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

Gemcabene has been tested in more than 1,100 subjects across 25 Phase 1 and Phase 2 clinical trials.

About Gemcabene

Our drug product candidate, gemcabene, is a novel, once daily, oral therapy designed to target known lipid metabolic pathways to lower levels of LDL C, hsCRP and triglycerides. Gemcabene has been tested as monotherapy and in combination with statins and other drugs in more than 1,100 subjects, which we define as healthy volunteers and patients, across 25 Phase 1 and Phase 2 clinical trials and has demonstrated promising evidence of efficacy, safety and tolerability.

We believe that gemcabene’s efficacy across the clinical and non-clinical trials support our development plan focused initially on orphan indications such as HoFH, FCS, and FPL disease with subsequent potential expansion into broader indications such as HeFH and ASCVD, SHTG, as well as mixed dyslipidemia and possibly nonalcoholic steatohepatitis/non-alcoholic fatty liver disease (NASH/NAFLD). We plan to develop gemcabene for multiple clinical indications given its: (1) promising clinical data and mechanism in these indications; (2) cost effective manufacturing process; (3) convenient oral dosing; (4) viability as adjunct combination therapy; and (5) large commercial potential.

A Differentiated Product Profile

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 more than 1,100 subjects across 25 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) or liver injury when given as monotherapy or when added to statin therapy in clinical trials.
  • Pleiotropic MOA providing multiple biological benefits. Gemcabene mainly distributes to the liver where it has its effects as the active molecule. Gemcabene has a mechanism of action that involves: (1) enhancing the clearance of VLDL and (2) blocking the overall production of hepatic triglyceride and cholesterol synthesis. 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 an elevation of HDL C.
  • Significant lipid lowering of LDL C, high sensitivity C reactive protein (hsCRP) and triglycerides (TGs). In company-sponsored 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.
  • 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.

Mechanism of Action

Gemcabene’s mechanism of action is multifaceted. In the liver gemcabene acts in two major ways to reduce levels of circulating LDL-C and triglycerides: 1) inhibition of the two metabolic pathways that synthesize precursors (i.e., cholesterol and fatty acids) of VLDL-C, LDL-C and triglycerides and 2) stimulation of a liver mechanism known as the remnant receptor pathway that removes particles that contain cholesterol and triglycerides from the blood. Gemcabene’s stimulation of this remnant receptor pathway involves enhanced removal of an LDL-C precursor known as very low-density lipoprotein remnants. With regard to gemcabene’s anti-inflammatory properties, in human clinical trials and animal studies to date, gemcabene has been shown to significantly reduce plasma levels of CRP. Furthermore, in preclinical studies of dyslipidemia as well as NASH, gemcabene inhibited production of a number of known pro-inflammatory molecules (e.g., CRP, CCR2, CCR5, IL-6, TNF-alpha, MCP-1 and MIP1-beta) as well as pro-fibrotic factors (e.g., TIMP-1, MMP-2).

Production Mechanism

Gemcabene, which has been shown to lower plasma ApoB-lipoprotein concentrations in mice and in humans, appears to regulate remnant receptor via SULF2 in the liver, as illustrated in the diagram below. In the left panel of the diagram, under normal conditions, the VLDL remnant receptor, also known as syndecan-1, a receptor containing heparin sulfate proteoglycan, has a high capacity to bind and remove VLDL and VLDL remnants from circulating blood. Under normal conditions, the intrahepatic levels of the mRNA for the enzyme sulfatase-2 are low and likely allow syndecan-1 to maintain intact negatively charged sulfate groups that bind the positively charged apoE of VLDL and VLDL-remnants. In the right panel, in a disease such as diabetes, the intrahepatic mRNA levels of the enzyme sulfatase 2 levels are highly elevated and may cause reduced levels of sydecan-1 sulfation, and thereby lessen the capacity of the receptor to bind and remove VLDL and VLDL remnants from the circulation. In diabetic mice, gemcabene has been shown to markedly reduce elevated hepatic sulfatase-2 mRNA levels and plasma triglycerides.

