InterMune Reports Virologic Response of Ritonavir-Boosted Danoprevir (RG7227/ITMN-191) in Patients with Chronic Hepatitis C

InterMune Reports Virologic Response of Ritonavir-Boosted Danoprevir (RG7227/ITMN-191) in Patients with Chronic Hepatitis C


-- Regimen Delivered Potent Viral Response and was Safe and Well-Tolerated --


BRISBANE, Calif., April 15 /PRNewswire-FirstCall/ -- InterMune, Inc. (Nasdaq: ITMN) today announced results of all three cohorts from a 15-day Phase 1b multiple-ascending-dose (MAD) study of low doses of danoprevir (also known as RG7227 and ITMN-191) boosted by low-dose ritonavir (RTV) in patients chronically infected with hepatitis C virus (HCV) genotype-1. The results announced today were reported in an oral presentation at the 45th Annual Meeting of the European Association for the Study of the Liver (EASL) in Vienna, Austria by Edward Gane, M.D., Associate Professor, University of Auckland, and Director, Auckland Clinical Studies Limited.


Summary of Virologic Response by Treatment


Picture 16.png

(1) LLOQ = lower limit of quantification by Roche TaqMan Assay (<43 IU/mL)

(2) LLOD = lower limit of detection by Roche TaqMan Assay (<15 IU/mL)

(3) LLOQ <25 IU/mL and LLOD = 9.3 IU/mL for historical data (NHSC-003)


Dr. Gane commented, "The results from this study indicate that robust viral kinetics in treatment- naive patients can be achieved by ritonavir boosting of very low doses of danoprevir. We look forward to the results of the two 12-week cohorts in prior SOC null responders recently added to this study which will provide further insights into the antiviral efficacy and safety profile of low doses of ritonavir-boosted danoprevir."


Dan Welch, Chairman and CEO of InterMune commented, "Importantly, 18 of 25 patients (72%) treated with ritonavir-boosted danoprevir had HCV RNA levels below the limit of detection after only 15 days in this study. These results are at least as strong as those of the 14-day observation period of the 12 week Phase 2b study using un-boosted, high doses of danoprevir with exposure substantially higher than ritonavir-boosted doses. The potential impact of lower systemic exposure on the long-term safety profile of danoprevir will be further evaluated in future studies. The collective results to date appear to confirm that our objective with ritonavir-boosting is realistic."


Viral Kinetic and Pharmacokinetic Performance of Ritonavir-Boosted Danoprevir


The Phase 1b study examined three dosage cohorts of danoprevir to date: 100 mg twice daily, 200 mg once daily, and 200 mg twice daily. Each was administered for 15 days in combination with 100 mg ritonavir on the same schedule, and with standard-dose PEGASYS and COPEGUS, the current standard of care (SOC).


The combination of danoprevir 100 mg administered twice daily with 100 mg twice-daily ritonavir resulted in 78% of patients achieving a level of HCV RNA below the lower limit of quantification (LLOQ; <43 IU/mL, 7 out of 9 patients total), and 67% of patients having HCV RNA levels below the lower limit of detection (LLOD; <15 IU/mL, 6 out of 9 patients total) by day 15.


A 200 mg once-daily dose of danoprevir with a 100 mg once-daily dose of ritonavir resulted in 63% of patients with HCV RNA levels below LLOQ (5 out of 8 patients total) and 50% of patients with HCV RNA levels below LLOD (4 patients out of 8 patients total) after only 15 days. At the highest daily dose, 200 mg twice-daily danoprevir in combination with 100 mg twice-daily ritonavir, 100% of patients achieved HCV RNA below LLOQ and LLOD (8 out of 8 patients total) after 15 days.


No patient experienced virologic rebound in any dosage group during the 15-day study.


The pharmacokinetic profile of ritonavir-boosted danoprevir was more favorable than that observed in previously reported studies conducted with much higher doses of un-boosted danoprevir. At 100 mg danoprevir dosed twice daily with 100 mg ritonavir, AUC and Cmax were approximately 16-fold and 23-fold lower, respectively, than that provided by 900 mg twice-daily un-boosted danoprevir (historical Phase 1 and 2 data).


Safety and Tolerability


The ritonavir-boosted combination showed a favorable safety and tolerability profile. The most commonly reported adverse events (AEs) were headache, nausea and diarrhea and these had a similar incidence to previously reported studies of danoprevir in combination with standard of care (SOC).


