The new InterMune study represents an in-depth characterization of the mechanism of inhibition of the HCV NS3/4A serine protease by ITMN-191. Full characterization of the inhibition mechanism indicated that ITMN-191's true biochemical potency of 36 picomolar (pM) was approximately ten-fold better than previously inferred (~ 250 pM reported at DDW 2006). The presented data also suggest that ITMN-191 binds to the NS3/4A protease target in a two-step binding mechanism in which ITMN-191 initially associates with NS3/4A in a collision complex that isomerizes to a long-lived but non-covalent drug-target complex. The half life of the complex between ITMN-191 and NS3/4A was estimated to be five hours or more, and inhibition of protease activity of NS3/4A was stable over this same time period. Slow dissociation of ITMN-191 from the NS3/4A protease may have a relevant in vivo consequence, as a two-hour exposure of ITMN-191 to tissue culture cells that harbor an HCV replicon resulted in an antiviral effect equal to that delivered by continuous exposure of ITMN-191.
Lawrence M. Blatt, Ph.D., Chief Scientific Officer of InterMune, said, "This preclinical study of ITMN-191 provides a better understanding of its attractive potency and binding characteristics. While ITMN-191 is a non-covalent, reversible inhibitor of the protease, the onset of inhibition and slow dissociation compare favorably with those observed with covalent protease inhibitors currently in development. The immediate onset of inhibition and slow dissociation observed with ITMN-191 suggest that liver concentrations may underestimate its antiviral activity, since ITMN-191 will likely remain bound to the protease target after unbound drug is cleared from the liver."
Preclinical toxicology and pharmacokinetic studies in multiple species suggest that ITMN-191 has attractive characteristics, including significant liver exposure, slow dissociation from the NS3/4 protease, high in vitro potency and specificity, and an advantageous cross-resistance profile, including considerable effectiveness against variants of the NS3/4A protease that are resistant to other HCV protease inhibitors currently in development. The preclinical pharmacokinetic results support the exploration of twice-daily oral dosing. In early May 2007, InterMune reported that it had completed dosing in a Phase 1a single ascending-dose (SAD) trial of ITMN-191 in healthy subjects. No serious adverse events were reported in the SAD trial. Preliminary safety data from the SAD trial suggests that ITMN-191 was well tolerated and safe at the doses intended for the Phase 1b multiple-ascending dose (MAD) trial of ITMN-191. InterMune currently anticipates that the MAD trial will begin in the third quarter of 2007 and initial top-line viral kinetic data reported in the fourth quarter of 2007. InterMune and Roche have a collaboration agreement for the research, development and commercialization of ITMN-191 (referred to as R7227 within the Roche research and development programs) and second-generation HCV protease inhibitor compounds.
About HCV and HCV Protease Inhibitors
According to the Centers for Disease Control and Prevention (CDC), an estimated 3.9 million Americans (1.8%) have been infected with HCV, of whom 2.7 million are chronically infected. It is estimated that there are 170 million people worldwid e afflicted with this disease. While currently available therapies can cure many patients, there is considerable need for the development of novel therapeutic approaches. The HCV NS3/4 protease is an attractive drug target because of its potential involvement in viral replication and suppressive effects on host response to viral infection. Inhibitors of the HCV protease, such as ITMN-191, represent a promising new class of drugs for HCV.
DDW is the largest international gathering of physicians, researchers and academics in the fields of gastroenterology, hepatology, endoscopy and gastrointestinal surgery. Jointly sponsored by the American Association for the Study of Liver Diseases, the American Gastroenterological Association (AGA) Institute, the American Society for Gastrointestinal Endoscopy and the Society for Surgery of the Alimentary Tract, DDW takes place May 19-24, 2007, at the Washington Convention Center, Washington, DC. The meeting showcases approximately 5,000 abstracts and hundreds of lectures on the latest advances in GI research, medicine and technology. For more information, visit http://www.ddw.org.
InterMune is a biotechnology company focused on the research, development and commercialization of innovative therapies in pulmonology and hepatology. InterMune has a pipeline portfolio addressing idiopathic pulmonary fibrosis (IPF) and hepatitis C virus (HCV) infections. The pulmonology portfolio includes the Phase 3 program, CAPACITY, which is evaluating pirfenidone as a possible therapeutic candidate for the treatment of patients with IPF and a research program focused on small molecules for pulmonary disease. The hepatology portfolio includes the HCV protease inhibitor compound ITMN-191 in Phase 1a, a second-generation HCV protease inhibitor program, and a research program evaluating a new target in hepatology. For additional information about InterMune and its R&D pipeline, please visit http: //www.intermune.com.
Except for the historical information contained herein, this press release contains certain forward-looking statements that involve risks and uncertainties, including without limitation the statements related to the progress, future patient enrollment in and timing of our clinical trials and announcements of results thereof. All forward-looking statements and other information included in this press release are based on information available to InterMune as of the date hereof, and InterMune assumes no obligation to update any such forward-looking statements or information. InterMune's actual results could differ materially from those described in InterMune's forward-looking statements. Factors that could cause or contribute to such differences include, but are not limited to, those discussed in detail under the heading "Risk Factors" in InterMune's annual report on Form 10-K filed with the SEC on March 30, 2007 (the "Form 10-K"), and other periodic reports filed with the SEC, including the following: (i) risks related to the development of our product and product candidates; (ii) risks related to timely patient enrollment and retention in clinical trials, including the use of third parties to conduct such clinical trials; (iii) risks related to achieving positive clinical trial results; (iv) risks related to our intellectual property rights; and (v) risks related to the uncertain, lengthy and expensive clinical development and regulatory process, including having no unexpected safety, toxicology, clinical or other issues. The risks and other factors discussed above should be considered only in connection with the fully discussed risks and other factors discussed in detail in the Form 10-K and InterMune's other periodic reports filed with the SEC.
SOURCE InterMune, Inc.
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