Clinical Trials

Date: 2017-08-07

Type of information: Results

phase: 2b

Announcement: results

Company: Gemphire Therapeutics (USA - Mich)

Product: gemcabene

Action mechanism:

• Gemcabene is a lipid-lowering small molecule. Its mechanism of action is designed to enhance the clearance of very low-density lipoproteins (VLDLs) in the plasma and inhibition of the production of cholesterol and triglycerides in the liver. The combined effect of these mechanisms has been clinically observed to result in a reduction of plasma non-HDL-C, VLDL-C, LDL-C, apolipoprotein B and triglycerides. In addition, gemcabene has been shown to markedly lower C-reactive protein in humans and improve insulin sensitization.
• Gemcabene’s MOA is liver-directed involving downregulation of hepatic apolipoprotein C-III (apoC-III) mRNA expression and decrease of plasma apoC-III levels. Gemcabene has also been shown to reduce liver sulfatase-2 mRNA levels, known to be elevated in diabetic and obese patients. Elevated sulfatase-2 is thought to reduce the effectiveness of the liver VLDL-remnant receptor (also known as Syndecan-1), that normally plays a role in removing triglyceride containing particles from the plasma. Gemcabene also reduces acetyl-CoA carboxylase (ACC1) and CCR2/CCR5 receptor mRNA levels, markers involved in the progression of NASH/NAFLD.

Disease: patients with hypercholesterolemia not adequately controlled on high-intensity or moderate-intensity stable statin therapy, including patients with heterozygous familial hypercholesterolemia (HeFH) and atherosclerotic cardiovascular disease (ASCVD), who have baseline LDL-C (“bad cholesterol”) values ? 100 mg/dL

Therapeutic area: Rare diseases - Genetic diseases - Cardiovascular diseases

Country: US

Trial details:

• The randomized, placebo-controlled, double-blind Phase 2b trial, “A 12-Week, Phase 2 Study of Gemcabene in Hypercholesterolemia Patients on Stable Moderate and High-Intensity Statins (ROYAL-1)” will enroll up to 104 adult patients at clinical sites in the United States. Patients with HeFH, ASCVD, or otherwise uncontrolled, may be included with baseline LDL-C value ? 100 mg/dL. Subjects will be randomized 1:1 to gemcabene 600 mg QD or placebo.
• The primary endpoint is the percent change from baseline of LDL-C at 12 weeks. Secondary endpoints include the change from baseline in non-HDL-C, total cholesterol, triglycerides, ApoB, and hsCRP at the 12-week time point.The purpose of this study is to assess the efficacy, safety, and tolerability of multiple doses of gemcabene 600 mg QD compared to placebo in patients with hypercholesterolemia not adequately controlled on high-intensity or moderate-intensity stable statin therapy. (NCT02634151)

Latest news:

• • On August 7, 2017, Gemphire Therapeutics announced top-line data based upon the preliminary review of the limited top-line data set from the completed double-blind, placebo-controlled, randomized Phase 2b ROYAL-1 trial. The study evaluated the efficacy, safety, and tolerability of oral gemcabene 600 mg dosed once daily. It enrolled patients who were not adequately controlled, with an existing LDL-C value ?100 mg/dL (2.59 mmol/L) and a TG value < 500 mg/dL (5.65 mmol/L), on stable high- or moderate-intensity statin and/or ezetimibe therapy. Patients were stratified according to background statin intensity and diabetes status. One hundred and five subjects were enrolled at sites in the US and randomized to either gemcabene 600 mg or placebo for a total of 12 weeks.
• Fifty-six (56) females and 49 males with a mean age of 61 years were enrolled. The mean baseline LDL-C was 130 mg/dL. Gemcabene 600 mg produced a mean percent change in LDL-C of -17.2% vs -5.5% for placebo (ANCOVA: p=0.0057). Gemcabene 600 mg produced a median percent change in hsCRP of -40.0% (ranked ANCOVA: p<0.0001) vs -6.1% for placebo. Additional secondary results and subpopulations assessments will be provided once the full dataset has been analyzed.
• There were no serious adverse events in the study. Adverse events (AEs) were generally mild to moderate in intensity and consistent with previously reported AEs. Three subjects discontinued from the study, 1 from the gemcabene and 2 from the placebo groups. The subject randomized to gemcabene discontinued because of reported dizziness. No subjects in the study had a transaminase elevation > 3x ULN. One placebo subject had a creatine kinase elevation > 5x ULN on consecutive measurements. No gemcabene subjects had consecutive elevations in creatine kinase > 3 x ULN. The lack of liver or muscle toxicities in ROYAL-1, on top of the highest doses of statin therapy, is consistent with previous safety data from 19 prior completed studies.
• • On November 28, 2016, Gemphire Therapeutics announced enrollment of its first patients in ROYAL-1, a Phase 2b trial designed to investigate gemcabene in the treatment of patients with hypercholesterolemia not adequately controlled on high-intensity or moderate-intensity stable statin therapy. It is designed to enroll a broad patient population, including patients with heterozygous familial hypercholesterolemia (HeFH) and atherosclerotic cardiovascular disease (ASCVD), who have baseline LDL-C (“bad cholesterol”) values ? 100 mg/dL. Gemphire currently anticipates the 12-week study to complete enrollment and all patient follow-up visits in the second half of 2017.

Is general: Yes