Muvalaplin, an Oral Small Molecule Inhibitor of Lipoprotein(a) Formation

Abstract

ImportanceLipoprotein(a) (Lp[a]) is associated with atherosclerotic disease and aortic stenosis. Lp(a) forms by bonding between apolipoprotein(a) (apo[a]) and apo B100. Muvalaplin is an orally administered small molecule that inhibits Lp(a) formation by blocking the apo(a)-apo B100 interaction while avoiding interaction with a homologous protein, plasminogen.ObjectiveTo determine the safety, tolerability, pharmacokinetics, and pharmacodynamic effects of muvalaplin.Design, Setting, and ParticipantsThis phase 1 randomized, double-blind, parallel-design study enrolled 114 participants (55 assigned to a single-ascending dose; 59 assigned to a multiple-ascending dose group) at 1 site in the Netherlands.InterventionsThe single ascending dose treatment evaluated the effect of a single dose of muvalaplin ranging from 1 mg to 800 mg or placebo taken by healthy participants with any Lp(a) level. The multiple ascending dose treatment evaluated the effect of taking daily doses of muvalaplin (30 mg to 800 mg) or placebo for 14 days in patients with Lp(a) levels of 30 mg/dL or higher.Main Outcomes and MeasuresOutcomes included safety, tolerability, pharmacokinetics, and exploratory pharmacodynamic biomarkers.ResultsAmong 114 randomized (55 in the single ascending dose group: mean [SD] age, 29 [10] years, 35 females [64%], 2 American Indian or Alaska Native [4%], 50 White [91%], 3 multiracial [5%]; 59 in the multiple ascending dose group: mean [SD] age 32 [15] years; 34 females [58%]; 3 American Indian or Alaska Native [5%], 6 Black [10%], 47 White [80%], 3 multiracial [5%]), 105 completed the trial. Muvalaplin was not associated with tolerability concerns or clinically significant adverse effects. Oral doses of 30 mg to 800 mg for 14 days resulted in increasing muvalaplin plasma concentrations and half-life ranging from 70 to 414 hours. Muvalaplin lowered Lp(a) plasma levels within 24 hours after the first dose, with further Lp(a) reduction on repeated dosing. Maximum placebo-adjusted Lp(a) reduction was 63% to 65%, resulting in Lp(a) plasma levels less than 50 mg/dL in 93% of participants, with similar effects at daily doses of 100 mg or more. No clinically significant changes in plasminogen levels or activity were observed.ConclusionMuvalaplin, a selective small molecule inhibitor of Lp(a) formation, was not associated with tolerability concerns and lowered Lp(a) levels up to 65% following daily administration for 14 days. Longer and larger trials will be required to further evaluate safety, tolerability, and effect of muvalaplin on Lp(a) levels and cardiovascular outcomes.Trial RegistrationClinicalTrials.gov Identifier: NCT04472676

Lepodisiran, an Extended-Duration Short Interfering RNA Targeting Lipoprotein(a)

“…Zerlasiran (SLN360), which is a short interfering RNA, and lepodisiran are currently being studied in phase 2 trials. A daily administered oral therapy, muvalaplin, that disrupts the association of apolipoprotein(a) and apolipoprotein B has recently shown safety and efficacy in lowering lipoprotein(a) concentrations . However, it remains uncertain whether any of these therapies will reduce major adverse cardiovascular events.…”

The current status of lipoprotein (a) measurement in clinical biochemistry laboratories in the UK: Results of a 2021 national survey

“…In conclusion, despite the urgent need to standardise and harmonise Lp(a) assays in the UK due to its clinical application in personalised cardiovascular risk assessment 12 and rapid progress in the development of novel, specific therapies that can potently lower serum Lp(a) concentrations, [14][15][16] clinical biochemistry laboratories in the UK still have a have much do to achieve these goals. The recommendations regarding Lp(a) measurement and reporting made in the 2019 HEART UK consensus statement have now been substantially adopted by the majority of in-house service providers who accept external referrals, but the majority of laboratories overall still report Lp(a) in mass units without evidence of traceability to the WHO/ IFCC reference assay.…”

Estimating the Prevalence and Characteristics of Patients Potentially Eligible for Lipoprotein(a)-Lowering Therapies in a Real-World Setting

“…A relevant Lp(a)-lowering effect has been recently shown also in a phase I trial on an oral drug, muvalaplin, introducing a different option for targeting Lp(a) in clinical development [11]. Muvalaplin is the first oral agent specifically developed to disrupt Lp(a) formation by blocking the initial noncovalent interaction between apo(a) and apo B-100 [11]. Of course, it should be noted that oncedaily administration of muvalaplin lowers Lp(a) levels to a lesser degree (~65%) than parenteral therapies currently in development, even though the molecule has not been associated with any serious adverse effects in the short term.…”

“…The available evidence shows that the monthly subcutaneous administration of these agents yields reductions in Lp(a) up to 95% that persist over time and are expected to be enough to optimize the risk of ASCVD, as far as reductions in Lp(a) plasma levels by 80-90% are expected to exert a clinically significant effect [10]. A relevant Lp(a)-lowering effect has been recently shown also in a phase I trial on an oral drug, muvalaplin, introducing a different option for targeting Lp(a) in clinical development [11]. Muvalaplin is the first oral agent specifically developed to disrupt Lp(a) formation by blocking the initial noncovalent interaction between apo(a) and apo B-100 [11].…”