Oral PCSK9 inhibitor Significantly Reduces LDL-C in Hypercholesterolemia

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Results from a Phase I trial showed significant LDL-C reduction with AZD0780 plus statin therapy in treatment-naive patients with hypercholesterolemia.

Positive data from a Phase 1 trial suggested the benefit of AZD0780, an oral small molecule PCSK9 inhibitor, administered in combination with statin treatment, for the reduction of low-density lipoprotein cholesterol (LDL-C).1

AZD0780 treatment showed a statistically significant reduction of more than 50% in LDL-C levels in combination with rosuvastatin treatment, with a nearly 80% total reduction from baseline, in treatment-naive patients with hypercholesterolemia.

“The role of PCSK9 in cholesterol management is well-established, and the compelling data generated with AZD0780 demonstrate the potential of this molecule for effective inhibition of this target and a possible next-generation treatment for people with cardiovascular diseases,” Sharon Barr, PhD, executive vice president, AstraZeneca BioPharmaceuticals R&D, said in a statement.2

Elevated LDL-C levels are a key risk factor for cardiovascular disease (CVD), with estimates approximating up to 2.6 million linked deaths.3 Current treatment options, while effective, have not halted the growing global burden of dyslipidemia.

Nearly three-quarters of patients with atherosclerotic cardiovascular disease (ASCVD) are not achieving their LDL-C target goals, leaving an unmet need for a more effective treatment for high-risk patients.4 Guideline reports suggest patients with ASCVD achieving >70% LDL-C reduction could lead to >90% of patients achieving LDL-C target levels.

Developed by AstraZeneca, AZD0780 is a first-in-class therapy for dyslipidemia that cannot be controlled by statins alone.1 Targeting PSCK9 is well-validated in lipid metabolism, and its inhibition has been shown to reduce LDL-C in plasma, leading to a reduced risk of long-term CVD or major cardiovascular events.

This Phase I trial assessed the safety, tolerability, pharmacokinetics, and pharmacodynamics of daily AZD0780 30 mg or 60 mg versus placebo (n = 15 for each arm) for 4 weeks, to determine its effect as a monotherapy. A secondary arm involved 35 patients with hypercholesterolemia, LDL-C <100 mg/dL to 190 mg/dL, who were treated with rosuvastatin 20 mg for 3 weeks followed by AZD0780 30 mg or placebo for an additional 4 weeks.

Based on preliminary data, food increased total exposure by approximately 30%, compared with dosing when fasting. Safety data revealed no serious adverse events, and the drug was generally safe and well-tolerated.

Upon analysis, AZD0780 as monotherapy reduced LDL-C levels by 30% (95% CI, –41 to –18) and 38% (95% CI, –48 to –30) at the 30 mg and 60 mg dose levels, respectively, compared with baseline. It did not meet statistical significance between doses.

Meanwhile, AZD0780 30 mg reduced LDL-C levels by 52% (95% CI, –57 to –45) after the rosuvastatin 20 mg run-in period, for an approximate 78% reduction in LDL-C from baseline with AZD0780 plus statin therapy. According to the Bliss independence model, the investigative team identified a synergistic effect between AZD0780 and rosuvastatin, compared with each as monotherapy.

Based on this finding, the relationship between AZD0780 and rosuvastatin could allow most patients with hypercholesterolemia to achieve the guideline-recommended LDL-C targets.

“AZD0780 inhibits PCSK9 via a novel, previously unexplored, mode of action that is compatible with traditional oral small molecule drug discovery,” Barr added. “We are progressing development of AZD0780 as an innovative, convenient oral option for patients who are currently unable to meet their LDL-C targets with statins alone to reduce their risk of CV events.”


  1. Vega RB, et al. The First Oral Small Molecule PCSK9 Inhibitor for the Treatment of Hypercholesterolemia: Results from a Randomized, Single-Blind, Placebo-Controlled Phase 1 Trial. European Atherosclerosis Society Congress; May 26-29; Lyon, France 2024.
  2. AZD0780, an oral PCSK9 inhibitor demonstrated significant LDL-C reduction on top of statin in Phase I trial. AstraZeneca. May 29, 2024. Accessed May 31, 2024.
  3. Zheng J, Wang J, Zhang Y, et al. The Global Burden of Diseases attributed to high low-density lipoprotein cholesterol from 1990 to 2019. Front Public Health. 2022;10:891929. Published 2022 Aug 16. doi:10.3389/fpubh.2022.891929
  4. Cannon CP, de Lemos JA, Rosenson RS, 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. Published online June 16, 2021. doi:10.1001/jamacardio.2021.1810