Can muvalaplin achieve safe and tolerable plasma concentrations adequate to reduce steady-state Lp(a) levels without modulating plasminogen activity in humans?

In a recent study published in JAMA, researchers evaluated the tolerability, safety, pharmacodynamics, and pharmacokinetic properties of muvalaplin.

Muvalaplin, an Oral Small Molecule Inhibitor of Lipoprotein(a) Formation A Randomized Clinical Trial
Study: Muvalaplin, an Oral Small Molecule Inhibitor of Lipoprotein(a) Formation A Randomized Clinical Trial. Image Credit: Shidlovski/Shutterstock.com

Background

Lipoprotein(a) has been linked to aortic stenosis and atherosclerosis. Lipoprotein(a) is formed by the interaction of apolipoprotein(a) with apolipoprotein B100. Muvalaplin, a small molecule drug, suppresses lipoprotein(a) synthesis by inhibiting the apolipoprotein(a)-apolipoprotein B100 association while avoiding contact with plasminogen, a similar protein when administered orally.

Despite the excellent decrease in low-density lipoprotein cholesterol (LDL-C) concentration, the remaining risk of cardiovascular events supports the need for novel medicines that change other risk variables implicated in the development of atherosclerotic cardiovascular disease. Lipoprotein(a) has been linked to aortic stenosis and atherosclerotic cardiovascular disease, according to growing data.

About the study

In the present randomized clinical trial, researchers investigated whether muvalaplin could attain safe and tolerable plasma concentrations sufficient to decrease steady-state lipoprotein(a) levels without altering plasminogen activity among humans.

The randomized, parallel-design, double-blind, placebo-controlled study at a facility in the Netherlands comprised 114 individuals, of whom 55 and 59 were allocated to the single- and multiple-dosage groups, respectively. The outcome measures of the phase 1 trial were the tolerability, safety, pharmacodynamics, and pharmacokinetics of muvalaplin.

The single-escalating dosage therapy was used to assess the impact of one dose of the drug ranging between 1-800 mg ingested by healthy persons regardless of lipoprotein(a) levels. The multiple-escalating dosage therapy assessed the influence of administering regular doses of 30 to 800 milligrams of Muvalaplin or placebo therapy for two weeks in individuals with lipoprotein(a) levels ≥30 mg/dL.

The study comprised healthy adults aged 18 to 69 years with body mass index (BMI) values equal to or less than 30. Adverse event monitoring, clinical laboratory examinations, vital signs, 12-lead electrocardiogram, physical examination, and body weight were all included in the safety assessments.

Lipoprotein(a), total cholesterol, triglycerides (TG), LDL-C, high-density lipoprotein cholesterol (HDL-C), and apo B100 levels were measured during exploratory pharmacodynamic monitoring. Plasminogen concentration, plasminogen activity, high-sensitivity C-reactive protein (hs-CRP), 2-antiplasmin, plasminogen activator inhibitor 1, and tissue plasminogen activator antigen were all monitored pharmacodynamic indicators.

Results

Out of 114 randomized individuals, 105 completed the trial. Among single-ascending dosage group individuals, the mean age was 29 years, 35 were female (64%), 2 were American Indians or Alaskan Natives (4%), 50 were white (91%), and three were multiracial (5%). Among the multiple-escalating dosage group individuals, the mean age was 32 years; 34 were female (58%); three were Alaska Native or American Indian (5%), 47 were white (80%), six were black (10%), and three were multiracial (5%).

Among individuals in the single ascending dose group, the baseline median lipoprotein(a) levels were 10 mg/dL and the LDL cholesterol levels were 104 mg/dL, and among the multiple-ascending group, the corresponding levels were 58 mg/dL and 116 mg/dL, respectively. Muvalaplin reached maximal serological concentration between two and five hours after dosing, across the 10 to 800 mg dose range, and demonstrated a multiphasic reduction thereafter.

Muvalaplin showed no tolerance issues or side effects of clinical significance. The majority of adverse events associated with treatment were of modest severity, transient in nature, and resolved without ramifications. There were no fatalities or serious adverse effects reported.

Over two weeks, oral doses ranging between 30 and 800 mg increased muvalaplin concentrations in serum, with a half-life that ranged between 70 and 414 hours increasing with doses between 30 and 500 mg. Muvalaplin reduced serological lipoprotein(a) levels after 24 hours of the initial dose, with additional decreases occurring with each subsequent dose.

The maximal placebo-adjusted reduction in lipoprotein(a) levels ranged between 63% and 65%, with serological lipoprotein(a) levels below 50 mg per dL among 93% of individuals, with equivalent results at regular doses of ≥100 mg. At the clinical level, no significant differences were observed in plasminogen activity or levels.

Lipoprotein(a) levels were reduced from baseline on the second day of repeated doses. Lipoprotein(a) levels reverted to baseline after 29 days for the 30 mg dosage, 43 days for the 100 mg dose, and 64 days for the dosage range between 300 and 800 mg. Other indicators, such as total cholesterol, LDL-C, HDL-C, TG, and apoB100 levels, did not change significantly when muvalaplin was compared to placebo at any dose.

Conclusions

Overall, the study findings showed that muvalaplin was tolerable and lowered lipoprotein(a) levels by ≤65% after two weeks of regular treatment. The demonstrated pharmacological characteristics and safety of muvalaplin in healthy participants support further clinical evaluation in people with increased lipoprotein(a) levels.

Further research is required, including bigger sample sizes and longer follow-ups, to determine the effects, tolerability, and safety of the small molecule inhibitor of lipoprotein(a) on lipoprotein(a) levels in serum and cardiometabolic outcomes.

Journal reference:
Pooja Toshniwal Paharia

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Pooja Toshniwal Paharia

Dr. based clinical-radiological diagnosis and management of oral lesions and conditions and associated maxillofacial disorders.

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