First data with muvalaplin, an oral small molecule inhibitor of lipoprotein(a) formation

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Macrovascular Residual Risk Studies

8 January 2024

In this phase I trial, muvalaplin reduced lipoprotein(a) [Lp(a)] levels by up to 65% without any safety concerns, providing a basis for further clinical development.

Nicholls SJ, Nissen SE, Fleming C, et al. Muvalaplin, an oral small molecule inhibitor of lipoprotein(a) formation: a randomized clinical trial. JAMA 2023;e2316503. doi: 10.1001/jama.2023.16503.

STUDY SUMMARY

Objective:

To investigate the safety, tolerability, pharmacokinetics, and pharmacodynamic effects of muvalaplin.

Study design:

Phase I randomized, double-blind, parallel-design trial. The trial comprised both a single ascending dose period (in subjects with any Lp(a) level) and a multiple ascending dose period (in subjects with Lp(a) levels ≥ 30 mg/dL)

Study population:

Healthy subjects with or without Lp(a) ≥ 30 mg/dL.

Main study variable:

Outcomes included safety, tolerability, pharmacokinetics, and exploratory pharmacodynamic biomarkers.

Methods:

In the single ascending dose period, subjects received a single dose of muvalaplin ranging from 1 mg to 800 mg or placebo. In the multiple ascending dose period, subjects with Lp(a) ≥ 30 mg/dL received daily doses of muvalaplin (30 mg to 800 mg) or placebo for 14 days.

Results:

In total, 114 subjects were randomized, 55 (mean age 29 years, 64% female) assigned to the single ascending dose period and 59 (mean age 32 years, 58% female) assigned to the multiple-ascending dose period, of whom 105 completed the trial.

Muvalaplin reduced Lp(a) plasma levels within 24 hours after the first dose, with further reduction in Lp(a) concentration with repeated dosing. In the multiple dosing group, muvalaplin led to a maximum placebo-adjusted reduction in Lp(a) levels of 63% to 65%. At daily doses of 100 mg or more, 93% of subjects achieved an Lp(a) level <50 mg/dL.

There were no tolerability concerns, clinically significant adverse events or clinically significant changes in plasminogen levels or activity associated with muvalaplin dosing.

Authors’ conclusion:

Muvalaplin, a selective small molecule inhibitor of Lp(a) formation, was not associated with tolerability concerns and lowered Lp(a) levels up to 65% following daily administration for 14 days. Longer and larger trials will be required to further evaluate safety, tolerability, and effect of muvalaplin on Lp(a) levels and cardiovascular outcomes.

COMMENT

Lipoprotein(a) is now recognized as a causal risk factor for cardiovascular outcomes, and a contributor to residual cardiovascular risk in high-risk patients (1). Given that conventional lipid-lowering therapy does not provide sufficient Lp(a) reduction, current management of elevated Lp(a) concentration is focused on reduction in global cardiovascular risk (1). Lipoprotein apheresis does lower Lp(a) in high-risk patients who cannot be satisfactorily treated with pharmacotherapy but has practical and cost disadvantages (2). Therefore, novel agents that lower Lp(a) levels by inhibiting the synthesis of apolipoprotein(a) are under investigation. These include an antisense oligonucleotide (pelacarsen), and two short interference RNA (siRNA) drugs (olpasiran and SLN360). These have been shown to be effective in lowering Lp(a) concentration and generally well tolerated (3-5), and studies are underway to investigate their potential to reduce cardiovascular outcomes in high-risk patients with elevated Lp(a) levels (6,7).

As these agents are injectable, a major advance would be the development of a novel oral treatment targeting Lp(a) that would be more accessible for patients. The current study reports the first-in-man data with muvalaplin, an oral small molecule inhibitor of Lp(a) formation. Although preliminary, the study shows that daily dosing with muvalaplin over 2 weeks reduced Lp(a) concentration by up to 65% and was well tolerated. On the basis of these promising data, further trials are ongoing.

References

1. Kronenberg F, Mora S, Stroes ESG, et al. Lipoprotein(a) in atherosclerotic cardiovascular disease and aortic stenosis: a European Atherosclerosis Society consensus statement. Eur Heart J 2022;43:3925-46.
2. Julius U, Tselmin S, Schatz U, et al. Actual situation of lipoprotein apheresis in patients with elevated lipoprotein(a) levels. Atheroscler Supp. 2019;40:1–7.
3. Tsimikas S, Karwatowska-Prokopczuk E, Gouni-Berthold I, et al. Lipoprotein(a) reduction in persons with cardiovascular disease. N Engl J Med 2020;382:244–55.
4. O'Donoghue ML, Rosenson RS, Gencer B, et al; OCEAN(a)-DOSE Trial Investigators. Small interfering RNA to reduce Lipoprotein(a) in cardiovascular disease. N Engl J Med 2022;387:1855-64.
5. Nissen SE, Wolski K, Balog C, et al. Single ascending dose study of a short interfering RNA targeting Lipoprotein(a) production in individuals with elevated plasma Lipoprotein(a) levels. JAMA 2022;327:1679-87.
6. A Phase III Study, aiming at the evaluation of cardiovascular endpoints, was started in 2020 (HORIZON trial; ClinicalTrials.gov Identifier: NCT04023552).
7. Olpasiran Trials of Cardiovascular Events and Lipoprotein(a) Reduction (OCEAN(a)) - Outcomes Trial (ClinicalTrials.gov Identifier: NCT05581303).

Key words

lipoprotein(a); cardiovascular risk; muvalaplin