Advancing a class on top of statins
Novel Lipid-Altering Drug Candidate

Gemcabene has been tested in over 900 patients across 11 Phase 1 and 8 Phase 2 studies.

About Gemcabene

We believe gemcabene possesses a differentiated product profile compared to other therapies in the market and in clinical development. Key attributes of our product candidate include the following:

  • Cost-effective, once-daily, oral therapy. Gemcabene is a small molecule formulated as a tablet and is cost effective to manufacture. As a once-daily, oral therapy, gemcabene, if approved, would be more convenient than other non-statin therapies, many of which require frequent injections or multiple daily doses. We expect to take a value-based approach to pricing across all the target indications.
  • Promising safety and tolerability. Gemcabene was observed to be well tolerated in over 900 subjects across 20 Phase 1 and Phase 2 trials both as monotherapy and in combination with statins. No subjects died and no subjects experienced a serious adverse event (SAE) that was considered to be related to gemcabene. Adverse events (AEs) reported were generally mild to moderate in intensity. Gemcabene did not appear to increase the reporting of myalgia (muscle pain) when added to statin therapy and no treatment related events of myalgia were reported in any gemcabene monotherapy arm in the dyslipidemia trials.
  • First-in-class mechanism. Gemcabene’s pleotropic mechanism of action hits multiple established targets that lower LDL-C, TG, and hsCRP in plasma. Gemcabene has been observed to reduce production of cholesterol and triglyceride pathways inside the liver. This gemcabene effect may be due to inhibition of acetyl CoA carboxylase (ACC) and HMG-CoA Synthase in the liver. Gemcabene has also been shown to enhance clearance of VLDL in the plasma. This is likely due to gemcabene’s effect on reduction of apoC-III gene expression and reduction of plasma apoC-III levels, which may facilitate the uptake of VLDL remnants via hepatic remnant receptors. Gemcabene’s effects on hsCRP may be due to its effect on reduction of IL-6 expression, as well as its direct effects on inhibiting transcription factors C/EBP-β and NF-kB interaction with the CRP gene.
  • Significant lipid-lowering of LDL-C, high-sensitivity C-reactive protein (hsCRP) and triglycerides. In Phase 2 trials, patients with hypercholesterolemia treated with gemcabene as monotherapy were observed to have significantly lowered LDL-C by approximately 30% from baseline and significantly lowered hsCRP by approximately 40% from baseline. In addition, patients with hypertriglyceridemia (≥200 mg/dL) were observed to have significantly lowered triglycerides by approximately 40%, and based on post-hoc analysis, gemcabene was observed to lower triglycerides by up to 60% in patients with severe triglyceride levels (≥500 mg/dL). Our product candidate’s ability to meaningfully lower levels of multiple key lipids attributable to cardiovascular disease may expand its use across multiple indications within the dyslipidemia and NASH Market.
  • Additive effect in combination with statins. In a Phase 2 trial in patients with uncontrolled hypercholesterolemia while on stable statin therapy (Trial 2017-018), gemcabene was observed to significantly lower LDL-C by an additional 25% to 31% from baseline. This data indicates that gemcabene may better treat a large population of patients who are unable to reach their lipid goal with statins and other currently prescribed therapies, including those medications commonly used for diabetes and NASH patients.
  • No drug-drug interactions when combined with high-intensity statin doses. In two Phase 1 trials, gemcabene was tested in combination with high-intensity statin doses, 80 mg simvastatin and 80 mg atorvastatin. No clinically relevant drug-drug interactions were observed. In addition, gemcabene has been formulated as a fixed-dose combination tablet with various atorvastatin doses, which may offer additional convenience and compliance to patients.

A Differentiated Product Profile

Gemcabene is a monocalcium salt of a dialkyl ether dicarboxylic acid being developed as a novel lipid-lowering small molecule to be used as an adjunctive therapy to reduce LDL-C, hsCRP, and TGs. Gemcabene is a first-in-class oral drug candidate with pleiotropic properties similar to statins as shown in trials to date.

