SOUTH SAN FRANCISCO, Calif.--(EON: Enhanced Online News)--Tobira Therapeutics presented positive results from an evaluation of cenicriviroc (CVC) in two animal models of liver fibrosis at the American Association for the Study of Liver Diseases (AASLD) annual meeting (The Liver Meeting®) in Washington, DC. CVC is a novel, oral, once-daily, dual CCR2 and CCR5 antagonist in late-stage clinical development for the treatment of HIV infection as part of fixed-dose combination regimens, and in planning for clinical development in liver fibrosis and other diseases in which antagonism of CCR2 and CCR5 may have a therapeutic effect.
“Significant Anti-Fibrotic Activity of Cenicriviroc, a Dual CCR2/CCR5 Antagonist in a Rat Model of Thioacetamide-Induced Liver Fibrosis and Cirrhosis”
“The data presented today illustrate the potential clinical utility of targeting CCR2 and CCR5 with CVC in the treatment of liver fibrosis, a disease for which there is currently no approved therapies,” said Scott Friedman, M.D., Dean for Therapeutic Discovery and Chief of the Division of Liver Diseases at Mount Sinai School of Medicine. “The safety and tolerability profile of CVC observed in Phase 2 studies in HIV makes it a good candidate for clinical evaluation in patients with liver disease.”
“These promising results in liver fibrosis build upon Phase 2 clinical safety and efficacy data from the HIV clinical program and demonstrate the multiple indications in which a CCR2 and CCR5 antagonist like CVC may play an important therapeutic role as an oral anti-fibrotic agent,” said Andrew Hindman, Tobira’s President and Chief Executive Officer.
Two experiments evaluated the effects of CVC at two doses in well-validated animal models of liver disease. CVC treatment was associated with an anti-fibrotic effect in both models. The first experiment evaluated a diet-induced mouse model of non-alcoholic steatohepatitis (NASH). These data were presented by Dr. Friedman during an oral presentation entitled “Anti-Fibrotic and Anti-Inflammatory Activity of the Dual CCR2 and CCR5 Antagonist Cenicriviroc in a Mouse Model of NASH” (Abstract ID #30). The second experiment evaluated a thioacetamide acid (TAA) induced rat model of liver fibrosis and cirrhosis. These data were presented in a poster session entitled, “Significant Anti-Fibrotic Activity of Cenicriviroc, a Dual CCR2/CCR5 Antagonist in a Rat Model of Thioacetamide-Induced Liver Fibrosis and Cirrhosis” (Abstract ID # LB-7).
NASH mouse model: CVC was evaluated in a streptozotocin-induced model of NASH. Over a nine-week experiment, three groups of animals (n=6/group) were administered CVC doses of 0 (vehicle), 20 (low dose) or 100 (high dose) mg/kg/day. After nine weeks biochemical, gene expression, and histologic evaluations of the liver were conducted. The primary finding showed the percentage of fibrosis area (by Sirius red staining) was significantly decreased by CVC treatment relative to vehicle control (0.29 ± 0.14, 0.20 ± 0.06 and 0.61 ± 0.23 for CVC low dose, CVC high dose and vehicle, respectively; p<0.01).
Liver fibrosis and cirrhosis rat model: CVC was evaluated in a TAA-induced model of liver fibrosis and cirrhosis. Over a twelve-week experiment, three groups of animals (n=4-8/group) received CVC doses of 0 (vehicle), 30 (low dose) and 100 (high dose) mg/kg/day, across three different periods of exposure to TAA to evaluate different degrees of liver damage. Biochemical, gene expression and histologic evaluations of the liver were conducted. When started concurrently with TAA (Group 1; Early Intervention), both the CVC low dose (Group 1a) and high dose (Group 1b) showed significantly reduced fibrosis by 49% and 38%, respectively (p<0.001), as assessed by collagen morphometry. When treatment started four weeks after TAA-induced injury (Group 2; Emerging Fibrosis), a statistically significant anti-fibrotic effect was observed for CVC low dose (Group 2a, 36% collagen reduction; p<0.001), but not for CVC high dose (Group 2b). When treatment was started at eight weeks (cirrhosis present) and continued for four weeks (Group 3; Cirrhosis Reversal), there was no significant effect of CVC on fibrogenic gene expression or fibrosis.
Chemokines and Liver Fibrosis: Chemokine receptor types 2 (CCR2) and 5 (CCR5) are expressed on monocytes, macrophages, Kupffer cells and hepatic stellate cells (HSCs), which contribute to inflammation in the liver. There is increasing evidence of the role of CCR2 and CCR5 in the pathogenesis of liver disease1–7: these two co-receptors promote the recruitment of macrophages3–5, play key roles in the migration of hepatic stellate cells (HSCs) during liver injury3,4 and promote hepatic fibrosis in mice3,4.
Cenicriviroc (CVC) is a novel, oral, once-daily, fixed-dose combinable, dual antagonist of chemokine receptors CCR2 and CCR5 with nanomolar potency. CVC is entering Phase 3 clinical development for the treatment of HIV-1 infection, and in planning for clinical development in liver fibrosis and other indications in which CCR2 and CCR5 play a role. The CCR2 receptor is found on monocytes, macrophages, dendritic and hepatic stellate cells, which are implicated in several inflammation-mediated diseases, including liver fibrosis. The CCR5 receptor is the target used by the HIV virus to infect human T-cells. CVC has been well tolerated with more than 500 subjects treated in single- and multiple-dose studies conducted to date, including 115 HIV-1 infected adults treated over a 48-week duration in Phase 2b (NCT01338883) 8. Tobira’s HIV Phase 3 development program will evaluate CVC in fixed-dose combination tablets with other antiretroviral agents, for use in the treatment of HIV infection.
About Tobira Therapeutics
Tobira Therapeutics is a privately held biopharmaceutical company developing innovative therapies for treatment of HIV infection, fibrosis, GVHD, and certain oncology indications. The company’s lead development candidate is cenicriviroc (CVC), a novel, oral, once-daily, fixed-dose combinable, dual inhibitor of chemokine receptors CCR2 and CCR5 in late-stage clinical development for the treatment of HIV. Tobira is backed by a syndicate of leading life science investors including Domain Associates, Frazier Healthcare Ventures, Montreux Equity Partners, Novo Ventures and Canaan Partners. Learn more at www.TobiraTherapeutics.com.
1. Saiman and Friedman, Frontiers in Physiology, June 2012; 2. Zimmermann and Tacke, Inflammation & Allergy – Drug Targets, 2011; 3. Seki et al., The Journal of Clinical Investigation, July 2009; 4. Seki et al. Hepatology, July 2009; 5. Miura et al. American Journal of Physiology – Gastrointestinal & Liver Physiology, June 2012; 6. Ochoa-Callejero et al. PLOS ONE, January 2013; 7. Mitchell et al., The American Journal of Pathology, May 2009; 8. Feinberg et al. EACS 2013, PS4/1