Study to Evaluate the Effects of MBX-8025 in Patients With HoFH

Open-label, single arm, non-controlled, dose ascending (50 mg/day, 100 mg/day and 200 mg/day) with three consecutive dose escalation periods.

After signing an informed consent subject will enter a screening period and a run-in stabilization period. At the end of run-in period patients will enter treatment phase. MBX-8025 in ascending doses (50 mg, 100 mg, and 200 mg) will be given within three consecutive 4 weeks periods, for a total of 12 weeks. At the end of treatment, subjects will enter a follow-up period.

Inclusion criteria

• Must have given written informed consent (signed and dated) and any authorizations required by local law and be able to comply with all study requirements.
• Male or female with HoFH confirmed by genotype (two mutant alleles at the LDL-Receptor (LDL-R) gene locus or double heterozygotes LDL-R/Apo-B).
• 18 years of age or older.
• Existing lipid lowering therapies (statins, cholesterol absorption inhibitors, bile acid sequestrants, nicotinic acid and their combinations, low-density lipoprotein (LDL) LDL-C apheresis) on a stable regimen for at least four weeks before screening visit.
• Stable lipid lowering diet compatible with a Step I diet of the American Heart Association (AHA).
• Fasting LDL-C ≥ 4.8 mmol/L (≥ 185.6 mg/dL) during screening.
• For females or males of reproductive potential, use of at least one barrier contraceptive and a second effective birth control method during the study and for at least two weeks after the last dose.

Exclusion criteria

• Treatment with lomitapide or mipomersen within two months of screening.
• Heart Failure (HF) with New York Heart Association (NYHA) class III and class IV or a Left ventricular ejection fraction (LVEF) of less than 30%.
• Uncontrolled cardiac arrhythmia during the past three months of screening.
• Myocardial infarction, unstable angina, percutaneous coronary intervention, coronary artery bypass graft or stroke during the past three months of screening.
• Planned cardiac surgery, or planned revascularization, in the next four months.
• Uncontrolled hypertension.
• Aspartate transaminase (AST) or Alanine transaminase (ALT) ≥ 3 times the Upper Limit of Normal (ULN).
• Unexplained creatine kinase (CK) ≥ 5 times the upper limit of normal (ULN).
• For females, pregnancy or breast-feeding.
• Any other condition(s) that would compromise the safety of the patient or compromise the quality of the clinical study as judged by the Investigator and/or Medical Monitor.