Mechanism of Action

Gemcabene has a dual mechanism of action that involves blocking the overall production of hepatic triglyceride and cholesterol synthesis and enhancing the clearance of VLDL. Based on prior clinical trials, the combined effect for these mechanisms has been observed to result in a reduction of plasma VLDL-C, LDL-C, triglycerides and hsCRP, as well as elevation of high-density lipoprotein cholesterol (HDL-C).

Production Mechanism
Clinical Experience

As described below, gemcabene has been evaluated in over 900 patients to date and has completed requisite toxicity and efficacy studies with consistent results. Gemcabene is being studied in clinical trials and is currently an unapproved drug.

Nonclinical

  • Completed many MOA studies with PPAR and lipid metabolic pathways (Bisgaier 1998)
  • Completed many exploratory efficacy studies in mice and rats
  • Completed over 30 nonclinical GLP tox studies, including:
    • 26-week repeated dose rats and monkeys
    • 52-week repeated dose monkeys

Phase 1 Clinical

  • Completed 11 Phase 1 studies, including:
    • Safety and tolerability
    • PK and dose response
    • PK combo with statins

Phase 2 Clinical

  • Completed 9 Phase 2 studies, including:
    • Study 1027-018: Add on for patients not at goal on stable statins
    • Study 1027-004: Monotherapy high triglycerides (TG) patients (Bays 2003)
    • Study 1027-014, Study 1027-008, & Study A4141001: Monotherapy and combination statin studies

Clinical evidence of efficacy of gemcabene in reducing LDL-C levels has been demonstrated in multiple clinical trials. Gemcabene’s clinical profile has shown it provides an additional 25% to 31% lowering of LDL-C on top of background maximal stable statin therapy (Study 018). If approved, gemcabene may provide a tolerable and convenient oral treatment option for dyslipidemia patients. In addition, because gemcabene has been shown to substantially lower an anti-inflammatory marker hsCRP, it may potentially further benefit cardiovascular health of patients.

Selected clinical trials are summarized in the table below:

Selected Studies

Study Identifier

Study

LDL-C Lowering

Interventions

No. of Subjects

Treatment Duration

Phase 1

1027-003

Pharmacokinetics and Pharmacodynamics of Gemcabene in Healthy Volunteers

32% Monotherapy

Gemcabene (50, 150, 450, 750/600, 900 mg)
Placebo

N=50

4 weeks QD

1027-008

DDI: Effect of Gemcabene on the Pharmacokinetics of Simvastatin in Healthy Volunteers

56% Combined with Statin

Gemcabene (900 mg)
Simvastatin (80 mg)

N=20

15 days QD

A4141002

DDI: Effect of Gemcabene on the Pharmacokinetics of Atorvastatin in Healthy Volunteers

NA

Gemcabene (300, 900 mg)
Atorvastatin (80 mg)

N=20

22 days QD

Phase 2

1027-004

Efficacy and Safety of Gemcabene in Patients with Low HDL-C and Either Normal or Elevated Triglycerides

25%* patients with TG <200 mg/dL)

Gemcabene (150, 300, 600, 900 mg)
Placebo

N=161

12 weeks (QD)

1027-014

Effect of Gemcabene on Insulin Sensitivity in Nondiabetic Subjects

40% Monotherapy

Gemcabene (900 mg)
Placebo

N=53

4 weeks (QD)

1027-018

Efficacy and safety of Gemcabene in Hypercholesterolemic Patients on Stable Statin Therapy

31%* Add on to Stable Statin

Gemcabene (300, 900 mg)
Placebo

N=66

8 weeks (QD)

A4141001

Efficacy and Safety of Gemcabene in Hypercholesterolemic Patients as Monotherapy or in Combination with Atorvastatin

29%* Monotherapy

54%* Combined with Statin

Gemcabene (300, 600, 900 mg)
Atorvastatin (10, 40, 80 mg)
Placebo

N=277

8 weeks (QD)

DDI = drug-drug interaction; QD = once daily; TG = triglycerides.

* indicates results were statistically significant when compared to placebo.

