Ionis Announces Positive Data for ETESIAN Phase 2b Study of Antisense Drugs Targeting PCSK9 at the 2022 American College of Cardiology Scientific Session

  • ETESIAN’s Phase 2b study of ION449 (AZD8233) met its primary and secondary endpoints; ION449 was generally well tolerated
  • ION449 demonstrated a best-in-class potential efficacy profile for a self-administered subcutaneous monthly dose regimen
  • Study findings warrant further clinical development of ION449 for patients with hypercholesterolemia and high cardiovascular risk

CARLSBAD, Calif., April 4, 2022 /PRNewswire/ — Ionis Pharmaceuticals, Inc. (Nasdaq: IONS), the leader in antisense therapies, and its partner, AstraZeneca, today announced positive data from the ETESIAN Phase 2b study of ION449 (AZD8233), an investigational antisense drug designed to lower blood cholesterol levels in patients with hypercholesterolemia targeting proprotein convertase subtilisin/kexin type 9 (PCSK9). These data were presented at the 71st Annual Scientific Session and Exposition of the American College of Cardiology.

The objective of the ETESIAN Phase 2b study was to evaluate the efficacy, safety, and tolerability of ION449 in patients with high-risk hypercholesterolemia. The study met its primary endpoint by reducing serum LDL-C levels by up to 79%. Both the 50 mg and 90 mg doses achieved statistically significant and clinically significant reductions in LDL-C levels from baseline of 73% (95% confidence interval). [CI]: 77%, 68%, and 79% (95% CI: 83%, 76%), respectively, versus 2% (95% CI: 17%, -15%) for placebo. LDL-C reductions were maintained through week 14 (6 weeks after the last dose).

The trial also met secondary endpoints, including significantly reducing PCSK9 levels by up to 94%. The 50 mg and 90 mg doses achieved reductions in PCSK9 levels of 89% (95% CI: 91%, 86%) and 94% (95% CI: 95%, 92%), respectively, versus 5% (95% CI: 23%, -18%) for placebo. Sustained reductions in PCSK9 levels were maintained through week 14 (6 weeks after the last dose). Reducing PCSK9 levels leads to lower levels of LDL-C in the bloodstream, which is known to reduce the risk of developing coronary heart disease.

ION449 was generally well tolerated during the 12-week treatment period and 12-week follow-up period in the study.

“The positive results of the ETESIAN study, together with the clinical studies to date, reinforce our confidence that ION449 (AZD8233) is a potential new treatment option that may change the current standard of care for patients affected by hypercholesterolemia who have problems cardiovascular disease,” said Brett P. Monia, Ph.D., CEO of Ionis.

“Today, we are pleased to announce that ETESIAN’s Phase 2b for ION449 (AZD8233) demonstrated a clear dose response for PCSK9 and LDL-C levels. The results underscore the potential best-in-class efficacy profile of ION449 (AZD8233). ) and further support the development of ION449 (AZD8233) as a monthly self-administered next-generation PCSK9 inhibitor,” said Mene Pangalos, Executive Vice President and President of BioPharmaceuticals R&D at AstraZeneca.

ION449 is being developed by AstraZeneca as part of a collaboration between Ionis and AstraZeneca.

About ION449

ION449 (AZD8233) dosed once a month subcutaneously, is an investigational drug using advanced Ionis technology. LIgand-Cconjugated TOntisense technology platform (LICA). It is designed to reduce plasma levels of proprotein convertase subtilisin/kexin type 9 (PCSK9). PCSK9 is integrally involved in the regulation of LDL cholesterol. Genetic studies have shown that people with a lifetime reduction in LDL-C due to reduced PCSK9 function have a substantially reduced risk of cardiovascular disease. Pharmacological inhibition of PCSK9 substantially reduces LDL-C. ION449 is designed to reduce hepatic production of PCSK9 and lower the plasma level of LDL-C and thus reduce the risk of cardiovascular disease.

