Pharmacokinetics, Pharmacodynamics, and Safety Evaluation of Bempedoic Acid in Pediatric Patients with Heterozygous Familial Hypercholesterolemia

Trial ID: 2024-515864-30-00
Protocol: 1002-041
Sponsor: Esperion Therapeutics Inc.

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Diseases & Conditions

Type IIa hyperlipidaemia Hypercholesterolaemia

Objectives

The primary objective of this study is to assess the **pharmacokinetics** (PK) of bempedoic acid (ETC-1002) in pediatric patients aged 6 to 17 years with heterozygous familial hypercholesterolemia (HeFH) treated for 8 weeks. Understanding the PK profile is crucial for determining the appropriate dosing regimen and ensuring the therapeutic efficacy and safety of bempedoic acid in this specific population.

Secondary objectives include:

To assess the PK of ESP15228 (active metabolite).
To evaluate the relationship between bempedoic acid exposure and LDL-C-lowering response.
To assess the absolute and percent change from baseline to Weeks 8 and 16 in LDL-C, total cholesterol (TC), non-high-density lipoprotein cholesterol (non-HDL-C), and high-sensitivity C-reactive protein (hsCRP).
To monitor the acceptability (taste and ease of swallowing) of the age-appropriate formulations.
To assess the safety and tolerability of bempedoic acid in pediatric patients with HeFH treated with escalating, multiple oral doses based on body weight for 8 and 16 weeks.

Participants

The clinical trial involves a total of **27 participants** diagnosed with **heterozygous familial hypercholesterolemia** (HeFH). The study population consists of pediatric patients aged **6 to 17 years**, including both male and female subjects. Participants were selected based on specific criteria, including a confirmed diagnosis of HeFH and a requirement to be on stable lipid-modifying therapy (LMT) prior to and throughout the trial. The trial does not involve a vulnerable population. Participants are required to have a fasting LDL-C level of at least 130 mg/dL while on stable LMT. Lifestyle considerations such as diet and physical activity are not specified, but participants must be willing to swallow tablets and adhere to the study protocol. The trial does not impose specific birth control requirements for male participants, while female participants must adhere to acceptable methods of contraception if applicable. The sponsor has not provided additional information regarding the general health status or lifestyle habits of the participants.

Plans and Procedures

The clinical trial is designed to evaluate the **pharmacokinetics** and safety of **bempedoic acid** in pediatric patients aged 6 to 17 years with **heterozygous familial hypercholesterolemia** (HeFH). This is a Phase II, open-label study with an estimated duration from August 2023 to May 2025. Participants will be administered **bempedoic acid** in the form of a film-coated tablet, taken orally once daily. The trial will span a maximum treatment period of 16 weeks, with the primary objective being the assessment of the pharmacokinetics of **bempedoic acid** over an 8-week period.

The trial will commence with a screening visit to confirm eligibility based on specific inclusion criteria, such as age, weight, and a confirmed diagnosis of HeFH. Participants must be on a stable lipid-modifying therapy (LMT) regimen prior to the first treatment visit. The study will include multiple visits: an initial treatment visit (T1), followed by regular follow-up visits to monitor safety, efficacy, and pharmacokinetic parameters. The primary endpoints include the observed trough plasma concentration of **bempedoic acid** and model-based pharmacokinetic parameters such as area under the plasma concentration-time curve (AUCss), average plasma concentration (Cavg,ss), and maximum plasma concentration (Cmax,ss).

Secondary endpoints will assess the plasma concentration of the active metabolite ESP15228, the dose-response relationship concerning LDL-C lowering, and the acceptability of the formulation. The end-of-study visit will conclude the trial, evaluating the overall safety and efficacy outcomes. Participant involvement is expected to last up to 16 weeks, with conditions for early termination including adverse events or non-compliance with the study protocol. The trial is not categorized as low intervention, and the study design does not include a control group or blinding, given its open-label nature.

Treatment

The clinical trial involves the administration of **bempedoic acid**, a chemical compound developed by Esperion Therapeutics Inc. The experimental medication is provided in the form of a **film-coated tablet**. The active substance, **bempedoic acid**, is administered orally. The dosage regimen for the trial specifies a maximum daily dose of 180 mg, with a total maximum dose of 20,160 mg over the course of the treatment period. The treatment duration is set for a maximum of 16 weeks. The trial is designed to evaluate the pharmacokinetics, pharmacodynamics, and safety of bempedoic acid in pediatric patients aged 6 to 17 years with heterozygous familial hypercholesterolemia (HeFH).