Phase 1 Highlights:

Drug-Drug Interaction Trials to Assess PK on Statins (Trials 1027 008 and A4141002)

Two open-label, multiple dose, Phase 1 trials were conducted to assess PK of gemcabene in combination with high intensity statins. In Trial 1027-008, 900 mg of gemcabene was co administered with 80 mg simvastatin in 20 healthy volunteers. In Trial A4141002, 300 mg and 900 mg of gemcabene were co-administered with 80 mg atorvastatin in 20 healthy volunteers. In both trials, treatment with gemcabene in combination with statins was observed to be well tolerated by volunteers. Furthermore, as presented in the figures below, the PK profiles with and without 900 mg gemcabene were observed to be similar, suggesting no clinically relevant drug-drug interactions with either 80 mg simvastatin or 80 mg atorvastatin.

PK Profiles of High Intensity Statins Co-administered with Gemcabene

PK Profiles of High Intensity Statins Co administered with Gemcabene

Phase 2 Highlights: Add-on Statin Study 018 Results

In trial 1027-018, patients treated with gemcabene were observed to have significantly lowered LDL-C from baseline at 300 mg and 900 mg by 25% (p=0.005) and 31% (p<0.001), respectively. Of clinical interest, patients treated with gemcabene were observed to have significantly lowered hsCRP, apoB and total cholesterol. At 900 mg, patients treated with gemcabene were observed to have significantly lowered hsCRP by 54% (p<0.001). At 300 mg and 900 mg, patients treated with gemcabene were observed to have significantly lowered apoB by 20% (p=0.033) and 24% (p=0.003), respectively. At 300 mg and 900 mg, patients treated with gemcabene were observed to have significantly lowered total cholesterol by 18% (p=0.008) and 22% (p<0.001), respectively. It was further observed that all four (4) patients treated with 900 mg gemcabene on high intensity statins had a mean LDL-C reduction of 24%. In addition, patients on low intensity (n=5) and moderate-intensity (n-12) statins were observed to have a mean LDL-C lowering of 41% and 24%, respectively. Across clinical trials, the pharmacodynamic response observed at 900 mg was similar to the anticipated target dose of 600 mg of gemcabene.

Median Percentage Change from Baseline at Week 8 in Patients with Hypercholesterolemia on Background Stable Statin Therapy

Phase 2 Highlights: Triglycerides Study 004 Results

In trial 1027-004, patients with triglyceride levels greater than 200 mg/dL (hypertriglyceridemic patients), treated with gemcabene at 150 mg and 300 mg were observed to have lowered triglycerides by 27% (p=0.002) and 39% (p<0.001), respectively compared to baseline. Although patients treated with gemcabene at 600 mg and 900 mg were observed to have lower triglycerides, the lowering effect was not significant when compared to placebo. Therefore, the anticipated dose for treatment of patients with elevated triglyceride levels is 300 mg. Notably, patients treated with gemcabene were observed to have significantly lowered LDL C by 19% (p<0.001) and 20% (p<0.001) at 600 mg and 900 mg, respectively, compared to baseline.

A post hoc analysis of the nine patients with severe triglyceride levels (≥500 mg/dL; baseline means of two weeks prior and time zero was approximately 600 mg/dL) treated with 150 mg and 300 mg suggest gemcabene has the potential to lower triglycerides by as much as 60%.

Triglyceride Media Percent Change From baseline at Week 12 in Patients with High to Severe Hypertryglyceridemia
Publications and Presentations

Frias J, Kastelein J, Bakker-Arkema R, Masson L, Golden L, Bisgaier C, Stein, 2017, Gemcabene Add-on Therapy to High- and Moderate-Intensity Statin Stratums in Hypercholesterolemic Patients (ROYAL-1, a Phase 2b Study)
Poster

Bisgaier, Oniciu, and Williams, 2017, An Orally Administered Small Molecule that Inhibits Hepatic Sulfatase-2 Expression in Vivo
Poster

Oniciu et al, 2017, Gemcabene Attenuates the NAFLD Activity and Fibrosis Scores and Downregulates Hepatic Inflammatory Genes in the STAM™ Murine Model of NASH-HCC
Poster

Oniciu & Bisgaier, 2017, In Vitro Models Concur with Clinical Results to Confirm Pleiotropic Mechanisms of Action for Gemcabene
Poster

Effect of Gemcabene on Insulin Sensitivity in Non-Diabetic, Obese Subjects
Poster 

Stein et al, 2016, Efficacy and Safety of Gemcabene as Add-on to Stable Statin Therapy in Hypercholesterolemic Patients
Article

