LIVONIA, Mich.—Aimed at lowering inflammation and reducing fat associated with liver disease, Gemphire Therapeutics Inc. plans to soon launch a Phase 2 trial of gemcabene, a daily tablet to treat nonalcoholic steatohepatitis (NASH) and nonalcoholic fatty liver disease (NAFLD) in general, of which NASH is the most serious form. There are currently no treatments for NAFLD/NASH approved by the FDA.
Gemphire’s decision to move forward in Phase 2 comes on the heels of recent compelling preclinical data for gemcabene, demonstrating efficacy in an animal model of NASH/NAFLD.
“We are delighted to share the results of our preclinical study, demonstrating exciting proof-of-concept data for gemcabene in NASH, including its anti-fibrotic and anti-inflammatory features,” stated Mina Sooch, president and CEO of Gemphire. “Moving forward with Phase 2 clinical development in NAFLD/NASH is now a key priority for us, and is in line with our strategy to expand the breadth of indications for gemcabene beyond the 14 million dyslipidemia patients in need of cholesterol and triglyceride reduction that we are also pursuing.”
Given the high prevalence of NAFLD in general and the serious health problems faced by those who progress to NASH in the developed world—an estimated 6 million are diagnosed in the United States alone, a number projected to increase further given the current trends in diabetes and obesity—Sooch sees this as “a sizable additional opportunity to the cardiovascular disease market.”
Gemcabene “has the potential to add complementary mechanisms that lower both triglycerides (fat) and inflammation, which we believe prevents the progression of fibrosis,” she says.
One previous study investigated the effects of gemcabene on the widely used STAMT M mouse model of NASH/fibrosis. In this model, diabetic mice fed a high-fat diet rapidly develop fatty liver disease. When the mice were administered gemcabene, a hepatoprotective effect preventing liver disease progression was observed, in contrast to the control group.
“In our prior Phase 2 studies, we saw there was significant triglyceride lowering in the 40- to 60-percent range among patients with elevated TG baseline,” Sooch says. “Gemcabene was also observed to have class-leading reductions in inflammation. Importantly, there were no liver toxicities seen at doses between 150 to 900 mg up to 12 weeks as monotherapy or combo with statins/other drugs across 895 patients—and no cumulative toxicities in 26- to 52-week monkey studies.
“We also had preclinical models that showed drastic reduction in triglycerides in rat hepatocytes relevant to NASH,” she adds.
“We believe that inflammation and triglycerides are the two biggest culprits to the liver damage in a majority of NASH patients,” Sooch says. “Gemcabene’s pleiotropic mechanism of action has significant effects on both TG and inflammation as well as LDL-C, working to reduce production of cholesterol and TG in the liver and enhance clearance of VLDL in the plasma.”
In addition, she notes, “most NASH patients suffer from other lipid-driven comorbidities (obesity, diabetes, metabolic syndrome), which places them at high risk for cardiovascular disease. The number one cause of mortality in NASH patients is not liver disease but cardiovascular disease.”
“The cardiovascular burden in the U.S. is expanding at an alarming rate,” Sooch says. “The American Heart Association (AHA) just announced last week that the prevalence of cardiovascular disease was 41.5 percent in 2015, due to the rising effects of obesity and the earlier onset of type 2 diabetes.” At this rate, the AHA estimates that 45 percent of the U.S. population will have at least one cardiovascular condition by 2035.
According to Sooch, gemcabene’s “strongest attribute is perhaps its ability to significantly lower triglycerides, with only one pill needed once per day. This is extremely important for the approximately 3 million patients in the U.S. with severe hypertriglyceridemia as they try to manage their risk of pancreatitis. Gemcabene can be taken without food and is safely combined with all doses of statins, unlike fibrates, niacin and fish oils.”
Together, these cardiovascular and NASH indications “represent an estimated 20 million patients at risk for cardiovascular disease and NASH, for a combined market cost of $33 billion by 2025,” she says. “The market opportunity outside of the U.S. is even larger.”
The complete NASH preclinical results will be submitted for publication in 2017, she says.
Gemcabene’s “dual mechanism of action includes inhibition of hepatic de-novo cholesterol and triglyceride synthesis,” says Dr. Charles L. Bisgaier, co-founder and chief scientific officer of Gemphire. “Gemcabene also reduces hepatic apoC-III and CRP gene expression. We believe these properties of gemcabene are well suited to address the key functional aspects of NAFLD/NASH and to target the underlying disease pathology. Our current accepted IND for dyslipidemia indications is with the Metabolism and Endocrine Division of the FDA, and we will be submitting a new IND for the NAFLD/NASH indication to the GI Division.”