Mechanism of Action

Clinical Indications

Large US Market Opportunities for Gemcabene

ORPHAN INDICATIONS

Homozygous Familial Hypercholesterolemia (HoFH)

HoFH is a rare genetic disease that is usually caused by mutations 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 HoFH patients are often 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 6,000 to 45,000 patients in the rest of the world based on an estimated prevalence rate of one in 160,000 to one in one million.

Current available treatments for HoFH generally include a combination of dietary intervention, statins, ezetimibe and other approved LDL C lowering therapies, including lipoprotein apheresis. However, even when combination therapies are utilized, many patients still have high LDL C levels and are still at high risk of cardiovascular disease. The FDA has approved two non statin therapies for HoFH, Juxtapid, marketed by Aegerion Pharmaceuticals, Inc. (Aegerion), and Kynamro, marketed by Sanofi. Although these drugs have demonstrated efficacy, they have significant safety and tolerability concerns, including boxed warnings for liver toxicity on the product labels. Recently, the FDA has also approved Amgen’s PCSK9 inhibitor, Repatha, for HoFH patients, but this therapy has limitations due to its mechanism of action reliant on functional LDL receptors. In clinical trials, Repatha has shown substantially less LDL C lowering from baseline in patients with HoFH compared to LDL-C lowering in patients with other hypercholesterolemia indications.

On February 6, 2014, gemcabene received Orphan Drug Designation by the FDA for treatment of HoFH. We believe that pursuing the HoFH indication may enable gemcabene to reach the market sooner than for other indications due to: (1) approval pathway based on a single, small Phase 3 trial; (2) no requirement for cardiovascular outcomes trials; and (3) potential for priority review by the FDA in light of the unmet medical need in this orphan population. Furthermore, we believe that gemcabene’s potential to treat patients in the most severe segment of the dyslipidemia market on top of statins and other lipid lowering therapies (including ezetimibe, Repatha, and Praluent) will enhance brand awareness among key thought leaders and physicians.

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

Familial Cholesterolemia Syndrome (FCS)

FCS is a rare disease caused by a mutation in one or more genes of the lipoprotein lipase (LPL) complex, which breaks down triglycerides. FCS can result from mutations in LPL gene itself, or from mutations in apoC-II, GPIHBP1, LMF1 factor 1, or apoA-V. When any part of the LPL complex is defective, there is a massive accumulation of chylomicrons in the blood. Diagnosis based on fasting triglyceride levels >880 mg/dL, and patients often experience recurrent abdominal pain and/or pancreatitis. FCS represents ~3000-5000 patients worldwide (~1000 in the US). There are currently no FDA-approved treatments for FCS.

Familial Partial Lipodystrophy (FPL)

FPL is a rare genetic disorder and orphan disease characterized by an abnormal distribution of fatty (adipose) tissue. As the body is unable to store fat correctly, a buildup can occur around all vital organs and in the blood (hypertriglyceridemia). FPL can also cause an abnormal buildup of fats in the liver (hepatic steatosis), which can result in an enlarged liver (hepatomegaly) and abnormal liver function. FPL can lead to loss of metabolic control and a variety of metabolic abnormalities, including diabetes, cardiovascular disease, hypertriglyceridemia and NASH.

BROADER INDICATIONS

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. Based on a 1.1% prevalence rate in the United States, as published by the American Heart Association, we estimate there are approximately 3.5 million patients with SHTG in the United States and 75 million patients in the rest of the world.

Current available treatments for SHTG 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.

We believe that pursuing SHTG may enable gemcabene to reach a large population of patients with triglyceride levels above 500 mg/dL and offer a convenient, oral, once daily dosing with no food effects that may have the potential to result in better efficacy than standard of care, while being well tolerated with statins.

