Yakov Datsenko

Faldaprevir combined with pegylated interferon alfa-2a and ribavirin in treatment-naïve patients with chronic genotype1 HCV: SILEN-C1 trial†‡

Faldaprevir (BI 201335) is a potent, hepatitis C virus (HCV) NS3/4A protease inhibitor with pharmacokinetic properties supportive of once‐daily (QD) dosing. Four hundred and twenty‐nine HCV genotype (GT)‐1 treatment‐naïve patients without cirrhosis were randomized 1:1:2:2 to receive 24 weeks of pegylated interferon alfa‐2a and ribavirin (PegIFN/RBV) in combination with placebo, faldaprevir 120 mg QD with 3 days of PegIFN/RBV lead‐in (LI), 240 mg QD with LI, or 240 mg QD without LI, followed by an additional 24 weeks of PegIFN/RBV. Patients in the 240 mg QD groups achieving maintained rapid virologic response (mRVR; viral load [VL] <25 IU/mL at week 4 and undetectable at weeks 8‐20) were rerandomized to cease all treatment at week 24 or continue receiving PegIFN/RBV up to week 48. VL was measured by Roche TaqMan. Sustained virologic response (SVR) rates were 56%, 72%, 72%, and 84% in the placebo, faldaprevir 120 mg QD/LI, 240 mg QD/LI, and 240 mg QD groups. Ninety‐two percent of mRVR patients treated with faldaprevir 240 mg QD achieved SVR, irrespective of PegIFN/RBV treatment duration. Eighty‐two percent of GT‐1a patients who received faldaprevir 240 mg QD achieved SVR versus 47% with placebo. Mild gastrointestinal disorders, jaundice resulting from isolated unconjugated hyperbilirubinemia, and rash or photosensitivity were more common in the active groups than with placebo. Discontinuations resulting from adverse events occurred in 4%, 11%, and 5% of patients treated with 120 mg QD/LI, 240 mg QD/LI, and 240 mg QD of faldaprevir versus 1% with placebo. Conclusion: Faldaprevir QD with PegIFN/RBV achieved consistently high SVR rates with acceptable tolerability and safety at all dose levels. The 120 and 240 mg QD doses are currently undergoing phase 3 evaluation. (HEPATOLOGY 2013;57:2143–2154)

Baseline Hepatitis C Virus (HCV) NS3 Polymorphisms and Their Impact on Treatment Response in Clinical Studies of the HCV NS3 Protease Inhibitor Faldaprevir

ABSTRACT A challenge to the treatment of chronic hepatitis C with direct-acting antivirals is the emergence of drug-resistant hepatitis C virus (HCV) variants. HCV with preexisting polymorphisms that are associated with resistance to NS3/4A protease inhibitors have been detected in patients with chronic hepatitis C. We performed a comprehensive pooled analysis from phase 1b and phase 2 clinical studies of the HCV protease inhibitor faldaprevir to assess the population frequency of baseline protease inhibitor resistance-associated NS3 polymorphisms and their impact on response to faldaprevir treatment. A total of 980 baseline NS3 sequences were obtained (543 genotype 1b and 437 genotype 1a sequences). Substitutions associated with faldaprevir resistance (at amino acid positions 155 and 168) were rare (<1% of sequences) and did not compromise treatment response: in a phase 2 study in treatment-naive patients, six patients had faldaprevir resistance-associated polymorphisms at baseline, of whom five completed faldaprevir-based treatment and all five achieved a sustained virologic response 24 weeks after the end of treatment (SVR24). Among 13 clinically relevant amino acid positions associated with HCV protease resistance, the greatest heterogeneity was seen at NS3 codons 132 and 170 in genotype 1b, and the most common baseline substitution in genotype 1a was Q80K (99/437 [23%]). The presence of the Q80K variant did not reduce response rates to faldaprevir-based treatment. Across the three phase 2 studies, there was no significant difference in SVR24 rates between patients with genotype 1a Q80K HCV and those without Q80K HCV, whether treatment experienced (17% compared to 26%; P = 0.47) or treatment naive (62% compared to 66%; P = 0.72).