Efficacy and Safety of Gemcabene as Add-on to Stable Statin Therapy in Patients with Hypercholesterolemia
Poster 

Correlation of InVitro and Human Drug Interaction Studies with Gemcabene
Poster 

An Oral, Multiple-Dose Tolerance, Pharmacokinetic, and Pharmacodynamic Study of Gemcabene in Healthy Volunteers
Poster 

Lipid-lowering Agent Gemcabene Down-Regulates Acute Phase C-reactive Protein via C/EBP-δ-mediated Transcriptional Mechanism and Attenuates Inflamation and Osteoarthritis in Animal Models
Poster 

Bays et al, 2003, Effectiveness and Tolerability of a New Lipid-Altering Agent, Gemcabene, in Patients With Low Levels of High-Density Lipoprotein Cholesterol
Article 

Gemcabene Monotherapy and in Combination with Atorvastatin Lowers High Sensitivity C-Reactive Protein (hsCRP) in a Phase 2 Clinical Trial
Poster 

Bisgaier et al, 1998, A Novel Compound that Elevates High Density Lipoprotein and Activates the Peroxisome Proliferator Activated Receptor
Article 

Gemcabene and Atorvastatin Alone and Combined Markedly Reduce LDL-C in LDL Receptor-Deficient Mice, a Model of Homozygous Familial Hypercholesterolemia
Poster  Image 

A Novel New Chemical Entity, Gemcabene, Shows Significant Lipid Regulation in PPARα Knock­‐out Mice, Supporting a Mechanism Independent of PPARα
Article 

Gemphire Profile”

Clinical Indications

Large US Market Opportunities for Gemcabene

Homozygous Familial Hypercholesterolemia (HoFH)

HoFH is a rare genetic disease that is usually caused by mutation in both alleles of the LDL receptor gene responsible for removing LDL from the blood. As a result of having defective or deficient LDL receptor function, HoFH patients exhibit severely high LDL-C levels, are at very high risk of experiencing premature cardiovascular events, such as a heart attack or stroke, and develop premature and progressive atherosclerosis. LDL-C levels in untreated HoFH patients are typically in the range of 500 mg/dL to 1,000 mg/dL, compared to a normal target range of 70 mg/dL to 100 mg/dL. Unless treated, most patients with HoFH do not survive adulthood beyond 30 years of age. There are approximately 300 to 2,000 HoFH patients in the United States and approximately 6,000 to 45,000 patients in the rest of the world, with a prevalence rate of about one in 160,000 to one in one million. Gemcabene received FDA Orphan Product Designation in Feb 2014 for treatment of HoFH.

Gemphire is proud to be a supporter of the FH Foundation .

Heterozygous Familial Hypercholesterolemia (HeFH)

The HeFH patient population is generally comprised of individuals who have one defective gene that leads to elevated LDL-C levels between 190 mg/dL and 500 mg/dL. These patients are prone to cardiovascular events. The incidence of patients with HeFH is estimated to be one in 200, and accordingly, we estimate there are approximately 1.5 million patients with HeFH in the United States and 30 million in the rest of the world.

Currently approved treatments for patients with HeFH include statins, ezetimibe, bile acid sequestrants and the recently approved injectable PCSK9 inhibitors. Despite the availability of various treatments, many patients are still unable to achieve recommended LDL-C levels.

Atherosclerotic Cardiovascular Disease (ASCVD)

ASCVD represents patients who have had a cardiovascular event and are unable to meet their LDL-C lowering goal less than 70 mg/dL with maximally tolerated statin therapy. This population also includes many patients who, in addition to not being able to meet their LDL-C lowering goal, have elevated triglyceride levels greater than 150 mg/dL and less than 500 mg/dL, categorized as mixed dyslipidemia. If both cholesterol and triglyceride levels are high, it is difficult for physicians to optimize the right combination of current therapies to reach lipid level goals, as for many patients, lowering the level of one may increase the level of the other. According to the National Cholesterol Education Program Adult Treatment Panel III and Third Joint European Task Force guidelines, nearly 40% of patients already being treated with statins are unable to achieve their goal levels of LDL-C and triglycerides, and of this population, approximately 50% of the patients have had a cardiovascular event. We estimate that approximately 7.5 million patients in the United States and 45 million patients in the rest of the world have a need for additional therapies to effectively and safely bring them closer to their LDL-C and triglyceride lowering goals.