Nonalcoholic Steatohepatitis (NASH)

NAFLD (“fatty liver” where patients have fat in their liver, but no inflammation or liver damage) affects 10-30% of Americans. NASH is a severe form of fatty liver disease with the presence of hepatocyte ballooning, inflammation and fibrosis in the organ. In the United States, NASH affects up to approximately 2-5% of the population roughly at 6 million adult NASH patients and 2 million pediatric NASH patients. 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 fibrosis, cirrhosis, 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. Based on the current understanding of pathophysiological mechanisms associated with NASH, several compounds are in clinical development. The Clinical Trials website lists many trials for NASH. These compounds target the regulation of dyslipidemia (e.g., acetyl CoA carboxylase inhibitors, bile acid/fatty acid conjugates), inflammation (e.g., combined CCR2/CCRCR5 inhibitor) and/or fibrosis (e.g., obeticholic acid). Recently, it was announced that obeticholic acid achieved statistically significant improvement in liver fibrosis without worsening of NASH in a Phase 3 study.

Gemcabene may be effective in treating patients for NASH given its mechanism of action around inflammation and triglycerides, especially for obese and diabetic patients. If approved, we expect gemcabene to be used as an oral combination with statins and other drugs approved for NASH with complementary mechanisms.

Atherosclerotic Cardiovascular Disease (ASCVD) and Heterozygous Familial Hypercholesterolemia (HeFH)

ASCVD and HeFH patients are at elevated risk of experiencing a cardiovascular event. Herein we combine these two groups of patients because historically they are frequently grouped together for the purposes of conducting clinical trials and seeking regulatory approvals.

ASCVD represents patients who have experienced or are at risk of a cardiovascular event and are unable to meet their LDL-C lowering goal of 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, often have elevated triglyceride levels and may benefit in reduction of both their elevated LDL-C and TG from gemcabene. We estimate that approximately 10 million patients in the United States and 200 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.

The HeFH patient population is generally comprised of individuals who have one defective gene that leads to elevated LDL-C levels at or above 190 mg/dL. These patients are prone to premature cardiovascular events. The incidence of patients with HeFH is estimated to be approximately one in 200 to one in 500, and, accordingly, we estimate there are approximately 0.5 to 1.5 million patients with HeFH in the United States and 15 to 30 million in the rest of the world.

Currently approved treatments for both ASCVD and HeFH include statins, ezetimibe, bile acid sequestrants, niacin, fibrates and injectable 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.

We believe that there is a meaningful number of underserved ASCVD/HeFH patients who are: (1) unable to reach LDL C and triglyceride goals on maximally tolerated statin therapy; (2) require LDL C reduction beyond the 6% reduction observed when statin dose is doubled; or (3) unable to tolerate higher doses of statins. Nonetheless, if gemcabene is ultimately approved for ASCVD/HeFH, it may potentially offer patients, especially cardiometabolic patients, a preferred well tolerated combination therapy with a statin and/or ezetimibe that is convenient, oral, once daily, cost effective, and impacts multiple factors, LDL-C, hsCRP and triglycerides, that all add to the residual cardiovascular risk in these patients. We believe obtaining approval for ASCVD/HeFH patient populations will enable gemcabene to reach a large market of patients with the inability to attain their LDL C goal using current therapies (including high intensity statins, ezetimibe and PCSK9 inhibitors).

Clinical Program

We believe that gemcabene’s efficacy across the clinical and non-clinical trials support our development plan focused initially on orphan indications such as HoFH, FCS, and FPL disease with subsequent potential expansion into broader indications such as HeFH and ASCVD, SHTG, as well as mixed dyslipidemia and possibly nonalcoholic steatohepatitis/non-alcoholic fatty liver disease (NASH/NAFLD).

This “orphan-first” strategy has multiple potential advantages. Historically, clinical trials for these orphan indications are smaller and FDA approvals have previously been based on surrogate endpoints (e.g., serum LDL-C or serum TGs). Consequently, we believe we can design efficient development plans to provide gemcabene as a treatment alternative for HoFH patients as well as FCS and FPL patients. If approved for one or more of these indications, this could enable us to go to market initially by treating patients in the most severe segment of the dyslipidemia market, which could subsequently lead to trials in broader indications representing millions of individuals, such as SHTG and potentially ASCVD and NASH. This strategy of “orphan-first” trials can enhance brand awareness among key thought leaders and physicians and has the potential to provide a more rapid, less expensive path through trials and regulatory approvals. It also provides the potential for initiating sales with a small, focused sales force.

