Either you have JavaScript disabled or your browser does not support Javascript . To work properly, this page requires JavaScript to be enabled.
How to enable JavaScript in your browser?

Danoprevir - Array BioPharma/Roche/Ascletis

Drug Profile

Danoprevir - Array BioPharma/Roche/Ascletis

Alternative Names: ASC-08; Ganovo; ITMN-191; ITMN-B; R-7227; RG-7227; RO-5190591

Latest Information Update: 16 Apr 2020

At a glance

  • Originator Array BioPharma; InterMune
  • Developer Ascletis; Roche
  • Class Antivirals; Carboxylic acids; Cyclopropanes; Isoindoles; Macrocyclic compounds; Pyrrolidines; Small molecules; Sulfonamides
  • Mechanism of Action Hepatitis C virus NS3 protein inhibitors; Hepatitis C virus NS4 protein inhibitors
  • Orphan Drug Status

    Orphan designation is assigned by a regulatory body to encourage companies to develop drugs for rare diseases.

    No
  • New Molecular Entity Yes

Highest Development Phases

  • Marketed Hepatitis C
  • Clinical Phase Unknown COVID 2019 infections

Most Recent Events

  • 24 Mar 2020 Safety and efficacy data from clinical trial in COVID-2019 infections released by Ascletis Pharma
  • 18 Mar 2020 Ascletis Pharmaceutical initiates phase IV trial for COVID-2019 infections (Combination therapy) in China (PO) (NCT04345276)
  • 17 Feb 2020 Clinical trials in COVID-2019 infections (Combination therapy, Treatment-experienced) in China (PO) (NCT04291729)

Development Overview

Introduction

Danoprevir is an orally available, second-generation, non-covalent, small-molecule, reversible inhibitor of the hepatitis C virus (HCV) NS3/NS4A protease, which was originated by Array Biopharma (a subsidiary of Pfizer) and InterMune (a subsidiary of Roche), and then sold to Roche. The product acts as a direct acting antiviral agent. The oral formulation is approved and available for HCV infections in China, and clinical development for the same indication is underway in several countries worldwide. Ascletis, the licensee in China, believes that danoprevir in combination with ravidasvir [see AdisInsight drug profile 800035127] may offer an effective interferon-free regimen for the treatment of HCV. Clinical development for the regimen is underway in Taiwan and in China for COVID-2019 infections.

An intravenous formulation was in phase I development in the Netherlands. However the development has been discontinued.

Danoprevir emerged as a lead candidate from a research programme aimed at developing selective, small-molecule HCV NS3/4 protease inhibitors [see AdisInsight drug profile 800017954]. Roche is also developing a fixed-dose combination (FDC) tablet of ritonavir-boosted danoprevir for the treatment of hepatitis C [see AdisInsight drug profile 800036203].

In September 2014, InterMune was acquired by Roche [1] .

In July 2019, Array Biopharma was acquired by Pfizer [2] .

Company Agreements

In July Pfizer completed the acquisition of Array Biopharma. Array Biopharma will become a subsidiary of Pfizer. In June 2019, Pfizer entered into a definitive merger agreement with Array Biopharma. The acquisition will help in expanding the pipeline of Pfizer with multiple high-potential targeted investigational cancer therapies and adds a large portfolio of royalty-generating out-licensed medicines. This transaction is expcetd to close in second half of 2019. [3] [2]

In June 2018, Ascletis BioScience entered into a strategic co-operation agreement with CR Pharmaceutical. Under the terms of the agreement, both the companies will work together for the distribution of danoprevir (Ganovo®). Additional details were not disclosed. [4]

In September 2014, Roche and InterMune announced that Roche's wholly owned subsidiary Klee Acquisition Corporation has accepted for payment all shares validly tendered pursuant to its tender offer for all outstanding shares of common stock of InterMune Inc, at $US74.00 per share in cash. Following this transaction, InterMune became a wholly owned subsidiary of Roche.

In August 2014, Roche announced that it has commenced a cash tender offer for all outstanding shares of common stock of InterMune, Inc at a price of US$74.00 per share.

In August 2014, Roche and InterMune Inc entered into a definitive merger agreement for Roche to fully acquire InterMune at a price of $US74.00 per share in an all-cash transaction, corresponding to a total transaction value of $US8.3 billion on a fully diluted basis. The merger agreement has been approved by the boards of InterMune and Roche. Under the terms of the agreement, Roche will promptly commence a tender offer no later than 29 August 2014 to acquire all of the outstanding shares of InterMune's common stock at a price of $US74.00 per share in cash and InterMune will file a recommendation statement containing the unanimous recommendation of the InterMune board that InterMune's shareholders tender their shares to Roche. The closing of the tender offer will be subject to the tender of a number of shares that represents a majority of the total number of outstanding shares on a fully diluted basis. Following completion of the tender offer, Roche will acquire all remaining shares at the same price of $US74.00 per share through a second step merger. The closing of the transaction is expected to take place in 2014. The acquisition of InterMune will allow Roche to broaden and strengthen its respiratory portfolio globally. [5] [6] [7]

In April 2013 Roche and Ascletis entered into a collaboration to develop and commercialize Roche’s investigational drug danoprevir in China for the treatment of Hepatitis-C Virus. Under the terms of the agreement, Ascletis will fund and be responsible for the development, regulatory affairs and manufacturing of danoprevir in greater China, including Taiwan, Hong Kong and Macau and receive payments upon reaching certain development and commercial milestones from Roche. Ascletis and Roche will collaborate for the clinical development and the commercialization. The contract also involves royalties. [8]

In October 2010, InterMune, Inc. sold worldwide development and commercialisation rights to danoprevir (also known as RG 7227 or ITMN 191) to Hoffman-La Roche Inc. and F. Hoffman-La Roche Ltd. for $175 million in cash. In connection with this transaction, the collaboration agreement that InterMune and Roche entered into in October 2006 has been terminated. In addition, the companies are actively exploring ways to continue their ongoing work together on other HCV research programs. InterMune noted that as a result of this transaction, the company will make no further investment in danoprevir and that, including net proceeds from the transaction, it currently expects to have a cash balance of approximately $US290 million at the end of 2010.

In September 2008, InterMune, Inc. earned a $US15 million development milestone under its development collaboration with Roche for the hepatitis C virus compound ITMN 191 (referred to as R7227 at Roche), currently in a phase 1b clinical trial in combination with Pegasys® (peginterferon alfa-2a) and Copegus® (ribavirin). Under the terms of their 2006 collaboration agreement, the clinical program for ITMN 191 is now being transitioned to Roche which, starting in phase 2, will have primary responsibility for completing the global development and registration program.

In July 2007, InterMune, Inc. and its partner Roche submitted an amended Clinical Trial Authorization (CTA) with the relevant European regulatory authority, the final step before initiating a phase 1b study of hepatitis C virus (HCV) protease inhibitor ITMN 191 in chronic hepatitis C patients. The CTA amendment takes into consideration new competitor information, preclinical and in-vitro data and pharmacokinetic observations from a phase 1a study which was completed in May of 2007. InterMune earned a $US10 million development milestone from Roche as part of the ongoing corporate collaboration. Assuming a timely approval of the CTA amendment by the European regulatory authority and the Ethics Committee for the clinical trial sites, InterMune expects to initiate the phase 1b multiple ascending dose (MAD) study late in the current quarter, or in the beginning of the next quarter. The study is designed to assess the effect on viral kinetics, viral resistance, pharmacokinetics and safety and tolerability of multiple ascending doses of ITMN 191 given as a monotherapy. InterMune plans to administer ITMN 191 for a period of 14 days to three ascending dose cohorts of treatment-naive patients infected with HCV genotype 1. Twice per day (BID) and three-times per day (TID) dosage regimens will be studied. The study can be extended to additional cohorts of treatment-naive patients, based on results from the first three planned cohorts. In addition, a single cohort of non-responder patients will be studied.

In January 2007, InterMune, Inc. successfully completed large-scale synthesis and delivery to its partner Roche of active pharmaceutical ingredient for hepatitis C virus (HCV) drug candidate ITMN 191, currently in a phase 1a clinical trial. The milestone triggered a $US10 million payment to InterMune from Roche as part of the companies′ collaboration to develop and commercialize protease inhibitors for the treatment of HCV.

In November 2006, InterMune, Inc. announced that on 30 October 2006, it closed its exclusive license and collaboration agreement with Roche for the exclusive worldwide development and commercialization of InterMune′s hepatitis C virus (HCV) protease inhibitor program. InterMune will receive an upfront payment of $US60 million. Roche is now funding 67% of the global development costs associated with ITMN-191, InterMune′s lead HCV protease inhibitor drug candidate. Assuming the successful development and commercialization of ITMN-191 in the US and other countries, InterMune could receive up to $US470 million in milestones, including a potential $US35 million within the next 12 months.

In October 2006, Roche and InterMune, Inc. entered into an exclusive worldwide collaboration agreement to develop and commercialize products from InterMune′s HCV protease inhibitor program. The agreement includes InterMune′s lead candidate compound ITMN 191, expected to enter clinical trials before the end of the year. The companies will also collaborate on a research program to identify, develop and commercialize novel second-generation HCV protease inhibitors. Roche will exclusively license ITMN 191 and will have the right to exclusively license further HCV protease inhibitor development candidates resulting from the research collaboration. For ITMN 191, InterMune will conduct phase I studies, and thereafter Roche will lead clinical development and commercialization. Upon closing, InterMune will receive from Roche an upfront payment of $US60 million. In addition, assuming the successful development and commercialization of ITMN 191 in the US and other countries, InterMune could potentially receive up to $US470 million in milestones, including $US35 million within the next 12 months. For ITMN 191, Roche will fund 67% of the global development costs and the companies will co-commercialize the product in the US and share profits on a 50-50 basis. InterMune will receive royalties outside the US. InterMune may opt-out of either co- development or co-commercialization for ITMN 191 in which case InterMune would receive higher royalties on ex-US sales, and royalties instead of profit sharing in the US. The economic terms for ITMN 191 could also apply to additional compounds that InterMune and Roche develop and commercialize. The transaction will close following the expiration or early termination of the waiting period under the Hart-Scott-Rodino Antitrust Improvement Act of 1976, as amended. [9] [10] [11] [12] [13] [14] [15]

In July 2005, InterMune, Inc. and Array BioPharma Inc. extended and expanded their collaboration to discover and develop small molecule inhibitors of the hepatitis C virus (HCV) NS3/4 protease. The program, has produced several candidates that InterMune is advancing toward Investigational New Drug (IND)-enabling studies. Array will continue to conduct process research and cGMP scale-up of drug candidates to support clinical development. Under the terms of the agreement, InterMune will fund drug discovery, preclinical and process development at Array. InterMune maintains responsibility for clinical development and commercialization of the resulting products. Array will be entitled to receive milestone payments, as well as royalties.

In December 2004, Array BioPharma Inc. expanded the intellectual property rights granted to InterMune, Inc. relating to certain compounds discovered under their existing hepatitis C drug discovery collaboration agreement that was established in September 2002. Array will receive a one-time payment of $US2 500 000 from InterMune in exchange for these expanded rights. All other economic terms under this agreement remain unchanged. In addition, under the terms of a new agreement, Array granted InterMune an exclusive option through 31 March 2005 to access Array′s small molecule drug discovery platform for targets of interest to InterMune in hepatology. Should InterMune select a new target, Array would be entitled to receive research funding as well as potential future milestone payments and royalties under this second collaboration.

In November 2004, InterMune, Inc. announced the presentation of preclinical data on the discovery and characterization of a number of potent and selective small molecule inhibitors of the hepatitis C (HCV) NS3/4 protease. These molecules are part of InterMune′s HCV protease inhibitor program. InterMune and Array BioPharma worked in collaboration to discover small molecule inhibitors of the HCV NS3/4 protease. InterMune and Array BioPharma have extended their collaboration, which started in 2002. Under this extension, Array will perform process research and cGMP scale-up through phase I clinical trials of drug candidates resulting from the program. In addition, Array will create second-generation compounds as back-up candidates for the program.

