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Good to go with INDIGO-1
LIVONIA, Mich.—Gemphire Therapeutics Inc. closed June on a high note with the announcement that gemcabene safely and effectively lowered triglycerides (TGs) in the Phase 2b INDIGO-1 trial in patients with severe hypertrigylceridemia (SHTG), successfully meeting the primary endpoint.
Patients with SHTG have triglycerides greater than 500 mg/dL, and such high levels are linked to a higher risk of cardiovascular disease and acute pancreatitis. High triglyceride levels can also result in organ failure. Current first-line treatments for this condition, as per ATP III guidelines, are primarily focused on diet changes and taking fibrates, prescription fish oils and/or niacin.
The trial was a dose-ranging, double-blind, placebo-controlled, randomized study in patients with SHTG—triglycerides at or above 500 mg/dL and below 1500 mg/dL—with or without background statin therapy. Patients received either 300 mg of gemcabene, 600 mg of gemcabene or placebo once daily. Median percent change in triglycerides from baseline to the end of the study was the primary endpoint.
The 600 mg group began with a median triglyceride baseline of 637 mg/dL and saw a median decrease of 47 percent in triglycerides, compared to a median drop of 27 percent for placebo patients. The 600 mg arm saw a greater decrease in median triglyceride levels than the 300 mg arm. Absolute levels of TGs were also assessed, and in the 600 mg arm, median TG levels dropped from 637 mg/dL to 333 mg/dL, compared to a placebo drop from 658 mg/dL to 538 mg/dL. Sixty-seven percent of patients in the 600 mg gemcabene arm reached a serum TG level under 500 mg/dL, with some achieving more than a 70-percent decrease from baseline.
Secondary endpoints included a number of atherogenic and inflammatory biomarkers, and the 600 mg cohort posted promising numbers in these categories as well: statistically significant placebo-corrected percent decreases were observed for serum LDL-C (24 percent), non-HDL-C (16 percent), VLDL-C [very-low-density lipoprotein cholesterol] (19 percent), apoB (12 percent), apoE (14 percent), apoCIII (11 percent) and SAA (23 percent); (p-values <0.05; ranked ANCOVA).
Dr. Steven Gullans, CEO of Gemphire, pointed out in a conference call regarding these data that “Another secondary endpoint was patient response to gembacne as add-on to statins. In the 600 mg gemcabene group on statins, there was a significant decrease in triglycerides of 52 percent at the end of study, with a P-value equal to 0.0131.”
“We are pleased to reach this milestone of meeting both primary and multiple secondary endpoints and look forward to advancing gemcabene into Phase 3 trials,” said Gullans. “There are approximately 3.5 million SHTG patients in the United States in need of lowering their TG levels below 500 mg/dL to reduce their risk of developing acute pancreatitis. Our once-daily tablet has demonstrated promising evidence of safety, efficacy and tolerability in more than 1,100 subjects thus far. Moreover, in prior studies, 600 mg of gemcabene reduced LDL-C, hsCRP [high sensitivity C-reactive protein] and other biomarkers that are typically elevated in a broad range of dyslipidemic conditions.”
There’s a sizable global market as well, as Gullans added in the company's conference call that there are an estimated 75 million individuals with SHTG worldwide.
Gemcabene was safe and well tolerated as a monotherapy or as add-on to statins, with generally only mild to moderate adverse events (with lower frequency than seen in the placebo group) and no withdrawals due to adverse events.
Individuals with mixed dyslipidemia—LDL-C of 100 mg/dL or higher and TGs of 200 mg/dL or higher—are at high risk due to elevated cholesterol markers. While the number of such participants was limited in INDIGO-1, there were improvements in all primary and secondary endpoints for these patients, including a 30-percent reduction of TGs and a 28-percent reduction of LDL-C.
“We are using the information from our INDIGO-1 trial, particularly the dose finding results, together with the results from our previous Phase 1 and 2 clinical trials, to finalize our Phase 3 trial plans,” said Dr. Lee Golden, chief medical officer of Gemphire. “We expect to communicate more information regarding the structure and timing of our Phase 3 program once we have completed our End of Phase 2 meeting with the FDA, which we will request following the completion of the FDA’s review of the two-year carcinogenicity study, which is currently in progress.”
Gemcabene’s ability to lower triglycerides below 500 mg/dL is important, because “When you have triglycerides below 500 [mg/dL], you essentially do not have chylomicrons present. Chylomicrons are the largest triglyceride-rich lipoproteins which are strongly associated with the risk of pancreatitis, rather than just the triglyceride level. So bringing patients below 500 [mg/dL] will significantly reduce the risk they have of having severe chylomicronemia and developing pancreatitis,” Dr. Evan Stein, Director Emeritus of the Metabolic & Atherosclerosis Research Center, said in the conference call regarding the INDIGO-1 results.
Beyond the encouraging results in SHTG, Gemphire reported in a press release that the data also support the company’s intent to advance gemcabene as a treatment for nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis, (NASH) as “Patients in the present study had profiles typical of cardiometabolic patients who often suffer from diabetes, dyslipidemia and obesity, which puts them at high risk for NAFLD/NASH.”