In this study, no non-experimental treatments such as standard-of-care therapy, placebo, or comparator treatments are specified. The focus is solely on the administration of bempedoic acid. Participant compliance with the dosing schedule will be monitored throughout the trial to ensure adherence to the prescribed regimen. The trial does not include any additional medicinal products or devices. The pharmaceutical form and administration route are consistent across all participants, ensuring uniformity in the treatment protocol.

Efficacy

The efficacy of **bempedoic acid** in pediatric patients with heterozygous familial hypercholesterolemia (HeFH) will be assessed through a series of primary and secondary endpoints. The primary endpoints include the observed trough plasma concentration of ETC-1002 following 8 weeks of steady-state dosing, as well as model-based pharmacokinetic (PK) parameters such as the area under the plasma concentration-time curve (AUCss), average plasma concentration (Cavg,ss), and maximum plasma concentration (Cmax,ss). These parameters will provide insights into the drug's pharmacokinetics in the target population.

Secondary endpoints will further evaluate the efficacy by measuring the observed trough plasma concentration of ESP15228, the active metabolite, after 8 weeks of steady-state dosing. Additionally, the plasma concentration at 4 hours (C4hr) of both ETC-1002 and ESP15228 following the first dose will be assessed. The relationship between ETC-1002 dose and exposure and the LDL-C-lowering response will also be examined. Changes in lipid parameters, including percent and absolute changes from baseline to Weeks 8 and 16 in LDL-C, total cholesterol (TC), non-HDL-C, and high-sensitivity C-reactive protein (hsCRP), will be measured. Furthermore, the acceptability of the age-appropriate formulations, in terms of taste and ease of swallowing, will be evaluated.

Inclusion and Exclusion Criteria

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Inclusion Criteria

The patient's parent(s)/guardian(s) must be willing to provide written informed consent and the patient must provide informed assent before any study-specific procedures are performed
The patient must be aged 6-17 years old and willing to swallow tablets
The patient must weigh at least 16 kg
The patient must have a diagnosis of HeFH prior to receiving the first dose of study medication at Treatment Visit T1 per MEDPED (Make Early Diagnosis to Prevent Early Deaths project) criteria by meeting at least one of the following clinical criteria: (a.) Documented diagnosis of HeFH determined by positive genetic testing; or (b.) Documented LDL-C or TC meeting one or more of the following criteria: (i.) LDL-C >200 mg/dL (5.2 mmol/L) or total cholesterol (TC) >270 mg/dL (7.0 mmol/L), with no first- second- or third-degree relative with documented FH diagnosis (general population); or (ii.) LDL-C >155 mg/dL (4.0 mmol/L) or TC >220 mg/dL (5.7 mmol/L), and also having a first-degree relative with documented familial hypercholesterolemia (FH) diagnosis; or (iii.) LDL-C >165 mg/dL (4.3 mmol/L) or TC >230 mg/dL (5.9 mmol/L), and also having a second-degree relative with documented FH diagnosis; or (iv.) LDL-C >170 mg/dL (4.4 mmol/L) or TC >240 mg/dL (6.2 mmol/L), and also having a third-degree relative with documented FH diagnosis
Current treatment with approved stable LMTs, including an optimal dose of statin with or without other LMT(s), at stable dose for at least 4 weeks prior to Treatment Visit T1 (6 weeks for fibrates; however, gemfibrozil is not allowed in patients taking a statin as per co-administration instructions defined in the statin label) Patient must remain on that stable dose throughout the duration of the trial. Optimal dose of statin will be determined by the investigator using their medical judgment and available sources, including the patient’s self-reported history of LMT. A patient’s optimal dose of statin is defined as meeting one of the following criteria: a. the highest approved dose of statin prescribed for the age of the patient based on regional practice or local guidelines; or b. less than the highest approved dose of statin, including no statin, prescribed for the age of the patient based on regional practice or local guidelines (including no statin) if: i. the patient has previously taken 2 or more statin therapies at any dose and not able to tolerate or unresponsive due to their mutations (null); or ii. the patient has previously taken 1 or more statin therapies at any dose and is unwilling to attempt another statin at any dose or advised by a physician to not attempt another statin at any dose. Patient/parent and investigator attestation to the patient’s unwillingness to attempt and/or physician advice to not attempt additional statin therapy will be recorded.
The patient must have a fasting LDL-C level ≥130 mg/dL (3.4 mmol/L) while on sstable LMT as defined in inclusion criteria 5
The patient may be male or female. Females must not be pregnant (or planning to become pregnant within 30 days after the last dose of investigational medicinal product [IMP]) breastfeeding and must be sexually inactive or willing to use 1 acceptable method of birth control. The minimal requirement for use of acceptable contraception is from the time the informed consent form (ICF) is signed, during the study period, and for at least 30 days after the last dose of IMP. Acceptable methods of birth control include: a. placement of an intrauterine device (IUD) with or without hormones, b. established use of oral, implanted, topical, or injectable, or hormonal method of contraception associated with inhibition of ovulation, or c. barrier methods, including condom or occlusive cap with spermicidal foam or spermicidal jelly, There are no protocol-specific birth control requirements for males who have partners that can become pregnant.

