Fatty liver disease, or the accumulation of fat in liver cells, is a "silent epidemic," says Dr. Peter Traber, president, CEO and chief medical officer of Galectin Therapeutics (NASDAQ:GALT).
In an interview with BioTuesdays.com, he says multiple liver diseases lead to fibrosis, and end-stage fibrosis, or cirrhosis, leads to liver failure, medical complications and death. "With fatty liver disease, the most common liver disease, there are very few symptoms until patients reach late-stage disease, with advanced fibrosis and then cirrhosis."
There is no approved medical therapy for liver fibrosis, and the only current therapy is a liver transplant. Dr. Traber points out that fatty liver disease with fibrosis, or non-alcoholic steatohepatitis (NASH), has a prevalence of nine-to-15 million people in the U.S., of which 25% to 30% will develop cirrhosis. Dr. Traber further points out that NASH cirrhosis is projected to be the No. 1 reason for a liver transplant.
Galectin is focusing on diseases where galectin proteins play a major role in diseases that involve scarring of organs, such as inflammation, organ fibrosis and cancer. These proteins act as a kind of glue to bind to sugar molecules that are part of other proteins, he explains. High levels of galectins, most notably galectin-3, are most closely related with the pathologic processes in fatty liver disease and fibrosis.
Dr. Traber, a former senior VP of clinical development and medical affairs, and chief medical officer of GlaxoSmithKline, says that when targeted inhibition of galectin-binding in humans has been achieved, "we think it will be very important for many disease indications."
The company has developed two classes of galectin inhibitors: galactomannan (GM) and galacto-rhamnogalaturonate (GR) carbohydrate polymers. The two drugs it currently has in development - GM-CT-01 and GR-MD-02 - are designed to target galectin-3 and inhibit its binding function.
GR-MD-02 and GM-CT-01 both reverse cirrhosis in rat model
Dr. Traber says Galectin has conducted multiple preclinical studies and confirmed a "robust effect on inhibition and regression of fibrosis, as well as reduction in inflammation and cell death in the liver." Studies have also found that GR-MD-02 is generally more effective than GM-CT-01, he adds.
The company is currently enrolling NASH patients with advanced fibrosis in a dose escalation Phase 1 study. In addition to safety and pharmacokinetics, the study will explore biomarkers for efficacy for single and multiple doses of GR-MD-02 over four weekly doses of the drug.
"This is not a Phase 1 study in the normal sense because we are looking at patients with the targeted disease," Dr. Traber points out. "We think it's pretty significant that the FDA allowed us to go into patients with advanced fibrosis. And our starting dose is within the presumptive therapeutic range as determined in preclinical animal studies."
The trial is designed to study at least three cohorts of eight patients each, of which six are in the treatment group and two receive placebo, and potentially up to five cohorts, with a maximum of 40 patients at six clinical sites in the U.S. The study is not powered to be statistically significant, and data from the first cohort will be reported by the end of 2013.
Galectin is also planning for a Phase 2 clinical trial in the third quarter next year with 120-to-160 biopsy-proven NASH patients with advanced fibrosis. Top-line data would be available by the first half of 2016.
Last week, the FDA granted GR-MD-02 fast track designation for NASH with hepatic fibrosis. "We are very pleased that the FDA sees the clinical value of GR-MD-02 and the seriousness of fatty liver disease," he adds.
Dr. Traber says most drugs being developed in the sector are targeting earlier stages of NASH, including the onset of fat accumulation and inflammation with little fibrosis. "We think our approach is warranted because it can take a decade or more for NASH to develop into fibrosis and cirrhosis, which makes it difficult to determine which NASH patients will develop fibrosis or cirrhosis."
He contends that only Galectin and Gilead Sciences (NASDAQ:GILD) have programs focused on advanced fibrosis, which is the key cause of liver failure in patients. "And we think we have an advantage over Gilead because of the multiple points in NASH pathogenesis that GR-MD-02 works on."
Galectin is also using GR-MD-02 to study fibrosis in other organs. Earlier this year, the company reported a reversal of fibrosis in the kidneys of diabetic mice, and earlier this month, the company said that GR-MD-02 had a robust effect on reducing lung fibrosis using a mouse model that simulates human disease. GM-CT-01 had a somewhat reduced effect.
Dr. Traber says the company is having ongoing partnering discussions with large pharmaceutical companies but that nothing is imminent. "These discussions will provide a foundation for partnering opportunities at the most opportune time."
In Galectin's cancer program, Dr. Traber explains that the vast majority of cancers secrete large amounts of galectins, which have multiple roles in tumor pathogenesis, including tumor cell invasion, metastasis and angiogenesis.
The vast majority of cancers secrete large amounts of galectins which have multiple roles in tumor pathogenesis
"Our focus is tumor immunotherapy based on the hypothesis that the combination of galectin inhibitors and immunotherapies will enhance the ability of the immune system to recognize and kill tumor cells in metastatic melanoma, which is our initial cancer indication," he adds.
"However, we don't have the resources to conduct research programs in both fibrosis and cancer, so we have established collaborations with the Ludwig Cancer Institute in Brussels, and the Robert W. Franz Cancer Research Center, Earle A. Chiles Research Institute in Portland, Oregon, because they have clinical trial expertise in melanoma, do research in tumor immunology and have the ability to conduct clinical trials and assist in funding."
Dr. Traber says researchers in Brussels have found that tumor cells secrete galectin-3, which binds to, and blocks the actions of, tumor-infiltrating T-lymphocytes, the major immune cell in the body's defense against cancers. In addition, research has shown that GM-CT-01 blocked galectin-3 and, in turn, restored the ability of the T-lymphocytes to kill tumor cells.
Potential sites for galectin inhibition in tumor immunology
In addition to this so-called "Galectin Effect," he says researchers in Portland have found that when galectin-3 was inhibited in vivo with GR-MD-02, there was enhanced accumulation of CD8 T-cells as well as a lowering of the tumor defense mechanisms. Experiments in tumor-bearing mice, using various immune modulatory drugs in combination with galectin inhibitors, have shown enhanced efficacy against the tumors with the combination treatment. A Phase 1 clinical trial in melanoma with a combination of GR-MD-02 and Bristol Myers-Squibb's Yervoy is in the design phase, he adds.