Lipid-efficacy RCT · JAMA 2025
KRAKEN trial
Oral Muvalaplin for Lowering of Lipoprotein(a): A Randomized Clinical Trial.
The bottom line
Oral muvalaplin produced large, dose-dependent reductions in lipoprotein(a) over 12 weeks with no safety or tolerability concerns, though whether this translates into fewer cardiovascular events is still unknown.
Primary lipid endpoint metUS status: Investigational
At a glance
- Medicine
- Muvalaplin orally administered at dosages of 10 mg/d (n = 34), 60 mg/d (n = 64), or 240 mg/d (n = 68)
- Compared with
- Placebo (n = 67)
- People
- 233
- Who took part
- 233 participants with lipoprotein(a) concentrations of 175 nmol/L or greater with atherosclerotic cardiovascular disease, diabetes, or familial hypercholesterolemia at 43 sites in Asia, Europe, Australia, Brazil, and the United States
- Design
- Phase 2, placebo-controlled, randomized, double-blind trial
- Follow-up
- 12 weeks
- Main question
- Placebo-adjusted percentage change from baseline in lipoprotein(a) molar concentration at week 12, using an assay to measure intact lipoprotein(a) and a traditional apolipoprotein(a)-based assay
Main result
Muvalaplin resulted in placebo-adjusted reductions in lipoprotein(a) of 47.6% (95% CI, 35.1%-57.7%), 81.7% (95% CI, 78.1%-84.6%), and 85.8% (95% CI, 83.1%-88.0%) for the 10-mg/d, 60-mg/d, and 240-mg/d dosages, respectively, using an intact lipoprotein(a) assay and 40.4% (95% CI, 28.3%-50.5%), 70.0% (95% CI, 65.0%-74.2%), and 68.9% (95% CI, 63.8%-73.3%) using an apolipoprotein(a)-based assay.
Effect on LDL cholesterol
Not reported (lipoprotein(a) and apolipoprotein B reported; dose-dependent reductions in apolipoprotein B observed at 8.9% (95% CI, -2.2% to 18.8%), 13.1% (95% CI, 4.4%-20.9%), and 16.1% (95% CI, 7.8%-23.7%) at 10 mg/d, 60 mg/d, and 240 mg/d, respectively)
Other results
Secondary end points included the percentage change in apolipoprotein B and high-sensitivity C-reactive protein; no change in high-sensitivity C-reactive protein was observed
Safety
No safety or tolerability concerns were observed at any dosage.
In the trial's own words
“Muvalaplin resulted in placebo-adjusted reductions in lipoprotein(a) of 47.6% (95% CI, 35.1%-57.7%), 81.7% (95% CI, 78.1%-84.6%), and 85.8% (95% CI, 83.1%-88.0%) for the 10-mg/d, 60-mg/d, and 240-mg/d dosages, respectively, using an intact lipoprotein(a) assay and 40.4% (95% CI, 28.3%-50.5%), 70.0% (95% CI, 65.0%-74.2%), and 68.9% (95% CI, 63.8%-73.3%) using an apolipoprotein(a)-based assay.”
Quoted from the abstract of JAMA 2025, checked word for word against PubMed. PubMed 39556768 · Full paper (DOI)
How this medicine works, where it stands and what it costs: Muvalaplin
Common questions
What did the KRAKEN trial find?
Oral muvalaplin produced large, dose-dependent reductions in lipoprotein(a) over 12 weeks with no safety or tolerability concerns, though whether this translates into fewer cardiovascular events is still unknown.
Who was in KRAKEN?
233 people. 233 participants with lipoprotein(a) concentrations of 175 nmol/L or greater with atherosclerotic cardiovascular disease, diabetes, or familial hypercholesterolemia at 43 sites in Asia, Europe, Australia, Brazil, and the United States.
What was KRAKEN's main result?
Muvalaplin resulted in placebo-adjusted reductions in lipoprotein(a) of 47.6% (95% CI, 35.1%-57.7%), 81.7% (95% CI, 78.1%-84.6%), and 85.8% (95% CI, 83.1%-88.0%) for the 10-mg/d, 60-mg/d, and 240-mg/d dosages, respectively, using an intact lipoprotein(a) assay and 40.4% (95% CI, 28.3%-50.5%), 70.0% (95% CI, 65.0%-74.2%), and 68.9% (95% CI, 63.8%-73.3%) using an apolipoprotein(a)-based assay.
How much did LDL cholesterol change in KRAKEN?
Not reported (lipoprotein(a) and apolipoprotein B reported; dose-dependent reductions in apolipoprotein B observed at 8.9% (95% CI, -2.2% to 18.8%), 13.1% (95% CI, 4.4%-20.9%), and 16.1% (95% CI, 7.8%-23.7%) at 10 mg/d, 60 mg/d, and 240 mg/d, respectively)
Related trials
- ALPACA (2025)Lepodisiran produced large, dose-dependent and durable reductions in serum lipoprotein(a) with generally mild injection-site reactions, but this trial did not assess cardiovascular outcomes.
- ALPACA (zerlasiran phase 2) (2024)In patients with established atherosclerotic cardiovascular disease and very high Lp(a), zerlasiran safely lowered Lp(a) levels by more than 80% on average over 36 weeks compared with placebo.
- OCEAN(a)-DOSE (2022)Olpasiran markedly and dose-dependently lowered lipoprotein(a) levels in patients with established atherosclerotic cardiovascular disease and elevated Lp(a), with similar overall adverse event rates to placebo, but whether this translates into reduced cardiovascular events remains to be determined.
- Pelacarsen phase 2 (2020)In patients with cardiovascular disease and elevated Lp(a), the antisense drug APO(a)-LRx (pelacarsen) lowered Lp(a) levels in a dose-dependent manner, with no significant safety signals versus placebo, though cardiovascular outcomes were not assessed in this trial.
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