In September 2002, InterMune, Inc. and Array BioPharma Inc. announced a drug discovery collaboration agreement to create small molecule therapeutics targeting hepatitis. InterMune will fund drug discovery research conducted by Array based on the number of Array scientists working on the research phase of the agreement and will be responsible for all development and commercialization. Array will be entitled to receive milestone payments based on the selection and progress of clinical drug candidates, as well as royalties on net sales of products derived from the collaborative efforts. Other terms were not disclosed. [16] [17] [18] [19]

In September 2004, InterMune, Inc. entered into a nonexclusive agreement with Chiron Corporation granting InterMune a license to discover, develop and commercialize small molecule therapeutic agents against certain hepatitis C targets that are covered by patents owned by Chiron. [20] [21]

Key Development Milestones

In June 2018, danoprevir (Ganovo®) was approved and launched by the China Food and Drug Administration (CFDA) for the treatment of viral hepatitis C. The CFDA approval was based on the positive results obtained from the phase III trials [see below]. In December 2016, the company announced that the CFDA accepted the New Drug Application for danoprevir in hepatitis C infections [22] [23] [24] [25] . In September 2018, Ascletis Pharma reported that danoprevir was listed in the Basic Medical Insurance of Tianjin--Capped Reimbursement-Per-Patient Pilot Program to support outpatients with hepatitis C by providing timely access to most innovative treatments and to eliminate hepatitis C in China by 2030 [26] . In October 2018, Ascletis Pharma announced that danoprevir is eligible for Shaoxing government funding subsidy, under which 70% of the DAA expenses will be reimbursed by local government for the HCV patients who are Shaoxing residents and treated at the designated hospitals [27] .

In April 2016, Ascletis received priority review status from China Food and Drug Administration for its interferon-free regimen including danoprevir and ravidasvir in treatment of HCV Genotype 1 patients [28] .

Treatment-naive patients

In May 2017, Ascletis Pharmaceuticals completed a phase III trial that evaluated the safety and efficacy of danoprevir, in combination with Peg-IFN and RBV, in treatment-naive non-cirrhotic patients, who have chronic hepatitis genotype 1 (ASC08201503; NCT03020082). Evaluation of the proportion of participants with sustained virologic response was the primary endpoint of the trial. The open label trial was initiated in June 2016, and enrolled 127 patients in China [29] . Efficacy data from the trial was released in January 2018 [30] .

In June 2016, Ascletis announced that it has initiated clinical trials of its its interferon-free regimen consisting of danoprevir, in combination with ravidasvir, in HCV Genotype 1 patients in Mainland China [28] [31] .

In June 2018, Ascletis completed a phase II/III trial that evaluated the safety and efficacy of danoprevir in combination with ravidasvir [see AdisInsight Drug profile800035127] in treatment naive patients with chronic hepatitis C (ASC-ASC16-II/III-CTP-1-01; NCT03362814). Evaluation of the percentage of participants achieving sustained virologic response and adverse events leading to permanent discontinuation of study drug were the primary endpoints of the trial. The randomised, double blind, placebo control trial was initiated in July 2017, and enrolled 424 patients in China. In November 2018, efficacy results from this trial were released by Ascletis [32] [33] . Additional safety and efficacy results from the trial were presented by Ascletis Bioscience in 69th Annual Meeting of the American Association for the Study of Liver Diseases - 2018 (AASLD-2018) [34] .

In February 2017, Ascletis completed a phase II study that evaluated the efficacy, safety and pharmacokinetics of ritonavir-boosted danoprevir, in combination with Peg-IFN and RBV, in treatment-naive non-cirrhotic patients, who have chronic hepatitis GT1 (ASC08201502; NCT03020004). The trial was initiated in January 2016, and enrolled 70 patients in China [35] .

In February 2017, Ascletis completed the phase II EVEREST study that evaluated the antiviral activity, safety and pharmacokinetics of its interferon free regimen containing danoprevir and ravidasvir, in treatment-naive patients with HCV genotype 1 non-cirrhotic (ASC162001; NCT03020095). The trial was intiated in August 2015 and enrolled 38 patients in Taiwan. In June 2016, Ascletis released interim safety and efficacy data from the EVEREST study that demonstrated the 100% virological response rate (EOT), after 12-week of treatment [28] . The clinical trial application to initiate the trial was approved by the Taiwan Food and Drug Administration (TFDA) in August 2015 [36] [37] . Earlier, in June 2015, Ascletis reported that clinical trial applications for the regimen had been filed and accepted by the China Food and Drug Administration (CFDA) & the TFDA [38] ..

Roche completed a phase IIb study of ritonavir-boosted danoprevir, peginterferon alfa-2a and ribavirin in treatment-naive patients with chronic hepatitis C genotypes 1 and 4, in March 2013 (NCT01220947; EudraCT2010-019584-10; DAUPHINE). The trial enrolled 421 patients in the US, Canada, Austria, Brazil, France, Germany, Italy, Mexico, Puerto Rico, Spain and the UK [39] . Results have been presented [40] .

In July 2012, Roche and InterMune completed a phase IIb clinical trial investigating the efficacy and tolerability of adding danoprevir to standard of care (SOC) therapy (peginterferon alfa-2a plus ribavirin) in patients with chronic HCV genotype 1 infections (NCT00963885; EudraCT2009-009608-38; ATLAS). The trial enrolled 229 patients in the US, Australia, Canada, Austria, France, Germany and Italy. Interim 12-week results were announced in April 2010. In the first part of the trial, patients were randomised to 12 weeks of danoprevir (300 mg tid, 600 mg bid, or 900 mg bid for 12 weeks) followed by 12 weeks of SOC therapy, or SOC therapy for 48 weeks. In part 2, patients were randomised to 24 weeks of triple therapy (danoprevir + standard therapy), or 48 weeks of SOC therapy alone. In November 2009, InterMune announced that three patients in the blinded 900 mg q12h dosage cohort experienced an ACTG Grade 4 elevation in ALT levels, one of whom experienced an elevation of total bilirubin while also receiving concomitant allopurinol. After their review of unblinded data from these patients, the study′s independent Data Monitoring Committee (DMC) recommended that the 900mg q12h cohort be discontinued and that all other cohorts of the study continue [41] [42] [43] [44] [45] [46] .

In November 2013, Roche completed the phase II ANNAPURNA trial of the combination of danoprevir, setrobuvir [see AdisInsight drug profile 800014226], ritonavir and ribavirin, with or without mericitabine [see AdisInsight drug profile 800025214], in patients with HCV genotype 1 infection who were either treatment-naive or had not responded to earlier interferon-based therapy (NP28266; NCT01628094; EudraCT2012-000638-21). The randomised, open-label trial enrolled 110 patients in the US, Australia, Germany, New Zealand and Poland; recruitment was originally initiated in June 2012 [47] .

Roche initiated a phase II clinical trial in March 2011, to assess ritonavir-boosted danoprevir in combination with mericitabine [see separate profile] with and without ribavirin in interferon-naive patients with chronic hepatitis C genotype 1. The randomised, double-blind trial completed enrolment of 170 patients in the US, France, Germany and New Zealand, in March 2012 (INFORM-SVR; NCT01278134; EudraCT2010-022067-35) [48] . The trial was completed in October 2012 and results have been reported [40] .

In February 2010, InterMune announced that given the importance of generating longer-term safety and SVR data for ritonavir-boosted danoprevir in combination with mericitabine, the previously planned INFORM-2 four-week study will not be conducted. This trial was to investigate the efficacy and tolerability of twice-daily dosing with danoprevir or mericitabine, alone and in combination with peginterferon alfa-2a and/or ribavirin, in patients with genotype 1 hepatitis C infections [49] .

InterMune completed a phase Ib trial in Europe of danoprevir monotherapy in 40 treatment-naive patients with HCV genotype 1 infection. The principal goal of the multiple ascending dose trial was to select the range of doses of danoprevir that, when administered in combination with peginterferon alfa-2a (Pegasys®) and ribavirin (Copegus®), would likely offer the optimal protease inhibitor-based triple combination regimen in terms of efficacy, safety and tolerability. Positive results have been reported. Roche has also begun work on a modified-release formulation of danoprevir with the aim of potentially developing a once-daily formulation [50] [51] [52] .

InterMune conducted a 14-day phase Ib trial of danoprevir + standard therapy (peginterferon-alfa-2b + ribavirin) in 50 treatment-naive patients with genotype 1 HCV infections. This randomised trial compared the efficacy, tolerability and pharmacokinetics of different dosing regimens of danoprevir + standard therapy and standard therapy alone. The trial included five cohorts of patients and evaluated both twice daily and three times daily regimens administered with a meal for 14 days, and a single dose on study day 15. Results were reported at EASL 2009 [44] [53] [54] .

In January 2010, Pharmasset, Roche and InterMune completed the INFORM-1 clinical trial in Australia and New Zealand (NCT00801255). This randomised, placebo controlled trial, investigated the efficacy and tolerability of 14 days of combination therapy with danoprevir and mericitabine in patients infected with hepatitis C virus genotype 1. Positive preliminary results have been reported [55] [49] [56] [57] .

COVID-2019-infections

In March 2020, Ascletis Pharmaceuticals initiated a phase IV trial to assess the safety and efficacy of danoprevir in combination with ritonavir in patients with COVID-2019 infections (NCT04345276; ASC-CTP-HS-01). The open-label trial will enroll approximately 40 patients in China [58] .

In February 2020, Ascletis Pharma initiated and dosed first patient in a phase IV trial to evaluate oral danoprevir in combination with ritonavir for the treatment of COVID-2019-infections (ASC-CTP-NC-01; NCT04291729). The non-randomised, open-label clinical trial intends to enrol approximately 50 patients in China. In March 2020, the company announced that total 11 patients (two naive and nine experienced) were enrolled and all of 11 patients were discharged as they are satisfied with the discharge standards. The company released safety and efficacy results of the study in March 2020 [59] [60] [61] [62] .

Treatment-experienced patients

In March 2013, Roche completed a phase II clinical study evaluating the sustained virological response, pharmacokinetics and safety of several combinations of danoprevir/ritonavir with ribavirin plus mericitabine, with or without peginterferon alfa-2a, in patients with hepatitis C genotype 1 who had failed previous standard therapy (NCT01331850; EudraCT2010-019585-90; Matterhorn). Enrolment of 381 patients was completed in the third quarter of 2011, in the US, Canada, Brazil, Mexico, Puerto Rico, Austria, France, Germany, Italy, Poland, Spain, the UK and Australia [63] .

Preliminary, top-line results from two cohorts of the phase Ib, 15-day study of low-dose danoprevir, co-administered with low-dose ritonavir and standard of care (SOC) in patients with chronic HCV showed that the majority of patients given ritonavir with 100mg danoprevir twice-daily or 200mg danoprevir once-daily were HCV RNA negative at the end of therapy. In light of these data, InterMune planned to develop danoprevir in combination with ritonavir [41] . Results of the phase Ib trial presented at the 45th Annual Meeting of the European Association for the Study of the Liver (EASL-2010) confirmed the earlier preliminary results [64] .

A completed phase Ib study investigated the effect of danoprevir monotherapy on insulin sensitivity in 50 treatment-naïve or treatment-experienced (peginterferon/ribavirin) patients with hepatitis C in the US, France and Germany. Results have been reported [65] [66] .

Pharmacokinetic studies

A phase I single-blind pharmacokinetic study was initiated by Roche in July 2012 to examine the pharmacokinetics, tolerability and bioavailability of danoprevir, ritonavir and ciclosporin. The study expected to recruit 29 healthy volunteers (aged 18 to 55 years) in the Netherlands and was scheduled to be completed in early 2013 [67] .

Roche has completed a phase I trial that evaluated the relative bioavailability of danoprevir and ritonavir in healthy volunteers (NP27945; RPU425UD-114254; NCT01483729). This randomised, open-label study involved 36 healthy volunteers and was conducted in New Zealand [68] .

In February 2012, Roche completed a phase I trial to assess the effect of a single dose of danoprevir with low-dose ritonavir on the QC/QTc interval in healthy volunteers (NP25298; EudraCT2011-001413-13; NCT01398293). The randomised, double-blind, double-dummy, placebo-controlled, positive-controlled, 4-way crossover trial enrolled 52 subjects in France [69] .