Currently approved treatments for both primary hypercholesterolemia and ASCVD include statins, ezetimibe, bile acid sequestrants, niacin, fibrates and recently approved PCSK9 inhibitors. While these drugs have demonstrated efficacy in lipid-lowering in this population, they do not sufficiently address the patients with mixed dyslipidemia who need to lower both LDL-C and triglycerides.

Severe Hypertriglyceridemia (SHTG)

Elevated triglycerides are often caused by an inherited disorder or exacerbated by uncontrolled diabetes mellitus, obesity, hypothyroidism and sedentary habits. A recent scientific statement on ‘‘Triglycerides and Cardiovascular Disease’’ issued by the American Heart Association based on a review of the pivotal role of triglycerides in lipid metabolism, reaffirmed that triglycerides are not directly atherogenic, but represent an important biomarker of cardiovascular disease. Patients with severe triglycerides greater than 500 mg/dL, or SHTG, have increased risk of developing pancreatitis, a painful and potentially life-threatening inflammation of the pancreas, and Type 2 diabetes. There are approximately 3.5 million patients in the United States and 30 million patients in the rest of the world with SHTG.

Currently available treatments consist of dietary modifications to lower the intake of fatty foods and the use of fibrates, prescription fish oils and niacin. These treatments are often inadequate in lowering triglyceride levels below 500 mg/dL, the level at which patients are at an increased risk for developing pancreatitis. Due to the severely elevated triglyceride levels in this patient population, reducing triglyceride levels below 500 mg/dL may require reductions in triglyceride levels of 40% or more. Current therapies, even in combination, are often insufficient in achieving such a result. In addition, many of the existing treatments do not combine well with statins for treating SHTG.

Nonalcoholic Steatohepatitis (NASH)

Nonalcoholic steatohepatitis (NASH) is a severe disease of the liver caused by inflammation and a buildup of fat in the organ.  In the United States, NASH affects up to approximately 2-5% of the population.  An additional 10-30% of Americans have fat in their liver, but no inflammation or liver damage, a condition called NAFLD or “fatty liver.”  The underlying cause of NASH is unclear, but it most often occurs in persons who are middle-aged and overweight or obese.  Many patients with NASH have elevated serum lipids, diabetes or pre-diabetes.  Progression of NAFLD/NASH can lead to liver cirrhosis, fibrosis, hepatocellular carcinoma, liver failure and liver-related death.  Liver transplantation is currently the only treatment for advanced cirrhosis with liver failure.  At this time, there are no approved treatments by the FDA for NAFLD/NASH.

Gemcabene may have the opportunity to treat patients for NASH. In the plasma, gemcabene significantly reduces both hsCRP (-26% to -54%) and triglycerides (-39% to -60%), which may help reduce the inflammation state and amount of fat in the blood in patients that suffer from NASH. In the liver, gemcabene also lowers both TG and cholesterol in the synthesis pathway (see right chart), by inhibiting ACC as a fatty acid mimetic, resulting in reduced fat accumulation in the liver. Gemcabene has demonstrated proof of concept efficacy in a NASH STAMTM model.

Nonalcoholic Steatohepatitis (NASH)
Clinical Program

Gemphire has launched 3 Phase 2b studies: COBALT-1 (HoFH patients; NCT02722408 ), ROYAL-1 (HeFH/ASCVD patients; NCT02634151), and INDIGO-1 (SHTG patients; NCT02944383).

If you would like to learn more about our clinical development program, contact us. Gemcabene has completed Phase 1 and Phase 2 trials in the target indications as shown below:

Program Pipeline
Note:
We have initiated 2 year mice and rat carcinogenicity studies given our classification by the FDA as a PPAR agonist (which limits our clinical exposure up to 6 months until studies are completed). Recent in-vitro assays show little to no evidence of direct binding to the mouse, rat or human PPARα, PPARβ or PPARγ when compared to known reference agents, therefore we believe the PPARα effects seen in rodents are likely secondary.