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     . 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  . 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  .
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  .
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  . Efficacy data from the trial was released in January 2018  .
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   .
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   . 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)  .
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  .
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  . The clinical trial application to initiate the trial was approved by the Taiwan Food and Drug Administration (TFDA) in August 2015   . 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  ..
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  . Results have been presented  .
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       .
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  .
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)  . The trial was completed in October 2012 and results have been reported  .
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  .
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    .
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    .
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     .
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  .
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     .
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  .
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  . 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  .
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   .
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  .
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  .
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  .
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)  . 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)  . 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)   .
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  .
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  .
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)  . 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   . 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   . 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    .
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   .
Promising results of in vitro studies of the combination of danoprevir with the HCV polymerase inhibitors, mericitabine and balapiravir have been reported  .
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  . In the second quarter of 2009, InterMune also completed 6-month and 9-month chronic toxicology studies in rats and monkeys  .