Roche has completed a phase I trial that evaluated the effect of multiple doses of danoprevir + ritonavir on the steady-state pharmacokinetics of methadone in patients who are on stable methadone maintenance therapy for the treatment of opiate addiction (NP25644; NCT01389544) [70] . Roche has also completed phase I trials that evaluated the interaction between ketoconazole and danoprevir with ritonavir, and ciclosporin and danoprevir with ritonavir, in healthy volunteers (NCT01164488; NCT01514968) [71] . Ongoing phase I trials are investigating the potential interactions of danoprevir when given concomitantly with ritonavir and tenofovir disoproxil fumarate or atazanavir, and when given concomitantly with ritonavir and efavirenz (NCT01592305; NCT1588002) [72] [73] .

Roche has completed a phase I study to evaluate the effect of two different meal types, as well omeprazole and ranitidine, on the pharmacokinetics of danoprevir co-administered with ritonavir (NP25291; NCT01392755). The randomised, open-label study enrolled 32 healthy volunteers in the US [74] .

In February 2014, Roche completed a phase I trial that evaluated the pharmacokinetics of oral danoprevir + ritonavir in healthy subjects and subjects with hepatic impairment (NP25290; NCT01185873). The open-label, non-randomised trial enrolled 81 volunteers in the US, Czech Republic and Slovakia [75] .

Results of a phase I study of ritonavir-boosted danoprevir in healthy volunteers demonstrated that the co-administration of low-dose ritonavir increased danoprevir concentration 12 hours post dose by 18 times, with the effect on Cmin being roughly 6 times and 3 times greater than the effect on Cmax and AUC, respectively. These results guided the selection of the substantially lower doses of danoprevir investigated in the phase Ib multiple ascending dose (MAD) trial in HCV patients, initiated in August 2009 (NP22660; EudraCT2009-012426-36; NCT01185860) [76] . This study was designed to assess the pharmacokinetics, viral kinetics and safety profiles of ascending doses of once-daily and twice-daily danoprevir, co-administered with ritonavir and standard doses of peginterferon-alfa-2a (Pegasys®) and ribavirin (Copegus®) in this patient population. Preliminary results from this study were reported [41] [77] . InterMune stated in April 2010 that it had amended the MAD study to evaluate 12 weeks of low doses of ritonavir-boosted danoprevir plus peginterferon-alfa-2a and ribavirin in non-responders to peginterferon-alfa-2a and ribavirin [78] [45] . This trial enrolled 59 patients in the EU and New Zealand.

InterMune has completed a phase Ia clinical trial of danoprevir in Europe. The double blind, placebo-controlled single ascending dose study evaluated safety, tolerability and pharmacokinetics of danoprevir in 64 healthy individuals. Preliminary results suggested that the drug was well tolerated and safe. Pharmacokinetic results of this trial have been reported [51] [79] [80] .

Danoprevir has demonstrated potency against mutant HCV strains. Preclinical data that examined potency and binding kinetics of the drug showed that it binds to the NS3/4A protease complex in a two-step binding mechanism: an initial collision complex association and a subsequent long-lived non-covalent drug-target complex [81] [82] .

Promising results of in vitro studies of the combination of danoprevir with the HCV polymerase inhibitors, mericitabine and balapiravir have been reported [51] .

A 13-week chronic toxicology study in monkeys has been successfully completed, to support the intended longer duration of dosing of danoprevir planned in the phase II clinical development programme that is to be conducted by Roche [52] . In the second quarter of 2009, InterMune also completed 6-month and 9-month chronic toxicology studies in rats and monkeys [56] .

Patent Information

In February 2009, InterMune was issued US Patent 7 491 794, which is a composition of matter patent that covers danoprevir. The nominal 20-year patent term extends to 13 October 2024 [83] .

Drug Properties & Chemical Synopsis

  • Route of administration IV, PO
  • Formulation Tablet, unspecified
  • Class Antivirals, Carboxylic acids, Cyclopropanes, Isoindoles, Macrocyclic compounds, Pyrrolidines, Small molecules, Sulfonamides
  • Target Hepatitis C virus NS3 protein; Hepatitis C virus NS4 protein
  • Mechanism of Action Hepatitis C virus NS3 protein inhibitors; Hepatitis C virus NS4 protein inhibitors
  • WHO ATC code

    J05A-E (Protease inhibitors)

  • EPhMRA code

    J5B1 (Viral hepatitis products)

  • Chemical name 4-Fluoro-2,3-dihydro-1H-isoindole-2-carboxylic acid (2R,6S,12Z,13aS,14aR,16aS)-6-(tert-butoxycarbonylamino)-14a-[N-(cyclopropylsulfonyl)carbamoyl]-5,16-dioxo-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]-diaza-cyclopentadecin-2-yl ester
  • Molecular formula C35 H46 F N5 O9 S
  • SMILES C1C=C2CN(CC2=C(C=1)F)C(OC1CC2N(C1)C(C(NC(OC(C)(C)C)=O)CCCCCC=CC1C(C1)(NC2=O)C(=O)NS(C1CC1)(=O)=O)=O)=O
  • Chemical Structure
  • CAS Registry Number 850876-88-9

Biomarkers Sourced From Trials

Indication Biomarker Function Biomarker Name Number of Trials

hepatitis C

Outcome Measure

cytochrome P450 family 4 subfamily F member 3

1

Biomarker

Drug Name Biomarker Name Biomarker Function
Danoprevir - Array BioPharma/Roche/Ascletis cytochrome P450 family 4 subfamily F member 3 Outcome Measure
For more detail, check out BiomarkerBase: the leading source of information about biomarkers used in drug development and diagnostic tests, tracking a comprehensive list of biomarker uses worldwide by over 800 companies

Development Status

Summary Table

Indication Qualifier Patient Segment Phase Countries Route / Formulation Developers Event Date
COVID 2019 infections in combination with ritonavir Combination therapy, Treatment-naive Clinical Phase Unknown China PO / Tablet Ascletis 17 Feb 2020
COVID 2019 infections in combination with ritonavir Combination therapy, Treatment-experienced Clinical Phase Unknown China PO / Tablet Ascletis 17 Feb 2020
Hepatitis C - Combination therapy, Treatment-naive Marketed China PO / unspecified Ascletis 27 Jun 2018
Hepatitis C - Combination therapy, Treatment-naive Phase II Taiwan PO / unspecified Ascletis 23 Jun 2016
Hepatitis C - Combination therapy, Treatment-naive Phase II Australia, Austria, Brazil, Canada, France, Germany, Italy, Mexico, New Zealand, Poland, Puerto Rico, Spain, USA, United Kingdom PO / Tablet Roche 30 Jun 2012
Hepatitis C - Combination therapy, Treatment-experienced Phase II Australia, Austria, Brazil, Canada, France, Germany, Italy, Mexico, Poland, Puerto Rico, Spain, USA, United Kingdom PO / Tablet Roche 31 May 2011
Hepatitis C - In volunteers No development reported (I) Czech Republic, Slovakia PO / unspecified Roche 28 Mar 2018
Hepatitis C - In volunteers Discontinued (I) Netherlands IV / unspecified Roche 19 Jun 2018

Commercial Information

Involved Organisations

Organisation Involvement Countries
Array BioPharma Originator USA
InterMune Originator USA
Array BioPharma Owner USA
Roche Owner Switzerland
CR Pharmaceutical Market Licensee Hong-Kong
Ascletis Licensee China, Hong Kong, Macau, Taiwan
Novartis Technology Provider Switzerland

Brand Names

Brand Name Organisations Indications Countries
Ganovo Ascletis Hepatitis C China

Credit Suisse Market Status

Indication Region Company Phase Expected Launch Year Probability of Success% Patent Expiry Year Expected Generic Entry Last Update
Hepatitis C Wrld (25% US) - II-b 2021 20 - 01 Jan 2029 02 Apr 2020

Credit Suisse Financial Forecast

Indication Region 2016 2017 2018 2019 2020 2021 2022 2023 2024 2025 Last Update
Hepatitis C Wrld (25% US) 0 0 0 0 0 25 75 0 0 0 02 Apr 2020
Total 0 0 0 0 0 25 75 0 0 0

Scientific Summary

  • Adverse Events Occasional: Gastrointestinal disorders; Neutropenia

Pharmacokinetics

Clinical

In a phase Ib study in 40 patients with hepatitis C infection, AUC0-24 , Cmax , and Cmin values for danoprevir at 200mg every 8h were 500 ng h/mL, 91 ng/mL and 2.78 ng/mL, respectively. The dose-exposure relationship was not uniformly proportional [92] .

In a phase 1b multiple-ascending-dose (up to 600mg daily) study, the pharmacokinetics of danoprevir were more than dose proportional at higher doses [51] .

In the INFORM-1 phase I trial in patients with hepatitis C virus infection, the pharmacokinetics of RG 7128 and danoprevir did not change when combined.The median α-half-life and β phase slopes for danoprevir added to either RG 7128 or standard of care yielded similar profiles [88] .

In a phase 1a single-ascending-dose study in healthy volunteers, the pharmacokinetics of danoprevir were linear over the dose-range of 100mg to 800mg. When the drug was given with food, the trough and area under the curve (AUC) increased 40-50% compared with that given without food [51] .

Preclinical

In vivo

studies revealed favourable high liver exposures of danoprevir across multiple species (rats, dogs, monkeys) at potentially clinically relevant dosing concentrations. In Sprague-Dawley rats, modest structural changes following a single oral dose of danoprevir resulted in large exposure differences in compound ratios between the liver, plasma and heart. Danoprevir resulted in an average liver Cmax of 3098-fold the replicon EC90 value, and much lower exposures in plasma (10-fold less) and the heart (50-fold less). Following a 7-day, oral twice-daily dosing regimen of 30 mg/kg in rats, average danoprevir concentrations in liver at apparent Cmax and trough were 1646-fold and 152-fold the EC90 value, respectively, after the last dose on day 7. Following a similar 7-day oral regimen in dogs (15 mg/kg dose), average danoprevir concentrations in the liver at apparent Cmax and trough were 3048-fold and 158-fold the EC90 value, respectively, after the last dose. The same dosing regimen in monkeys resulted in danoprevir liver concentrations at apparent Cmax and trough were 238-fold and 52-fold the EC90 value, respectively, after the last dose. Liver : plasma ratios of the drug were 2.4 : 1 in rats, 51 : 1 in dogs, and 70 : 1 in monkeys. These results supported the exploration of twice-daily, oral dosing of danoprevir for the treatment of chronic HCV infection [97] [98] .

Adverse Events

Clinical

Results from a clinical study for danoprevir for treatment of COVID-2019 demonstrated safety and was well tolerated. The trial enrolled eleven patients [59] [62] .

Phase II/III:

In a phase II/III trial, administration of ravidasvir in combination with danoprevir was well tolerated. One patient discontinued treatment due to allergy and death of one patient was not related to the treatment. TEAEs were not observed. Grade 1 to grade 2 of abnormal liver function tests were observed. Grade 3 and above AEs were 11% (35/318) and 8% (9/106) in treatment, versus placebo group [34] [33] .

Phase II

an interim 12-week safety analysis showed that serious adverse events were generally balanced across all treatment groups in an ongoing phase IIb trial in which danoprevir + peginterferon alfa-2a + ribavirin was compared with peginterferon alfa-2a + ribavirin alone, when administered as first-line therapy in patients with genotype 1 hepatitis C. In the randomised, double-blind, multicentre, parallel trial, 232 such patients receiving peginterferon alfa-2a + ribavirin received additional therapy with danoprevir 300mg three times daily, 600mg twice daily, or 900mg twice daily, or placebo. The incidence of treatment-emergent grade 4 (>10 times the upper limit of normal) elevations in ALT was 0%, 1%, 6% and 0% in patients receiving danoprevir 300mg three times daily, 600mg twice daily, 900mg twice daily and placebo, respectively. In danoprevir recipients, discontinuation of drug treatment reversed the elevations in ALT. Drug dosing was stopped in the danoprevir 900mg twice daily arm based on this safety signal. Treatment-emergent grade 3 or 4 neutropenia was noted in 24%, 25%, 31% and 16% of patients receiving danoprevir 300mg three times daily, 600mg twice daily, 900mg twice daily and placebo, respectively. The incidence of rash and anaemia was similar across all treatment groups [45] .

Interim results from the phase II EVEREST study demonstrate that danoprevir in combination with ravidasvir was found to be safe in treatment-naive Chinese HCV Genotype 1 non-cirrhotic patients [28] [37] .

