Primary:To evaluate the effect of MBX-8025 on LDL-C.Secondary:To evaluate the effects of MBX-8025 on other lipid parameters. To evaluate the safety and tolerability of MBX-8025. To evaluate steady-state trough plasma levels of MBX-8025 and its…
ID
Source
Brief title
Condition
- Metabolic and nutritional disorders congenital
- Lipid metabolism disorders
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
LDL-C.
Secondary outcome
Total cholesterol, HDL-C, VLDL-C, non-HDL-cholesterol, apolipoprotein B,
apolipoproteïi A-l, lipoprotein (a), triglycerides, apolipoprotein C-lll,
RLP-cholesterol. Adverse events. Steady-state trough plasma levels of MBX-8025
and its metabolites.
Background summary
Homozygous Familial Hypercholesterolemia (HoFH) is a rare, severe clinical
disorder characterized by very high LDL-C levels (usually of more than 12.9
mmol/L), cutaneous and tendionous xanthomata, and early onset of cardiovascular
disease. The main cause of HoFH is a substantial reduction in LDL receptor
function. Conventional therapies such as statins and ezetimibe are the most
commonly used drugs for HoFH. However, due to their mechanism of action, their
result in LDL-cholesterol reductions ranges between 15% to 25%. Consequently,
plasma LDL apheresis is still considered the treatment of choice for HoFH.
Apheresis is a selective mechanical filtration of blood to remove LDL, but it
is a complex and inconvenient procedure that is not widely available. Apheresis
transiently reduces LDL-C levels and must be repeated every 1 to 2 weeks.
Recently two additional drugs, lomitapide (US and EU) and mipomersen sodium
(US) have been available for the treatment of HoFH. Both compounds have
demonstrated potent LDL-C lowering properties in HoFH subjects. However, not
all HoFH subjects are able to decrease their LDL-C to recommended levels,
either due to incomplete efficacy or poor tolerability and significant safety
issues. Both lomitapide and mipomersen carry the risk of hepatotoxicity.
MBX-8025 has an effect on lowering LDL-C through mechanisms that may not
involve the LDL-C receptor, MBX-8025 has been shown to decrease LDL-C, while
also leading to improvements in TG, HDL-C, TC and FFA. The use of MBX-8025 to
treat HoFH represents an important opportunity to address an unmet clinical
need in healthcare.
Study objective
Primary:
To evaluate the effect of MBX-8025 on LDL-C.
Secondary:
To evaluate the effects of MBX-8025 on other lipid parameters. To evaluate the
safety and tolerability of MBX-8025. To evaluate steady-state trough plasma
levels of MBX-8025 and its metabolites, M1, M2 and M3.
Study design
Open-label, single arm study, non-controlled, dose ascending (MBX-8025 OD, 50
mg/day, 100 mg/day and 200
mg/day). Dose increase every 4 weeks. Screening max. 2 weeks, run-in period 2
weeks, treatment period 12 weeks, follow-up 2 weeks.
MBX-8025 will be added to the existing therapy.
Approx. 8 patients, 3 in NL.
Independent DSMB.
Intervention
Treatment with MBX-8025.
Study burden and risks
Risk: side effects of study medication..
Burden: 10 visits in approx. 18 weeks. Duration 1-2 hours..
Diet.
3 times physical examination.
9 times blood tests (approx. 150 ml blood, 5-25 mL/visit).
6 times ECG.
7999 Gateway Blvd, suite 130
Newark CA 94560
US
7999 Gateway Blvd, suite 130
Newark CA 94560
US
Listed location countries
Age
Inclusion criteria
1. Written informed consent.
2. Male or female with HoFH confirmed by genotype (two mutant alleles at the LDL-Receptor gene locus)
3. 18 years of age or older
4. Existing lipid lowering therapies (statins, cholesterol absorption inhibitors, bile acid sequestrants, nicotinic acid and their combinations, LDL-C apheresis) on a stable regimen for at least four weeks before Screening Visit.
5. Stable lipid lowering diet compatible with a Step I diet of the American Heart Association.
6. Fasting LDL-C > 4.8 mmol/L during screening.
7. 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
1. Treatment with lomitapide or mipomersen within two months of screening.
2. Heart Failure NYHA class lll-IV or LVEF <30%.
3. Uncontrolled cardiac arrhythmia during the pastthree months of screening.
4. Myocardial infarction, unstable angina, PCI, CABG orstroke during the pastthree months prior to screening.
5. Planned cardiac surgery, or revascularization, in the next four months.
6. Uncontrolled hypertension.
7. AST or ALT >3 times the ULN.
8. Unexplained CK >5 times the ULN.
9. For females, pregnancy or breast-feeding.
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| EudraCT | EUCTR2014-004856-68-NL |
| CCMO | NL52715.060.15 |