Efficacy and Safety of Bempedoic Acid in Association With Anti-PCSK9 and Ezetimibe in Statin-intolerant Patients

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.

This is an investigator-initiated, phase 4, open-label, multicentre, 2-way crossover trial. The study will enlist statin-intolerant patients at high-risk and very high-risk of cardiovascular events, not reaching the LDL-C goal recommended by the 2019 ESC/EAS Guidelines for management of dyslipidaemias based on their individual risk estimate. The patients enrolled have to be intolerant to statin and have not changed their hypolipidemic therapy within 6 weeks prior recruitment.

Eligible participants as per the inclusion criteria will be randomized with 1:1 allocation ratio, without restrictions, into two treatment sequences of 12 weeks, respectively, separated by a washout period of 4 weeks.

Being the inclusion criteria of this study highly selective, the rationale behind the crossover design is the lower sample size needed, and the shorter times to complete the enrolment. Furthermore, since the patients will serve as their own controls, the influence by confounders will be reduced. Being the primary endpoint of this study result of laboratory measurements, the investigators assumed the absence of any carryover effect after the washout period of 4 weeks. Moreover, the investigators assumed the absence of any period effect on the study endpoint.

The phase 1 will start at week 0 (P1-0)and stop at week 12 (P1-12); the phase 2 will start at week 16 (P2-0), after the washout period, and stop at week 28 (P2-12).

The two study treatments will be:

* PCSK9 inhibitors (Evolocumab 140 mg or Alirocumab 75 mg or Alirocumab 150 mg) plus Ezetimibe 10 mg plus Bempedoic acid (Treatment A)
* PCSK9 inhibitors (Evolocumab 140 mg or Alirocumab 75 mg or Alirocumab 150 mg) plus Ezetimibe 10 mg (Treatment B) All patients will be randomly assigned to a Treatment A-Treatment B (AB Group) sequence or to a Treatment B-Treatment A (BA Group) sequence.

The investigators will record laboratory and clinical variables at study visits scheduled for weeks 0, 4, 12, 16, 20, 28. Blood samples will be collected and stored at each visit by the participating centres, and analysed by a central core laboratory (University of Salerno).

At the end of the study, the decision to continue or not treatment with bempedoic acid, as well as any other therapeutic decision, will be left to the treating physician.

Eligibility Criteria:
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