Potency, safety, and pharmacokinetics of the NS3/4A protease inhibitor BI201335 in patients with chronic HCV genotype-1 infection.

International audienceBACKGROUND & AIMS: BI201335 is a highly specific and potent HCV protease inhibitor. This multiple rising dose trial evaluated antiviral activity and safety in chronic HCV genotype-1 patients. METHODS: Thirty-four treatment-naïve patients were randomized to monotherapy with placebo or BI201335 at 20-240 mg once-daily for 14 days, followed by combination with pegylated interferon alfa/ribavirin (PegIFN/RBV) through Day 28. Nineteen treatment-experienced patients received 48-240 mg BI201335 once-daily with PegIFN/RBV for 28 days. HCV-RNA was measured with Roche COBAS TaqMan. RESULTS: In treatment-naïve patients, median maximal viral load (VL) reductions during 14-day monotherapy were -3.0, -3.6, -3.7, and -4.2 log(10) for the 20, 48, 120, and 240 mg groups. VL breakthroughs (≥1 log(10) from nadir) were seen in most patients on monotherapy and were caused by NS3/4A variants (R155K, D168V) conferring in vitro resistance to BI201335. Adding PegIFN/RBV at Days 15-28 led to continuous viral load reductions in most patients. In treatment-experienced patients, treatment with BI201335 and PegIFN/RBV achieved VL<25 IU/ml at Day 28 in 3/6, 4/7, and 5/6 patients in the 48, 120, and 240 mg dose groups. VL breakthroughs were observed during triple combination in only 3/19 patients. BI201335 was generally well tolerated. Mild rash or photosensitivity was detected in four patients. Mild unconjugated hyperbilirubinemia was the only dose-dependent laboratory abnormality of BI201335. BI201335 elimination half-life supports once-daily dosing. CONCLUSIONS: BI201335 combined with PegIFN/RBV was well tolerated and induced strong antiviral responses. These results support further development of BI201335 in HCV genotype-1 patients

Improved Responses to Pegylated Interferon Alfa-2b and Ribavirin by Individualizing Treatment for 24-72 Weeks

BACKGROUND & AIMS: Guidelines recommend that patients with chronic hepatitis C virus (HCV) infection be treated with pegylated interferon and ribavirin for 24, 48, or 72 weeks, based on their virologic response to treatment. We investigated the effects of treating patients for individualized durations. METHODS: We treated 398 treatment-nave patients who had HCV genotype 1 infections with pegylated interferon alfa-2b and ribavirin for 24, 30, 36, 42, 48, 60, or 72 weeks (mean of 39 weeks, termed individualized therapy); the duration of therapy was determined based on baseline viral load and the time point at which HCV RNA levels became undetectable (measured at weeks 4, 6, 8, 12, 24, and 30). Results were compared with those of 225 patients who received standard treatment for 48 weeks (mean of 38 weeks). RESULTS: Rates of sustained virologic response (SVR) were 55% among patients who received individualized treatment and 48% among those who received standard treatment (P<.0001 for non-inferiority). SVR rates, according to the time point at which HCV RNA levels became undetectable, did not differ significantly between groups. Patients with a rapid virologic response (undetectable levels of HCV RNA at week 4) who were treated for 24 to 30 weeks achieved high rates of SVR (86%-88%). Rates of SVR increased among slow responders who first tested negative for HCV RNA at week 24 and were treated for 60 to 72 weeks compared with those treated for 48 weeks (60%-68% vs 43%-44%). The CC polymorphism at IL28B rs129797860 was associated with an increased rate of SVR compared with the CT/TT polymorphism (P<.0001) at baseline but not among patients who had undetectable levels of HCV RNA following treatment. CONCLUSIONS: Individualizing treatment of patients with chronic HCV genotype 1 infections for 24 to 72 weeks results in high rates of SVR among rapid responders and increases SVR among slow responders

