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Chemistry: Generation 2+ LICA

IONIS-AGT-LRx is a ligand-conjugated (LICA) investigational antisense medicine designed to reduce the production of liver-derived angiotensinogen (AGT), a central component of the renin-angiotensin-aldosterone system (RAAS).

Inhibition of the RAAS pathway is a well-established therapeutic approach for treating patients with heart failure (HF). While RAAS pathway blockers, such as angiotensin converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs), are part of the standard of care, their use as monotherapy may result in incomplete RAAS blockade. However, two or more RAAS pathway blockers are not recommended, due to the negative side effects in the kidneys and risk of hypotension.

By targeting AGT, which lies furthest upstream in the RAAS pathway, IONIS-AGT-LRx  has the potential to achieve a more complete blockade of the RAAS axis compared to ACE inhibitors and ARBs.  Furthermore, the selective inhibition of AGT in the liver may provide a better safety profile by avoiding the kidney side effects seen with the current RAAS inhibitors, which is especially important for patients with chronic kidney dysfunction.

About Chronic Heart Failure with Reduced Ejection Fraction – Heart failure (HF) afflicts approximately 6.5 million patients in the United States and 26 million worldwide. As the population ages, HF incidence is increasing, and more than 550,000 patients are diagnosed with new HF each year. HF is responsible for more hospitalizations than all forms of cancer combined and is the most common diagnosis in hospital patients age 65 years and older. Every year over 1 million patients are hospitalized for HF in the US and Europe, accounting for 6.5 million hospital days. High rates of hospitalizations with frequent readmission (almost 25% of patients with HF are readmitted within 30 days) along with other direct and indirect costs, also place an enormous economic burden on healthcare systems. Despite new advances in medical therapy, the residual risk for patients with HF is still high.