An oral drug, muvalaplin, has demonstrated promising results in lowering lipoprotein(a) (Lp(a)) levels in a Phase 2 trial. The study, presented at the American Heart Association (AHA) Scientific Sessions, showed that muvalaplin significantly reduced Lp(a) levels in patients with elevated baseline levels, offering a potential new approach to managing cardiovascular risk associated with this genetically determined lipoprotein.
The Phase 2 trial involved 233 participants with serum Lp(a) concentrations of 175 nmol/L or greater. Participants were randomized to receive either placebo or one of three doses of oral muvalaplin (10 mg, 60 mg, or 240 mg) for 12 weeks. The study was conducted across 43 centers in multiple countries, including Australia, Brazil, China, Germany, Hungary, Japan, the Netherlands, and the United States, ensuring a diverse patient population.
The primary endpoint of the trial was the change in Lp(a) levels after 12 weeks. Results showed that muvalaplin significantly reduced Lp(a) levels in a dose-dependent manner. Specifically, the 10 mg dose resulted in a 47.4% reduction, the 60 mg dose an 81.6% reduction, and the 240 mg dose an 85.7% reduction in Lp(a) levels compared to placebo. According to lead study author Stephen Nicholls, MBBS, PhD, director of the Victorian Heart Institute at Monash University in Melbourne, Australia, muvalaplin functions by disrupting the binding of apo(a) to apoB, which prevents Lp(a) from forming.
Impact on Oxidized Phospholipids and Apolipoprotein B
In addition to Lp(a) reduction, the study also measured the impact of muvalaplin on oxidized phospholipids, which are thought to play a role in the relationship between Lp(a) and atherosclerotic disease. The results indicated that muvalaplin significantly reduced oxidized phospholipids. Furthermore, muvalaplin lowered Apolipoprotein B (ApoB) by as much as 16% compared with placebo, with no change in high-sensitivity C-reactive protein.
Safety and Tolerability
The safety profile of muvalaplin was favorable, with the percentage of serious adverse events being similar in the placebo arm (6%) and the 10 mg arm (5.9%), and lower in the 60 mg (3.2%) and 240 mg (2.9%) arms.
Clinical Context and Future Directions
Lp(a) is a genetically determined variant of LDL cholesterol, affecting approximately 1 in 5 people worldwide, and is recognized as an independent risk factor for cardiovascular disease (CVD). Currently, there are no approved treatments specifically targeting Lp(a). According to Erin D. Michos, MD, MHS, of Johns Hopkins, even in patients who are treated very intensively and get their LDL less than 70 on a statin, having high Lp(a) still carries some independent risks that can't be fully eliminated by our other risk modifying strategies.
Several other Lp(a) therapies are in development, including pelacarsen (antisense oligonucleotide by Ionis/Novartis) and olpasiran (siRNA therapy by Amgen). However, muvalaplin is the first oral therapy to show such promise.
Nicholls emphasized the importance of Lp(a) testing, noting that it is often not covered by payers, creating a barrier to identifying individuals at risk. Phase 3 trials and cardiovascular outcomes trials are the next steps for muvalaplin before it can be considered for market approval.
