Efficacy and Safety of Bempedoic Acid in Association With Anti-PCSK9 and Ezetimibe in Statin-intolerant Patients: a Randomized Crossover Trial

19092023

Statin intolerance occurs in up to 15-20% of treated patients. The combined use of Proprotein Convertase Subtilisin/Kexin type 9 (PCSK9) inhibitors with ezetimibe is commonly performed in these patients, and has been associated with an estimated LDL-C reduction of 65-70%. This drug combination may be insufficient to reach the LDL-C target in high- and very-high-risk patients with statin intolerance, also considering the goals recommended by the current international guidelines. Also, PCSK9 inhibitor dosage escalations frequently fail to achieve the target. Doubling the dosage of alirocumab from 75 mg to 150 mg, when administrated as monotherapy, determines a further reduction of only 3,6% of LDL-C serum level. The full dose of Evolocumab (420 mg every two weeks), was approved only in the setting of homozygous familiar hypercholesterolemia. Bempedoic acid is an oral, once-daily prodrug, metabolized in the liver to an active inhibitor of ATP-citrate lyase, blocking cholesterol synthesis upstream of 3-hydroxy-3-methylglutaryl-coenzyme A reductase and thereby increasing hepatic expression of the LDL receptor and decreasing circulating LDL-C levels. The CLEAR (Cholesterol Lowering via Bempedoic acid, an ACL-Inhibiting Regimen) Harmony trial demonstrated that bempedoic acid in addition to maximally tolerated statin therapy did not lead to a higher incidence of adverse events compared to placebo and significantly lowered LDL-C levels. In the CLEAR Serenity study, bempedoic acid showed a safe and effective profile compared with placebo in patients with statin intolerance. In the CLEAR Tranquility, it provided an oral therapeutic option complementary to ezetimibe in patients intolerant to high-dose statins who required additional LDL-C lowering. The synergistic effect of bempedoic acid plus PCSK9 inhibitors has been investigated by one phase 2 trial (NCT03193047), which showed a statistical superiority of bempedoic acid plus evolocumab strategy versus placebo plus evolocumab in terms of percent change in LDL-C up to 2 months. To date, no randomized phase 3 clinical trial have evaluated the effect of bempedoic acid in association with anti-PCSK9 and ezetimibe in statin-intolerant patients not attaining the recommended LDL-C target. The investigators hypothesized that the association of bempedoic acid with PCSK9 inhibitors and ezetimibe may be safe and effective in reducing LDL-C in statin-intolerant patients.

2024-05-01

2025-06-30

2025-06-30

Not yet recruiting

Early phase I

130

Inclusion Criteria: * High- or very-high-risk patients who do not reach the recommended LDL-C target despite lipid-lowering pharmacological therapy for primary or secondary prevention (≤70 mg/dl in high-risk patients, ≤55 mg/dl in very-high-risk patients and ≤40 mg/dl in patients with 2 major cardiovascular events within 2 years) * Patients treated with PCSK9 inhibitors plus ezetimibe for at least 12 weeks * Patients with statin intolerance, defined as inability to tolerate at least two statins, one at the lowest starting daily dose and another at any daily dose, either due to objectionable symptoms (real or perceived) or abnormal laboratory analysis, temporally related to statin treatment, reversible upon statin discontinuation, reproducible by rechallenge (restarting medication), and excluding other known factors) * Age ≥18 years Exclusion Criteria: * Fasting blood triglycerides greater than or equal to 500 mg/dL * Body Mass Index (BMI) greater than or equal to 50 kg/m2 * Severe chronic kidney disease (GFR\< 30 ml/min) or glomerular nephropathy * Recent history (\<4 weeks) of clinically significant cardiovascular disease or planning to undergo a major surgical or interventional procedure * Statin assumption (including low/medium dose and low/medium intensity statins) * Uncontrolled hypertension * Uncontrolled hypothyroidism or hyperthyroidism * Liver disease or dysfunction (Child-Pugh B) * Gastrointestinal conditions or procedures that could affect drug absorption * Active malignancy * Unexplained creatine kinase elevations \>3 times the upper limit of normal * Lipid-modifying therapies prohibited: mipomersen within 6 months of screening, lomitapide, or apheresis within 3 months of screening, inhibitor cholesterol ester transfer protein inhibitors within 2 years of screening (with the exception of evacetrapib, which must have been discontinued ≥3 months prior to screening); and red yeast rice extract and berberine-containing products within 2 weeks of screening * Participation in other studies * Unavailable to sign the informed consent

{'studyType': 'INTERVENTIONAL', 'phases': ['PHASE4'], 'designInfo': {'allocation': 'RANDOMIZED', 'interventionModel': 'CROSSOVER', 'interventionModelDescription': 'This is an investigator-initiated, phase 4, open-label, multicentre, 2-way crossover trial', 'primaryPurpose': 'PREVENTION', 'maskingInfo': {'masking': 'NONE'}}, 'enrollmentInfo': {'count': 130, 'type': 'ESTIMATED'}}

2024-04-24