A phase 1 clinical study showed a small molecule drug targeting lipoprotein (a) can reduce its level by 65%

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Overall, this phase I clinical trial demonstrated that oral administration of Muvalaplin was effective in lowering lipoprotein(a) levels without serious side effects.

When it comes to “bad cholesterol” that is harmful to cardiovascular health, many people think of low-density lipoprotein cholesterol (LDL-C). In fact, lipoprotein (a) is a more “malevolent” presence than LDL-C.

There is growing evidence that lipoprotein(a), which is similar to LDL-C but more viscous, is a causative factor in atherosclerosis and aortic stenosis, and that reduced levels are independently associated with reduced cardiovascular events [1]. There are currently no approved treatments on the market, and it is difficult to improve through lifestyle changes [2].

The results of the first small molecule drug for lowering lipoprotein(a), Muvalaplin, Phase I clinical trial were announced today in the journal JAMA and coincided with the recent annual meeting of the European Society of Cardiology (2023 ESC).

Professor Stephen J. Nicholls of the Victoria Heart Institute at Monash University in Australia led his team to complete this phase I clinical study. Data from 114 participants suggest that daily oral administration of Muvalaplin for 14 days reduces blood lipoprotein(a) levels by up to 65 percent without significant adverse effects [3].

Apolipoprotein (A) synthesized in the liver (apo[A]), and the apo B100 protein on low-density lipoprotein-like granules, form lipoprotein (A) by non-covalent binding.

Currently, antisense oligonucleotide (ASO) [4], small interfering RNA (siRNA) drugs [2,5] have been developed to reduce lipoprotein (a) levels by reducing liver synthesis of apo(a), and these drugs are currently in various clinical stages.

Notably, the phase II clinical data of the lipoprotein (a)-targeting siRNA drug Olpasiran, published in the New England Journal of Medicine last November, showed that it can reduce lipoprotein(a) levels by up to 11%. The latest data, also recently presented at the annual meeting of the European Society of Cardiology, suggest that lipoprotein(a) levels continue to decrease nearly a year after the last dose.

However, these drugs are injectable therapies.

Muvalaplin is a small molecule oral drug that inhibits lipoprotein (a) formation by blocking apo(a)-apo B100 interactions. Stephen J. Nicholls’ team completed the evaluation of Muvalaplin’s safety, drug resistance, and pharmacokinetics in this phase I clinical trial.

The main research and development directions of lipoprotein (a) and current clinical drugs

A total of 114 participants aged 18 to 69 years with a body mass index ≤30 were included in two groups: a single dose escalation group (n=55) with only a single dose and a multiple dose-escalation group (n=14) with daily administration for 59 days. A different proportion of participants in each group were treated with placebo or Muvalaplin.

The mean age of participants in the single-dose escalation group and the multiple-dose escalation group was 29 and 32 years old, with 64% and 58% female, 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.

The results showed that oral administration of 14-30 mg for 800 consecutive days resulted in an increase in the plasma concentration of Muvalaplin with a half-life of 70-414 hours. Within 24 hours after the first dose, Muvalaplin reduces plasma levels of lipoprotein (a), which is further reduced with repeated administration and is dose-dependent.

At the end of 14 days of treatment, daily doses ≥ 100 mg reduced participants’ lipoprotein (a) levels by 63%-65% compared with placebo, and 93% of participants had lipoprotein(a) levels below 50 mg/dL. At a daily oral dose of 300-800 mg, participants’ lipoprotein(a) levels continued to decline for dozens of days, rising to baseline 64 days after the last Muvalaplin dose.

Daily administration of Muvalaplin had no effect on plasma levels of total cholesterol, LDL-C, high-density lipoprotein cholesterol, triglycerides, and apo B100.

Treatment-related adverse events were mostly mild, transient, and resolved without sequelae. There were no dose-dependent adverse events, no deaths or serious adverse events. Among participants who took Muvalaplin orally daily, headache (20%), diarrhea (15%), and abdominal pain (10%) were the most common.

In addition, since apo(a), a component of lipoprotein (a), has close homology with plasminogen, it is theoretically possible to reduce lipoprotein (a) by Muvalaplin.

The results of the test showed a slight change in hemostatic indicators, as well as plasminogen activity, at high doses (up to a decrease of about 500% at a dose of 14 mg), but returned to baseline after discontinuation of the drug.

Levels of highly sensitive C-reactive protein in the blood did not show significant changes.

Overall, this phase I clinical trial demonstrated that oral administration of Muvalaplin was effective in lowering lipoprotein(a) levels without serious side effects. Longer, larger trials are needed to further evaluate the safety, tolerability, and effects of Muvalaplin on lipoprotein(a) levels and cardiovascular disease outcomes.

[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]Stephen J. Nicholls, MBBS, PhD1; Steven E. Nissen, MD2; Cynthia Fleming, RN, MSN3; et al. Muvalaplin, an Oral Small Molecule Inhibitor of Lipoprotein(a) Formation A Randomized Clinical Trial. JAMA. Published online August 28, 2023. doi:10.1001/jama.2023.16503
[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

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