Vitamin D levels vary during antiviral treatment but are unable to predict treatment outcome in HCV genotype 1 infected patients

Background: Different parameters have been determined for prediction of treatment outcome in hepatitis c virus genotype 1 infected patients undergoing pegylated interferon, ribavirin combination therapy. Results on the importance of vitamin D levels are conflicting. In the present study, a comprehensive analysis of vitamin D levels before and during therapy together with single nucleotide polymorphisms involved in vitamin D metabolism in the context of other known treatment predictors has been performed. Methods: In a well characterized prospective cohort of 398 genotype 1 infected patients treated with pegylated interferon-α and ribavirin for 24–72 weeks (INDIV-2 study) 25-OH-vitamin D levels and different single nucleotide polymorphisms were analyzed together with known biochemical parameters for a correlation with virologic treatment outcome. Results: Fluctuations of more than 5 (10) ng/ml in 25-OH-vitamin D-levels have been observed in 66 (39) % of patients during the course of antiviral therapy and neither pretreatment nor under treatment 25-OH-vitamin D-levels were associated with treatment outcome. The DHCR7-TT-polymorphism within the 7-dehydrocholesterol-reductase showed a significant association (P = 0.031) to sustained viral response in univariate analysis. Among numerous further parameters analyzed we found that age (OR = 1.028, CI = 1.002–1.056, P = 0.035), cholesterol (OR = 0.983, CI = 0.975–0.991, P<0.001), ferritin (OR = 1.002, CI = 1.000–1.004, P = 0.033), gGT (OR = 1.467, CI = 1.073–2.006, P = 0.016) and IL28B-genotype (OR = 2.442, CI = 1.271–4.695, P = 0.007) constituted the strongest predictors of treatment response. Conclusions: While 25-OH-vitamin D-levels levels show considerable variations during the long-lasting course of antiviral therapy they do not show any significant association to treatment outcome in genotype 1 infected patients

Risankizumab in patients with moderate to severe Crohn's disease: an open-label extension study

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. Here we aimed to assess the efficacy and safety of extended intravenous induction and subcutaneous maintenance therapy with risankizumab. METHODS: All patients who completed the 12-week induction phase of the double-blind phase 2 induction study were included in this open-label extension study. Patients who did not achieve deep remission, defined as clinical remission (Crohn's Disease Activity Index [CDAI] 50% CDEIS reduction from baseline); endoscopic remission, as defined previously; mucosal healing; and deep remission. Safety was assessed in patients who received at least one dose of the study drug during the open-label phases of the study. This study is registered with ClinicalTrials.gov, number NCT02031276. FINDINGS: Of the 108 patients who completed the 12-week double-blind induction trial, six patients were in deep remission and entered the 12-week washout phase. 102 patients were not in deep remission, 101 of whom received 12 weeks of 600 mg risankizumab (33 from the original placebo group, 34 from the 200 mg risankizumab group, and 34 from the 600 mg risankizumab group); the other patient declined to continue the study. At week 26, 54 (53%) of 101 patients treated with 600 mg rizankizumab were in clinical remission. Among patients included in the open-label extension trial, clinical remission rates at week 26 versus week 12 were: 18 (55%) versus six (18%) of 33 patients in the original placebo group; 20 (59%) versus seven (21%) of 34 patients in the original 200 mg risankizumab group; and 16 (47%) versus nine (26%) of 34 patients in the original 600 mg risankizumab group. 62 patients received risankizumab maintenance treatment, including the 54 patients who achieved clinical remission at week 26, the six patients who had achieved deep remission at week 12, and one patient because of a protocol violation. At week 52, clinical remission was maintained in 44 (71%) patients; 50 (81%) patients had a clinical response, 22 (35%) patients were in endoscopic remission, and 34 (55%) patients had an endoscopic response. 15 (24%) patients had mucosal healing and 18 (29%) patients achieved deep remission at week 52. Risankizumab was well tolerated with no new safety signals noted. The most frequent treatment-emergent adverse events were arthralgia (25 [22%] of 115 patients), headache (23 [20%]), abdominal pain (21 [18%]), nasopharyngitis (18 [16%]), nausea (18 [16%]), and pyrexia (15 [13%]). Most adverse events were mild or moderate and considered to be unrelated to study treatment. There were no treatment-related deaths. 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 until week 52 in most patients who were in clinical remission at week 26. Selective blockade of interleukin 23 warrants further investigation as a treatment for Crohn's disease. FUNDING: Boehringer Ingelheim.status: publishe