Amended Protocol – 12 Weeks of RTV-boosted Danoprevir


The companies reported that the Phase 1b MAD ritonavir-boosting study protocol has been amended to add two cohorts which will examine 12 weeks of low doses of ritonavir-boosted danoprevir plus SOC in prior SOC null responders. The doses to be examined in the expanded protocol are 100 mg twice daily and 200 mg once daily, each in combination with 100 mg ritonavir on the same schedule, plus the standard dose and regimen of SOC. The first patient in the amended protocol was enrolled in late March 2010.


About Ritonavir Boosting


Ritonavir boosting is an option to enhance and improve pharmacokinetic profiles of protease inhibitors. It is well established in the treatment of HIV where it leads to more convenient dosing, reduced resistance development and high efficacy. Not all HCV protease inhibitors are suitable for ritonavir boosting. InterMune announced on August 6, 2009, ritonavir boosting of danoprevir showed promise in a Phase 1 drug-drug interaction study in healthy volunteers. The results of this study demonstrated that the co-administration of low-dose ritonavir increased danoprevir concentration 12 hours post dose by approximately 27 times, with the effect on AUC being roughly 5 times and Cmax being roughly 3 times. These results guided the selection of the doses of danoprevir reported today in the Phase 1b MAD study in HCV patients.


About Danoprevir (RG7227/ITMN-191)


Danoprevir (also known as RG7227 and ITMN-191) is a potent, macrocyclic inhibitor of HCV NS3/4A protease activity being developed in collaboration with Roche. The safety and antiviral activity of danoprevir is expected to be further evaluated in a Phase 2b study of danoprevir in combination with low doses of ritonavir and the current standard of care, and is also under clinical investigation in combination with the NS5B nucleoside polymerase inhibitor RG7128 in the INFORM clinical development program.


About InterMune


InterMune is a biotechnology company focused on the research, development and commercialization of innovative therapies in pulmonology and hepatology. InterMune has an R&D portfolio addressing idiopathic pulmonary fibrosis (IPF) and hepatitis C virus (HCV) infections. The pulmonology portfolio includes pirfenidone for which InterMune has completed a Phase 3 program in patients with IPF (CAPACITY) and a New Drug Application (NDA) has been accepted for Priority Review by the FDA with a PDUFA date of May 4, 2010, and a Marketing Authorization Application (MAA) is under review by the European Medicines Agency (EMA). The hepatology portfolio includes the HCV protease inhibitor compound danoprevir (formerly RG7227 and ITMN-191) that entered Phase 2b in August 2009 and a second-generation HCV protease inhibitor research program. For additional information about InterMune and its R&D pipeline, please visit http://www.intermune.com/


SOURCE InterMune, Inc.
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InterMune Reports Top-Line Results From Phase 2b Study of Danoprevir (RG7227/ITMN-191) in Patients with Chronic Hepatitis C



Posted April 14, 2010


InterMune Reports Top-Line Results From Phase 2b Study of Danoprevir (RG7227/ITMN-191) in Patients with Chronic Hepatitis C


BRISBANE, Calif., April 14, 2010 /PRNewswire via COMTEX/ --InterMune, Inc. (Nasdaq: ITMN) today announced top-line results from the planned Week 12 interim analysis of the Phase 2b randomized, partially-blind study evaluating the hepatitis C virus (HCV) protease inhibitor danoprevir (also known as RG7227 and ITMN-191), administered for 12 weeks in combination with PEGASYS(R) (pegylated interferon alfa-2a) and COPEGUS(R) (ribavirin), compared with placebo for the same duration plus PEGASYS and COPEGUS. The virologic response results are summarized in the following table:

Picture 18.png


Dan Welch, Chairman, Chief Executive Officer and President of InterMune, said, "The RVR and cEVR results reported today are among the very best reported by any DAA compound to date, reinforcing our view that danoprevir may potentially play a meaningful role in the treatment of HCV patients. With Roche, we are now focused on making the critical dose and regimen selection decision for future development plans for ritonavir-boosted danoprevir, an approach that appears to deliver strong efficacy and offer attractive advantages of dosing convenience and increased safety margin."


