Tobira Therapeutics Reports Interim 12-Week Results from ORION Study

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Tobira Therapeutics, Inc.
TBRA
, a clinical-stage biopharmaceutical company focused on the development and commercialization of novel treatments for liver and inflammatory diseases, today announced top-line results from a 12-week interim analysis of the Phase 2a ORION study showing that treatment with cenicriviroc (CVC) in obese patients with prediabetes or diabetes and fatty liver disease was well tolerated and associated with improvements in insulin sensitivity. In obese patients, the over-expression of CCR2 and CCR5 receptors and their ligands in fat tissue has been shown to promote both inflammation and insulin resistance. Insulin resistance is associated with the development of non-alcoholic fatty liver (NAFLD) disease and is a key driver for disease progression to its more severe form, non-alcoholic steatohepatitis (NASH). "ORION was designed to evaluate whether CVC's anti-inflammatory mechanism may indirectly, by blocking CCR2/5, have a favorable effect on insulin sensitivity. Preliminary findings from the pre-planned 12-week interim analysis show that CVC treatment was associated with improvements in multiple glucose parameters. In addition to the previously known anti-inflammatory and anti-fibrotic effects, these preliminary data on improved insulin sensitivity are encouraging and further support the therapeutic potential for CVC in NASH," said Eric Lefebvre, M.D., chief medical officer of Tobira. "Additionally, CVC was observed to be safe and well tolerated in obese patients with fatty liver disease. Drug related adverse events were infrequent and comparable to placebo." ORION is a randomized, double-blind, placebo-controlled study exploring the metabolic effects of CVC in obese adults (BMI ≥ 30 kg/m2) with prediabetes or type 2 diabetes and suspected non-alcoholic fatty liver disease (NAFLD). The pre-planned week-12 analysis was designed to evaluate the safety and the 'time-to-effect' of CVC in advance of the full week-24 analysis. The study was not powered for statistical significance. The interim data analysis of this mechanistic study was based on 35 subjects, with a mean baseline fasting plasma glucose level of 122.31 mg/dL (SD; 33.73) and HbA1c of 6.25 (SD; 0.80). Over 50% of subjects were diagnosed with NASH. Over the 12-week treatment period, pre-defined as the interim analysis period, effects in exploratory efficacy endpoints were observed in multiple insulin resistance-related parameters compared to placebo (change at week 12 compared to baseline; placebo-subtracted difference [95% CI]), including a reduction in fasting plasma glucose of -11.52 mg/dL (CI; -28.35, 5.31) and HbA1c of -0.36 (CI; -0.74, 0.01). CVC treatment was also associated with a reduction of serum free fatty acid levels (AUC-2h) following a 75 gram oral glucose tolerance test of -4.9 mmol/L (CI; -11.4, 1.6) compared to placebo. CVC treatment was observed to be safe and well-tolerated with adverse events being comparable to placebo. The study will continue as planned and the primary analysis will be based on 24-week data from all 45 subjects enrolled and will include, in addition to insulin sensitivity parameters: inflammation biomarkers, effects on adipose tissue, changes in liver histology in the subset of subjects with NASH, and changes in liver magnetic resonance based imaging by LiverMultiScan at selected sites. "Being able to better regulate the metabolic drivers that promote fat storage in the liver is a significant development in liver disease research," said Stephen A. Harrison, M.D., chief of hepatology, division of gastroenterology, Brooke Army Medical Center. "A large amount of data has been generated demonstrating CVC is a potent anti-inflammatory and anti-fibrotic agent. These new data in obese patients with NAFLD or NASH suggest that CVC can address metabolic abnormalities as well. This is important, as this early population is reflective of patients who are at risk of progression, and these interim results suggest that CVC has the potential to impact NASH." The company plans to submit the full comprehensive data set from the ORION study, including insulin sensitivity parameters and inflammation biomarkers for presentation at a future medical meeting. The company also anticipates announcing topline data from CENTAUR, a phase 2b study in patients with NASH and fibrosis in the third quarter of 2016. Details about ORION can be found at www.clinicaltrials.gov using identifier NCT02330549.
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