UPDATE: CymaBay Offers Results from Pilot Phase 2 Study of MBX-8025 in Patients with Homozygous Familial Hypercholesterolemia

CymaBay Therapeutics, Inc. CBAY today 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 PPARδ agonist in HoFH. "This pilot study provides the first evidence that MBX-8025 has potential utility for the treatment of HoFH, an ultra-orphan disease in which patients remain in need of additional LDL-C lowering," said Harold Van Wart, Chief Executive Officer of CymaBay. Study objectives and design This 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. 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. "Despite the availability of new therapies, including PCSK9 inhibitors, most patients with HoFH remain far from their LDL-C targets and there is still a need for new therapeutic approaches," said Dr. Evan Stein, Director Emeritus of the Medpace Metabolic and Atherosclerosis Research Center. "The finding that MBX-8025 lowers LDL-C, despite the unexpected increase in PCSK9, suggests that studies on top of PCSK9 inhibitors may be warranted to further assess the potential of MBX-8025 treatment in patients with HoFH." "We are encouraged by the meaningful response in LDL-C reductions observed in a number of patients in the study and plan to evaluate the feasibility of conducting a pilot study of MBX-8025 in combination with a PCSK9 inhibitor," said Harold Van Wart.