Clinical Experience

Gemcabene has been assessed in 25 Phase 1 and Phase 2 clinical trials. Across these trials, over 1,500 adult subjects have participated, including healthy volunteers and patients with various underlying conditions (see summary table below). Of these subjects, over 1,100 have been exposed to at least one dose of gemcabene.

During 2016 to 2018, we initiated and completed three Phase 2b clinical trials for gemcabene in HoFH, hypercholesterolemia, including Heterozygous Familial Hypercholesterolemic (HeFH) and ASCVD patients on maximally tolerated statins, and SHTG. Previously we reported top line data from our 8 patient trial for HoFH (COBALT-1) in the second quarter of 2017, top line data from our 105 patient trial for hypercholesterolemia on high intensity statin therapy including HeFH and ASCVD patients (ROYAL-1) in the third quarter of 2017, and top line data from our 91 patient trial in SHTG patients (INDIGO-1) in the second quarter of 2018. As previously announced, all three of these trials achieved statistical significance for their primary endpoints.

Across the company-sponsored clinical trials, gemcabene was observed to be well tolerated at single doses up to 1,500 mg and multiple doses up to 900 mg/day. Safety of the subjects in these trials was evaluated by AE monitoring, clinical laboratory assessments, electrocardiograms (ECGs), physical examinations, and vital sign assessments.

In addition, gemcabene demonstrated promising clinical pharmacology attributes across 15 completed company-sponsored Phase 1 trials in healthy subjects, such as once daily dosing, no meaningful drug drug interactions with high intensity statins and no observed food effect.

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

Phase 2 Clinical

  • Completed 10 company-sponsored Phase 2 studies, including:
    • GEM-401 (INDIGO-1): Patients with SHTG
    • GEM-301 (ROYAL-1): Add on for patients not at goal for LDL-C on moderate- and high-intensity statins
    • GEM-201 (COBALT-1): Add on for patients with HoFH on stable lipid-lowering therapy
    • Study 1027-018: Add on for patients not at goal for LDL-C 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 as monotherapy has shown it can significantly lower LDL-C by approximately 30% from baseline in patients with hypercholesterolemia. Additionally, 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). Gemcabene has also been shown to substantially lower an anti-inflammatory marker hsCRP by approximately 40% from baseline, and in doing so may potentially further benefit cardiovascular health of patients. If approved, gemcabene may provide a tolerable and convenient oral treatment option for dyslipidemia 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)

GEM-201

Efficacy and Safety of Gemcabene in Patients With Homozygous Familial Hypercholesterolemia on Stable, Lipid-Lowering Therapy (COBALT-1)

30% Overall
39% HeFH Patients
15% HoFH Patients

Gemcabene (300, 600, 900 mg)

N=8

12 weeks (QD)

GEM-301

Efficacy and Safety of Gemcabene in Hypercholesterolemia Patients on Stable Moderate and High-Intensity Statins (ROYAL-1)

17% Combined with Moderate- and High- Intensity Statins

Gemcabene (600 mg)
Placebo

N=103

12 weeks (QD)

GEM-401

Efficacy and Safety of Gemcabene in Subjects With Severe Hypertriglyceridemia (INDIGO-1)

47% median decrease in TGs in gemcabene (600 mg) treated patients compared to 27% for placebo-treated patients (P=0.0063; ranked ANCOVA).

Gemcabene (300, 600 mg)
Placebo

N=91

12 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

Phase 2 Highlights: Trial in Patients with HoFH (GEM-201, COBALT-1)

This Phase 2 open-label, dose-finding trial assessed the efficacy, safety, and tolerability of gemcabene in patients with HoFH on stable, lipid-lowering therapy. COBALT-1 was a 12-week, dose-escalation trial with n=8 patients with a diagnosis of HoFH by genetic confirmation (including heterozygosity) or a clinical diagnosis based on either: (1) A history of an untreated LDL-C concentration >500 mg/dL (12.92 mmol/L) together with either appearance of xanthoma before 10 years of age, or evidence of heterozygous familial hypercholesterolemia in both parents; or (2) if history is unavailable, LDL-C >300 mg/dL (7.76 mmol/L) on maximally tolerated lipid-lowering drug therapy. Successive escalating doses of 300mg, 600mg, 900mg gemcabene were given every four weeks.

