IV (KIV)-2 domain. Individuals with smaller apo(a) isoforms (≤22 repeats) have 4–5 times higher plasma Lp(a) than larger isoforms (>22 repeats) [3]. As such, plasma Lp(a) levels vary widely, ranging from <0.2 nmol/L (0.1 mg/dL) to >750 nmol/L (300 mg/dL), with most people having values <75 nmol/L (30 mg/dL). Racial and ethnic differences in Lp(a) levels have been reported [4], and Lp(a) levels are higher in women than men, with diet and lifestyle measures having minimal effect [3]. Plasma Lp(a) levels are primarily determined by the rate of production, with the liver (and to a much lesser extent the kidneys and arterial wall) implicated in Lp(a) uptake and clearance [5].

An association between elevated Lp(a) and coronary artery disease (including myocardial infarction) have been long known; however, it was only in the past decade and a half that large observational, genome-wide association, and Mendelian randomization studies demonstrated that elevated Lp(a) is an independent and causative risk factor for atherosclerotic cardiovascular disease (ASCVD) and calcific aortic valve disease [4,6]. Lp(a)’s pro-atherosclerotic and pro-calcific properties are mediated, in large part, by the load of oxidized phospholipids bound to apo(a), which stimulate proinflammatory pathways [7].

The estimated prevalence of an elevated Lp(a) >100 nmol/L (40 mg/dL) is approximately one in five people. Like LDL-cholesterol, there is a continuous relationship between Lp(a) levels and ASCVD risk, which commences at ~50 nmol/L (20 mg/dL), ranging from ~1.2-fold increased relative risk at 75 nmol/L (30 mg/dL), ~2-fold at 250 nmol/L (100 mg/dL), and up to ~2.7-fold at 375 nmol/L (150 mg/dL), irrespective of baseline risk [3]. International guidelines have recognized elevated Lp(a) as a risk enhancing factor and recommended that Lp(a) be used in the assessment and stratification of ASCVD risk [3,4].

Although statins are first-line agents to reduce plasma LDL-cholesterol, they do not cause clinically significant changes in Lp(a) [8]. Lipoprotein apheresis, the only FDA-approved treatment for elevated Lp(a), can acutely lower Lp(a) ~60–70%, and although efficient, the procedure is time-consuming, and its cost and accessibility limit its routine use [9]. Niacin derivatives and proprotein convertase subtilisin/kexin type 9 (PCSK9)-targeted therapies, including two human monoclonal antibodies (alirocumab and evolocumab) and a small interfering RNA (siRNA) inhibitor (inclisiran), all reduce Lp(a) levels by ~20–25% [10], which is insufficient to mitigate Lp(a)-associated ASCVD risk. However, having fewer study participants with increased Lp(a) concentrations, as well as heterogeneity of drug effects across both LDL-cholesterol and Lp(a), has made it difficult to clearly separate effects.

The development of specific Lp(a)-targeted antisense oligonucleotides (ASO) and siRNA-based therapies has enabled significant lowering of Lp(a) by reducing hepatic apo(a) synthesis. Specific targeting of the drugs to the liver has been achieved by conjugation to N-acetylgalactosamine (GalNAc). The ASO pelacarsen (Novartis) demonstrated potent dose-dependent reductions of Lp(a) of up to 80% in phase II trials [11]. Two siRNA therapies, olpasiran (Amgen) and SLN360 (Silence Therapeutics), were shown to reduce Lp(a) by more than 95% [12,13]. When administered every 12 weeks, olpasiran maintained sustained Lp(a) lowering [12]. Results from the HORIZON (NCT04023552) and OCEAN(a) (NCT05581303) phase III trials of pelacarsen and olpasiran, respectively, assessing the impact of lowering Lp(a) on major adverse cardiovascular events (MACE) in patients with ASCVD, are awaited with interest.

