Oral Muvalaplin Lowered Lipoprotein(a): The KRAKEN Trial

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By Joseph Kim on

Key Takeaways:

  1. KRAKEN was an international, multicenter, placebo controlled, phase 2 trial that tested the effects of muvalaplin at different doses—10 mg, 60 mg or 240 mg, taken daily—vs placebo for 12 weeks.
  2. Muvalaplin reduced Lp(a) levels by up to 85.8% at the highest dose (240 mg/day), with 96.7% of participants in this group achieving Lp(a) levels below 125 nmol/L.
  3. The safety profile of muvalaplin was favorable, with mild to moderate gastrointestinal events being the most common side effects and no significant concerns regarding liver function or systemic inflammation markers.
  4. Muvalaplin represents a significant advancement in addressing elevated Lp(a) levels, offering a potential oral treatment option that could reduce cardiovascular risk in individuals with high Lp(a) concentrations.

Lp(a) is a genetically determined cardiovascular risk factor associated with atherosclerotic cardiovascular disease (ASCVD) and calcific aortic valve stenosis. Current treatment options for elevated Lp(a) levels are limited, and no approved pharmacologic therapies exist. Muvalaplin disrupts the initial binding of apolipoprotein(a) and apolipoprotein B, preventing the formation of Lp(a) particles. The phase 2 KRAKEN trial (Clinical Trials.gov number NCT05563246) aimed to assess the efficacy, safety, and tolerability of muvalaplin in reducing Lp(a) levels over 12 weeks.

This double-blind, placebo-controlled study enrolled 233 participants aged 40 years or older across 43 centers in eight countries. Participants were required to have baseline Lp(a) concentrations of 175 nmol/L or greater and a history of ASCVD, type 2 diabetes, or familial hypercholesterolemia. Subjects were randomized to receive muvalaplin at doses of 10 mg/day (n=34), 60 mg/day (n=64), or 240 mg/day (n=68), or placebo (n=67), for 12 weeks.

At week 12, muvalaplin reduced Lp(a) levels in a dose-dependent manner. With the intact Lp(a) assay, placebo-adjusted reductions were 47.6% (95% CI, 35.1%-57.7%) for 10 mg/day, 81.7% (95% CI, 78.1%-84.6%) for 60 mg/day, and 85.8% (95% CI, 83.1%-88.0%) for 240 mg/day. With the apolipoprotein(a)-based assay, placebo-adjusted reductions were 40.4% (95% CI, 28.3%-50.5%) for 10 mg/day, 70.0% (95% CI, 65.0%-74.2%) for 60 mg/day, and 68.9% (95% CI, 63.8%-73.3%) for 240 mg/day. Additionally, 96.7% of participants in the 240 mg/day group achieved Lp(a) levels below 125 nmol/L using the intact assay, compared to 6.0% in the placebo group (p<0.001).

Secondary endpoints included reductions in apolipoprotein B, which decreased by up to 16.1% (95% CI, 7.8%-23.7%) at the highest dose. High-sensitivity C-reactive protein levels showed no significant changes. Adverse events were mild to moderate, with gastrointestinal symptoms being the most common. Serious adverse events occurred in fewer than 6% of participants across all groups, with no significant differences in liver function parameters.

Dr. Stephen J. Nicholls, the study’s lead investigator, remarked, “Muvalaplin offers a promising therapy for reducing lipoprotein(a) levels in individuals at high cardiovascular risk. These findings are particularly striking for an oral medication.” The results support the continued evaluation of muvalaplin in phase 3 studies to determine its potential to reduce cardiovascular morbidity and mortality.