Open-label extension of a phase 2 trial of risankizumab in patients with moderate-to-severe Crohn's disease

Background: Risankizumab, an anti-interleukin-23 antibody, was superior to placebo in achieving clinical and endoscopic remission at week 12 in a randomised, phase 2 induction study in patients with moderately to severely active Crohn’s disease. The efficacy and safety of extended intravenous induction and/or subcutaneous maintenance therapy with risankizumab was assessed. Methods: Following 12-week, double-blind, randomised, induction treatment comparing 200 mg or 600 mg intravenous risankizumab to placebo every 4 weeks, patients without deep remission, defined as clinical (Crohn’s Disease Activity Index <150) and endoscopic remission (Crohn’s Disease Endoscopic Index of Severity [CDEIS] ≤4 [≤2 for patients with isolated ileitis]), received open-label 600 mg intravenous risankizumab (every 4 weeks) and patients in deep remission underwent washout until week 26 (Period 2). At week 26, patients in clinical remission received maintenance treatment (Period 3) with 180 mg subcutaneous risankizumab (every 8 weeks). Efficacy endpoints included clinical and endoscopic response and remission at weeks 26 (Period 2) and 52 (Period 3) respectively; safety was assessed through both periods. Study registration: ClinicalTrials.gov, NCT02031276. Findings: In Period 2, 101 patients were treated with 600 mg risankizumab resulting in an increase in clinical remission rates at week 26 versus week 12 for all original designated treatment groups: 55% versus 18%, 59% versus 21%, and 47% versus 26% for placebo, 200, and 600 mg risankizumab, respectively. Of the 62 patients receiving maintenance treatment, 54 completed treatment. At week 52, clinical remission was maintained by 71% of patients; endoscopic remission and response (>50% CDEIS reduction from baseline) was achieved by 35% and 55% of patients, respectively, and 29% of patients achieved deep remission. Risankizumab was well tolerated with no new safety signals. Interpretation: Extended induction treatment with open-label intravenous risankizumab was effective in increasing clinical response and remission rates at week 26. Open-label subcutaneous risankizumab maintained remission till week 52 in most patients who were in clinical remission at week 26. Selective blockade of interleukin-23 warrants further evaluation as treatment for Crohn’s disease.Boehringer Ingelhei

Faldaprevir and deleobuvir for HCV genotype 1 infection

BACKGROUND: Interferon-free regimens would be a major advance in the treatment of patients with chronic hepatitis C virus (HCV) infection. METHODS: In this phase 2b, randomized, open-label trial of faldaprevir (a protease inhibitor) and deleobuvir (a nonnucleoside polymerase inhibitor), we randomly assigned 362 previously untreated patients with HCV genotype 1 infection to one of five groups: faldaprevir at a dose of 120 mg once daily and deleobuvir at a dose of 600 mg three times daily, plus ribavirin, for 16, 28, or 40 weeks (TID16W, TID28W, or TID40W, respectively); faldaprevir at a dose of 120 mg once daily and deleobuvir at a dose of 600 mg twice daily, plus ribavirin, for 28 weeks (BID28W); or faldaprevir at a dose of 120 mg once daily and deleobuvir at a dose of 600 mg three times daily, without ribavirin, for 28 weeks (TID28W-NR). The primary end point was a sustained virologic response 12 weeks after the completion of therapy. RESULTS: The primary end point was met in 59% of patients in the TID16W group, 59% of patients in the TID28W group, 52% of patients in the TID40W group, 69% of patients in the BID28W group, and 39% of patients in the TID28W-NR group. The sustained virologic response 12 weeks after the completion of therapy did not differ significantly according to treatment duration or dosage among ribavirin-containing regimens. This response was significantly higher with TID28W than with TID28W-NR (P=0.03). Rates of a sustained virologic response 12 weeks after the completion of therapy were 56 to 85% among patients with genotype 1b infection versus 11 to 47% among patients with genotype 1a infection and 58 to 84% among patients with IL28B CC versus 33 to 64% with non-CC genotypes. Rash, photosensitivity, nausea, vomiting, and diarrhea were the most common adverse events. CONCLUSIONS: The rate of a sustained virologic response 12 weeks after the completion of therapy was 52 to 69% among patients who received interferon-free treatment with faldaprevir in combination with deleobuvir plus ribavirin. (Funded by Boehringer Ingelheim; SOUND-C2 ClinicalTrials.gov number, NCT01132313.)