Patient demographic, biochemical and genetic characteristics.

<p>A VitD deficiency (<20 ng/ml) was observed in 251 (64,1%) out of 391patients. A liver fibrosis stage of 0–2 was observed in 321 (84,9%) out of 378 patients, while 57 (15%) out of 378 patients showed a liver fibrosis stage of 3–4.</p><p><i>Abbreviations</i>: BMI: body-mass-index, ALT: alanine aminotransferase, AST: aspartate aminotransferase, gGT: gamma-glutamyl-transferase, HOMA: homeostatic model assessment of insulin resistance, AP: alkaline phosphatase, TSH: thyroid stimulating hormone, IP10: interferon-γ-inducible-protein-10, HCV: hepatitis C virus.</p><p><i>Missing data</i>: Cholesterol levels were missing in 14 patients, Baseline Vitamin D levels were missing in 7 patients, Baseline IP10 levels were missing in 7 patients, Baseline viral load values were missing in 16 patients, Liver biopsy status was missing in 20 patients. HOMA-index values were missing in 74 patients, Triglyceride levels were missing in 15 patients, AP levels were missing in 4 patients, Ferritin levels were missing in 10 patients, Vitamin D levels on week 24 were missing in 69 patients, IP10 levels on week 1 were missing in 23 patients, IP10 levels on week 4 were missing in 42 patients, TSH values were missing in 6 patients, Genotype of the <i>IL28B</i>-gene was missing in 31 patients, Genotype of the <i>CYP27B1</i>-gene was missing in 32 patients, Genotype of the <i>CYP2R1</i>-gene was missing in 32 patients, Genotype of the <i>DHCR7</i>-genes was missing in 24 patients, Genotype of the <i>CYP24A1</i>-gene was missing in 24 patients, Genotype of the <i>DBP</i>-genes was missing in 24 patients.</p

The <i>DHCR7-TT-</i>genotype of the <i>rs12785878</i> SNP shows a significant association to stage of fibrosis.

<p>The <i>DHCR7-TT-</i>genotype of the <i>rs12785878</i> SNP shows a significant association to stage of fibrosis.</p

Uni- and multivariate analysis of predictors of SVR to antiviral therapy.

<p>Only patients with complete data for the remaining covariates (277 out of 398) and with significant variations in the univariate analysis were included in multivariate analyses. Missing data and abbreviations are illustrated in the legend of <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0087974#pone-0087974-t001" target="_blank">Table 1</a>. A VitD deficiency (<20 ng/ml) was observed in 251 (64,1%) out of 391patients. A liver fibrosis stage of 0–2 was observed in 321 (84,9%) out of 378 patients, while 57 (15%) out of 378 patients showed a liver fibrosis stage of 3–4.</p

VitD concentrations vary dependent on the month of sample obtainment (1A), whereas fluctuations between baseline-VitD and TW24-VitD-values (ΔVitd) are observed as well (1B).

<p>VitD concentrations vary dependent on the month of sample obtainment (1A), whereas fluctuations between baseline-VitD and TW24-VitD-values (ΔVitd) are observed as well (1B).</p

Variations of IP10-levels in patients with and without SVR at baseline, week 1 and 4 upon treatment initiation.

<p>Variations of IP10-levels in patients with and without SVR at baseline, week 1 and 4 upon treatment initiation.</p