​​AZD0780, a novel oral PCSK9 inhibitor, demonstrated significant LDL cholesterol (LDL-C) reduction in PURSUIT Phase IIb trial

​New late-breaking clinical trial data presented at ACC and published simultaneously in JACC show benefit of investigational medicine AZD0780 on top of standard of care

WILMINGTON, Del.--(BUSINESS WIRE)-- Positive results from the PURSUIT Phase IIb trial for AstraZeneca’s AZD0780 demonstrated a statistically significant low-density lipoprotein cholesterol (LDL-C) reduction when administered on top of standard-of-care statin therapy, as compared with placebo.^1,2 AZD0780 is an investigational once-daily oral PCSK9 inhibitor for patients currently not reaching their LDL-C lowering goal despite standard-of-care-lipid lowering therapies such as statins.^1,2

These new data were presented today at the American College of Cardiology’s (ACC) Annual Scientific Session & Expo in Chicago, Illinois, US and published simultaneously in JACC.^1,2

At 12 weeks, AZD0780 30mg taken once-daily (when added to the standard-of-care statin therapy and administered without any fasting or food restrictions) led to a 50.7% reduction in LDL-C [95% CI: -59.0%, -42.4%, p<0.001]. Similar efficacy was observed regardless of whether trial participants received moderate- or high- intensity statin doses at baseline.^1,2 In addition, AZD0780 30mg enabled 84% [95%CI: 74.4%-90.7%] of trial participants to meet their American Heart Association/American College of Cardiology guideline-recommended LDL-C target (<70 mg/dL), compared to 13% [95%CI: 7.2%-22.3%] of participants on background statin therapy alone.^1,2

High LDL-C (≥70 mg/dL), a common type of dyslipidemia, is a key risk factor for atherosclerotic cardiovascular disease, including stroke and heart attack, and a significant public health concern.³ It is estimated that more than 70% of patients worldwide are currently not reaching guideline-recommended LDL-C targets.^4-7

Dr. Michael J Koren, MD, CEO & Medical Director of Jacksonville Center for Clinical Research, Florida, US and PURSUIT Principal Investigator, said: “The PURSUIT Phase IIb trial demonstrates the potential of AZD0780 to provide a much-needed once-daily oral treatment option to deliver greater LDL cholesterol lowering on top of standard of care for millions of patients who remain at risk for serious cardiovascular events including premature death. These results are particularly important because the majority of patients with atherosclerotic disease today do not reach their LDL-C goals, despite availability of lipid-lowering therapies such as statins and injectable PCSK9 inhibitors.”

Sharon Barr, Executive Vice President, BioPharmaceuticals R&D, AstraZeneca, said: “These new data reflect AZD0780’s ability to reduce LDL cholesterol in patients who need more options to manage their cholesterol and related risks when standard-of-care therapy is not enough. As a novel small molecule oral PCSK9 inhibitor that can be taken without fasting restrictions, AZD0780 has the potential to be a game changer that could offer LDL-C lowering with greater convenience for patients. Our work in dyslipidemia builds on our strong heritage in cardiovascular, renal and metabolic diseases where we are advancing novel therapies, alone or in combination with other molecules in our extensive portfolio, that could redefine treatment standards and patient outcomes.”

AZD0780 was generally well tolerated, and adverse events (AEs) were comparable between the total AZD0780 treatment groups (38.2%) and placebo (32.6%).^1,2 The frequency of treatment discontinuations due to AEs was similar across AZD0780 (1.5%) and placebo (2.3%) groups.^1,2

Data from PURSUIT are consistent with Phase I findings presented at European Atherosclerosis Society (EAS) 2024.⁸

Notes

About Dyslipidemia
Elevated LDL-C levels in plasma is a key risk factor for cardiovascular disease and is estimated to cause 4.4 million deaths worldwide annually.³ Despite current treatment options, the global burden of dyslipidemia is on the rise.⁴ More than 70% of patients with atherosclerotic cardiovascular disease (ASCVD) are still not achieving their LDL-C target, so there remains a vast unmet need among high-risk patients for more varied and effective treatment options.^4-7

PURSUIT
PURSUIT is a Phase IIb, multicenter, randomized, parallel-group, double-blind, placebo-controlled, dose-ranging study to evaluate the efficacy, safety and tolerability of AZD0780 in participants with dyslipidemia.²

PURSUIT assessed the efficacy, safety and tolerability of different doses of AZD0780 on LDL-C levels in patients with hypercholesterolemia. 428 patients on stable standard-of-care therapy with moderate- or high-intensity statins with or without ezetimibe with LDL-C levels ≥70 and <190 mg/dL were randomized (1:1:1:1:1) to receive AZD0780 (1 mg, 3 mg, 10 mg and 30 mg daily) or matching placebo. 426 patients started treatment.²

The primary objective of the study was to measure the effect of different doses of AZD0780 given once daily on LDL-C levels in patients with dyslipidemia receiving standard-of-care statins. The effect of AZD0780 versus placebo on other lipid parameters and inflammatory markers was also investigated. The concentration of AZD0780 in blood at specific timepoints was measured, and the safety and tolerability of AZD0780 evaluated.²