Although ASOs and siRNA-based therapies effectively lower Lp(a), injection site reactions, although mild, may hinder their use. A single-center phase I trial (NCT04472676) of the first orally administered inhibitor of Lp(a), muvalaplin (Eli Lilly), previously known as LY3473329, has recently been reported by Nicholls and colleagues [14]. Muvalaplin is a small molecule that prevents Lp(a) formation by binding to the apo(a) KIV domains 7 and 8, thus preventing the initial noncovalent interaction with the lysine in apoB-100. The single ascending dose (1–800 mg) study in 55 healthy participants with a range of Lp(a) levels (median 10 mg/dL) showed a dose-dependent maximum plasma concentration of muvalaplin reached 2–5 h post dosing followed by a multiphasic distribution, with an elimination half-life of 12–67 h. The multiple ascending dose study included 59 participants with a median Lp(a) of 58 mg/dL, taking muvalaplin (30, 100, 300, 500 or 800 mg) daily for 14 days. The plasma elimination half-life values ranged from 3 days to 15 days with minimal to no accumulation. Total plasma exposure increased with dosing but was not proportional. Reductions in Lp(a) were seen as early as day 2 and a maximum reduction of 63% to 65% for doses of 100 mg or more was observed on days 14 and 15, and effects persisted for almost 2 months for doses ≥300 mg. In both cohorts other lipid parameters, including total cholesterol, LDL-cholesterol, and apoB, did not significantly change, although a modest correlation between changes in Lp(a) and apoB and LDL-cholesterol levels was found.

Reported adverse events deemed to be related to the study drug were mild and few in number (headache in three participants after a single 800 mg dose; acne in one participant with 30 mg ascending dose), with one moderate event (vomiting) observed in one participant after a single 800 mg dose [14]. No hematological adverse events were observed and, importantly, given apo(a)’s homology to plasminogen, muvalaplin had only a minimal effect on plasminogen activity (up to 14% reduction) that was independent of dose, suggesting that fibrinolysis will not be affected.

2. Expert opinion

Accumulating evidence has implicated Lp(a) as an independent and causal risk factor for ASCVD and calcific aortic valve disease. As such, there is much interest in the development of specific Lp(a)-targeting therapies to reduce residual cardiovascular risk. Muvalaplin is the first oral agent specifically developed to lower levels of Lp(a) by disrupting its formation in the liver. In a first-in-human phase I trial in patients with low to moderately increased Lp(a) levels, muvalaplin resulted in dose-dependent lowering of Lp(a) with no tolerability issues or clinically significant adverse effects, like the injectable therapies targeting Lp(a) in development (olpasiran and pelacarsen). The maximum reduction of Lp(a) was comparatively less than that observed with injectable Lp(a)-specific therapies in current development, although the level of Lp(a) reduction needed to decrease MACE is not established. Muvalaplin, being an oral agent, gives advantages in view of patient acceptability, convenience, and potentially price, which may all significantly impact on patient compliance (Table 1). In addition, in the muvalaplin trial Lp(a) was measured in mass, rather than in the recommended molar units, which is likely to detect apo(a) bound to muvalaplin in the circulation and therefore has the potential to underestimate Lp(a) lowering with this agent.

Table 1. Comparison of Lp(a) lowering pharmacological agents.

Drug	Route of Administration	Mechanism of Action	Lp(a) Lowering Efficacy	Current Development Phase	Reference
Muvalaplin (LY3473329)	Oral	Small molecule, which prevents Lp(a) formation by blocking interaction of apo(a) with apoB-100	63–65% at daily doses of 100 mg or more	Phase II	[14]
Pelacarsen (IONIS-APO(a)-LRx, AKCEA-APO(a)-LRx, TQJ230)	Subcutaneous injection	GalNAc-conjugated ASO, which causes apo(a) mRNA degradation mediated by mRNA-antisense duplex formation	72% at 60 mg every 4 weeks; 80% at 20 mg weekly	Phase III	[11]
Olpasiran (AMG 890)	Subcutaneous injection	GalNAc-conjugated siRNA, which causes apo(a) mRNA degradation mediated by RNA-induced silencing complex	70–100% at doses of 10 mg every 12 weeks and 225 mg every 24 weeks respectively	Phase III	[12]

Two additional trials of muvalaplin are nearing completion, estimated for early 2024. The first will examine the pharmacokinetics of muvalaplin in participants with renal impairment compared to participants with normal renal function (NCT05778864), while the second, KRAKEN, is a phase II, randomized double-blind placebo-controlled study in an estimated 233 participants with elevated Lp(a) at high risk for cardiovascular events (NCT05563246). There is a need for well-designed clinical trials, with defined Lp(a) thresholds and diverse population groups, using an apo(a) isoform-independent assay with appropriate calibrators (traceable to the WHO/IFCC reference material) and reported in molar units, to assess cardiovascular outcomes in initially secondary and eventually primary prevention [15].

Declaration of interests

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This paper was not funded.