Elevated LDL-C levels are a key risk factor in the development of cardiovascular disease, including heart attack, stroke, and peripheral arterial disease. Higher levels of LDL-C in the blood are directly related to an increased risk of vascular disease, while lowering LDL-C leads to a significantly decreased risk. Despite the presence of various lipid-lowering agents, many patients are unable to achieve recommended levels of LDL-C and remain at increased risk of cardiovascular disease. The development of additional highly potent LDL-C lowering drugs may address this persistent unmet need.


ETESIAN is a randomized, double-blind, placebo-controlled, dose-ranging Phase 2b study in patients with hypercholesterolemia. The primary objective was to assess the effect of different doses of ION449 (AZD8233) on LDL-C compared to placebo at Week 12 in patients taking statins. Secondary endpoints included changes in PCSK9 levels and evaluation of the safety and tolerability of ION449.

The study included 119 participants, ages 18 to 75, who had LDL-C levels between 70 and 190 mg/dL and were receiving moderate- or high-intensity statin therapy.

Three dose levels of ION449 (15 mg, 50 mg, 90 mg), administered monthly by subcutaneous injection, were evaluated over the 12-week dosing period. All active arms demonstrated reductions in LDL-C and PCSK9 levels at week 12 compared to placebo.

Percent changes from baseline to week 12 in LDL-C with the 15 mg, 50 mg, and 90 mg monthly doses were -39% (95% confidence interval). [CI] –48%, –29%), –73% (95% CI: –77%, –68%), –79% (95% CI: –83%, –76%), respectively. The percent changes from baseline to week 12 in PCSK9 levels at the 15 mg, 50 mg, and 90 mg monthly doses were -58% (95% CI, -66%, -48%), -89% ( 95% CI: –91%, –86%), –94% (95% CI: –95%, –92%), respectively. In general, ION449 was well tolerated. Adverse events (AEs) were similar between the 15 mg, 50 mg, and placebo groups. Most AEs were mild to moderate, including transient, moderate, and treatment-emergent elevations in liver enzyme levels in the 90 mg group.

About Ionis Pharmaceuticals, Inc.

For more than 30 years, Ionis has been the leader in RNA-targeted therapy, pioneering new markets and changing standards of care with its novel antisense technology. Ionis currently has three commercialized medicines and a late-stage pipeline highlighted by industry-leading cardiometabolic and neurological franchises. Our scientific innovation began and continues with the knowledge that sick people depend on us, fueling our vision of becoming a leading, fully integrated biotech company.

To learn more about Ionis, visit and follow us on Twitter @ionispharma.

Ionis Forward-Looking Statements

This press release includes forward-looking statements about the Ionis business and the therapeutic and commercial potential of Ionis technologies, ION449 and other products in development. Any statement that describes the goals, expectations, financial or other projections, intentions or beliefs of Ionis is a forward-looking statement and should be considered a statement of risk. Such statements are subject to certain risks and uncertainties, including those related to the impact that COVID-19 could have on our business, and including, among others, those related to our commercial products and drugs in development, and in particular those inherent to the process of discovering, developing, and commercializing drugs that are safe and effective for use as human therapy, and in the effort to build a business around those drugs. Ionis’ forward-looking statements also involve assumptions that, if never materialized or proven correct, could cause its results to differ materially from those expressed or implied by such forward-looking statements.

While Ionis’ forward-looking statements reflect the good faith judgment of its management, these statements are based solely on facts and factors currently known to Ionis. As a result, he is cautioned not to rely on these forward-looking statements. These and other risks related to Ionis’ programs are described in more detail in Ionis’ annual report on Form 10-K for the year ended December 31, 2021, which is on file with the SEC. Copies of these and other documents are available from the Company.

In this press release, unless the context otherwise requires, “Ionis”, “Company”, “we”, “our” and “us” refer to Ionis Pharmaceuticals and its subsidiaries.

Ionis Pharmaceuticals® is a registered trademark of Ionis Pharmaceuticals, Inc.

cision See original content for media download: -2022-american-college-of-cardiology-scientific-session-301516409.html

SOURCE Ionis Pharmaceuticals, Inc.

Company codes: NASDAQ-NMS:IONS


Leave a Comment