Date: 2014-03-06
Type of information: Results
phase: 3
Announcement: results
Company: Boehringer Ingelheim (Germany)
Product: faldaprevir (BI 201335) in combination with peginteferon and ribavirin
Action
mechanism: Faldaprevir (BI 201335) is a next wave once-daily protease inhibitor.
Disease: HCV/HIV co-infection
Therapeutic area: Infectious diseases
Country: Brazil, France, Germany, Italy, Spain, Switzerland, UK, USA
Trial
details: STARTVerso™ 4 is an open-label, sponsor blinded, Phase 3 study assessing the efficacy and safety of Boehringer Ingelheim\'s investigational oral protease inhibitor faldaprevir in combination with PegIFN/RBV. The study includes 308 individuals co-infected with HCV and HIV who were treatment-naive (TN) or had relapsed after previous HCV therapy with PegIFN/RBV, and were either HIV treatment-naive or being treated with ART. The trial includes patients with cirrhosis (17% had F4 cirrhosis or Fibroscan >13 kPa).
- Group 1: 12 or 24 weeks of faldaprevir 240mg once-daily in addition to 24 or 48 weeks of PegIFN/RBV
- Group 2: 24 weeks of faldaprevir 120mg once-daily in addition to 24 or 48 weeks of PegIFN/RBV.
(NCT01399619)
Latest
news: * On June 20, 2014, Boehringer Ingelheim has re-evaluated its strategy in hepatitis C, and as a result the company has decided not to move forward in this therapeutic area. The HCV treatment environment has significantly and rapidly evolved since the submission of the faldaprevir marketing applications to regulatory bodies around the world. There are now several new treatment options available for patients and additional all-oral options are expected to be approved in 2014. This decision was taken as there is no longer an unmet medical need for the faldaprevir interferon-based regimen that was the subject of the application. Boehringer Ingelheim will withdraw all pending marketing applications for faldaprevir worldwide and is discontinuing further development. * On March 6, 2014, Boehringer Ingelheim has announced results from STARTVerso®4 in patients with HCV/HIV co-infection. Hepatitis C viral cure 12 weeks after the conclusion of treatment (SVR12) was achieved by 72% of all patients in the trial. Patients were enrolled in either 120mg or 240mg faldaprevir dose groups. Further, 80% of all patients were eligible for randomization to a shortened duration of treatment (24 versus 48 weeks) because they achieved protocol-defined early treatment success (ETS) and 86% of these patients achieved SVR12. In each faldaprevir dose group, 71% (120mg) and 72% (240mg) of patients achieved SVR12. SVR12 results were consistent across patients regardless of HCV genotype-1 subtype (GT1a or GT1b), presence of compensated cirrhosis, dose and duration of faldaprevir, and duration of PegIFN/RBV. In a post hoc analysis, 75% of patients with the Q80K variant achieved SVR12 compared with 71% of patients who did not have the variant. Serious adverse events (AEs) were reported in 32 patients (10%). To date, 24 patients have prematurely discontinued faldaprevir due to AEs. The most frequent AEs in STARTVerso®4 were nausea (37%), fatigue (34%), diarrhea (27%), headache (25%) and weakness (23%). Patients will be followed to 24 weeks after the conclusion of treatment (SVR24). In separate poster presentations at CROI, investigators described the results from analyses that evaluated drug-drug interactions of faldaprevir with common HIV medications, including: efavirenz, atazanavir/ritonavir, darunavir/ritonavir, raltegravir and tenofovir. In each of these analyses, there was no clinically relevant effect of faldaprevir on the pharmacokinetics of any of the HIV medications studied. Patients in STARTVerso®4 already taking ritonavir-boosted HIV protease inhibitors (darunavir or atazanavir) or efavirenz were enrolled into the 120mg and 240mg faldaprevir groups, respectively.
