Clinical Trials

Date: 2017-06-28

Type of information: Results

phase: 2b

Announcement: results

Company: Gemphire Therapeutics (USA - Mich)

Product: gemcabene (CI-1027)

Action mechanism:

• Gemcabene is a once-daily, oral therapy that may be suitable for patients who are unable to achieve normal levels of LDL-C or triglycerides with currently approved therapies, primarily statins. Gemcabene's mechanism of action is designed to enhance the clearance of very low-density lipoproteins (VLDLs) in the plasma and inhibit the production of cholesterol and triglycerides in the liver. The combined effect for these mechanisms has been observed to result in a reduction of plasma VLDL-C, LDL-C, and triglycerides, as well as markedly lowering C-reactive protein. Gemcabene is liver-directed and reduces apoC-III mRNA and plasma levels and may also inhibit acetyl-CoA carboxylase (ACC) which has applications in NASH/NAFLD.

Disease: homozygous familial hypercholesterolemia (HoFH)

Therapeutic area: Rare diseases - Genetic diseases - Cardiovascular diseases

Country: Canada, Israel, USA

Trial details:

• COBALT-1 is an  open-label Phase 2b trial that will enroll up to eight adult patients at clinical sites in the United States, Canada, and Israel.  Patients meeting eligibility requirements will be treated with an initial dose of 300 mg gemcabene, which will be increased to 600 mg at 4 weeks and then 900 mg at 8 weeks.  All patients will continue to receive their lipid-lowering background therapy. Patients were excluded if they were undergoing apheresis or taking mipomersen or lomitapide.  All enrolled patients were further evaluated for known DNA mutations causing HoFH.  The primary endpoint for each dose of gemcabene (300, 600 and 900 mg) was mean percent change in LDL-C from baseline at 4, 8, and 12 weeks respectively.  Secondary endpoints include mean percent change from baseline in hsCRP, apoB, non-HDL-C, TG, VLDL-C and total cholesterol.  Safety was being assessed by AE monitoring, clinical laboratory assessments, electrocardiograms, physical examinations and vital signs. (NCT02722408)

Latest news:

• • On June 28, 2017, Gemphire Therapeutics announced top-line data on the LDL-C primary endpoint from the completed open label Phase 2b COBALT-1 trial.  COBALT-1 evaluated gemcabene in homozygous familial hypercholesterolemia (HoFH) patients who are on stable maximally tolerated lipid-lowering therapies to assess the efficacy, safety, and tolerability of multiple rising doses of gemcabene. The study enrolled patients clinically or genetically diagnosed as HoFH, who were on a variety of background therapies including the highest doses of statins and/or ezetimibe and/or PCSK9 inhibitors.  These therapeutic classes represent the current initial drug therapies for HoFH.  Eight subjects (5 male and 3 female, all Caucasian, average age 53 years) on previously prescribed therapy (which included statins, ezetimibe, evolocumab, cholestyramine, and omega-3 fatty acids) were enrolled from sites in the US, Canada and Israel. Patients were sequentially administered oral gemcabene once daily (dosage escalating from 300 mg to 600 mg and then 900 mg every 4 weeks) for a total duration of 12 weeks. The mean baseline LDL-C was 351 mg/dL (range from 138-623 mg/dL).  Gemcabene 300 mg lowered LDL-C by a mean of 25% (p=0.0063; range -55% to +1%), gemcabene 600 mg lowered LDL-C by a mean of 30% (p=0.0047; range -51% to +2%), and gemcabene 900 mg lowered LDL-C by a mean of 29% (p=0.0035; range -54% to +6%).  The complete data for COBALT-1 will be submitted to a cardiovascular conference for presentation, as well as for publication in a peer reviewed journal. Adverse events (AEs) were mild to moderate in intensity across all doses of gemcabene and consistent with previously reported AEs. There were no serious AEs or withdrawals due to AEs in the COBALT-1 study.
• Additional analyses of 6 subjects that met the more stringent European Atherosclerosis Society (EAS) Consensus Panel diagnosis of HoFH had a mean baseline LDL-C of 374 mg/dL (range 138 to 623 mg/dL). Gemcabene 300, 600 and 900 mg lowered LDL-C by a mean of 18% (p=0.0059; range -32% to +1%), 23% (p=0.0010; range -44% to +2%), and 21% (p=0.0019; range -33% to +6%), respectively, in such subjects. Three subjects known at enrollment to have ‘negative’ (<2%) LDL-receptor activity had a mean baseline LDL-C of 551 mg/dL (range 430 to 623 mg/dL) but still responded to gemcabene: 300 mg lowered LDL-C by a mean of 10% (range -30% to +1%), 600 mg lowered LDL-C by a mean of 15% (range -44% to +2%), and 900 mg lowered LDL-C by a mean of 12% (range -24% to +6%).
• • On  January 30, 2017, Gemphire Therapeutics announced interim data on the LDL-C primary endpoint from the ongoing open label COBALT-1 trial. Interim results on two genetically confirmed HoFH patients through 8 weeks of treatment (4 weeks on 300 mg of gemcabene followed by 4 weeks on 600 mg of gemcabene) are reported herein.  Both subjects were on a background of high intensity statin therapy (atorvastatin 80 mg or rosuvastatin 40 mg), and one subject was also on ezetimibe before receiving gemcabene.  Gemcabene lowered mean LDL-C by 23% and 28% at doses of 300 mg and 600 mg, respectively.  Adverse events (AEs) have been mild to moderate in intensity across all doses of gemcabene; there have been no serious AEs or withdrawals due to AEs in the COBALT-1 study.
• COBALT-1 Interim Data Results

Patient	Gender	HoFH Entry Criteria	Maximal Lipid-Lowering Therapies	Baseline LDL-C mg/dL	% Change From Baseline, Gemcabene 300 mg/day (4 weeks)		%Change From Baseline, Gemcabene 600 mg/day (4 weeks)
1	Male	Genotype (Compound Heterozygous)	Rosuvastatin 40mg	138	-28.7	%	-32.4	%
2	Male	Genotype (Compound Heterozygous)	Atorvastatin 80mg Ezetimibe 10mg	195	-18.3	%	-22.9	%

• • On September 26, 2016, Gemphire Therapeutics announced enrollment of its first patient in COBALT-1, a Phase 2b trial designed to investigate gemcabene in the treatment of homozygous familial hypercholesterolemia (HoFH).  The purpose of this study is to assess the efficacy, safety, and tolerability of multiple rising doses of gemcabene in patients with HoFH who are on stable, lipid-lowering therapy, including statins, ezetimibe and Repatha®. Gemphire currently anticipates the 12-week study to complete enrollment and all patient follow-up visits in the first half of 2017, with top-line data readout expected in June 2017.

Is general: Yes