Interferon-free treatment of chronic hepatitis C with faldaprevir, deleobuvir and ribavirin: SOUND-C3, a Phase 2b study.

BACKGROUND & AIMS The safety and efficacy of the interferon-free combination of faldaprevir (NS3/A4 protease inhibitor), deleobuvir (BI 207127, non-nucleoside polymerase inhibitor), and ribavirin in treatment-naïve patients chronically infected with HCV genotype-1 was explored. METHODS SOUND-C3 was a multicenter, open-label Phase 2b study. Treatment-naïve patients chronically infected with HCV genotype-1a (IL28B CC genotype only; n = 12) and genotype-1b (n = 20) were assigned to 16 weeks of treatment with faldaprevir 120 mg once daily, deleobuvir 600 mg twice daily, and weight-based ribavirin. Patients with compensated liver disease, including cirrhosis, were eligible for inclusion in this study. The primary endpoint was sustained virological response 12 weeks after completion of therapy. RESULTS Sustained virological response rates 12 weeks after completion of therapy were 17% and 95% in patients infected with HCV genotype-1a and genotype-1b respectively. All four patients with cirrhosis achieved sustained virological response 12 weeks after completion of therapy. The most frequently reported adverse events of at least moderate intensity were anaemia (16%), nausea, vomiting and fatigue (9% each). Three (9%) patients discontinued because of adverse events. CONCLUSIONS The interferon-free regimen of faldaprevir, deleobuvir and ribavirin was efficacious in patients infected with genotype-1b and generally well tolerated

SILEN-C3, a Phase 2 Randomized Trial with Faldaprevir plus Pegylated Interferon α-2a and Ribavirin in Treatment-Naive Hepatitis C Virus Genotype 1-Infected Patients

International audienceFaldaprevir is an investigational hepatitis C virus (HCV) NS3/4A protease inhibitor which, when administered for 24 weeks in combination with pegylated interferon α-2a and ribavirin (PegIFN/RBV) in treatment-naive patients in a prior study (SILEN-C1; M. S. Sulkowski et al., Hepatology 57:2143–2154, 2013, doi:10.1002/hep.26276), achieved sustained virologic response (SVR) rates of 72 to 84%. The current randomized, open-label, parallel-group study compared the efficacy and safety of 12 versus 24 weeks of 120 mg faldaprevir administered once daily, combined with 24 or 48 weeks of PegIFN/RBV, in 160 treatment-naive HCV genotype 1 patients. Patients with maintained rapid virologic response (HCV RNA of <25 IU/ml at week 4 and undetectable at weeks 8 and 12) stopped all treatment at week 24, otherwise they continued PegIFN/RBV to week 48. SVR was achieved by 67% and 74% of patients in the 12-week and 24-week groups, respectively. Virologic response rates were lower in the 12-week group from weeks 2 to 12, during which both groups received identical treatment. SVR rates were similar in both groups for patients achieving undetectable HCV RNA. Most adverse events were mild or moderate, and 6% of patients in each treatment group discontinued treatment due to adverse events. Once-daily faldaprevir at 120 mg for 12 or 24 weeks with PegIFN/RBV resulted in high SVR rates, and the regimen was well tolerated. Differences in the overall SVR rates between the 12-week and 24-week groups were not statistically significant and possibly were due to IL28B genotype imbalances; IL28B genotype was not tested, as its significance was not known at the time of the study. These results supported phase 3 evaluation. (This study has been registered at ClinicalTrials.gov under registration no. NCT00984620)

Short article: Faldaprevir, deleobuvir and ribavirin in IL28B non-CC patients with HCV genotype-1a infection included in the SOUND-C3 phase 2b study.

