CymaBay Therapeutics (CBAY) Announces Clinically Meaningful Data from MBX-8025 Phase 2 in HoFH

March 17, 2016 4:02 PM EDT

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CymaBay Therapeutics, Inc. (NASDAQ: CBAY) 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.


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.

Conference Call

CymaBay will host a conference call today, March 17, 2016, at 4:30 p.m. ET / 1:30 p.m. PT to discuss the results of this pilot Phase 2 study. The call can be accessed by dialing 877-407-0784 (domestic) and 201-689-8560 (international) five minutes prior to the start of the call. A slide presentation to be used in connection with the call entitled “MBX-8025 Pilot Study in HoFH Top Line Data” has been posted on CymaBay’s website and can be accessed at A live audio webcast of the call can be accessed under the Investors section of CymaBay’s website at and will be available for 14 days following the call.

About MBX-8025

MBX-8025 is a potent and selective agonist of PPARδ, a nuclear receptor important for lipid transport, storage and metabolism in liver and muscle. MBX-8025 has shown favorable effects on lipid and other 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 particles, decreases in triglycerides and increases in HDL, as well as decreases in hsCRP, a biomarker of cardiovascular and systemic inflammation. MBX-8025 also decreased levels of alkaline phosphatase and gamma glutamyl transferase, which are markers of cholestasis. The U.S. Food and Drug Administration (FDA) has granted the Company orphan drug designation for MBX-8025 as a treatment for HoFH and Fredrickson types I and V hyperlipoproteinemia. CymaBay has also initiated a Phase 2 study of MBX-8025 in patients with primary biliary cholangitis.

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