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Galectin Therapeutics completed and reported on a successful Phase 1 clinical trial in NASH patients with advanced fibrosis. In a previous “CEO Perspective”, I described the general outline of our Clinical development program. We are using the galectin-3 inhibitor GR-MD-02 in a development program for potential treatment of patients with liver fibrosis, and specifically in those patients with NASH (non-alcoholic steatohepatitis) with advanced fibrosis or the most severe form of fibrosis, cirrhosis. The successful Phase 1 clinical trial was a critical step in this development program. What exactly did this trial show and why do we consider it successful? The Phase 1 trial was the first time GR-MD-02 was administered to humans, but in addition it was designed to get the most information possible. First, unlike many phase 1 trials that include normal volunteers, the people in our trial had NASH with advanced fibrosis as determined from a liver biopsy—in other words one of the targeted groups for this therapy. Second, the trial was a placebo controlled and blinded trial meaning some patients got water instead of drug and neither patients nor medical workers knew if they were receiving the drug or water. The study included three sequential cohorts of patients, with each cohort receiving an escalated dose of GR-MD-02 (2, 4, and 8 mg/kg) administered by IV infusion over one hour. Finally, each patient received a total of four doses. More details on the protocol can be found at https://clinicaltrials.gov/ct2/show/NCT01899859? term=GR-MD-02&rank=2 (https://clinicaltrials.gov/ct2/show/NCT01899859?term=GR-MD-02&rank=2). The most important aspect of a Phase 1 trial is an assessment of patient safety. In fact, that is the primary objective of Phase (http://galectintherapeutics.com/whowe-are/leadership/) Dr. Peter Traber is the President, Chief Executive Officer and Chief Medical Officer of Galectin Therapeutics (Nasdaq:GALT), the leading developer of therapeutics that target galectin proteins to treat fibrosis and cancer.
1 trials. We found that there were no serious adverse events and no treatment emergent adverse events related to our drug GRMD-02. Therapy emergent adverse events, all mild and transient, possibly related to study drug were reported in 4 subjects who received placebo and 2 subjects who received active drug. Thus, GR-MD-02 was found to be safe and well tolerated in this group of patients. This finding alone defines the study as a successful Phase 1 trial, but we gained a lot more information from the study. Measures of blood levels of GR-MD-02 were done at multiple time points while the patients received the drug. Why is this important? From these blood levels we can calculate the total patient exposure to the drug to patients; in other words how high the blood levels are over a period of time. We can then use these exposure levels in humans to correlate with exposure levels in
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multiple studies which assessed the efficacy and safety of the drug in animal models. An analysis of this information showed us that the doses given to humans were in the ranges that were both safe and had an effect on NASH and fibrosis in animal studies. This is very valuable information for designing further studies of the drug. Although the duration of this Phase 1 study was short, we additionally wanted to get an understanding of whether the drug was having any effect on the underlying disease in the treated patients. Liver biopsy assessment of fibrosis has historically been the gold standard for evaluating the effect of an anti-fibrotic drug, but liver biopsies cannot be safely repeated in a short clinical study because of the potential risks of taking a second biopsy too soon following the initial biopsy. Therefore, we evaluated a number of biomarkers (blood tests) that may reflect the state of fibrosis in the liver. There are currently no validated serum biomarkers for evaluation of potential therapeutic changes over time in NASH or fibrosis. Therefore, we evaluated a panel of
(http://galectintherapeutics.com/) Galectin Therapeutics is a biotechnology company focused on discovery and development. We apply our leadership in galectin science and drug development to create new therapies for fibrotic disease and cancer.
serum tests to explore potential biomarkers for use in future studies. Most of the putative biomarkers showed high variability within the same individual in placebo and GR-MD-02 patients, rendering them not useful as reliable biomarkers. The FibroTest ® score, a composite of five different blood tests that has been correlated with the extent of liver fibrosis (1), was significantly reduced by GR-MD-02 treatment in cohort 3. The reduction in FibroTest Scores were almost entirely due to a reduction in alpha-2 macroglobulin levels, one of the blood tests that make up the FibroTest, as shown in the figure below. This figure shows that the first two dosage groups of GR-MD-02 (cohort 1 and 2) did not have a significant difference in the change of
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alpha-2 macroglobulin as compared to placebo-treated patients. Note that some have incorrectly stated that cohort 2 was worse than placebo (eg, it went up) when in fact the difference was not significant and, thus due to randomness of blood values; in other words there was no difference between placebo or the first two cohorts. However, if one looks at cohort 3 (the highest dose used), there was a statistically significant reduction at three different time points for the blood sampling; just before the second dose, 3 days following the fourth dose, and 14 days following the fourth dose. Additional blood samples were taken in cohort 3 to evaluate biomarkers more effectively and to correlate with both cohort 1 and 2. For those readers not used to evaluating statistics, a p value of less than 0.001 means that there is less than a one in a thousand chance that the difference from placebo is due to chance.