Frank Duff, M.D., Head of Roche's Clinical Development for Virology, said, "Future development of danoprevir is expected to be conducted in combination with ritonavir at total daily doses that are 10-25% of those examined in this study. The pharmacokinetics/pharmacodynamics and safety data from this large, well-controlled study, in addition to other data being collected, will be very helpful in our efforts to choose the optimal dose and regimen for the ritonavir-boosted danoprevir global development program, including the all-oral, direct-acting antiviral INFORM component of the program."


Safety and Tolerability


The analysis of the safety data is preliminary in nature and additional evaluation is ongoing. In the interim safety analysis, serious adverse events (SAEs) were generally balanced across all four treatment groups. The incidence of treatment-emergent Grade 4 (>10x ULN) ALT elevations was 0%, 1%, 6% and 0% in the 300 mg three-times daily, 600 mg twice daily, 900 mg twice daily and placebo groups, respectively. In the danoprevir treatment groups, these elevations occurred generally between weeks 6-8 or later and were reversible after discontinuation of danoprevir. Dosing of the 900 mg arm was stopped based on this safety signal. Treatment-emergent Grade 3 or Grade 4 neutropenia was reported in 24%, 25%, 31% and 16% of patients in the 300 mg three-times daily, 600 mg twice daily, 900 mg twice daily and placebo groups, respectively. The incidence of rash and anemia was comparable across all treatment groups, including the placebo group (SOC + placebo).


About the Study


The Phase 2b triple combination study, conducted at 45 sites globally, was designed to define the safety and efficacy profile of danoprevir for a treatment duration of 12 weeks as part of a total treatment duration of 24 or 48 weeks. The study was conducted by Roche as part of its collaboration with InterMune for the development of protease inhibitors. 232 patients were randomized to one of four treatment groups - three of which received a 12-week regimen of danoprevir at either 300 mg three times daily, 600 mg twice daily or 900 mg twice daily, in combination with PEGASYS and COPEGUS, followed by 12 or 36 weeks of therapy with PEGASYS and COPEGUS for a total of 24 or 48 weeks. The fourth group was a control arm receiving PEGASYS and COPEGUS for 48 weeks. In November of 2009, InterMune reported that due to a safety signal, dosing in the 900 mg group had been stopped. Patients already receiving treatment in this group continued on PEGASYS and COPEGUS. A total of 13 patients who were originally randomized to this group but had not received the study drug were later re-randomized to the other dose groups and are not included in the efficacy analysis. A total of 212 patients were included in the efficacy analysis population.


Similar virologic response was observed in all danoprevir treatment groups throughout the 12 weeks and after 12 weeks of treatment. Viral response of patients at the highest dose of 900 mg twice daily was not meaningfully different from that observed in patients who received 600 mg twice daily or 300 mg three times daily. Due to the 900 mg arm being terminated early, most of the patients in this 900 mg arm did not receive 12 weeks of triple therapy.


Other Studies with Danoprevir


InterMune announced in January 2010 that based upon promising preliminary results from a Phase 1b multiple-ascending-dose (MAD) study of ritonavir-boosted danoprevir, the full results of which are to be presented on April 15 at EASL, that the further development of danoprevir was expected to be in combination with low-dose ritonavir. The companies have amended the on-going Phase 1b MAD 15-day ritonavir-boosting study to evaluate 12 weeks of low doses of ritonavir-boosted danoprevir plus SOC, PEGASYS and COPEGUS, in prior SOC null responders. In addition, the companies plan to launch a Phase 2b study of ritonavir-boosted danoprevir plus SOC, PEGASYS and COPEGUS in late Q3 or early Q4 of 2010.


Regarding the direct-acting antiviral (DAA) program, the companies will evaluate the pharmacokinetics/pharmacodynamics and safety results of the Phase 2b study reported today, as well as those of the 4-week and amended 12-week Phase 1b MAD study of ritonavir-boosted danoprevir plus SOC, and possibly other data, to determine the dose and dosing regimen to take forward in the DAA program. The ritonavir-boosted DAA study to evaluate SVR may begin in the second half of 2010; the exact timing will be based on emerging data from the on-going studies.


About Danoprevir (RG7227/ITMN-191)


Danoprevir (also known as RG7227 and ITMN-191) is a potent, macrocyclic inhibitor of HCV NS3/4A protease activity, and has produced multi-log(10) reductions in levels of HCV in chronic HCV patients, when administered for 14 days as monotherapy and when combined with PEGASYS(R) (peginterferon alfa-2a) and COPEGUS(R) (ribavirin, USP). Danoprevir was safe and well-tolerated in these studies.