Efficacy: Patients were administered oral gemcabene once daily, with dosage escalating from 300 mg to 600 mg and then 900 mg every 4 weeks, for a total duration of 12 weeks. On various baseline aggressive lipid lowering therapies, the eight FH patients had a mean baseline LDL-C level of 351 mg/dl prior to add-on gemcabene treatment. Treatment with gemcabene 600 mg, the Company’s target commercial dose, resulted in an absolute reduction of 93 mg/dL for the overall population and 92 mg/dL and 94 mg/dL for the HoFH and HeFH patients, respectively. The results for the primary endpoint of mean percent change in LDL-C from baseline at each dose and related time point are presented below.

Primary Endpoint: Change in LDL-C mg/dL Levels by Dose of Gemcabene
   300mg, week 4 600mg, week 8 900mg, week 12
 Overall population (n=8)

-25%
p=0.0063

-30%
p=0.0047

-29%
P=0.0035

HeFH (n=5)

-34%
p<0.0001

-39%
p<0.0001

-40%
p<0.0001

 HoFH (n=3)

-10%
p=0.3601

-15%
p=0.1920

-12%
p=0.2912

As shown the table below, gemcabene impacted multiple secondary endpoints, showing reductions from baseline in total cholesterol (TC), triglycerides (TG), non-HDL, apoB, apoE, high sensitivity C-Reaction Protein (hsCRP), and other relevant biomarkers. Importantly, gemcabene 600 mg showed a 34.7% reduction in hsCRP.

% Change in Secondary Endpoints by Dose
  Gemcabene 300mg
Week 4
% Change from Baseline
Gemcabene 600mg
Week 8
% Change from Baseline
Gemcabene 900mg
Week 12
% Change from Baseline
Total Cholesterol (mg/dL) -21.3% -24.6% -24.6%
Non-HDL-C (mg/dL) -23.8% -27.2% -26.5%
ApoB (mg/dL) -18.8% -24.8% -22.4%
ApoE (mg/dL) -19.5% -23.0% -19.2%
ApoC-III (mg/dL) -7.8% -9.7% -6.5%
VLDL-C (mg/dL) -13.5% -8.4% -7.2%
Triglycerides (mg/dL) -12.6% -9.1% -7.2%
HDL-C (mg/dL) -11.9% -13.3% -12.9%
hsCRP* (mg/dL) 34.0% -34.7% -27.9%

Safety: Safety was assessed by adverse event (AE) monitoring, clinical laboratory assessments, electrocardiograms, physical examinations and vital signs. AEs were mild to moderate in intensity across all doses of gemcabene and consistent with previously reported AEs. The majority of AEs were gastrointestinal. There were no serious AEs or withdrawals due to AEs in the COBALT-1 trial. There was no evidence of hepatic or muscle injury in the trial.

Phase 2 Highlights: Trial in Patients with Hypercholesterolemia on High- and Moderate-Intensity Statin Therapy (GEM-301, ROYAL-1)

ROYAL-1 was designed to largely address the safety of gemcabene in patients on the highest doses of statins. In patients with hypercholesterolemia, despite being on moderate and high-intensity statins, gemcabene produced significant reductions in both atherogenic and inflammatory markers without evidence of increased muscle or liver toxicities. A total of 105 hypercholesterolemic patients, including ASCVD or HeFH, were randomized 1:1 to either gemcabene 600 mg or placebo with 50 (24 gemcabene 600 mg; 26 placebo) patients on baseline high-intensity statins (atorvastatin 40 mg or 80 mg QD; or rosuvastatin 20 mg or 40 mg QD) and 55 (29 gemcabene 600 mg; 26 placebo) patients on baseline moderate-intensity (MI) statins (atorvastatin 10 mg or 20 mg QD; rosuvastatin 5 mg or 10 mg QD; or simvastatin 20 or 40 mg QD). Baseline LDL-C was 127 mg/dL and 134 mg/dL in the moderate and high-intensity statin stratum, respectively. The double-blind treatment phase of the trial was 12 weeks.