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Exclusion Criteria

The patient has a diagnosis of HoFH or compound HeFH;
The patient has a fasting triglyceride (TG) level ≥400 mg/dL (4.5 mmol/L)
The patient has uncontrolled hypothyroidism, including a value for thyroid-stimulating hormone (TSH) < lower limit of normal (LLN) or >1.5 × the upper limit of normal (ULN)
The patient has liver disease or dysfunction, including: a. positive serology for hepatitis B surface antigen (HBsAg) and/or hepatitis C virus antibodies (HCV-AB), or b. serum alanine aminotransferase (ALT) or aspartate aminotransferase (AST) value ≥2 × ULN and/or serum total bilirubin (TB) value ≥2 × ULN
The patient has renal dysfunction or glomerulonephritis, including an estimated glomerular filtration rate (eGFR) <75 mL/min/1.73 m2 (as determined by the central laboratory using the Revised ["Bedside"] Schwartz formula)
The patient has Stage 2 hypertension (based on gender, age and height; see Appendix 4)
The patient has a gastrointestinal condition that may affect drug absorption
The patient has a history of hematologic or coagulation disorders, anemia, or a hemoglobin (Hgb) level <11.5 g/dL
The patient has type 1 or type 2 diabetes, or newly diagnosed impaired glucose tolerance (within 3 months of Screening)
The patient had an active malignancy, including those requiring surgery, chemotherapy, and/or radiation, in the past 5 years. Nonmetastatic basal or squamous cell carcinoma of the skin and cervical carcinoma in situ are allowed
The patient has an unexplained (ie, not associated with recent trauma or physically strenuous activity) serum creatine kinase (CK) value >3 × ULN at any time before randomization. Patients with an explained elevation in serum CK must have single repeat serum CK value ≤3 × ULN before enrollment
The patient has a history of drug or alcohol abuse within the last 2 years or is unwilling to refrain from alcohol consumption for the duration of the study, or uses any illicit drugs, or has a history of amphetamine or derivatives abuse or cocaine abuse. Patients who are using amphetamine derivatives prescribed by and who are under the care of a health care practitioner can be enrolled after evaluation by the Investigator
The patient has donated blood, undergone multiple blood draws in a clinical study, experienced major trauma, received a blood transfusion, or undergone surgery, with or without blood loss, within 30 days before enrollment
The patient has used any experimental or investigational drugs within 30 days before screening and throughout the trial
The patient has previously participated in a clinical study of bempedoic acid
The patient is taking any of the following medications or therapies, except as indicated below: a. Mipomersen or lomitapide (current or within 6 months of Screening). b.PCKS9 inhibitors including evolocumab or alirocumab (current or within 3 months of Screening). c. Lipid apheresis (current or within 8 weeks of Screening or intends to have lipidapheresis treatments throughout the trial). d. Systemic corticosteroids (current or within 4 weeks prior to enrollment; topical and inhaled corticosteroids are allowed). e. Red yeast rice extract (also known as monascus purpureus extract or Cholestin) containing products (current or within 4 weeks of Screening); f. Lipid altering nutritional supplements including berberine, psyllium (Metamucil®),green tea extract, sitostanol (found in oral nutritional supplements and some margarines, such as Benecol), beta-sitosterol(found in oral nutritional supplements and some margarines, such as Promise Activ), pantothine and policosanol (current or within 4 weeks of Screening); g. Bile acid sequestrants, fibrates, omega 3 fatty acids, or niacin, unless the dose has been stable for ≥6 weeks and will remain stable throughout the trial. h. Simvastatin >20 mg or pravastatin >40 mg (current or within 4 weeks of Screening).
The patient has a history or evidence of any other clinically significant condition, or planned or expected procedure that in the opinion of the Investigator, may compromise the patient's safety or ability to complete the study
The patient has a situational (ie, geographical) finding that, in the Investigator's opinion, may compromise the patient's safety or ability to complete the study
The patient is an employee or contractor of the facility that is conducting the study or is a family member of the Investigator, subInvestigator, or any Sponsor personnel

Trial Status by Country

Country	Status	Start of Recruitment	Planned Patients
Denmark	Not Recruiting	01 Aug 2023	6
Germany	Not Recruiting	01 Aug 2023	7
The Netherlands	Not Recruiting	01 Aug 2023	—
Spain	Not Recruiting	01 Aug 2023	7
Netherlands	—	—	7