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JAMA: Major Breakthrough in Cholesterol-Lowering Medication! Phase 1 Clinical Data for the World’s First Oral Small Molecule Drug Targeting Lipoprotein(a) Revealed – Can Reduce Lipoprotein(a) Levels by 65% | Clinical Milestone
When it comes to “bad cholesterol” that threatens cardiovascular health, many think of low-density lipoprotein cholesterol (LDL-C). However, lipoprotein(a) is an even more sinister presence than LDL-C.
Increasing evidence suggests that lipoprotein(a), which is similar to LDL-C but more adhesive, is a causal factor in atherosclerosis and aortic valve stenosis, with its reduction independently associated with a decrease in cardiovascular events [1]. Currently, there are no approved treatments on the market, and lifestyle changes are often insufficient [2].
On Aug 29, the first small molecule drug for lowering lipoprotein(a) levels, Muvalaplin, has revealed its Phase 1 clinical trial results in the JAMA journal, coinciding with the recent European Society of Cardiology Congress (ESC) in 2023.
Professor Stephen J. Nicholls and his team at Monash University’s Victoria Heart Institute in Australia conducted this Phase 1 clinical study. Data from 114 participants showed that daily oral intake of Muvalaplin for 14 days can reduce lipoprotein(a) levels in the blood by up to 65%, with no significant adverse reactions [3].
Lipoprotein(a) (apo[a]), synthesized in the liver, forms lipoprotein(a) by non-covalently binding to apo B100 protein on low-density lipoprotein-like particles.
Currently, antisense oligonucleotides (ASOs) [4], small interfering RNA (siRNA) drugs [2,5] have been developed to lower lipoprotein(a) levels by reducing hepatic apo(a) synthesis, and these drugs are at different clinical stages.
Notably, Olpasiran, an siRNA drug targeting lipoprotein(a), demonstrated remarkable Phase 2 clinical data, published in the New England Journal of Medicine in November of last year, showing a reduction in lipoprotein(a) levels of up to 96%. Its latest data, also presented at the recent European Society of Cardiology Congress, indicates sustained reduction in lipoprotein(a) levels nearly a year after the last Olpasiran administration.
However, these drugs require injection.
Muvalaplin is an oral small molecule drug that inhibits lipoprotein(a) formation by blocking the interaction between apo(a) and apo B100. In this Phase 1 clinical trial, Stephen J. Nicholls’ team assessed Muvalaplin’s safety, resistance, pharmacokinetics, and more.
Lipoprotein(a) and the main research and development directions of current clinical drugs
The study included 114 participants aged 18 to 69, with a body mass index ≤30, divided into two groups: a single-dose escalation group (n=55) receiving only a single dose and a multiple-dose escalation group (n=59) receiving Muvalaplin daily for 14 days. Each group had varying proportions of participants receiving a placebo or Muvalaplin treatment.
The average ages of participants in the single-dose and multiple-dose escalation groups were 29 and 32, with 64% and 58% female participants, and baseline median lipoprotein(a) levels of 10.3 mg/dL and 58.3 mg/dL, and baseline median LDL-C levels of 104.4 mg/dL and 116.0 mg/dL, respectively.
Results showed that continuous oral intake of 30-800 mg doses of Muvalaplin led to increased Muvalaplin plasma concentrations with a half-life of 70-414 hours. Muvalaplin reduced plasma lipoprotein(a) levels within 24 hours of the first dose, further reducing with repeated doses and displaying dose-dependent reductions.
At the end of the 14-day treatment, daily doses of ≥100 mg led to a 63%-65% reduction in participants’ lipoprotein(a) levels compared to the placebo, with 93% of participants having lipoprotein(a) levels below 50 mg/dL. When taking daily oral doses of 300-800 mg, participants’ lipoprotein(a) levels continued to decline over several days, returning to baseline levels 64 days after the last Muvalaplin administration.
Daily Muvalaplin intake had no impact on total cholesterol, LDL-C, high-density lipoprotein cholesterol, triglyceride, or apo B100 levels in plasma.
Lipoprotein(a)-lowering effect of oral treatment with Muvalaplin
Treatment-related adverse events were mostly mild, transient, and resolved without sequelae. There were no dose-dependent adverse events, and no deaths or serious adverse events. Among participants taking daily oral Muvalaplin, the most common side effects were headache (20%), diarrhea (15%), and abdominal pain (10%).
Additionally, because apo(a), a component of lipoprotein(a), shares homology with plasminogen, there were concerns that reducing lipoprotein(a) with Muvalaplin could affect hemostasis and coagulation function.
Test results showed slight changes in hemostasis markers and plasminogen activity at high doses (up to a 14% reduction at a 500 mg dose), but they returned to baseline levels after discontinuation.
There were no significant changes in high-sensitivity C-reactive protein levels in the blood.
Changes in plasminogen activity during treatment
Overall, this Phase 1 clinical trial indicates that oral Muvalaplin effectively lowers lipoprotein(a) levels with no serious side effects. Longer-term and larger-scale trials are needed to further evaluate the safety, tolerability, and impact of Muvalaplin on lipoprotein(a) levels and cardiovascular disease outcomes.
References:
[1] Bittner VA, Szarek M, Aylward PE, et al; ODYSSEY OUTCOMES Committees and Investigators. Effect of alirocumab on lipoprotein(a) and cardiovascular risk after acute coronary syndrome. J Am Coll Cardiol. 2020;75(2):133-144. doi:10.1016/j.jacc.2019.10.057
[2] 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(20):1855-1864. doi:10.1056/NEJMoa2211023
[3] https://jamanetwork.com/journals/jama/fullarticle/2808864
[4] Tsimikas S, Karwatowska-Prokopczuk E, Gouni-Berthold I, et al; AKCEA-APO(a)-LRx Study Investigators. Lipoprotein(a) reduction in persons with cardiovascular disease. N Engl J Med. 2020;382(3):244-255. doi:10.1056/NEJMoa1905239
[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(17):1679-1687. doi:10.1001/jama.2022.5050
(source:internet, reference only)
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