Ritonavir-boosted danoprevir 200mg, 100mg, or 50mg for 24 weeks was generally well tolerated when given in combination with peginterferon alfa-2a + ribavirin in the phase IIb, randomised, DAUPHINE trial being conducted in 421 treatment-naive hepatitis C patients with genotype 1 or 4 infection [40] .

Ritonavir-boosted danoprevir + ribavirin + mericitabine was well tolerated and not associated with treatment-emergent liver toxicities, neutropenia, or any new safety signals in 169 treatment-naive patients with genotype 1 hepatitis C infection participating in the randomised phase IIb INFORM-SVR trial [40] .

Phase I

danoprevir was generally safe and well tolerated in a phase Ib study of the drug in combination with peginterferon alfa-2a and ribavirin in treatment-naive patients with HCV genotype 1 infection. No serious adverse events (SAE) or Grade 4 adverse events (AEs) were reported during treatment with danoprevir. AEs observed for both danoprevir and placebo groups were predominantly mild to moderate in severity, and were similar to the AE profile of standard of care. No AEs led to treatment discontinuation. There were four Grade 3 AEs during study treatment, two of which (sciatica and back pain) were considered unrelated to treatment. The other two were neutropenia and indirect bilirubin elevation. Neutropenia occurred in similar frequency and severity in both the placebo and the danoprevir groups. Minor and transient elevations in indirect bilirubin levels were observed in a small number of placebo and danoprevir-treated patients and were considered to be not clinically significant. No other laboratory or ECG findings during the study treatment were attributable to danoprevir [44] [50] [53] .

Top-line data from a European phase Ib study of danoprevir monotherapy in approximately 40 treatment-naive patients with HCV genotype 1 infection showed that up to a total daily dose of 600mg, danoprevir was safe and well tolerated. No serious adverse events were reported and no patient discontinued the study due to an adverse event. Adverse events in this phase Ib trial were generally mild and transient in nature [51] [52] .

Results from a phase Ia trial in 64 healthy volunteers showed that a range of doses from 2mg to 1600mg of danoprevir were well tolerated with no serious adverse events. The most common adverse events were mild and were gastrointestinal-related. A higher frequency of mild and transient diarrhoea and abdominal pain occurred with the highest dosing (1600mg). There were no clinically significant laboratory abnormalities [51] [80] .

Preliminary results from a phase I trial (INFORM-1) in HCV-infected adults showed that the combination of RG 7128 and danoprevir appeared to be safe and well-tolerated for 14 days. There were no treatment-related serious adverse events, dose modifications, or discontinuations [57] [90] . According to updated results from this trial, RG 7128 and danoprevir were not associated with treatment-emergent resistance [49] .

Pharmacodynamics

Summary

Clinical

In a subset of 40 patients who received danoprevir monotherapy, 14 experienced viral rebound. Analysis of NS3 isolated from rebound patients showed that all carried R155K substitution at end of treatment; three had drug-resistant viral variants at day 3 or day 7. In patients apparently lacking substitutions by population analysis, some carried variants of <7% at day 3 or day 7. The incidence of rebound in subtype 1b (n = 4) was lower than in subtype 1a (n = 10). Median time from start of therapy to viral load increase of 0.5 log10 IU/mL above nadir was similar in subtypes 1a and 1b (eight days, 2h vs seven days, 4h, respectively). With the exception of one patient, clonal sequencing did not indicate single nucleotide substitutions as intermediates of the doubly substituted codon required for R155K in subtype 1b [86] .

In the INFORM-1 phase I trial, baseline NS3/4A and NS5B sequence was determined for all patients with hepatitis C virus infection. Population, clonal sequence and phenotypic analysis for cohort A were performed at day 4 of danoprevir monotherapy and at day 7 of RG 7128/danoprevir combination therapy. For cohorts B-D wherein patients received a 14-day combination therapy, analyses were performed on any patient that experienced viral load rebound. In cohort A, no evidence of viral resistance was seen. In cohorts B-D, one patient had a 1.4 log10 IU/mL increase in viral load from nadir. There was no evidence of danoprevir resistance following sequence and phenotypic analysis of the NS3 region. Viral load for this patient was undetectable after 12 weeks of standard of care. Baseline population sequence of one patient who received RG 7128/danoprevir showed the presence of E168 in NS3; an amino acid associated with danoprevir resistance. This patient achieved a continuous viral load reduction on RG 7128/danoprevir treatment (viral load of 139 IU/mL at day 14 ) [87] .

In the INFORM-1 phase I trial in patients with hepatitis C virus infection, with either RG 7128 (r2 = 0.92) or standard of care [SOC] (r2 = 0.85), an Emax PK/PD model of danoprevir Cmin versus D14 log10 HCV RNA change from baseline fit the data well for danoprevir. In patients on combination therapy, those with danoprevir Cmin > 0.5 ng/mL, had similar antiviral responses with either 500 or 1000mg RG 7128 (D14 median HCVRNA change = –5.1 log10 IU/mL.). In patients with danoprevir Cmin < 0.5 ng/mL, those who received RG 7128 500mg achieved a median HCV RNA change of –3.5 log10 IU/mL versus –4.8 with those who received 1000mg [88] .

In a phase I study in patients with chronically infected hepatitis C virus genotype 1, treatment with danoprevir resulted in a significant reduction in circulating IP 10 levels, which correlated with the magnitude and kinetics of changes in viral load. The antiviral effect of danoprevir also led to a reduction in neopterin, a circulating biomarker of liver inflammation. In the study, treatment-naive subjects and previous non-responders received danoprevir for 14 days [84] .

Preclinical

The combination of danoprevir with the active moiety of polymerase inhibitors RG 7128 or balapiravir significantly enhanced clearance of the HCV replicon (14-day replicon clearance assay) and reduced or suppressed the emergence of drug-resistant viral variants (3-week colony formation assay model) [51] .

Peginterferon alfa-2a greatly improved danoprevir potency in vitro in two replicon systems. Furthermore, one of the replicon systems (which had reduced sensitivity to danoprevir) demonstrated hypersensitivity to peginterferon alfa-2a [96] .

In an in vitro study, the combination of danoprevir with ITMN 8020 (an allosteric inhibitor of the HCV NS5B polymerase) enhanced antiviral activity and suppression of drug-resistant variants of hepatitis C virus. In the HCV clearance assay, cells containing an HCV genotype-1b replicon were treated for two weeks with danoprevir, ITMN 8020, or a combination of the agents in the absence of G418 selection for replicon retention. In the colony formation assay, cells were treated with danoprevir at nearly 1.1, 11, or 17 times its EC50 either alone or in combination with ITMN 8020 at nearly 1, 10, or 15 times its EC50. In an HCV clearance assay, danoprevir at 15 times its EC50 eliminated HCV replicon in the absence of G418 selective pressure for replicon retention; ITMN 8020 at 15 times its EC50 did not. There was replicon clearance with the addition of danoprevir (at 1.9 times its EC50) plus ITMN 8020 (at 15 times its EC50). In the colony formation assay in the presence of G418 selective pressure for replicon retention, ITMN 8020 (at 15 times its EC50) reduced but failed to eliminate cell colonies resulting from HCV replicon persistence. However, addition of danoprevir (at 11 times its EC50) prevented formation of any cell colonies, suggesting the combined antiviral effects of danoprevir and ITMN 8020 forced replicon elimination in a dose-dependent manner [91] .

In an in vitro model of hepatitis C, danoprevir alone and in combination with peginterferon alfa-2a resulted in complete and durable clearance of replicon RNA after a 14-day treatment at a level of 45nM. The NS3 replicon underwent dynamic changes when exposed to increasing concentrations of danoprevir [95] .

Antimicrobial Activity

Summary

Danoprevir demonstrated potency in biochemical and replicon assays, with EC50 value of < 2 nmol/L. In the A156S NS3/4 protease-resistant mutant, danoprevir had an IC50 value of 2.4 nmol/L, 1000-fold more potent than VX 950. For the D168V mutation, conferring resistance to BILN 2061, danoprevir demonstrated an EC50 value of < 2 nmol/L, against the D168V NS3/4 protease [99] .

Danoprevir retained activity against variants that exhibited reduced sensitivity to other experimental HCV protease inhibitors in development. A single variant with reduced sensitivity to other HCV protease inhibitors also showed diminished potency to danoprevir. These factors contribute to the compound's favourable cross-resistance profile. Tight binding between danoprevir and the HCV protease has been credited for the experimentally observed high potency of danoprevir and activity against variants of the protease that are resistant to other HCV protease inhibitors [98] .

The antiviral activity of danoprevir was studied in vitro in combination with Roche's hepatitis C NS5B polymerase inhibitor R 1479. The antiviral activity of both compounds was enhanced when used in combination [95] .

Preclinical data that examined potency and binding kinetics of the drug showed a biochemical potency of 36pM [81] .

Data from a study evaluating the biochemical potencies and inhibition kinetics of danoprevir against proteases from multiple HCV genotypes have shown that danoprevir was bound to the majority of HCV NS3/4A protease 1-6 genotypes. Its proposed binding through a two-step mechanism, similar to that proposed for a replicon-derived protease sequence, included formation of an initial complex with NS3/4A with a subsequent isomerisation to a more stable complex from which danoprevir dissociated slowly. The IC50 values for genotype 1a, 1b, 4, 5 and 6 proteases were similar to the IC50 value of 0.8 nmol/L, previously obtained in replicon-derived protease assays. In the enzyme-inhibitor complex activity assays, all tested proteases showed slow dissociation of danoprevir, except of genotype 3a [94] .

Drug Interactions

Summary

Ritonavir 100mg twice daily increased AUC0-∞, Cmax and C12h values of danoprevir by 5.69-fold, 3.14-fold and 50.6-fold, respectively in a single center, open-label, phase I study in 14 (12 completed) healthy volunteers. Multiple dosing of ritonavir for 10 days similarly increased AUC0-∞, Cmax and C12h values by 5.46-fold, 3.19-fold and 26.9-fold, respectively. Danoprevir dose and dosing frequency can be potentially reduced when co-administered with ritonavir thus allowing to achieve a high Cmin values while providing similar or lower AUC and Cmax values compared with unboosted regimen [85] .

Therapeutic Trials

Clinical

Results from a clinical study for danoprevir in treatment of COVID-2019 demonstrated normal body temperature for at least 3 days, significantly improved respiratory symptoms, lung imaging showing obvious absorption and recovery of acute exudative lesion; and two consecutive RT-PCR negative tests of SARS-CoV-2 nucleotide acid (respiratory track sampling with interval at least one day). After initiation of danoprevir/ritonavir treatment, the first negative RT-PCR test occurred at a median of two days, ranging from one to eight days, and the obvious absorption in CT scans occurred at a median three days, ranging from two to four days. The trial enrolled eleven patients [59] [62] .

Phase III

Results from a phase III trial in patients with hepatitis C showed that danoprevir achieved a cure rate of 97% within 3 months of treatment compared with a success rate of 60% after 12-18 months of treatment with Peg-IFN + ribavirin [30] [29] .

In a phase II/III trial, administration of ravidasvir in combination with danoprevir resulted in a 99% (306/309, 95%CI :97.19%-99.80%,PPS) and 96% (306/318, 95%CI : 93.50%-98.04%,ITT) SVR12 after 12 weeks. In patients with baseline NS5A resistance mutations, the combination therapy displayed a cure rate of 100% (SVR12). The trial enrolled a total of 424 patients [34] [32] [33] .

Phase II

interim 12-week results of an ongoing phase IIb trial showed that the addition of danoprevir to peginterferon alfa-2a + ribavirin was associated with a higher early virological response rate versus peginterferon alfa-2a + ribavirin alone, when administered as first-line therapy in patients with genotype 1 hepatitis C. In the double-blind, multicentre, parallel trial, 232 such patients receiving peginterferon alfa-2a + ribavirin were randomised to receive additional therapy with danoprevir 300mg three times daily, 600mg twice daily, or 900mg twice daily, or placebo. However, 13 patients who were originally randomised to receive danoprevir 900mg twice daily but had not received the study drug were later re-randomised to the other dose groups and were not included in the efficacy analysis. The efficacy analysis population included a total of 212 patients. At week 12, undetectable virological response rates were 88%, 89%, and 92% in recipients of peginterferon alfa-2a + ribavirin + danoprevir 300mg three times daily, 600mg twice daily and 900mg twice daily, respectively, versus 43% with peginterferon alfa-2a + ribavirin + placebo [45] .

