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Increased anti-hepatitis C synergy at higher doses between INX-189 and ribavirin

1 December 2011

 INV-189 in combination with ribavirin viral reduction after 7 days

INV-189 in combination with ribavirin viral reduction after 7 days

Click for full sized image  148.3 Kb

 

Inhibitex, the US biopharmaceutical company, which is working on potential anti-viral drugs with Prof Chris McGuigan’s laboratory in the Cardiff School of Pharmacy & Pharmaceutical Sciences, have just reported  top-line safety and antiviral data from an ongoing Phase 1b extension trial of INX-189, which is designed to further evaluate the safety, tolerability, pharmacokinetics and antiviral activity of various doses of INX-189, administered as monotherapy or in combination with RBV, for seven days in treatment-naïve patients infected with chronic HCV genotype 1.  In the ongoing trial, 100 mg INX-189, dosed once-daily for seven days in combination with RBV, continued to demonstrate potent and dose-dependent synergistic antiviral activity with a median HCV RNA reduction from baseline of -3.79 log10 IU/mL.  Further, 100 mg INX-189 in combination with RBV was well tolerated and there were no serious adverse events.  For comparison purposes, in a clinical trial completed earlier this year, 100 mg INX-189 dosed as monotherapy once-daily for seven days resulted in a median -2.53 log10 IU/mL reduction in HCV RNA levels.  In this same clinical trial, the Company also reported antiviral data indicating that INX-189, when dosed once-daily at 9 and 25 mg in combination with RBV for seven days, demonstrated dose-dependent, synergistic antiviral activity. (See diagram for a composite of current clinical results)

 

3D structure/image of INX-189 anti-hepatitis C drug

3D structure/image of INX-189 an anti-hepatitis C drug synthesised in the School

 More information here 

Hepatitis C is a disease which affects some 170 million individuals worldwide (3% of the human population) and current treatment  is unsatisfactory requiring a weekly injection plus a daily tablet.   Therapy often continues for nearly a year and is unsuccessful in many patients.

 

Inhibitex plans to further expand its ongoing Phase 1b extension trial to evaluate once-daily doses of 200 mg INX-189 in combination with RBV; 300 mg INX-189 as monotherapy; and 200 mg INX-005 (a single isomer of INX-189) as monotherapy, respectively, for seven days.  The Company anticipates that the Phase 1b extension trial will be completed in the first quarter of 2012. 

Additionally, the Company reported that it plans to submit a protocol amendment this quarter to its ongoing Phase 2 study in genotype 2 and 3 HCV-infected patients to include the evaluation of 100 mg and 200 mg of INX-189 dosed once-daily in combination with RBV for 12 weeks.

 

Professor McGuigan,. who is also a member of the Board of Directors of Inhibitex, warmly welcomed this news. 

 

“We believe the significant increase in antiviral activity demonstrated with 100 mg INX-189 in combination with RBV, as compared to 100 mg INX-189 dosed as monotherapy, further confirms the antiviral synergy between INX-189 and RBV that we have consistently observed in preclinical and clinical results to-date,” stated Dr. Joseph Patti, Senior Vice President and CSO of Inhibitex, Inc“We look forward to further exploring this antiviral synergy with 200 mg of INX-189 and expanding the scope of our ongoing and planned Phase 2 clinical trials to include interferon-free combinations of INX-189 with other antiviral agents in HCV genotype 1, 2, and 3 patients in 2012.”

 

 

For  recent scientific papers describing the development of INX-189 see

 

INX-08189, a Phosphoramidate Prodrug of 6-O-Methyl-2’-C-Methyl Guanosine, is a Potent Inhibitor of Hepatitis C Virus Replication with Excellent Pharmacokinetic and Pharmacodynamic Properties.  

J.H. Vernachio, B. Bleiman, K.D. Bryant, S. Chamberlain, D. Hunley, J. Hutchins, B. Ames, E. Gorovits, B. Ganguly, A. Hall, A. Kolykhalov, Y. Liu, J. Muhammad, N. Raja, R.C. Walters, J. Wang, K. Williams, J.M. Patti, G. Henson, K. Madela, M. Aljarah, A. Gilles, C. McGuigan    

Antimicrob Agents, Chemother, 2011, 1843-1851.

 

Design, synthesis and evaluation of a novel double pro-drug: INX-08189.  A new clinical candidate for hepatitis C virus

Christopher McGuigan, Karolina Madela, Mohamed Aljarah, et al.   

Bioorganic & Medicinal Chemistry Letters 20 (2010) 4850–4854

and 

Phosphoramidate ProTides of 2’-C-Methylguanosine as highly potent inhibitors of hepatitis C virus. Study of their in vitro and in vivo properties.

 C. McGuigan, A. Gilles, K. Madela, M. Aljarah, et al.

J. Med. Chem., 2010, 4949-4957.

 

A current Powerpoint presentation from Prof McGuigan describing Pro Tides is available here. 

 

See also

 Full text of Inhibitex press release from 29th Nov. 2011 

 

Exciting news from Inhibitex about their anti-Hepatitis C drug, INX-189A major step forward for potential anti-Hepatitis C drug, INX-189, orginally synthesised in Cardiff

 

Inhibitex, Inc.   company web-site

..

Prof Chris McGuigan

Position:Professor of Medicinal Chemistry
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Telephone: +44 (0)29 208 74537 Extension: 74537