Eli Lilly's Oral Lp(a) Inhibitor Muvalaplin Shows Significant Cholesterol Reduction Within 24 Hours in Phase 1 Trial

▎WuXi

Edited by Kant Content Team

Recently, Eli Lilly and Company released the results of the first Phase 1 clinical trial in humans for their investigational oral lipoprotein(a) — Lp(a) inhibitor, muvalaplin, in the JAMA journal. The results showed that the drug has good safety and can significantly reduce cholesterol levels.The patient experienced a reduction in Lp(a) levels within 24 hours after the first dose. Subsequent administration of muvalaplin led to a further decrease in Lp(a).

Lp(a) is a lipoprotein particle assembled in the liver, formed by the bonding between apolipoprotein(a) and apoB100. Due to genetic variations, Lp(a) levels in each individual's blood can vary significantly and are not correlated with the individual’s LDL-C levels. Even if LDL-C is reduced to the target level (

Muvalaplin is an orally administered small molecule that inhibits Lp(a) formation by blocking the apo(a)-apoB100 interaction while avoiding interaction with the homologous protein plasminogen.

This published trial was a Phase 1, randomized, double-blind, parallel-design study, with a total of 114 subjects enrolled (55 assigned to the single ascending dose group; 59 assigned to the multiple ascending dose group).

Analysis shows that muvalaplin is not associated with tolerability issues or clinically significant adverse reactions. After 14 days of oral dosing ranging from 30 mg to 800 mg, muvalaplin plasma concentrations and half-life increased in subjects (ranging from 70 to 414 hours). Muvalaplin reduced subjects' Lp(a) plasma levels within 24 hours after the first dose, and further reductions in Lp(a) were observed with repeated dosing.The maximum placebo-adjusted reduction in Lp(a) was 63% to 65%, resulting in 93% of participants achieving Lp(a) plasma levels below 50 mg/dL., with a similar effect when given a daily dose ≥100 mg. No clinically significant changes in plasminogen levels or activity were observed.

According to the Eli Lilly website, muvalaplin is under review in Phase 2 clinical trials.

References:

[1] Nicholls, Stephen J et al. “Muvalaplin, an Oral SmallMolecule Inhibitor of Lipoprotein(a) Formation: A Randomized Clinical Trial.”JAMA, 10.1001/jama.2023.16503. 28 Aug. 2023, doi:10.1001/jama.2023.16503

[2] Lilly’s Cholesterol Pill Shows Early Promise in Phase IStudy. Retrieved August 29, 2023 from https://www.biospace.com/article/lilly-s-cholesterol-pill-shows-promise-in-phase-i-study/

[3] Medicines in Development. Retrieved August 29, 2023 from https://www.lilly.com/discovery/clinical-development-pipeline