Interim results from the phase II EVEREST study of danoprevir plus ravidasvir in treatment-naive Chinese HCV Gentoype I non-cirrhotic patients demonstrated a virological response rate (EOT) of 100%. The data was reported in 38 patients [28] [37] .

Ritonavir-boosted danoprevir 200mg, 100mg, or 50mg for 24 weeks was associated with 12-week sustained virological response rates (SVR12) of 93%, 83%, and 67%, respectively, in patients with genotype 1 hepatitis C while the combination was associated with SVR12 of 100% in patients with genotype 4 hepatitis C. In a group receiving response-guided therapy, an SVR12 rate of 74% was achieved with 12 weeks of danoprevir 100mg with rates of up to 90% and 97% in patients with genotype 1a, the most difficult-to-treat viral subtype, and genotype 1b infection. All patients (n=421) in the randomised, phase IIb DAUPHINE trial received peginterferon alfa-2a + ribavirin in addition to their assigned treatments [40] .

Ritonavir-boosted danoprevir + ribavirin + mericitabine for 24 weeks was associated with an SVR12 of 71% in 169 treatment-naive patients with genotype 1 hepatitis C infection participating in the randomised phase IIb INFORM-SVR trial. While on treatment, the incidence of viral breakthrough was low and viral suppression was high. This benefit, however, was not maintained off treatment in the majority of genotype 1a patients leading to an SVR12 of 26% [40] .

Phase I

the majority of treatment-naive patients with HCV infection achieved an undetectable level of HCV RNA after 15 days of treatment with danoprevir plus ritonavir and standard of care (SOC) in a phase Ib trial. The study evaluated low doses of once-daily (200mg) and twice-daily (100 and 200mg) danoprevir co-administered with low-dose ritonavir plus SOC [41] . The change from baseline at day 15 in median HCV RNA log10 was −5.13 and −4.80 in patients receiving danoprevir + ritonavir 100mg + 100mg twice daily (n = 9) and 200mg + 100mg once daily (n = 6), respectively. There was no viral load rebound in either group [64] .

In a phase I trial of patients with HCV infection who received danoprevir as monotherapy (n = 40), those infected with genotype 1b experienced less breakthrough than those with genotype-1a (4/24 vs. 10/16, respectively). The breakthrough was appeared to be associated with the occurrence of R155K and was not observed in either genotype when danoprevir was combined with standard of care [89] .

Data from a phase Ib study of danoprevir plus peginterferon alfa-2a and ribavirin in treatment-naive patients infected with HCV genotype 1 showed reductions in median HCV RNA of 5.4 log10 IU/mL and 5.7 log10 IU/mL from baseline after 14 days of treatment in the best performing cohorts who were given the triple combination every 12h (q12h) and every 8h (q8h), respectively. In all cohorts, HCV RNA was below the limit of quantification in 71% (32 of 45) of patients who received treatment with danoprevir for 14 days. Reductions in HCV RNA occurred rapidly in all q12h and q8h cohorts, and there was no evidence of viral rebound during the treatment [50] [53] .

Preliminary results from a phase I trial (INFORM-1) showed that the combination of RG 7128 and danoprevir provided significant antiviral potency and suppressed viral rebound. In the randomised, double-blind, ascending-dose trial, patients with HCV infection received the combination treatment for 14 days and did not receive pegylated interferon or ribavirin. At the highest drug doses tested, the median reduction in viral levels was −4.8 to −5.2 log10 IU/mL. The proportion of patients with viral levels lowered below 40 IU/mL during the dosing period was ≈63%. After 14 days, 25% of patients receiving the highest drug doses tested showed blood viral levels of <15 IU/mL. After 3 days' treatment with a low dose of the combination therapy, the mean reduction in viral load levels (−2.9 log10 IU/mL) was greater by 0.6 log10 IU/mL than that seen with single-agent administration (−0.46 log10 IU/mL and −1.84 log10 IU/mL for RG 7128 and danoprevir, respectively) [57] [90] .

In INFORM-1 trial, 13 days treatment with danoprevir (900mg, bid) + RG 7128 (1000mg, bid) enhanced the efficacy of subsequent standard of care (SOC; peginterferon + ribavirin). The highest effect was seen in treatment naive patients; the week 4 rapid virologic response (RVR) and week 12 complete early virologic response (cEVR) rates during SOC were 88% and 86% of patients, respectively, in this group. The combination reduced the HCV RNA below the lower limit of quantification (LLOQ; <43 IU/mL) in 88% of treatment-naive patients, and HCV RNA below the lower limit of detection (LLOD; <15 IU/mL) in 63% of treatment-naive patients. The percentages of null-responders with HCV RNA below the LLOQ and LLOD were 50% and 25%, respectively; null responders were defined as patients with HCV RNA reduction <1 log10 IU/mL in 4 weeks, or <2 log10 IU/mL in 12 weeks of prior treatment with pegylated interferon + ribavirin. Following treatment with RG 7128 (1000mg, bid) and danoprevir (600mg, bid), the proportions of treatment-experienced patients with HCV RNA below the LLOQ and LLOD were 50% and 13%, respectively. Twice daily treatment was associated with a continual decline in HCV RNA during the study period; during the second phase, viral decline displayed a biphasic pattern with the rate of decline similar to that observed when a single direct acting antiviral is added to pegylated interferon + ribavirin [55] [49] .

Top-line data from a European phase Ib study of danoprevir monotherapy in approximately 40 treatment-naive patients with HCV genotype 1 infection have shown that administration of danoprevir resulted in rapid and significant reductions in HCV RNA. Patients were treated among four cohorts in which they received danoprevir gelatin capsules with food in the following doses: (i) 100mg every 12 hours (total daily dose 200mg); (ii) 100mg every 8 hours (total daily dose 300mg); (iii) 200mg every 12 hours (total daily dose 400mg); and (iv) 200mg every 8 hours (total daily dose 600mg). The mean maximum reduction in HCV RNA in the corresponding four cohorts were 1.6 log10 IU/mL (97.49%), 2.6 log10 IU/mL (99.75%), 3.4 log10 IU/mL (99.96%) and 3.9 log10 IU/mL (99.99%), respectively. The day 14 median reductions in HCV RNA were 0.7 log10 IU/mL (80.05%) in the 100mg every 12 hours cohort, 1.7 log10 IU/mL (98.01%) in the 100mg every 8 hours cohort, 3.1 log10 IU/mL (99.92%) in the 200mg every 12 hours cohort, and 3.8 log10 IU/mL (99.98%) in the 200mg every 8 hours cohort. In an exploratory cohort of refractory patients (who had failed to achieve a 2.0 log10 reduction in HCV RNA with prior standard-of-care treatment or had detectable HCV RNA after 24 weeks of treatment), treatment with danoprevir 300mg every 12 hours resulted in a median reduction of 2.5 log10 in HCV RNA on day 14. Data from this trial were to be used to determine the danoprevir doses to be used in a triple combination regimen with peginterferon alfa-2a (Pegasys®) and ribavirin (Copegus®) [51] [52] [93] .