BACKGROUND SOUND-C3 was a multicentre, open-label, phase 2b study exploring the safety and efficacy of the interferon-free combination of faldaprevir (an NS3/A4 protease inhibitor), deleobuvir (BI 207127, a non-nucleoside polymerase inhibitor) and ribavirin in treatment-naive patients with chronic hepatitis C virus (HCV) genotype-1 infection. Results in patients with HCV genotype-1b and in IL28B CC genotype patients with HCV genotype-1a have been described previously. This report describes the results in IL28B non-CC genotype patients with HCV genotype-1a. METHODS Patients were randomized to receive faldaprevir 120 mg once daily with deleobuvir at either 800 mg twice daily (b.i.d.; N=26) or 600 mg three times daily (t.i.d.; N=25), and weight-based ribavirin for 24 weeks. The primary endpoint was sustained virological response 12 weeks after treatment (SVR12). RESULTS In each group, five patients completed 24 weeks of treatment. SVR12 rates were 19% (5/26) and 8% (2/25) in the b.i.d. and t.i.d. groups, respectively. On-treatment breakthrough [50% (13/26) and 68% (17/25) in the b.i.d. and t.i.d. groups, respectively] was the most frequent reason for not achieving SVR12. Adverse events led to premature treatment discontinuation in six (23%) patients in the b.i.d. group and in two patients (8%) in the t.i.d. group. The majority of adverse events were mild or moderate; the most frequently reported were nausea (67%), fatigue (35%) and diarrhoea (35%). CONCLUSION In this small study, the interferon-free regimen of faldaprevir, deleobuvir and ribavirin resulted in high rates of virological breakthrough and low rates of SVR12 in IL28B non-CC genotype patients infected with genotype-1a HCV (http://www.clinicaltrials.gov NCT01132313)

ITPA genotypes predict anemia but do not affect virological response with interferon-free faldaprevir, deleobuvir, and ribavirin for hcv infection

BACKGROUND & AIM Whether inosine triphosphatase (ITPA) gene polymorphisms predict anemia during interferon-free therapy in chronic hepatitis C virus (HCV)-infected patients is unknown. We examined the relationship between two ITPA polymorphisms, anemia, and sustained virological response 12 weeks post-treatment (SVR12) in patients receiving the NS3/4A protease inhibitor faldaprevir, the non-nucleoside polymerase inhibitor deleobuvir, and ribavirin. METHODS HCV genotype 1-infected, treatment-naïve patients (N = 362) were randomized and treated in one of five treatment arms with faldaprevir and deleobuvir with or without ribavirin. Two ITPA polymorphisms (rs1127354 and rs6051702) were genotyped and defined as ITPA-deficient (rs1127354 AA or AC; rs6051702 CC or CA) or ITPA-non-deficient (rs1127354 CC; rs6051702 AA) according to their association with ITPA deficiency. Baseline and on-treatment variables associated with anemia and SVR12 were identified using logistic regression. RESULTS In the pooled ribavirin-containing arms, 10.1% (32/316) of patients experienced on-treatment hemoglobin <10 g/dL, and 32.6% (103/316) experienced on-treatment hemoglobin <10 g/dL or a change from baseline ≥3.5 g/dL. Of the latter group, 99% (102/103) had the ITPA-non-deficient rs1127354 genotype. Other variables associated with on-treatment hemoglobin <10 g/dL or a decrease ≥3.5 g/dL were age, baseline hemoglobin, rs6051702 genotype, and plasma ribavirin concentration. In a multivariate analysis, high plasma ribavirin concentration, low baseline hemoglobin, HCV genotype 1b, and IL28B genotype CC were associated with higher SVR12. CONCLUSIONS The ITPA rs1127354 CC and rs6051702 AA genotypes may predict ribavirin-induced anemia during treatment with interferon-free, ribavirin-containing regimens. With this interferon-free regimen, SVR was associated with ribavirin levels, but not with anemia or ITPA genotypes. TRIAL REGISTRATION ClinicalTrials.gov: NCT01132313