Efficacy: Top-line data for ROYAL-1 showed gemcabene produced a mean percent decrease of 17% in LDL-C (vs 5% for placebo) and a median percent decrease of 40% in hsCRP (vs 6% for placebo). Gemcabene reduced LDL-C by 20% and hsCRP by 53% when added to moderate intensity statin therapy. Greater effects were observed in a cardiometabolic population, patients with mixed dyslipidemia, who have a particularly high atherogenic particle burden. In the mixed dyslipidemia group of patients, gemcabene 600 mg demonstrated a placebo adjusted LDL-C reduction of 23% (p < 0.05). Consistent with the mechanism of action of gemcabene, patients with mixed dyslipidemia showed greater reductions in LDL-C, non-HDL-C, ApoB, ApoE and TG of 23%, 19%, 26%, 34% and 33%, respectively.

Safety: Overall, gemcabene was well tolerated with a profile consistent with earlier trials. There were no SAEs and no deaths reported in the trial. 33 of 54 patients (61.1%) in the gemcabene group and 24 of 51 patients (47.1%) in the placebo group who reported at least one AE during the trial. The most prevalent AEs were those associated with infections. Reported AEs were similar for the MI and HI statin stratums. There was no difference in myalgias between placebo and gemcabene groups. There were no transaminase elevations > 3 x ULN and no clinically significant CK elevations.

Phase 2 Highlights: Trial in Patients with Severe Hypertriglyceridemia (GEM-401, INDIGO-1)

GEM-401 was a 12-week, randomized, double-blind, placebo-controlled, parallel-group, multicenter trial designed to evaluate the efficacy, safety, and tolerability of gemcabene administered orally to patients with severe hypertriglyceridemia. Patients were required to be on a self-reported, stable, low-fat, low-cholesterol diet and if on a stable dose of statins and/or ezetimibe (10 mg), statins and ezetimibe must have been started at least 12 weeks prior to the Screening Visit (S1). Patients were eligible for enrollment if they had a mean fasting TG value ≥ 500 mg/dL to < 1500 mg/dL. A total of 91 patients were randomized and treated (30 to the gemcabene 300 mg group, 30 to the gemcabene 600 mg group, and 31 in the placebo group). Of these, 89 patients completed the trial.

Baseline characteristics were similar between treatment groups and across statin strata with the exception of a higher number of female patients in the placebo group. Mean baseline TG was slightly higher in the placebo group (658.33 mg/dL) than in the gemcabene groups (641.17 mg/dL and 637.00 mg/dL in the 300 mg and 600 mg groups, respectively). There were 47 patients on stable statins and 44 patients not on stable statin.

Efficacy: The median percent change in TG from baseline was 47.32% (p = 0.0063) versus a change of 27.30% with placebo. In the gemcabene 300 mg group, treatment with gemcabene demonstrated a clinically significant, statistically non-significant TG lowering with a median percent change in TG from baseline of 32.95% (ranked ANCOVA p = 0.2350). The table below presents the percent change in TG from baseline to the End of Study (EOS) for Trial GEM-401.

Percent Change in Serum Triglycerides from Baseline to End of Trial for GEM-401 ANCOVA, FAS, LOCF
Lipid Parameter
Statistic
Placebo
(N = 31)
Gemcabene
300mg QD
(N = 30)

600mg QD
(N = 30)
TG      
Median baselinea
(mg/dL)
658.33 641.17 637.00
Median EOSb
(mg/dL)
538.00 477.00 332.75
Median Percent Change (%) -27.30 -32.95 -47.32
Ranked ANCOVA p-valuec   0.2350 0.0063
Median difference estimated   -7.63 -19.02

a. Baseline = average of Screening Visits (S1 and S2) or (S2 and S3) and Trial Day 1 (pre-dose) values, with each given equal weight.

b. EOS is the average of Week 10 and Week 12. If either Week 10 or Week 12 value is missing, then the single value (Week 10 or Week 12) is used. B both Week 10 and Week 12 values are missing, LOCF is applied.

c. Ranked ANCOVA results are obtained from SAS using a model where the outcome is ranked, randomized treatment group and randomized baseline statin (yes or no) are included as factors, and outcome (ranked) at baseline is included as a covariate.

d. Difference calculated gemcabene minus placebo. Estimates generated from Hodges-Lehmann method. ANCOVA = analysis of covariance; EOS = end of trial; FAS = full analysis set; LOCF = last observation carried forward; QD = once daily; TG = triglyceride.