Development History

Event Date Update Type Comment
02 Apr 2020 Financial Update Credit Suisse financial data update Updated 11 Apr 2020
24 Mar 2020 Scientific Update Safety and efficacy data from clinical trial in COVID-2019 infections released by Ascletis Pharma [59] Updated 27 Mar 2020
18 Mar 2020 Trial Update Ascletis Pharmaceutical initiates phase IV trial for COVID-2019 infections (Combination therapy) in China (PO) (NCT04345276) Updated 16 Apr 2020
17 Feb 2020 Phase Change - Clinical Clinical trials in COVID-2019 infections (Combination therapy, Treatment-experienced) in China (PO) (NCT04291729) [59] Updated 27 Mar 2020
17 Feb 2020 Phase Change - Clinical Clinical trials in COVID-2019-infections (Combination therapy, Treatment-naive) in China (PO) [61] Updated 02 Mar 2020
30 Jul 2019 Company Involvement Array BioPharma has been acquired by Pfizer Updated 02 Aug 2019
09 Nov 2018 Scientific Update Efficacy and adverse events data from a a phase II/III trial in Hepatitis C (Combination therapy, Treatment naive) presented at the 69th Annual Meeting of the American Association for the Study of Liver Diseases (AASLD-2018) [34] Updated 06 Dec 2018
05 Nov 2018 Scientific Update Efficacy data from a phase II/III trial in Hepatitis C released by Ascletis [32] Updated 13 Nov 2018
27 Jun 2018 Phase Change - Marketed Launched for Hepatitis C (Combination therapy, Treatment-naive) in China (PO) [23] [22] Updated 02 Aug 2018
26 Jun 2018 Licensing Status Ascletis and CR Pharmaceutical agree to co-promote danoprevir for Hepatitis C [4] Updated 02 Jul 2018
26 Jun 2018 Regulatory Status Ascletis announces intention to launch Danoprevir [4] Updated 02 Jul 2018
24 Jun 2018 Biomarker Update Biomarkers information updated Updated 31 Aug 2018
19 Jun 2018 Phase Change - Discontinued(I) Discontinued - Phase-I for Hepatitis C (In volunteers) in Netherlands (IV) Updated 19 Jun 2018
12 Jun 2018 Phase Change - Registered Registered for Hepatitis C (Combination therapy, Treatment-naive) in China (PO) - First Global Approval [24] Updated 13 Jun 2018
01 Jun 2018 Trial Update Ascletis Pharmaceuticals completes a phase II/III trial in Hepatitis C (Combination therapy, Treatment naive) in China (NCT03362814) [24] Updated 28 Jun 2018
28 Mar 2018 Phase Change - No development reported No recent reports of development identified for phase-I development in Hepatitis-C(In volunteers) in Czech Republic (PO) Updated 28 Mar 2018
28 Mar 2018 Phase Change - No development reported No recent reports of development identified for phase-I development in Hepatitis-C(In volunteers) in Netherlands (IV) Updated 28 Mar 2018
28 Mar 2018 Phase Change - No development reported No recent reports of development identified for phase-I development in Hepatitis-C(In volunteers) in Slovakia (PO) Updated 28 Mar 2018
11 Jan 2018 Scientific Update Efficacy data from a phase III trial in Hepatitis C released by Ascletis [30] Updated 27 Feb 2018
01 Jul 2017 Trial Update Ascletis Pharmaceuticals initiates enrolment in a phase II/III trial in Hepatitis C (Combination therapy, Treatment naive) in China (NCT03362814) Updated 11 Dec 2017
01 May 2017 Trial Update Ascletis Pharmaceuticals completes a phase III trial for Hepatitis C (Combination therapy; Treatment-naive) in China (NCT03020082) Updated 12 Jul 2017
01 Feb 2017 Trial Update Ascletis completes the phase II EVEREST trial in Hepatitis C (Combination therapy; Treatment-naive) in Taiwan (NCT03020095) Updated 12 Jul 2017
01 Feb 2017 Trial Update Ascletis Pharmaceuticals completes a phase II trial for Hepatitis C (Combination therapy; Treatment-naive) in China (NCT03020004) Updated 12 Jul 2017
27 Dec 2016 Phase Change - Preregistration Preregistration for Hepatitis C (Combination therapy, Treatment-naive) in China (PO) [25] Updated 03 Jan 2017
27 Dec 2016 Regulatory Status China FDA accepts NDA for danoprevir in Hepatitis C [25] Updated 02 Jan 2017
21 Jun 2016 Trial Update Ascletis Pharmaceuticals initiates enrolment in clinical trials for Hepatitis C (Combination therapy; Treatment-naive, Interferon-free regimen) in Mainland China [28] Updated 19 Jun 2018
21 Jun 2016 Scientific Update Interim safety and efficacy data from a phase II EVEREST trial in Chronic hepatitis C released by Ascletis [28] Updated 27 Jun 2016
01 Jun 2016 Phase Change - III Phase-III trials in Hepatitis C (Treatment-naive, Combination therapy) in China (PO) (NCT03020082) (Ascletis and Array BioPharma pipeline, December 2016) Updated 24 Jun 2016
01 Apr 2016 Regulatory Status Danoprevir and ravidasvir combination receives priority review status for Hepatitis B genotype I in China [28] Updated 04 Jul 2016
07 Mar 2016 Active Status Review Phase-II development is ongoing in USA, Puerto Rico, Australia, Brazil, Canada, Mexico, New Zealand and European Union (PO) Updated 07 Mar 2016
01 Jan 2016 Trial Update Ascletis Pharmaceuticals initiates enrolment in a phase II trial for Hepatitis C (Combination therapy; Treatment-naive) in China (NCT03020004) Updated 12 Jul 2017
31 Aug 2015 Phase Change - II Phase-II clinical trials in Hepatitis C (Treatment-naive, Combination therapy) in Taiwan (PO) before June 2016 [28] (NCT03020095) Updated 24 Jun 2016
30 Aug 2015 Regulatory Status Taiwan Food and Drug Administration approves Clinical Trial Application to initiate a phase II trial for interferon free regimen comprising danoprevir and ravidasvir in Hepatitis C [36] Updated 04 Sep 2015
30 Aug 2015 Trial Update Ascletis plans to initiate the phase II EVEREST trial for Hepatitis C (Combination therapy; Treatment-naive) in Taiwan [36] Updated 04 Sep 2015
24 Jun 2015 Regulatory Status China Food and Drug Administration & Taiwan Food and Drug Administration accepts Clinical Trial Applications for interferon free regimen comprising danoprevir and ravidasvir in Hepatitis C [38] Updated 25 Jun 2015
29 Sep 2014 Company Involvement InterMune has been acquired by Roche Updated 29 Oct 2014
01 Feb 2014 Trial Update Roche completes a phase I trial in healthy volunteers in the Czech Republic and Slovakia (NCT01185873) Updated 13 Aug 2012
30 Nov 2013 Trial Update Roche completes the phase II ANNAPURNA trial for Hepatitis C (treatment-naive, combination therapy) in USA, Australia, Germany, New Zealand and Poland (NCT01628094) Updated 11 Feb 2014
15 Apr 2013 Licensing Status Danoprevir licensed to Ascletis in China, Taiwan, Hong Kong and Macau for Hepatitis C [8] Updated 17 Apr 2013
01 Jan 2013 Trial Update Roche completes the phase II Matterhorn trial in Hepatitis C (treatment-experienced, combination therapy) in the US, Australia, Brazil, Canada, Mexico, Puerto Rico, Spain, Austria, France, Germany, Italy, Poland, Spain and the UK (NCT01331850) Updated 17 Apr 2013
01 Dec 2012 Trial Update Roche completes a Phase II trial in Hepatitis C (treatment-naive, combination therapy) in the US, Canada, Austria, Brazil, France, Germany, Italy, Mexico, Puerto Rico, Spain and the UK (NCT01220947) Updated 17 Apr 2013
01 Oct 2012 Trial Update Roche completes the phase II INFORM-SVR trial for Hepatitis C (combination therapy, Treatment-Naive) in USA, France, Germany and New Zealand (NCT01278134) Updated 19 Jun 2018
31 Jul 2012 Phase Change - I Phase-I clinical trials in Hepatitis C in Netherlands (IV) Updated 23 Aug 2012
17 Jul 2012 Trial Update Roche completes a phase II trial of danoprevir in combination with standard therapy in treatment-naive patients with chronic HCV genotype 1 infection in USA, Australia, Canada, Austria, France, Germany and Italy (NCT00963885) Updated 04 Jun 2010
30 Jun 2012 Phase Change - II Phase-II clinical trials in Hepatitis C (treatment-naive, combination therapy) in Poland (PO) (NCT01628094) Updated 11 Feb 2014
30 Jun 2012 Trial Update Roche initiates enrolment in the phase II ANNAPURNA trial for Hepatitis C (treatment-naive, combination therapy) in USA, Australia, Germany and New Zealand (NCT01628094) Updated 11 Feb 2014
19 Apr 2012 Scientific Update Efficacy and adverse events data from the phase IIb DAUPHINE and INFORM-SVR trials for Hepatitis C (combination therapy; treatment-naive) presented at the 47th Annual Meeting of the European Association for the Study of the Liver (EASL-2012) [40] Updated 21 Apr 2012
18 Apr 2012 Trial Update Roche completes a phase I drug-interaction trial in Hepatitis C in USA (NCT01389544) Updated 07 May 2012
16 Apr 2012 Trial Update Roche completes a phase I drug-interaction trial in Hepatitis C in USA (NCT01514968) Updated 07 May 2012
31 Mar 2012 Trial Update Roche completes a phase I trial in healthy volunteers in New Zealand (NCT01483729) Updated 26 Jul 2012
16 Mar 2012 Trial Update Roche completes a phase I trial in healthy volunteers in the US (NCT01392755) Updated 09 Apr 2012
16 Mar 2012 Trial Update Roche completes enrolment in the phase II INFORM-SVR trial for Hepatitis C (combination therapy) in USA, France, Germany and New Zealand (NCT01278134) Updated 27 Mar 2012
29 Feb 2012 Trial Update Roche completes a phase I drug-interaction trial in France (NCT01398293) Updated 14 May 2012
01 Dec 2011 Trial Update Roche initiates enrolment in a phase I trial in healthy volunteers in New Zealand (NCT01483729) Updated 19 Jun 2018
30 Sep 2011 Trial Update Roche completes enrolment in the phase II Matterhorn trial in Hepatitis C (treatment-experienced, combination therapy) in the US, Australia, Brazil, Canada, Mexico, Puerto Rico, Spain, Austria, France, Germany, Italy, Poland, Spain and the UK (NCT01331850) Updated 03 Nov 2011
19 Sep 2011 Trial Update Roche initiates enrolment in a phase I trial in Healthy volunteers in US (NCT01392755) Updated 07 Oct 2011
01 Aug 2011 Trial Update Roche initiates a phase I drug-interaction trial in France (NCT01398293) Updated 19 Jun 2018
30 Jun 2011 Trial Update Roche initiates enrolment in a phase I trial of danoprevir + ritonavir in patients who are on stable methadone maintenance therapy for the treatment of opiate addiction in USA (NCT01389544) Updated 18 Jul 2011
31 May 2011 Phase Change - II Phase-II clinical trials in Hepatitis C (treatment-experienced patients, combination therapy) in Puerto Rico, Mexico, Brazil and Australia (PO) (NCT01331850) Updated 03 Nov 2011
31 May 2011 Phase Change - II Phase-II clinical trials in Hepatitis C (treatment-experienced patients, combination therapy) in Austria, France, Germany, Italy, Poland, Spain and the UK (PO) (NCT01331850) Updated 29 Jul 2011
31 May 2011 Phase Change - II Phase-II clinical trials in Hepatitis C (treatment-experienced patients, combination therapy) in USA and Canada (PO) (NCT01331850) Updated 29 Jul 2011
03 Mar 2011 Trial Update Roche initiates enrolment in a Phase-II trial of ritonavir-boosted danoprevir with mericitabine with or without ribavirin for Hepatitis C in interferon-naive patients in USA (NCT01278134) Updated 16 Mar 2011
01 Feb 2011 Trial Update Roche initiates enrolment in the phase II INFORM-SVR trial in Hepatitis C (treatment-naive, combination therapy) in USA, France and Germany (NCT01278134) Updated 19 Jun 2018
01 Feb 2011 Phase Change - I Phase-I clinical trials in Hepatitis C (volunteers) in Czech Republic and Slovakia (PO) (NCT01185873) Updated 19 Jun 2013
01 Feb 2011 Trial Update Roche initiates enrolment in a phase I trial in Healthy volunteers in USA (NCT01185873) Updated 17 May 2012
01 Feb 2011 Phase Change - II Phase-II clinical trials of ritonavir-boosted danoprevir with mericitabine with or without ribavirin for Hepatitis C in interferon-naive patients in New Zealand (NCT01278134) Updated 29 Jul 2011
01 Nov 2010 Trial Update Roche initiates enrolment in a Phase II trial in Hepatitis C (treatment-naive, combination therapy) in USA, Canada, Austria, France, Germany and Italy (NCT01220947) Updated 19 Jun 2018
01 Nov 2010 Phase Change - II Phase-II clinical trials in Hepatitis C (treatment-naive, combination therapy) in Brazil, Mexico, Puerto Rico, Spain and the UK (PO) (NCT01220947) Updated 29 Jul 2011
07 Oct 2010 Licensing Status Roche acquires danoprevir from InterMune [14] [15] Updated 07 Oct 2010
18 Apr 2010 Scientific Update Efficacy data from a Phase-Ib trial in Hepatitis C presented at the 45th Annual Meeting of the European Association for the Study of the Liver (EASL-2010) [64] Updated 07 May 2010
18 Apr 2010 Scientific Update Efficacy data from the phase Ib INFORM-1 trial in Hepatitis C presented at the 45th Annual Meeting of the European Association for the Study of the Liver [55] Updated 27 Apr 2010
18 Apr 2010 Scientific Update Pharmacodynamics data from a phase I trial in Hepatitis C presented at the 45th Annual Meeting of the European Association for the Study of the Liver [84] Updated 23 Apr 2010
18 Apr 2010 Scientific Update Drug interactions data from a phase I trial in healthy volunteers presented at the 45th Annual Meeting of the European Association for the Study of the Liver (EASL-2010) [85] Updated 22 Apr 2010
14 Apr 2010 Scientific Update Interim efficacy and adverse events data from a Phase-IIb trial in Hepatitis C released by InterMune [45] Updated 20 Apr 2010
01 Mar 2010 Trial Update Roche completes the phase I INFORM 1 trial in Hepatitis C (Combination therapy) in Australia and New Zealand (NCT00801255) Updated 19 Jun 2018
12 Jan 2010 Scientific Update Interim efficacy data from a phase Ib trial in Hepatitis C infection released by InterMune [41] Updated 02 Feb 2010
17 Nov 2009 Trial Update InterMune announces that the 900mg q12h cohort is to be discontinued in its ongoing phase IIb study in treatment-naive patients with Hepatitis C [42] Updated 26 Nov 2009
03 Nov 2009 Scientific Update Pharmacodynamics data from a subset of patients in a clinical trial in Hepatitis C presented at the 60th Annual Meeting of the American Association for the Study of Liver Diseases (AASLD-2009) [86] Updated 19 Nov 2009
03 Nov 2009 Scientific Update Efficacy, adverse events, pharmacokinetics and pharmacodynamics data from the phase I INFORM-1 trial presented at the 60th Annual Meeting of the American Association for the Study of Liver Diseases (AASLD-2009) [49] , [87] , [88] Updated 06 Nov 2009
29 Sep 2009 Trial Update InterMune initiates dosing in a phase Ib, multiple-ascending dose (MAD) trial for chronic Hepatitis C genotype 1 infection [77] Updated 15 Oct 2009
31 Aug 2009 Phase Change - II Phase-II clinical trials in Hepatitis C (treatment-naive patients, combination therapy) in Canada and Australia (PO) (NCT00963885) Updated 29 Jul 2011
19 Aug 2009 Phase Change - II Phase-II clinical trials in Hepatitis C (treatment-naive, combination therapy) in USA, Austria, France, Germany and Italy (PO) (NCT00963885) Updated 21 Aug 2009
01 Aug 2009 Phase Change - I Phase-I clinical trials in Hepatitis C in Poland, France (PO) (NCT01185860) Updated 19 Jun 2018
01 Aug 2009 Trial Update Roche completes a phase I trial for Hepatitis C (Combination therapy) in Poland, France, New Zealand (NCT01185860) Updated 19 Jun 2018
26 Apr 2009 Scientific Update Efficacy data from a phase I trial (INFORM-1) in Hepatitis C presented at the 44th Annual Meeting of the European Association for the Study of the Liver (EASL-2009) [89] , [44] Updated 04 May 2009
26 Apr 2009 Scientific Update Interim safety and efficacy data from a phase I trial (INFORM-1) with ITMN 191 combination therapy presented at the 44th Annual Meeting of the European Association for the Study of the Liver (EASL-2009) [90] , [57] Updated 30 Apr 2009
25 Apr 2009 Scientific Update Pharmacodynamics data from an in vitro study in Hepatitis C presented at the 44th Annual Meeting of the European Association for the Study of the Liver (EASL-2009) [91] Updated 30 Apr 2009
12 Jan 2009 Scientific Update Efficacy and adverse events data from a phase Ib trial in Hepatitis C released by InterMune [53] Updated 15 Jan 2009
10 Nov 2008 Phase Change - I Phase-I clinical trials in Hepatitis C (combination therapy with R 7128) in Australia and New Zealand (PO) (NCT00801255) Updated 14 Nov 2008
10 Nov 2008 Trial Update Pharmasset, Roche and InterMune initiate dosing in the INFORM-1 trial for Hepatitis C in Australia and New Zealand Updated 14 Nov 2008
31 Oct 2008 Scientific Update Pharmacokinetics data from a phase Ib trial in hepatitis C presented at the 59th Annual Meeting of the American Association for the Study of Liver Diseases (AASLD-2008) [92] Updated 26 Nov 2008
24 Sep 2008 Scientific Update Efficacy, adverse events, and pharmacokinetics data from phase I trials and pharmacodynamics data from in vitro studies released by InterMune Updated 29 Sep 2008
29 May 2008 Phase Change - I Phase-I clinical trials of a triple combination therapy in Hepatitis C in European Union (PO) Updated 03 Jun 2008
02 Apr 2008 Phase Change - Preclinical Preclinical trials in Hepatitis C in European Union (PO, controlled release) Updated 14 Apr 2008
02 Apr 2008 Scientific Update Top-line efficacy & adverse events data from a phase Ib monotherapy trial in Hepatitis C released by InterMune [93] , [52] Updated 14 Apr 2008
31 Mar 2008 Phase Change - Preclinical Preclinical trials in Hepatitis C in European Union (PO) Updated 14 Apr 2008
31 Mar 2008 Regulatory Status InterMune files CTA applications with undisclosed European regulatory authorities for triple-combination therapy (ITMN 191 + pegylated interferon-α2a + ribavirin) for Hepatitis C Updated 14 Apr 2008
13 Nov 2007 Scientific Update Data presented at the 58th Annual Meeting of the American Association for the Study of Liver Diseases (AASLD-2007) added to the Viral Infections antimicrobial activity section [94] Updated 13 Nov 2007
26 Sep 2007 Scientific Update Results from a phase Ia clinical trial added to the adverse events section [80] Updated 01 Oct 2007
26 Sep 2007 Trial Update InterMune initiates enrolment in a phase Ib trial for hepatitis C in Europe Updated 01 Oct 2007
23 May 2007 Scientific Update Preclinical data added to the Viral Infections antimicrobial activity section [81] Updated 23 May 2007
03 May 2007 Trial Update InterMune completes dosing in its phase Ia single ascending dose study Updated 23 May 2007
24 Apr 2007 Scientific Update Preclinical data added to the Viral Infections antimicrobial activity and immunogenicity sections [95] Updated 24 Apr 2007
19 Dec 2006 Phase Change - I Phase-I clinical trials as monotherapy in Hepatitis C in European Union (PO) Updated 22 Dec 2006
06 Nov 2006 Scientific Update Data presented at the 57th Annual Meeting of the American Association for the Study of Liver Diseases (AASLD-2006) have been added to the Viral Infections pharmacodynamics section [96] Updated 22 Dec 2006
16 Oct 2006 Licensing Status ITMN 191 has been licensed to Roche worldwide Updated 22 Dec 2006
26 Sep 2006 Regulatory Status Clinical trial application (CTA) submitted to French Medicinal and Biological Products Evaluation Directorate Updated 22 Dec 2006
23 May 2006 Scientific Update Data presented at the Digestive Disease Week (DDW-2006) added to the pharmacokinetics and Viral Infections antimicrobial activity sections [97] , [98] Updated 22 Dec 2006
01 Apr 2006 Company Involvement Chiron Corporation has been acquired and merged into Novartis Updated 19 Jun 2018
13 Dec 2005 Scientific Update Data presented at the 56th Annual Meeting and Postgraduate Course of the American Association for the Study of Liver Diseases (AASLD-2005) added to the Viral Infections antimicrobial activity section [99] Updated 22 Dec 2006
22 Jul 2005 Licensing Status Array and InterMune have expanded and extended their collaboration agreement Updated 22 Dec 2006
07 Dec 2004 Licensing Status Array BioPharma has granted InterMune expanded rights under the hepatitis C virus protease inhibitor discovery agreement Updated 22 Dec 2006
13 Sep 2004 Licensing Status Intermune in-licenses patents for discovery of small molecule therapeutics against Hepatitis C from Chiron Corporation [20] Updated 19 Jun 2018
17 Oct 2002 Phase Change - Preclinical Preclinical trials in Hepatitis C in USA (PO) Updated 22 Dec 2006
30 Sep 2002 Licensing Status InterMune and Array BioPharma enter into a drug discovery collaboration for Hepatitis [16] Updated 19 Jun 2018

