Date: 2016-03-17
Type of information: Results
phase: 2
Announcement: results
Company: Cymabay Therapeutics (USA - CA)
Product: MBX-8025 (2-[4-[[(2R)-2-ethoxy-3-[4-(trifluoromethyl)phenoxy]propyl]thio]-2-methylphenoxy]acetic acid (1:1) lysine dihydrate)
Action
mechanism: PPAR agonist. MBX-8025 is a selective agonist of peroxisome proliferator-activated receptor delta (PPAR?), a nuclear receptor important for lipid transport, storage and metabolism in liver and muscle. MBX-8025 has shown favorable effects on lipid and metabolic parameters in a Phase 2 study in patients with mixed dyslipidemia. Treatment effects observed include lowering of LDL-C with selective depletion of pro-atherogenic dense LDL-C particles, decreases in triglycerides and increases in high density lipoprotein, as well as decreases in hsCRP, a biomarker of cardiovascular inflammation. The FDA has granted the Company orphan drug designation for MBX-8025 for the treatment of HoFH. MBX-8025 has also received orphan designation for Fredrickson types I and V hyperlipoproteinemia.
Disease: homozygous familial hypercholesterolemia
Therapeutic area: Rare diseases - Genetic diseases - Metabolic diseases
Country:
Trial
details: This study was an open label, dose escalation study of 12 weeks duration conducted at five centers in Europe and Canada. Thirteen patients were enrolled, all of whom had genetically confirmed HoFH, including two subjects who had functionally negative mutations in their LDL receptor (LDL-R) genes. All of the subjects were taking ezetimibe and were on maximum statin therapy. None of the study participants received lomitapide, mipomersen or a PCSK9 inhibitor. Eight patients were undergoing concomitant apheresis on a weekly or biweekly schedule. Despite being on maximal conventional therapy, the average baseline LDL-C was 368 mg/dL. Subjects received once daily treatment with 50 mg of MBX-8025 for 4 weeks, after which the dose was escalated to 100 and 200 mg in successive 4-week periods. The goals of the study were to evaluate the effect on LDL-C as well as a spectrum of other lipid-related parameters, including PCSK9 levels, and to collect safety information.
Latest
news: * On March 17, 2016, CymaBay Therapeutics announced top line results from its pilot Phase 2 clinical study of MBX-8025 in patients with homozygous familial hypercholesterolemia (HoFH). The study demonstrated that the range of responses to MBX-8025 was broad, but that MBX-8025 provided a clinically meaningful reduction in low-density lipoprotein cholesterol (LDL-C) for a subset of patients. This is the first study to demonstrate the potential utility of a PPAR? agonist in HoFH. * On April 23, 2015, CymaBay Therapeutics announced the initiation of a Phase 2 study of MBX-8025 in patients with homozygous familial hypercholesterolemia (HoFH). The Phase 2 trial is an open label, dose-escalation study that will target enrollment of 8 patients at sites in Europe and North America. Following enrollment, patients will initially receive a 50 mg dose of MBX-8025 once daily that will be increased first to 100 mg and eventually 200 mg of MBX-8025 over the course of 3 months.
Results: Two per-protocol analyses were performed on 12 subjects. The data for one subject was excluded because of multiple missed apheresis visits throughout the study which caused marked fluctuations in LDL-C levels. A responder analysis was carried out which reflects the largest decrease in LDL-C observed during treatment for each subject. Three subjects (25%) exhibited a greater than or equal to 30% decrease. Five subjects (42%) had a greater than or equal to 20% decrease, including one patient that was receptor negative, and 7 (58%) had a greater than or equal to 15% decrease. Five subjects (42%) had a less than 15% decrease. The average maximum decrease in the study was 19%. Because of the high baseline LDL-C levels in these individuals, these percentage decreases correspond to significant absolute decreases in LDL-C (mean decrease of 109 mg/dL for the subjects with a greater than or equal to 15% decrease). Although reductions in LDL-C tended to be greater at the higher doses, no clear dose response was observed.
In a second analysis, the mean change in LDL-C for each subject was calculated by averaging values across all doses and dosing periods while on treatment. The overall mean change for all 12 subjects was a decrease of 10%. Eight of these subjects had a mean decrease in LDL-C of 16%, including 3 with a greater than 20% decrease. This included one patient that was receptor negative. This was offset by 4 patients who showed a mean increase of 4%.
Mean PCSK9 was elevated at baseline (544 +/- 133 ng/mL), as anticipated for patients with HoFH, and increased significantly during treatment by a mean of 43%. During the study, decreases in the mean levels of alkaline phosphatase (30%), gamma glutamyl transferase (27%) and total bilirubin (22%), which are markers of cholestasis, were also observed. There were three SAEs, none drug related, and three treatment discontinuations for AEs possibly related to MBX-8025. CymaBay Therapeutics plans to evaluate the feasibility of conducting a pilot study of MBX-8025 in combination with a PCSK9 inhibitor.
In a clinical study conducted in patients with mixed dyslipidemia, MBX-8025 was shown to reduce LDL-C. Data from a preclinical model of human HoFH indicate that MBX-8025 lowers LDL-C in the absence of a fully functional LDL-R.
