Efficacy and Safety of Gemcabene in Patients With Homozygous Familial Hypercholesterolemia on Stable, Lipid-Lowering Therapy (COBALT-1)

Inclusion criteria

• Provision of written and signed informed consent (by patient or legal guardian) prior to any study-specific procedure;
• Male or female ≥17 years of age at time of consent;
• Diagnosis of HoFH by genetic confirmation (including compound heterozygosity) or a clinical diagnosis based on either (1) a history of an untreated LDL-C concentration >500 mg/dL (12.92 mmol/L) together with either appearance of xanthoma before 10 years of age, or evidence of heterozygous familial hypercholesterolemia in both parents or, if history is unavailable, (2) LDL-C >300 mg/dL (7.76 mmol/L) on maximally tolerated lipid-lowering drug therapy;
• Currently on a stable, low-fat, low-cholesterol diet in combination with a pre-existing, regulatory-approved, not excluded lipid-lowering therapy (i.e., statins, monoclonal antibodies to PCSK9, cholesterol absorption inhibitors, bile acid sequestrants, or nicotinic acid, or any combination thereof) at a stable dose for at least 4 weeks prior to the Screening Visit;
• Fasting LDL-C value >130 mg/dL (3.36 mmol/L) at the Screening Visit;
• Physical examination, including vital signs, that is within normal limits or clinically acceptable to the Investigator;
• Weight ≥50 kg;
• Female patients must not be pregnant or lactating. Women of child-bearing potential must have a negative serum pregnancy test at the Screening Visit and negative urine dipstick on Day 1 prior to dosing in order to qualify for the study. Women who are surgically sterile or are clinically confirmed to be post-menopausal (i.e., documented amenorrhea for ≥1 year in the absence of other biological or physiological causes) are not considered to be of child-bearing potential; and
• Women of child-bearing potential must agree to use acceptable methods of contraception throughout the duration of the study and for 30 days after the last dose of study drug. For this study, double-barrier contraception is required.

Exclusion criteria

• Other forms of primary hyperlipoproteinemia and secondary causes of hypercholesterolemia (e.g., nephrotic syndrome or hypothyroidism);
• Abnormal liver function test at the Screening Visit (aspartate aminotransferase or alanine aminotransferase >2 × the upper limit of normal [ULN]; total bilirubin >1.5 × ULN; or alkaline phosphatase >2 × ULN based on appropriate age and gender normal values). Patients with bilirubin >1.5 × ULN and history of Gilbert's syndrome may be included; reflexive direct bilirubin testing will be used to confirm Gilbert's syndrome;
• Moderate (Grade B) or severe (Grade C) chronic hepatic impairment according to the Child Pugh classification;
• Active liver disease (e.g., cirrhosis, alcoholic liver disease, hepatitis B virus [HBV], hepatitis C virus [HCV], autoimmune hepatitis, liver failure, liver cancer), history of liver transplant, or known diagnosis of human immunodeficiency virus (HIV);
• Triglycerides value >400 mg/dL (4.52 mmol/L) at the Screening Visit;
• Moderate to severe renal insufficiency defined as an estimated GFR <30 mL/min/1.73m2 (calculated using The Chronic Kidney Disease Epidemiology Collaboration equation) at the Screening Visit;
• Abnormal urinalysis (proteinuria greater than trace or any male or non-menstruating female with greater than trace hematuria), confirmed by reflexive urine protein:creatinine ratio testing;
• Uncontrolled thyroid disease: hyperthyroidism or hypothyroidism as defined by thyroid stimulating hormone (TSH) below the lower limit of normal or >1.5 × ULN, respectively, at the Screening Visit. If controlled, treatment should be stable for at least 3 months prior to the Screening Visit;
• Type 1 diabetes mellitus or uncontrolled type 2 diabetes mellitus (hemoglobin A1c [HbA1c] value >8%), or any diabetic patient taking insulin and/or thiazolidinediones;
• New York Heart Association Class III or IV heart failure;
• Myocardial infarction, severe or unstable angina pectoris, coronary angioplasty, coronary artery bypass graft, or other major cardiovascular events resulting in hospitalization within 3 months of the Screening Visit. Patients with adequately treated stable angina, per Investigator assessment, may be included;
• Uncontrolled cardiac arrhythmia or prolonged QT on the Screening Visit or Day 1 prior to dosing ECG (QTcF >450 msec for men and >470 msec for women) or known family history of prolonged QT or unexplained sudden cardiac death;
• Uncontrolled hypertension, defined as sitting systolic blood pressure >180 mmHg or diastolic blood pressure >110 mmHg, and confirmed by repeat measurement;
• Currently receiving cancer treatments or, in the Investigator's opinion, at risk of relapse for recent cancer;
• Use of fibrate lipid-lowering agent 6 weeks prior to the Screening Visit;
• Hypersensitivity to or a history of significant adverse reactions to any fibrate lipid lowering agent;
• Use of apheresis (LDL or plasma) 8 weeks prior to the Screening Visit;
• Use of lomitapide 2 months prior to the Screening Visit;
• Use of mipomersen 5 months prior to the Screening Visit;
• Use of any excluded medications or supplements (e.g., potent cytochrome P450 [CYP] 3A4 inhibitors);
• History of drug or alcohol abuse within the past year or inability to comply with protocol requirements, including subject restrictions;
• Previously treated with gemcabene;
• Participation in another clinical study of an investigational agent or device concurrently or within 1 month prior to the Screening Visit, or use of an investigational agent within 1 month or 5 half-lives (if known), whichever is longer, prior to the Screening Visit; or
• Any other finding which, in the opinion of the Investigator, would compromise the patient's safety or participation in the study.