In patients in the baseline qualifying TG ≥ 880 mg/dL strata the median percent decrease from baseline in TG was -55.64% (n=6) in the gemcabene 600 mg group and -37.56% (n=6) in the gemcabene 300 mg group vs a median percent reduction of -36.98% (n=7) with placebo. The result of the ranked ANCOVA was not statistically significantly different than placebo for either treatment group. The gemcabene 600 mg group showed a statistically significant median percent change from baseline in LDL-C as compared with the placebo group at Week 12 ( 7.94% vs 25.43%, p = 0.0244) and EOS ( 13.36% vs 14.73%, p = 0.0307). None of the median percent changes from baseline in LDL-C in the gemcabene 300 mg group were statistically significantly different from placebo.

It was also of interest to determine if the effects of gemcabene were consistent among patients with both isolated SHTG and mixed dyslipidemia and to determine the optimal patient population type of patients. Regardless of statin status, 34 patients had LDL-C ≥ 100 mg/dL at baseline. In this patient population defined by baseline TGs of 530 mg/dL and LDL-C of 120 mg/dL, gemcabene 600 mg showed a statistically significant change from baseline difference from placebo of -30% for TGs, -28% for LDL-C, -38% for non-HDL-C, -61% for VLDL-C, -28% for Apo B, and -43% for Apo E.

Safety: In all patients, including those receiving statins, gemcabene was well-tolerated. Adverse events were reported by approximately half of the patients in the gemcabene groups and by more than half of the patients in the placebo group. The majority of these AEs were considered mild in severity. A total of 4 and 2 patients, respectively in the gemcabene 600 mg and 300 mg groups experienced AEs related to the trial drug, compared to 4 in the placebo group. There were no withdrawals due to Treatment Emergent Adverse Events (TEAEs), 1 SAE in a placebo patient, and no deaths. The patients who experienced potentially clinically significant post baseline laboratory abnormalities with consecutive occurrences, eventually saw their values return to or near their normal ranges. One patient in the gemcabene 600 mg group had a confirmed transient increase in ALT > 3 x ULN and 1 subject in the gemcabene 600 mg group had confirmed transient increase in serum creatinine > 0.3 mg/dL.

Publications and Presentations
Bisgaier, C.L., D.C. Oniciu, and R.A.K. Srivastava, Comparative Evaluation of Gemcabene and PPAR Ligands in Transcriptional Assays of Peroxisome Proliferator-Activated Receptors: Implication for the Treatment of Hyperlipidemia and Cardiovascular Disease. J Cardiovasc Pharmacol, 2018;72:3-10.
Article

Oniciu, D.C., et al., Gemcabene Downregulates Inflammatory, Lipid-Altering and Cell-Signaling Genes in the STAM Model of NASH. PLoS One, 2018. 13(5): p. e0194568.
Article

Srivastava, R.A.K., et al., Gemcabene, a First-in-Class Lipid-Lowering Agent in Late-Stage Development, Down-Regulates Acute-Phase C-Reactive Protein Via C/EBP-Delta-Mediated Transcriptional Mechanism. Mol Cell Biochem, 2018.
Article

Oniciu, D.C., R.A. Srivastava, and C. Bisgaier, Gemcabene Regulates VLDL-Remnant Trafficking and Inflammation Genes with Potential Impact on Cardiovascular Disease. Abstract # XVIII P4. 005, International Symposium on Atherosclerosis (ISA) 2018.
Poster