References

  1. FDA Approves Esbriet(Rm) (pirfenidone) for the Treatment of Idiopathic Pulmonary Fibrosis (IPF) in the United States.

    Media Release
  2. Pfizer Completes Acquisition of Array Biopharma.

    Media Release
  3. Pfizer to Acquire Array BioPharma.

    Media Release
  4. Ascletis and CR Pharmaceutical Commercial Group Co., Ltd. Signed Strategic Cooperation Agreement.

    Media Release
  5. Roche and InterMune Reach Definitive Merger Agreement.

    Media Release
  6. Roche commences tender offer for InterMune, Inc. for US$74.00 per share in cash.

    Media Release
  7. Roche purchases shares in tender offer for InterMune, Inc.

    Media Release
  8. Roche and Ascletis enter collaboration to advance treatment options for Chinese patients with Hepatitis C.

    Media Release
  9. Roche and InterMune Sign Agreement to Collaborate on the Research, Development and Commercialization of Hepatitis C Protease Inhibitors.

    Media Release
  10. InterMune Closes Collaboration Agreement With Roche.

    Media Release
  11. InterMune Achieves Manufacturing Milestone in HCV Collaboration With Roche.

    Media Release
  12. InterMune Submits CTA Amendment for ITMN-191 and Provides Update on Clinical Development Program.

    Media Release
  13. InterMune Earns Development Milestone in HCV Protease Inhibitor Collaboration With Roche.

    Media Release
  14. InterMune Sells Danoprevir Rights to Roche for $175 Million.

    Media Release
  15. Roche buys full rights to danoprevir from InterMune.

    Media Release
  16. InterMune and Array BioPharma Announce Drug Discovery Collaboration Focused on Hepatitis.

    Media Release
  17. InterMune Announces Presentation of Data on Potent HCV Protease Inhibitor Drug Candidates.

    Media Release
  18. Array BioPharma Grants InterMune Expanded Rights Under Hepatitis C Discovery Agreement.

    Media Release
  19. InterMune and Array BioPharma Expand Hepatitis C Drug Discovery Collaboration.

    Media Release
  20. InterMune Signs Agreement with Chiron Corporation to License Access to Hepatitis C Genome.

    Media Release
  21. Chiron Grants Nonexclusive HCV License to InterMune; Agreement Further Enables Development of HCV Therapeutics to Address Disease.

    Media Release
  22. Ascletis' NDA for Its All-oral HCV Treatment Accepted by CFDA.

    Media Release
  23. Ascletis Filed NDA for Its All-oral HCV Treatment.

    Media Release
  24. Ascletis Receives NDA Approval from China FDA for Ganovo.

    Media Release
  25. Ascletis' New Drug Application for HCV Treatment Danoprevir Accepted by CFDA.

    Media Release
  26. Ganovo Enrolled in the Basic Medical Insurance of Tianjin--Capped Reimbursement-Per-Patient Pilot Program.

    Media Release
  27. Ascletis' Ganovo is Eligible for Shaoxing Government Funding Subsidy Program to Treat HCV Patients.

    Media Release
  28. Ascletis Publishes Interim Data of Phase II Study in Taiwan for its Interferon-free HCV Regimen.

    Media Release
  29. A Multi-centered, Open Label, Phase III Study on Efficacy, Safety of Ritonavir-boosted ASC08 (Danoprevir) in Combination With Peg-IFN and RBV in Treatment-Naive Non-Cirrhotic Patients Who Have Chronic Hepatitis Genotype 1

    ctiprofile
  30. Chinese biotech company Ascletis seeks third round of funding that could exceed US$100 million.

    Media Release
  31. A clinical trial to evaluate the safety and efficacy of the interferon (IFN)-free regimen containing danoprevir and ravidasvir for the treatment of hepatitis C

    ctiprofile
  32. Ascletis to Present Phase II / III Clinical Study for Its All-oral HCV Treatment at the 69th Annual meeting of AASLD.

    Media Release
  33. A Phase2/3, Multi-center, Randomized, Double-blind, Placebo-parallel Controlled Study to Investigate the Efficacy and Safety of Ravidasvir in Combination With Danoprevir/r and Ribavirin(RBV) in Treatment-naive, Non-cirrhotic, Chronic Hepatitis C Genotype 1 Infected Subjects.

    ctiprofile
  34. Wei L, Xu X, Guan Y, Zheng S, Sheng J, Yang X, et al. Efficacy and Safety of All-Oral, 12-Week Ravidasvir Plus Ritonavir-Boosted Danoprevir and Ribavirin in Treatment-Naive Non-Cirrhotic HCV Genotype 1 Patients : Results from a Phase 2/3 Clinical Trial in China. AASLD-2018 2018; abstr. 1001.

    Available from: URL: http://www.aasld.org/events-professional-development/liver-meeting
  35. A Phase 2,Multicenter,Open-Label Study to Investigate the Efficacy, Safety and Pharmacokinetics of Ritonavir-boosted Danoprevir in Combination With Peg-IFN and RBV in Treatment-Naive Non-Cirrhotic Patients Who Have Chronic Hepatitis GT1

    ctiprofile
  36. Ascletis Initiates Phase II Clinical Trial of Its Interferon-Free HCV Regimen in Taiwan.

    Media Release
  37. Phase 2 Study To Investigate the Efficacy, Safety And Pharmacokinetics Of Ravidasvir In Combination With Ritonavir-boosted Danoprevir And Ribavirin In Treatment-naive Non-cirrhotic Taiwanese Patients Who Have Chronic Hepatitis C Genotype 1

    ctiprofile
  38. Ascletis as the First Chinese Company to File Clinical Applications for Interferon-Free HCV Treatment.

    Media Release
  39. A Randomized, Open label, Multicenter, Dose and Duration Finding Study to Evaluate the Sustained Virologic Response of the HCV Protease Inhibitor Danoprevir (RO5190591) Boosted with Low Dose Ritonavir (danoprevir/r) in Combination with Pegasys and Copegus versus Pegasys and Copegus alone in Treatment-Naive Patients with Chronic Hepatitis C Genotype 1 or 4 Virus Infection.

    ctiprofile
  40. Roche reports high rates of sustained viral clearance with investigational hepatitis C treatment danoprevir.

    Media Release
  41. InterMune Provides Program Update and 2010 Milestones for RG7227 (ITMN-191).

    Media Release
  42. InterMune Announces Modification to On-Going Phase 2b Study of ITMN-191 in Patients with Chronic HCV Infection.

    Media Release
  43. Roche and InterMune Initiate Phase 2b Clinical Trial of RG7227/ ITMN-191 in Patients With Chronic Hepatitis C.

    Media Release
  44. InterMune Reports Presentation of Triple Combination Study of ITMN-191 at European Association for the Study of the Liver (EASL).

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

    Media Release
  46. A Randomized, Partially-blind Study on the Safety, Tolerability and Effect on Virological Response of Treatment With the HCV Protease Inhibitor RO5190591 in Combination With Pegasys and Copegus, Versus Pegasys and Copegus Alone, in Treatment-Naïve Patients With Hepatitis C Genotype 1 Virus Infection

    ctiprofile
  47. Randomized, Open-Label, Multicenter Study of Safety, Efficacy, and Tolerability of the Combination of RO5466731, RO5190591, Ritonavir, and Copegus With or Without RO5024048 in HCV Genotype 1 Infected Patients Who Are Either Treatment Naive or Null Responders to Previous Interferon-Based Treatment

    ctiprofile
  48. INFORM-SVR: A Randomized, Multi-Center Study of Interferon-Free Treatment with a Combination of a Polymerase Inhibitor (RO5024048) and a Ritonavir boosted HCV Protease Inhibitor (RO5190591/r, DNV/r) with or without Copegus in Interferon Naïve HCV Genotype 1 Infected Patients

    ctiprofile
  49. INFORM-1 Results: Robust Antiviral Suppression Achieved with Combination of Nucleoside Analog Polymerase Inhibitor RG7128 and Protease Inhibitor RG7227.