The reduction in alpha-2 macroglobulin (A2MG) is of interest because this protein is a relevant marker for fibrosis. In fact, in a recent human study, A2MG was found by the authors to be “the most important serum biomarker for liver fibrosis” among the multiple markers they evaluted (2). It is known to inhibit multiple proteases, including collagenase, which has been hypothesized to promote fibrosis. It is expressed in liver cells, a subset of macrophages, and stellate cells, where its expression is increased as they are converted to collagen producing cells. Finally, clinical studies show that alpha-2 macroglobulin increases with increasing liver fibrosis as assessed by liver biopsy. The reduction seen in alpha-2 macroglobulin suggests there may be changes in the fibrogenic process that might lead to an improvement in fibrosis with longer term therapy. It was decided before cohort 3 started to add a physical evaluation of the liver, FibroScan® to assess directly for liver fibrosis in patients who were being treated at facilities who had Fibroscan® equipment. FibroScan® uses an electromechanical vibrator and pulse-echo ultrasound to evaluate the elastic shear wave in liver tissue. The volume of liver tissue assessed is ~100-times greater than volume assessed by liver biopsy. The stiffness of the liver is recorded as a pressure measurement of kPa (kilopascals) and the stiffness of the liver has been shown to correlate with the degree of liver fibrosis as assessed by liver biopsy. For this reason, FibroScan® represents a promising non-invasive, out-patient method for measuring changes in liver fibrosis over time, including patients with NASH (3). Technically adequate FibroScan® evaluations were obtained scans at baseline, Day 38 and Day 63 in 5 patients administered GR-MD-02 and 3 patients administered placebo. As shown in the figure below, there was essentially no change in the liver stiffness for the three placebo patients, with all FibroScan scores within 20% of baseline. In contrast, 3 of the 5 patients treated with GR-MD-02 had a reduction in liver stiffness below 20% of the baseline value, with two patients having a reduction of 50% from baseline. While these numbers of patients are small, this suggests that liver stiffness may decrease in NASH patients with advanced fibrosis who received GR-MD-02.
The results of this Phase 1 study was successful in providing information on the design of a Phase 2 clinical trial to demonstrate efficacy. First, and most importantly, GR-MD-02 was safe and well tolerated at single and multiple doses of 2, 4, and 8mg/kg. Pharmacokinetics (blood levels) revealed drug exposure in humans at the 8 mg/kg dose that was equivalent to the upper range of the targeted therapeutic dose determined from effective doses in NASH animal models, thus providing support for the proposed Phase 2 dosing regimen. Additionally, there was evidence of an effect on a relevant disease marker, with a dose dependent reduction in FibroTest ® scores due to a reduction in alpha-2 macroglobulin levels. And finally, there was a trend that suggested liver stiffness, which may be related to a reduction in fibrotic tissue, is reduced by GR-MD-02. While health related outcomes or liver biopsies was not appropriate to be evaluated in this short-term treatment Phase 1 trial, it does appear that there was an effect of GR-MD-02 on the disease process. On the basis of this Phase 1 study, Galectin has initiated two phase 2 clinical trials to evaluate the possible reversal of liver fibrosis in NASH, the most common form of liver disease. The NASH-CX trial will focus on reversal of fibrosis in the most severe form of fibrosis called cirrhosis and the NASH-FX trial will attempt to show reversal of advanced fibrosis in a pre-cirrhotic stage. More information on Galectin’s clinical trials can be found at clinicaltrials.gov NASH-CX: https://clinicaltrials.gov/ct2/show/NCT02462967?term=GR-MD-02&rank=3 (https://clinicaltrials.gov/ct2/show/NCT02462967?term=GR-MD-02&rank=3) NASH-FX: https://clinicaltrials.gov/ct2/show/NCT02421094?term=GR-MD-02&rank=4 (https://clinicaltrials.gov/ct2/show/NCT02421094?term=GR-MD-02&rank=4) These “CEO Perspectives” will be a regular feature of our communication activities and may contain forward looking statements within the meaning of the Private Securities Litigation Reform Act of 1995. These statements relate to future events and use words such as “may”, “could”, “expect” and others. These statements include those regarding the hope that Galectin’s development program for GR-MD-02 will lead to the first therapy for the treatment of fatty liver disease with advanced fibrosis and cirrhosis. For a discussion of additional factors impacting Galectin’s business, see the Company’s Annual Report on Form 10-K for the year ended December 31, 2014, and subsequent filings with the SEC. You should not place undue reliance on forward-looking statements. Although subsequent events may cause its views to change, management disclaims any obligation to update forward-looking statements Please look for future editions in which multiple aspects of our development programs for unmet medical needs will be addressed. Reference List 1. Poynard T, Morra R, Halfon P, Castera L, Ratziu V, Imbert-Bismut F, et al. Meta-analyses of FibroTest diagnostic value in chronic liver disease. BMC Gastroenterol 2007;7:40. 2. Atanasova E, Martinova F, Jelev D, Antonov K, de Mey C, Mateva L, et al. Alpha-2 macroglobulin is the simplest serum biomarker for liver fibrosis and fibrogenesis in chronic hepatitis C. MedInform 2015;1(2):153-164. 3. Wong VW, Vergniol J, Wong GL, Foucher J, Chan HL, Le BB, et al. Diagnosis of fibrosis and cirrhosis using liver stiffness measurement in nonalcoholic fatty liver disease. Hepatology 2010 Feb;51(2):454-462.
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advanced liver fibrosis (http://perspectives.galectintherapeutics.com /tag/advanced-liverfibrosis/), clinical trial (http://perspectives.galectintherapeutics.com /tag/clinical-trial/), Galectin Therapeutics (http://perspectives.galectintherapeutics.com /tag/galectintherapeutics/), GR-M D-02 (http://perspectives.galectintherapeutics.com /tag/gr-m d-02/), NASH (http://perspectives.galectintherapeutics.com /tag/nash/), nonalcoholic steatohepatitis (http://perspectives.galectintherapeutics.com /tag/nonalcoholicsteatohepatitis/), Peter Traber (http://perspectives.galectintherapeutics.com /tag/peter-traber/), phase 1 trial (http://perspectives.galectintherapeutics.com /tag/phase-1-trial/)
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