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Generation 2+ LICA antisense drug

IONIS-AZ4-2.5-LRx, also known as AZD8233, is a Generation 2.5 ligand-conjugated antisense (LICA) drug designed to inhibit an undisclosed target to treat cardiovascular disease.



Generation 2+ LICA antisense drug

AKCEA-APOCIII-LRx is a Generation 2+ ligand-conjugated antisense (LICA) drug designed to inhibit the production of apoC-III for patients who are at risk for cardiometabolic disease due to elevated triglyceride levels. ApoC-III is a protein produced in the liver that regulates triglyceride metabolism in the blood and is an independent cardiovascular risk factor. People with elevated triglycerides are at increased risk for cardiovascular disease and for type 2 diabetes. People with severely elevated triglycerides, such as people with familial chylomicronemia syndrome (FCS), are at high risk for acute pancreatitis and other serious conditions. ApoC-III is also the target of WAYLIVRA, the first approved medicine for patients with FCS.

About ApoC-III and Triglycerides

ApoC-III is an important emerging target linking hypertriglyceridemia with cardiovascular disease (CVD). In several studies, apoC-III levels are an independent risk factor for CVD. Further, its presence on lipoproteins may increase their atherogenicity. A study in the New England Journal of Medicine reported that out of a sample of over 100,000 people, individuals with an apoC-III loss-of-function mutation had a reduced risk of clinical coronary heart disease. Each decrease of 1mg/dL in plasma levels of apoC-III was associated with a 4% decrease in the risk of incident coronary heart disease. Triglycerides may also play a role in cardiovascular risk. In two separate studies encompassing nearly 20,000 patients, as triglyceride levels increased, so did the risk of a cardiovascular event. In summary, apoC-III impacts triglyceride levels and may also increase inflammatory processes. This combination of effects makes apoC-III a valuable target for reducing the residual CVD risk in patients already on statin therapy, or for whom triglycerides are poorly controlled.


Generation 2+ LICA antisense drug

AKCEA-APO(a)-LRx, also known as TQJ230, is a Generation 2+ LICA antisense drug designed to reduce apolipoprotein(a) in the liver to offer a direct approach for reducing lipoprotein(a), or Lp(a), a very atherogenic and thrombogenic form of LDL. Elevated Lp(a) is recognized as an independent, genetic cause of coronary artery disease, heart attack, stroke and peripheral arterial disease. Currently, there is no effective drug therapy to specifically and robustly lower elevated levels of Lp(a). Lp(a) levels are determined at birth and, therefore, lifestyle modification, including diet and exercise, do not impact Lp(a) levels. Even patients who can control their LDL-C remain at high-risk of cardiovascular events if they have high levels of Lp(a).

AKCEA-APO(a)-LRx is being developed for patients who are at significant risk of CVD because of their elevated Lp(a). We believe AKCEA-APO(a)-LRx is the first and currently only drug in clinical development designed to selectively and robustly inhibit the production of Lp(a).

About Lp(a)

Lp(a) is a lipoprotein particle assembled in the liver that consists of an LDL-C-like particle and apolipoprotein(a). Lp(a) is considered a key driver for cardiovascular disease due to its association with an increased risk of coronary heart disease. There is evidence that elevated Lp(a) levels may contribute directly to heart attacks. Lp(a) levels in blood can vary greatly between individuals primarily due to genetic variations. Because elevated Lp(a) is a genetically determined condition that is not responsive to lifestyle changes, patients are unable to adequately control their Lp(a) levels through improved diet or increased physical activity. Moreover, current therapies are not able to reduce Lp(a) to recommended levels in patients who have high Lp(a). Although Lp(a) can be measured by a routine lipid blood panel, the lack of drugs to effectively lower Lp(a) has made treating patients with Lp(a)-driven cardiovascular disease difficult.


Generation 2+ LICA antisense drug

Vupanorsen, formerly known as AKCEA-ANGPTL3-LRx, is a Generation 2+ ligand-conjugated antisense (LICA) drug designed to reduce angiopoietin-like 3 protein, or ANGPTL3. Human genetic studies have shown that lower levels of ANGPTL3 are associated with lower plasma triglyceride (TG) and LDL-C and protection against certain cardiovascular diseases1-3. Studies in animals have demonstrated that targeted reduction of ANGPTL3 with antisense drugs results in substantially decreased TG and LDL-C4. A large number of patients with elevated risk of cardiovascular disease are not reaching recommended TG and LDL-C goals. Vupanorsen is being developed to reduce plasma levels of ANGPTL3 with the goal of lowering levels of plasma TG and LDL-C to potentially reduce the risk of future cardiovascular events.

About ANGPTL3 and Cardiovascular Disease
Angiopoietin-like-3, or ANGPTL3, is a well-established regulator of the blood lipids LDL-C and triglycerides. ANGTPL3 has also been identified as an important factor in cardiovascular disease (CVD). Studies have shown that people with a loss of function (LOF) mutations and/or decreased ANGPLT3 plasma levels have reduced risk for CVD. For example, genomic analysis of over 180,000 individuals with genetic variations that cause a LOF in ANGPTL3 demonstrated a 34% reduction in risk of coronary heart disease among carriers of ANGPTL3 LOF mutations1. In addition, circulating ANGPTL3 concentrations were found to be lower in healthy control subjects than in those who have had heart attacks. Additionally, individuals with complete ANGPTL3 deficiency showed no evidence of atherosclerosis relative to control subjects who had a mean total atherosclerotic plaque burden of about 39%. Thus, treatment to lower ANGPTL3 plasma levels could be an important advance in cardiovascular therapy for individuals at risk for ischemic heart disease who have elevated LDL-C and plasma triglycerides, which usually reflects elevated plasma remnant cholesterol.