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 nearly 1,100 subjects across 23 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.
- First-in-class mechanism. Gemcabene is a first-in-class, 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 (MOA) enhances 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 high sensitivity C-reactive protein (hsCRP) in humans and improve insulin sensitization. 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.
- Pleiotropic MOA provides many beneficial attributes. At a high level, gemcabene acts on the liver to reduce production of cholesterol, triglycerides, and hsCRP. It also enhances the liver clearance of cholesterol- and triglyceride-rich particles (e.g., VLDL remnants) via the remnant receptor clearance systems. The molecular details of the clearance mechanisms are actively being elucidated in preclinical studies. Notably, with regard to enhancing the VLDL remnant clearance pathway, gemcabene reduces hepatic apolipoprotein C-III (apoC-III) mRNA expression and plasma apoC-III levels thereby making VLDL more susceptible to lipoprotein lipase mediated lipolysis (breakdown of the VLDL triglyceride to fatty acids for delivery to muscle for energy and adipose for storage) and efficient clearance of the resulting VLDL remnants by the liver VLDL remnant receptor prior to their conversion to LDL. Furthermore, gemcabene was found to enhance VLDL remnant receptor (i.e., also known as syndecan-1) activity by decreasing mRNA levels of an enzyme (sulfatase-2) that inactivates the receptor. Interestingly, diabetic and obese patients generally present with elevated VLDL-C and triglycerides, likely related to their elevated liver sulfatase-2 levels. Other molecular players in gemcabene’s MOA include a reduction in acetyl-CoA carboxylase (ACC1) mRNA, a key metabolic step in fatty acid synthesis, and a decrease in CCR2/CCR5 receptor mRNA levels, which are involved in liver inflammation and the progression of NASH/NAFLD.
- 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 of gemcabene. Across multiple Phase 2 trials in patients with uncontrolled hypercholesterolemia, including background stable statin therapy, gemcabene was observed to significantly lower LDL‑C by an additional 21%, range of 17% to 31%, from baseline. In subjects with mixed dyslipidemia, baseline, LDL≥100mg/dL and TG ≥200 mg/dL and <500 mg/dL, gemcabene reduced LDL-C by 25%. 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.