Biotech companies develop drugs to fight genetic high cholesterol

In a move to fight genetic high cholesterol, which can be fatal, biotech companies are deploying siRNA and antisense oligonucleotides, according to a new study published in Nature.

Olpasiran by Amgen is a small interfering RNA (siRNA) drug tackling the most common inherited risk factor for cardiovascular disease: lipoprotein(a), which recently passed an important test.

Preliminary findings from a phase 2 trial demonstrate the medication can combat LDL(a). A multitude of genetic data has proven this low-density lipoprotein (LDL) particle as an independent and causative risk factor for mortality, heart attack, stroke, and aortic stenosis. However, it has gotten far less attention than other cardiovascular disease medication targets.

A tiny percentage of patients with genetically determined high lipoprotein (a)—also known as ‘Lp little a’ or Lp(a)—will see a reduced risk of heart disease thanks to this newly developed medication class.

However, companies also believe that a small part of the general public might benefit. Even if only a small portion of the 40% of individuals with high cholesterol are affected, this would still be a sizable market for businesses.

What is genetic high cholesterol – and who is at risk?

Genes determine how much Lp(a) circulates in a person’s circulation; food and exercise have no bearing. Therefore, focusing on this molecule may help certain people with increased Lp(a), some of whom are otherwise healthy and have no other recognized cardiovascular concerns. Sekar Kathiresan, Co-Founder and CEO of Verve Therapeutics and an expert on the genetics of cardiovascular disease, claims that “this is similar to a genetic disease.”

As stated in Table 1, several development initiatives aiming at reducing Lp(a) particles are now underway.

According to Kathiresan, Lp(a) is “a cousin” of LDL, which causes atherosclerosis. It is essentially an LDL with an additional protein attached. Lp(a) also contains apolipoprotein B100 (apoB100), whereas LDL’s protein fraction solely contains apoB100 (a). This additional protein contributes to Lp(a)’s prolonged’s circulating half-life by preventing the Lp(a) molecule from engaging with LDL receptors, which remove cholesterol from the circulation. Lp(a) particles are extremely atherogenic due to their persistence and high level of inflammatory oxidized phospholipids.

“About 15% of the population has a very significant risk of coronary artery disease from Lp(a),” says Kári Stefánsson, CEO of Amgen’s Reykjavik, Iceland-based Decode Genetics subsidiary.

There is, however, no agreed Lp(a) concentration threshold above which therapy is recommended. “It’s somewhat arbitrary as to where you draw that line,” says Kathiresan.

It is currently unclear precisely which individuals will benefit from lipoprotein(a)-lowering medications, as other variables that contribute to the pathological build-up of arterial plaque must also be taken into account to evaluate an individual’s total risk.

Amgen and Verve Therapeutics are members of the Biotechnology Innovation Organization (BIO).

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