The New Drug Application (NDA) for faldaprevir has been accepted for filing by the FDA. Faldaprevir is currently under review as a component of a combination antiviral treatment regimen for the treatment of chronic HCV infection in adult patients who are treatment-naïve or have been previously treated with interferon-based treatment, as well as those with compensated liver disease, cirrhosis, or HCV/HIV co-infection. The FDA target action date for faldaprevir is in the fourth quarter of 2014.
The NDA submission for faldaprevir is supported by Boehringer Ingelheim’s STARTVerso® (NCT01343888, NCT01297270, NCT01358864, NCT01399619) clinical trial program, a multi-study Phase 3 trial program that evaluated faldaprevir for 12 or 24 weeks in combination with pegylated interferon and ribavirin (PegIFN/RBV). The four trials that make up this program studied treatment-naïve, treatment-experienced, and HCV/HIV co-infected patients with chronic genotype-1 (GT1) HCV. The primary efficacy endpoint of each STARTVerso® trial is viral cure 12 weeks after the conclusion of treatment (SVR12).
* On December 16, 2013, Boehringer Ingelheim has presented data at HEP DART 2013. These data show that its second-generation protease inhibitor faldaprevir, when used in combination with pegylated interferon and ribavirin, was effective even with the presence of naturally-occurring mutant variants of the hepatitis C virus (HCV), such as the NS3 Q80K polymorphism. The Q80K mutant was detected in 23% (49/127, STARTVerso™1) and 40% (159/398, STARTVerso™2) of genotype-1a infected patients. Its presence was found to have no effect on the chances of viral cure (SVR12) in genotype-1 infected hepatitis C patients treated with faldaprevir* plus pegylated interferon and ribavirin.1 These data were presented last week at HEP DART 2013, taking place in Big Island, Hawaii. The HCV NS3/4A protease is essential for viral replication and is a key target for direct acting antiviral (DAA) treatments such as faldaprevir. The NS3 Q80K variant is the most commonly observed NS3 polymorphism in genotype-1a HCV and has been reported in up to 47% of genotype-1a infected patients. The variation in frequency is influenced by the geography, with the prevalence of Q80K being particularly high in the USA.
Faldaprevir was recently granted accelerated assessment by the European Medicines Agency. If approved by the European Commission, faldaprevir* could be available for marketing in the EU in the second half of 2014 as part of an interferon-based regimen. In addition, Boehringer Ingelheim aims to deliver one of the first interferon-free regimens for the treatment of hepatitis C infection. Pivotal Phase III HCVerso® data for the interferon-free regimen of faldaprevir*, deleobuvir* and ribavirin will be available in 2014.
* On March 4, 2013, Boehringer Ingelheim has announced the first interim results in HCV/HIV co-infected patients from the company\'s ongoing hepatitis C (HCV) clinical trial program, HCVerso™. These results, from the Phase 3 trial STARTVerso™ 4, were presented at the 20th annual Conference on Retroviruses and Opportunistic Infections (CROI) in Atlanta.
The interim results showed that 80% of HCV/HIV co-infected patients achieved early treatment success (ETS), as defined by the study protocol, when given an investigational HCV regimen that included faldaprevir (BI 201335). Results were consistent across patients regardless of HIV therapy or prior HCV treatment status, including patients who were HCV treatment-naive or had previously relapsed during HCV treatment with pegylated interferon and ribavirin (PegIFN/RBV). Patients who achieved ETS were eligible for randomization to a shortened duration of treatment (24 weeks versus 48 weeks). Investigators also reported on-treatment virologic response at week 12, which showed that 84% of all study patients had undetectable levels of hepatitis C virus.
The most frequent adverse events (AEs) in STARTVerso™ 4 were nausea (37%), fatigue (33%), diarrhea (27%), headache (23%), and weakness (22%). Serious AEs were reported in 32 patients (10%), including three deaths. To date, 18 patients have discontinued study participation due to AEs. The safety results of this study were comparable to those observed in HCV mono-infected treatment-naive patients in prior faldaprevir clinical studies. No patient on ART experienced a loss of HIV viral suppression during the study period.