Frias, J., et al., Gemcabene Add-on Therapy to High- and Moderate-Intensity Statin Stratums in Hypercholesterolemic Patients (ROYAL-1, a Phase 2b Study). Abstract # M2007-2017, AHA Scientific Sessions 2017.
Poster

Bisgaier, C., D.C. Oniciu, and J.K. Williams, An Orally Administered Small Molecule that Inhibits Hepatic Sulfatase-2 Expression In Vivo: A Novel Strategy to Correct Diabetic Dyslipoproteinemia with Implications for Residual Atherosclerotic Cardiovascular Disease (ASCVD) Risk. Abstract # S1068-2017, American Heart Association (AHA) Meeting 2017.
Poster

Oniciu, D.C., et al., Gemcabene Attenuates the NAFLD Activity and Fibrosis Scores and Downregulates Hepatic Inflammatory Genes in the STAM Murine Model of NASH-HCC. Abstract # 2087, The Liver Meeting 2017.
Poster

Oniciu, D.C. and C. Bisgaier, In Vitro Models Concur with Clinical Results to Confirm Pleiotropic Mechanisms of Action for Gemcabene. Abstract # 579, Arteriosclerosis, Thrombosis and Vascular Biology (ATVB) 2017.
Poster

Bakker-Arkema, R. and C. Bisgaier, Effect of Gemcabene on Insulin Sensitivity in Nondiabetic, Obese Subjects. Poster # 59, ACC 2017.
Poster 

Stein, E., et al., Efficacy and Safety of Gemcabene as Add-On to Stable Statin Therapy in Hypercholesterolemic Patients. J Clin Lipidol, 2016. 10(5): p. 1212-22.
Article

Koren, M., et al., Efficacy and Safety of Gemcabene as Add-on to Stable Statin Therapy in Patients with Hypercholesterolemia. National Lipid Association (NLA) 2016.
Poster 

McShane, M., L. Radulovic, and C. Bisgaier, Correlation of In Vitro and Human Drug Interaction Studies with Gemcabene. Abstract # 466, Arteriosclerosis, Thrombosis and Vascular Biology (ATVB) 2016.
Poster 

McShane, M. and C. Bisgaier, An Oral, Multiple-Dose Tolerance, Pharmacokinetic, and Pharmacodynamic Study of Gemcabene in Healthy Volunteers. Abstract # 482, Arteriosclerosis, Thrombosis and Vascular Biology (ATVB) 2016.
Poster 

Srivastava, R.A.K., et al., Lipid-lowering Agent Gemcabene Down-Regulates Acute Phase C-reactive Protein via C/EBP-δ-mediated Transcriptional Mechanism and Attenuates Inflammation and Osteoarthritis in Animal Models. Abstract # 417, Arteriosclerosis, Thrombosis and Vascular Biology (ATVB) 2016.
Poster 

Bays, H.E., et al., Effectiveness and Tolerability of a New Lipid-Altering Agent, Gemcabene, in Patients With Low Levels of High-Density Lipoprotein Cholesterol Am J Cardiol, 2003. 92(5): p. 538-43.
Article 

Stein, E., et al., Gemcabene Monotherapy and in Combination with Atorvastatin Lowers High Sensitivity C-Reactive Protein (hsCRP) in a Phase 2 Clinical Trial. Abstract # 13654, American Heart Association (AHA) 2015.
Poster 

Bisgaier, C.L., et al., A Novel Compound that Elevates High Density Lipoprotein and Activates the Peroxisome Proliferator Activated Receptor J Lipid Res, 1998. 39(1): p. 17-30.
Article 

Bisgaier, C. and B.J. Auerbach, Gemcabene and Atorvastatin Alone and Combined Markedly Reduce LDL-C in LDL Receptor-deficient Mice, a Model of Homozygous Familial Hypercholesterolemia. Abstract # 17824, American Heart Association (AHA) 2015.
Poster  Image 

Bisgaier, C. and R.A. Srivastava, A Novel New Chemical Entity, Gemcabene, Shows Significant Lipid Regulation in PPARα Knock-out Mice, Supporting a Mechanism Independent of PPARα. American Heart Association (AHA) 2015.
Presentation

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