AZD0780
AZD0780 is an oral, small molecule PCSK9 inhibitor that is being developed by AstraZeneca as an innovative therapy for patients with elevated low-density lipoprotein cholesterol (LDL-C) levels which cannot be controlled by statins alone.² PCSK9 is a well-known and validated target in LDL-C metabolism and inhibiting PCSK9 signalling has shown to be effective in reducing LDL-C levels in plasma.² Lower LDL-C levels are associated with a reduction in the risk of long-term cardiovascular disease and major cardiovascular events.⁹ AstraZeneca is investigating the potential of AZD0780 as an oral small-molecule for use as a monotherapy or in fixed-dose combinations with other therapies in our extensive portfolio. Data from PURSUIT are consistent with Phase I findings for AZD0780 which demonstrated a statistically significant reduction of 51% in LDL-C levels on top of rosuvastatin treatment, with 80% total reduction from baseline, in treatment-naive participants with hypercholesterolemia.²

AstraZeneca in CVRM
Cardiovascular, Renal and Metabolism (CVRM), part of BioPharmaceuticals, forms one of AstraZeneca’s main disease areas and is a key growth driver for the Company. By following the science to understand more clearly the underlying links between the heart, kidneys, liver and pancreas, AstraZeneca is investing in a portfolio of medicines for organ protection by slowing or stopping disease progression, and ultimately paving the way towards regenerative therapies. The Company’s ambition is to improve and save the lives of millions of people, by better understanding the interconnections between CVRM diseases and targeting the mechanisms that drive them, so we can detect, diagnose and treat people earlier and more effectively.

AstraZeneca
AstraZeneca is a global, science-led biopharmaceutical company that focuses on the discovery, development and commercialization of prescription medicines in Oncology, Rare Diseases and BioPharmaceuticals, including Cardiovascular, Renal & Metabolism, and Respiratory & Immunology. Based in Cambridge, UK, AstraZeneca operates in over 125 countries, and its innovative medicines are used by millions of patients worldwide. For more information, please visit www.astrazeneca-us.com and follow us on social media @AstraZeneca.

References

1. Koren M, et al. Efficacy and safety of AZD0780, an oral small molecule PCSK9 inhibitor for treatment of hypercholesterolemia: Results from a Ph2b randomized placebo-controlled clinical trial. Presented at: American College of Cardiology Annual Scientific Session (ACC 2025); 2025 Mar 29-31; Chicago, IL.
2. Koren MJ, et al. An oral, small molecule PCSK9 inhibitor for treatment of hypercholesterolemia: the PURSUIT randomized trial. J Am Coll Cardiol. 2025.
3. World Heart Federation. Cholesterol. Available at: https://world-heart-federation.org/what-we-do/cholesterol/#:~:text=High%20blood%20cholesterol%20is%20one,or%207.8%25%20of%20all%20deaths [Last accessed: March 2025].
4. Pirillo A, et al. Global epidemiology of dyslipidaemias. Nat Rev Cardiol. 2021;18(10):689-700.
5. Cannon CP, et al. Use of lipid-lowering therapies over 2 years in GOULD, a registry of patients with atherosclerotic cardiovascular disease in the US. JAMA Cardiol. 2021;6:1060-1068.
6. Ray KK, et al. Treatment gaps in the implementation of LDL cholesterol control among high- and very high-risk patients in Europe between 2020 and 2021: the multinational observational SANTORINI study. Lancet Reg Health Eur. 2023;29:100624.
7. Underberg J, et al. LDL-C target attainment in secondary prevention of ASCVD in the United States: barriers, consequences of nonachievement, and strategies to reach goals. Postgrad Med. 2022;134:752-762.
8. Vega R, et al. AZD0780, the first oral small molecule PCSK9 inhibitor for the treatment of hypercholesterolemia: results from a randomized, single-blind, placebo-controlled phase 1 trial. Atherosclerosis. 2024;395:118514.
9. Domanski MJ, et al. Time course of LDL cholesterol exposure and cardiovascular disease event risk. J Am Coll Cardiol. 2020;76(13):1507-1516.

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FAQ

What were the key results of AstraZeneca's AZD0780 PURSUIT Phase IIb trial?

AZD0780 achieved a 50.7% reduction in LDL-C over 12 weeks and enabled 84% of participants to reach their target LDL-C levels (<70 mg/dL), compared to 13% in the placebo group.

How is AZD0780 different from existing PCSK9 inhibitors?

AZD0780 is a novel oral PCSK9 inhibitor taken once daily without fasting restrictions, unlike existing injectable PCSK9 inhibitors.

What were the safety results for AZD0780 in the PURSUIT trial?

AZD0780 was generally well-tolerated with adverse events at 38.2% vs 32.6% for placebo, and treatment discontinuation rates of 1.5% vs 2.3%.

How many patients currently don't reach their LDL-C targets with existing treatments?

More than 70% of patients worldwide currently do not reach their guideline-recommended LDL-C targets with existing treatments.