First investigational oral therapy lowers Lp(a) in phase 2 study
Click Here to Manage Email Alerts
Key takeaways:
- An investigational oral drug lowered lipoprotein(a) levels by more than 80% at the highest dose for adults at high CV risk.
- There were no new safety concerns.
CHICAGO — Adults with elevated liproprotein(a) at high risk for a CV event saw substantial reductions over 12 weeks with muvalaplin, an investigational oral small molecule Lp(a) inhibitor, data from a phase 2 study show.
Evidence for a causal association between Lp(a) concentration, which is primarily genetically determined, and CV outcomes across ethnicities continues to build, and data show Lp(a) likely plays a “critical” role in both atherosclerotic CVD and calcific aortic valve disease independent of LDL, Stephen J. Nicholls, MBBS, PhD, director of the Victorian Heart Hospital and Institute and professor of cardiology at Monash University in Melbourne, Australia, said during a late-breaking clinical science presentation at the American Heart Association Scientific Sessions. Recent breakthroughs have shifted Lp(a) from a biomarker of ASCVD risk to a potential target of novel therapy. Several Lp(a) inhibitors are currently in phase 1, 2 and 3 testing, with several promising candidates emerging.
“There are currently no therapies in the clinic that are produced specifically for Lp(a) lowering,” Nicholls said during a press conference. “All therapies under investigation thus far are injectable and essentially target apolipoprotein A production in the liver. Muvalaplin is the first oral agent to be developed to lower Lp(a) levels and it works by disrupting bonding of apolipoprotein A and apolipoprotein B.”
High Lp(a), high CV risk
The KRAKEN study enrolled 233 adults aged 40 years and older across 44 sites in eight countries, all with an Lp(a) level of 175 nmol/L or higher. The median age of participants was 66 years; 33% were women and 66% were white. All participants were at high risk for a CV event, defined as a history of prior CAD, stroke, peripheral artery disease, familial hypercholesterolemia or type 2 diabetes.
Researchers randomly assigned participants to muvalaplin (Eli Lilly) 10 mg, 60 mg or 240 mg or placebo once daily for 12 weeks in a 1:2:2:2 ratio. Primary endpoint was placebo-adjusted percentage change in Lp(a) at 12 weeks. Secondary endpoints included the proportion of patients achieving an Lp(a) of less than 125 nmol/L at week 12 and percent change from baseline to week 12 for ApoB and high-sensitivity C-reactive protein levels.
For all endpoints, researchers used a new assay to measure intact Lp(a) as well as a traditional ApoA-based assay.
“The reason we did that was because when we treat patients with muvalaplin, the traditional apolipoprotein A assay will measure apolipoprotein A that is part of an Lp(a) particle, very small amounts of free circulating apolipoprotein A, but it will also measure apolipoprotein A that is bound to the drug,” Nicholls said. “The traditional apolipoprotein A assay wholly underestimates the degree of Lp(a) lowering you see with the drug.”
Compared with those assigned placebo, participants who received muvalaplin saw reductions in Lp(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) across the 10 mg, 60 mg and 240 mg daily doses, respectively, using the intact Lp(a) assay.
Large decreases in Lp(a)
When measured via the traditional ApoA-based assay, researchers observed Lp(a) reductions of 40.4% (95% CI, 28.3-50.5), 70% (95% CI, 65-74.2) and 68.9% (95% CI, 63.8-73.3) across the 10 mg, 60 mg and 240 mg doses of muvalaplin, respectively.
Researchers also observed dose-dependent drops in ApoB of 8.9%, 13.1% and 16.1% across the three doses, but no change in hsCRP.
There were no new safety concerns.
In a discussant presentation, Erin D. Michos, MD, MHS, FACC, FAHA, FASE, FASPC, professor of medicine and director of women’s cardiovascular health at Johns Hopkins Ciccarone Center for the Prevention of Cardiovascular Disease, said there is a large unmet need for effective Lp(a)-lowering therapies. Michos noted that while the findings for muvalaplin are promising, longer follow-up with a more diverse population, including more women, will be necessary, as well as validation of the newer intact Lp(a) assay, which is not yet clinically available.
“This is in the context that we still do not have definitive proof yet that lowering Lp(a) pharmacologically can actually reduce CV events, but we hope to learn that soon,” Michos said.
Reference:
Perspective
Back to Top
Although small in scale, this study offers important evidence supporting further investigation of muvalaplin for reducing Lp(a) and theoretically one’s future risk for atherosclerotic CVD. Because there are no FDA-approved therapies to lower Lp(a) and elevated Lp(a) confers residual CV risk, there is a lot of momentum to develop drugs that lower Lp(a). Right now those are all injectable medications and broadly categorized as RNA-based therapeutics, but muvalaplin is a novel oral compound that offers a novel mechanism by which to lower Lp(a).
Larger trials, including a CV outcomes trial, will ultimately be needed for this therapy to be approved.
Collapse
Nicholls SJ, et al. LBS.08. Presented at: American Heart Association Scientific Sessions; Nov. 16-18, 2024; Chicago.
Read more about
Click Here to Manage Email Alerts