Muvalaplin, a Potent Small Molecule Inhibitor of Lipoprotein(a)

Presented at the ESC congress 2023 by: Stephen Nicholls, PhD - Melbourne, Australia

Introduction and methods

As Lp(a) has a causal role in atherosclerotic disease and aortic stenosis, lowering Lp(a) levels may offer an opportunity to further reduce CVD risk. At present, there are no pharmacological agents available that specifically lower Lp(a) levels in clinical practice and those in clinical development are injectable therapies.

Lp(a) is an LDL-like lipoprotein that is formed by noncovalent binding of apo(a) kringle IV domains 7 and 8 to lysine residues of apoB with subsequent covalent disulfide bonding. The oral small molecule muvalaplin disrupts the initial noncovalent interaction between apo(a) and apoB. In this phase 1 trial, the safety, tolerability, pharmacokinetics, and exploratory pharmacodynamic biomarker effects of muvalaplin were investigated.

This was a randomized, double-blind, parallel-design study in which healthy participants with BMI ≤30 kg/m² were enrolled at 1 site in the Netherlands. Single ascending-dose treatment was assessed by randomizing participants with any Lp(a) level (n=55) to a single dose of muvalaplin (1–800 mg) or placebo. For multiple ascending-dose treatment, participants with Lp(a) ≥30 mg/dL (n=59) were assigned to daily doses of muvalaplin (30–800 mg) or placebo for 14 days. Of the 114 participants, 105 completed the trial.

Main results

• In the multiple ascending-dose study, peak plasma concentration was 2–4 hours and terminal half-life was 70.9–414.0 hours.
• There were no differences in the frequency of adverse events between the treatment groups. Common adverse events were headache, back pain, diarrhea, abdominal pain, nausea, and fatigue. Most adverse events were mild in severity and transient and resolved with no sequelae.
• Within 24 hours after the first dose, muvalaplin lowered Lp(a) plasma levels, with further Lp(a) reduction upon repeated dosing. The maximum placebo-adjusted relative Lp(a) reduction from baseline was 63%–65% for daily muvalaplin doses of ≥100 mg, and 93% of the participants achieved Lp(a) <50 mg/dL.
• In muvalaplin-treated patients, there were no significant changes in levels of total cholesterol, HDL-c, LDL-c, triglycerides, and apoB. In addition, there were no significant correlations between changes in Lp(a) level and apoB or LDL-c levels.
• As apo(a) shares conserved domains with plasminogen, the selectivity of muvalaplin for Lp(a) lowering was examined, but no clinically significant changes in plasminogen levels or activity were observed.

Conclusion

In this phase 1 trial, daily administration of muvalaplin for 14 days lowered Lp(a) levels up to 65%. There were no safety or tolerability concerns, nor a discernable effect on plasminogen activity. A phase 2 trial with muvalaplin in patients with elevated Lp(a) levels is currently ongoing.

• Our reporting is based on the information provided at the ESC Congress -

The results of this study were simultaneously published in JAMA.