    Media Release
  50. Forestier N, Larrey D, Marcellin P, Benhamou Y, Guyader D, Bradford W, et al. Antiviral activity and safety of ITMN-191 in combination with peginterferon alfa-2A and ribavirin in patients with chronic hepatitis C virus. 44th-EASL-2009 2009; (plus oral presentation).

    Available from: URL: http://www2.kenes.com
  51. InterMune to Present Four Abstracts on HCV Protease Inhibitor ITMN-191 at the AASLD Meeting.

    Media Release
  52. InterMune Announces Top-Line Results of Phase 1b Trial of ITMN-191 (R7227) and Provides Program Update.

    Media Release
  53. InterMune Reports Results from Triple Combination Study of ITMN-191.

    Media Release
  54. InterMune to Report Top-Line Results of Triple Combination Study of ITMN-191 in January 2009.

    Media Release
  55. Gane E, Roberts S, Stedman C, Angus P, Ritchie B, Elston R, et al. Early On-treatment Responses During Pegylated Ifn Plus Ribavirin Are Increased Following 13 Days of Combination Nucleoside Polymerase (Rg7128) and Protease (Rg7227) Inhibitor Therapy (Inform-1). 45th-EASL-2010 2010;.

    Available from: URL: http://www.easl.ch/easl2010
  56. InterMune Reports Second Quarter 2009 Financial Results and Business Highlights.

    Media Release
  57. Ground-Breaking Combination of All-Oral Agents Demonstrates Potential as Hepatitis C Treatment Regimen.

    Media Release
  58. An Open Clinical Trial to Evaluate Danoprevir Sodium Tablets Combined With Ritonavir in the Treatment of SARS-CoV-2 Infection

    ctiprofile
  59. Results from First Clinical Study Using Danoprevir to Treat Naive and Experienced COVID-19 Patients.

    Media Release
  60. Progress of the Small Sample Clinical Trial of Ganovo(Rm) and Ritonavir Combination Therapy on Novel Coronavirus Pneumonia.

    Media Release
  61. Clinical Trial of Ganovo(R)and Ritonavir Combination Therapy on Novel Coronavirus Pneumonia.

    Media Release
  62. An Open Clinical Trial to Evaluate GanovoDanoprevir Combined With Ritonavir in the Treatment of SARS-CoV-2 Infection

    ctiprofile
  63. A Randomized Open-label Study to Evaluate the Sustained Virologic Response of Danoprevir/Ritonavir and Copegus in Combination With RO5024048 and/or Pegasys in Chronic Hepatitis C Genotype 1 Patients Who Failed Previous Standard Therapy

    ctiprofile
  64. Gane E, Rouzier R, Stedman C, Wiercinska-Drapalo A, Horban A, Chang L, et al. Ritonavir Boosting of Low Dose Rg7227/itmn-191, Hcv Ns3/4a Protease Inhibitor, Results in Robust Reduction in Hcv Rna at Lower Exposures Than Provided by Unboosted Regimens. 45th-EASL-2010 2010;.

    Available from: URL: http://www.easl.ch/easl2010
  65. Moucari R, Forestier N, Larrey D, Guyader D, Couzigou P, Benhamou Y, et al. Danoprevir, an HCV NS3/4A protease inhibitor, improves insulin sensitivity inpatients with genotype 1 chronic hepatitis C. Gut 2010;.

    PubMed | CrossRef Fulltext
  66. Efficacy of multiple ascending doses of danoprevir on insulin sensitivity in treatment-naive patients or non-responders to peginterferon/ribavirin with genotype 1 hepatitis C.

    ctiprofile
  67. A Three-Part Study Evaluating the Pharmacokinetics of Intravenous (IV) Danoprevir (DNV)/Oral Low-Dose Ritonavir (RTV), the Absolute Bioavailability of DNV With and Without Oral Low-Dose RTV, and the Effect of Oral Cyclosporine on IV DNV/Oral Low-Dose RTV in Healthy Adult Volunteers

    ctiprofile
  68. A Relative Bioavailability Study of Danoprevir and Ritonavir in Healthy Volunteers

    ctiprofile
  69. A Single-center, Single-dose, Randomized, Double-blind, Double-dummy, Placebo-controlled, Positive-controlled, Four-way Crossover Study to Investigate the Effect of Danoprevir With Low Dose Ritonavir (DNV/r) on the QT/QTc Interval in Healthy Subjects

    ctiprofile
  70. Investigation of the Effect of Multiple Doses of Danoprevir/Ritonavir on Methadone in Subjects on Stable Methadone Maintenance Therapy (MMT)

    ctiprofile
  71. A Drug-Drug Interaction Study Between Danoprevir/Low-dose Ritonavir and Cyclosporine, a Potent Inhibitor of OATP, in Healthy Subjects

    ctiprofile
  72. A Study to Evaluate the Potential Drug-Drug Interaction Between Danoprevir When Coadministered With Low-Dose Ritonavir and Tenofovir Disoproxil Fumarate or Atazanavir in Healthy Adult Volunteers

    ctiprofile
  73. A Study to Evaluate the Potential Drug-Drug Interaction Between Efavirenz and Danoprevir With Low Dose Ritonavir When Administered Together in Healthy Adult Volunteers

    ctiprofile
  74. A Study to Evaluate the Effects of Two Different Meal Types, Omeprazole and Ranitidine on Danoprevir Pharmacokinetics When Coadministered With Ritonavir in Healthy Subjects

    ctiprofile
  75. The Effect of Hepatic Impairment on the Pharmacokinetics of RO5190591/Ritonavir: A Multiple-Center, Open-Label Study Following Multiple Oral Doses of RO5190591/Ritonavir to Subjects with Mild, Moderate, or Severe Hepatic Impairment and Healthy Subjects with Normal Hepatic Function

    ctiprofile
  76. A Multiple-Dose Study To Evaluate Safety, Tolerability, Pharmacokinetics and Antiviral Activity of Ritonavir-Boosted RO5190591 in Combination With Peginterferon Alfa-2a Plus Ribavirin in Patients With Chronic Hepatitis C Genotype 1.

    ctiprofile
  77. InterMune Announces Initiation of Ritonavir-Boosted ITMN-191/RG7227 Study in HCV Patients.

    Media Release
  78. InterMune Reports Second Quarter 2010 Financial Results.

    Media Release
  79. InterMune Announces First Quarter 2007 Financial Results and Business Highlights.

    Media Release
  80. InterMune Announces Start of Phase 1b Trial of ITMN-191.

    Media Release
  81. InterMune Presents Research on ITMN-191 in Hepatitis C at Digestive Disease Week Meeting.

    Media Release
  82. InterMune Presents HCV Protease Inhibitor Data at AASLD.

    Media Release
  83. InterMune Announces Issuance of U.S. Patent for ITMN-191.

    Media Release
  84. Schaefer CJ, Kossen K, Lim SR, Qin X, Lin J, Pan L, et al. ITMN-191/R7227 monotherapy in chronic HCV patients reduces plasma concentrations of IP-10 and neopterin. 45th-EASL-2010 2010;.

    Available from: URL: http://www.easl.ch/easl2010
  85. Fretland J, Leong G, Blotner S, Hill T, Smith P, Tran JQ. Impact of low dose ritonavir boosting on the pharmacokinetics of RG7227 (ITMN-191), a highly potent and selective inhibitor of the HCV NS3/4A protease. 45th-EASL-2010 2010;.

    Available from: URL: http://www.easl.ch/easl2010
  86. Sarrazin C, Lim S, Qin X, Susser S, Lange CM, Bradford WZ, et al. Kinetic analysis of viral rebound and drugresistant viral variant dynamics in patients treated with ITMN-191 (R7227) monotherapy suggest a high barrier to viral escape. 60th-AASLD-2009 2009; abstr. 1411.

    Available from: URL: http://www.aasld.org/thelivermeeting/Pages/default.aspx
  87. Pogam SL, Chhabra M, Ali S, Yan J-M, Ilnicka MJ, Kang H, et al. Combination therapy with nucleoside polymerase R7128 and protease R7227/itmn-191 inhibitors in genotype 1 HCV infected patients: Interim resistance analysis of inform-1 cohorts A-D. 60th-AASLD-2009 2009; abstr. 1585.

    Available from: URL: http://www.aasld.org/thelivermeeting/Pages/default.aspx
  88. Morcos PN, Kulkarni R, Ipe D, Jumbe S, Tran J, Bradford WZ, et al. Pharmacokinetics/pharmacodynamics of combination R7227 and R7128 therapy from inform-1 demonstrates similar early HCV viral dynamics when R7227 is combined with either peg-ifn/ribavirin (soc) or R7128. 60th-AASLD-2009 2009; abstr. 1594.

    Available from: URL: http://www.aasld.org/thelivermeeting/Pages/default.aspx
  89. Sarrazin C, Hong J, Lim S, Qin X, Susser S, Bradford B, et al. Incidence of virologic escape observed during ITMN-191 (R7227) monotherapy is genotype dependent, associated with a specific NS3 substitution, and suppressed upon combination with peginterferon alfa-2A/Ribavirin. 44th-EASL-2009 2009; abstr. 845.

    Available from: URL: http://www2.kenes.com
  90. Gane EJ, Roberts SK, Stedman C, Angus PW, Ritchie B, Elston R, et al. First-in-man demonstration of potent antiviral activity with a nucleoside polymerase (R7128) and protease (R7227/ITMN-191) inhibitor combination in HCV: safety, pharmacokinetics, and virologic results from INFORM-1. 44th-EASL-2009 2009; (plus oral presentation).

    Available from: URL: http://www2.kenes.com
  91. Tan H, Wang G, Moy C, Kossen K, Rajagopalan R, Misialek S, et al. Combination of the NS3/4A protease inhibitor ITMN-191 with the allosteric NS5B polymerase inhibitor ITMN-8020 enhances replicon clearance and reduces the emergence of drug resistant variants. 44th-EASL-2009 2009; abstr. 817.

    Available from: URL: http://www2.kenes.com
  92. Rubino C, Bradford WZ, Forrest A, Porter S, Blatt LM, Seiwert S, et al. Pharmacokinetic-pharmacodynamic relationships for ITMN-191 in a phase 1 multiple ascending dose trial in patients with genotype 1 chronic hepatitis C infection. 59th-AASLD-2008 2008;1140-1141 abstr. 1861.

    Available from: URL: http://www.aasld.org
  93. InterMune Provides Additional Information on ITMN-191 (R7227) MAD Study Results.

    Media Release
  94. Ravi Rajagopalan PT, Stevens S, Stoycheva A, Brandhuber B, Zhang H, Gale M, et al. Genotype coverage of the HCV NS3/4A protease inhibitor ITMN-191 (R7227): biochemical data reveals potent inhibition and slow dissociation with genotype 1-6 proteases. Hepatology 2007;46 (Suppl. 1)(4):855.

  95. InterMune Presents Research on ITMN-191 in Hepatitis C at EASL Annual Meeting.

    Media Release
  96. InterMune Presents at Two Liver Disease Conferences Research on ITMN-191 in Hepatitis C.

    Media Release
  97. Rieger R, Lee PA, Seiwert S, Andrews SW, Hingorani GP, Pope TK, et al. Pharmacokinetic analysis and liver concentrations of a series of macrocyclic peptidomimetic inhibitors of HCV Ns3/4a protease: identification of Itnm 191, a potent Ns3/4a protease inhibitor with high liver exposure across multiple species. Gastroenterology 2006;130 (Suppl. 2)(4):835 (plus poster) abstr. T1795.

  98. InterMune Presents New Preclinical Data on Its HCV Protease Inhibitor at Digestive Disease Week.

    Media Release
  99. Seiwert S, Andrews SW, Yang H, Tan H, Marifino B, Radhakrishnan R, et al. ITMN A and B, novel inhibitors of the HCV NS3/4 protease retain their potency against VX-950 and BILN-2016 resistant NS3/4 protease mutants and an IFN-A-2A resistanct HCV replicon. Hepatology 2005;42 (Suppl. 1)(4):537-538.

Back to top