66 SILEN-C2: SUSTAINED VIROLOGIC RESPONSE (SVR) AND SAFETY OF BI201335 COMBINED WITH PEGINTERFERON ALFA-2A AND RIBAVIRIN (P/R) IN CHRONIC HCV GENOTYPE-1 PATIENTS WITH NON-RESPONSE TO P/R

66 SILEN-C2: SUSTAINED VIROLOGIC RESPONSE (SVR) AND SAFETY OF BI201335 COMBINED WITH PEGINTERFERON ALFA-2A AND RIBAVIRIN (P/R) IN CHRONIC HCV GENOTYPE-1 PATIENTS WITH NON-RESPONSE TO P/R M.S. Sulkowski, M. Bourliere, J.-P. Bronowicki, A. Streinu-Cercel, L. Preotescu, T. Asselah, J.-M. Pawlotsky, S. Shafran, S. Pol, F.A. Caruntu, S. Mauss, D. Larrey, C. Hafner, Y. Datsenko, J.O. Stern, R. Kubiak, W. Bocher, G. Steinmann. Johns Hopkins University, Baltimore, MD, USA; Hopital Saint Joseph, Marseille, Hopital de Brabois, Vandoeuvre Cedex, France; “Prof. Dr. Matei Bals” Institute of Infectious Diseases, Bucharest, Romania; Hopital Beaujon, Clichy Cedex, Hopital Henri Mondor, Creteil, France; University of Alberta, Edmonton, AB, Canada; Hopital Cochin, Paris, France; Center for HIV and Hepatogastroenterology, Dusseldorf, Germany; Hopital Saint-Eloi, Montpellier Cedex, France; Boehringer Ingelheim Pharma, Biberach, Germany; Boehringer Ingelheim Pharmaceuticals, Ridgefield, CT, USA E-mail: msulkowski@jhmi.edu

STARTVerso1: A randomized trial of faldaprevir plus pegylated interferon/ribavirin for chronic HCV genotype-1 infection

BACKGROUND & AIMS The efficacy and tolerability of faldaprevir, a potent hepatitis C virus (HCV) NS3/4A protease inhibitor, plus peginterferon (PegIFN) and ribavirin (RBV) was assessed in a double-blind, placebo-controlled phase 3 study of treatment-naïve patients with HCV genotype-1 infection. METHODS Patients were randomly assigned (1:2:2) to PegIFN/RBV plus: placebo (arm 1, n = 132) for 24 weeks; faldaprevir (120 mg, once daily) for 12 or 24 weeks (arm 2, n = 259); or faldaprevir (240 mg, once daily) for 12 weeks (arm 3, n = 261). In arms 2 and 3, patients with early treatment success (HCV-RNA <25 IU/ml at week 4 and undetectable at week 8) stopped all treatment at week 24. Other patients received PegIFN/RBV until week 48 unless they met futility criteria. The primary endpoint was sustained virologic response 12 weeks post-treatment (SVR12). RESULTS SVR12 was achieved by 52%, 79%, and 80% of patients in arms 1, 2, and 3, respectively (estimated difference for arms 2 and 3 vs. arm 1: 27%, 95% confidence interval 17%-36%; and 29%, 95% confidence interval, 19%-38%, respectively; p < 0.0001 for both). Early treatment success was achieved by 87% (arm 2) and 89% (arm 3) of patients, of whom 86% and 89% achieved SVR12. Adverse event rates were similar among groups; few adverse events led to discontinuation of all regimen components. CONCLUSIONS Faldaprevir plus PegIFN/RBV significantly increased SVR12, compared with PegIFN/RBV, in treatment-naïve patients with HCV genotype-1 infection. No differences were seen in responses of patients given faldaprevir once daily at 120 or 240 mg.

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

ABSTRACT Faldaprevir 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).

Risankizumab, an IL-23 inhibitor, for ankylosing spondylitis: results of a randomised, double-blind, placebo-controlled, proof-of-concept, dose-finding phase 2 study

Objectives To evaluate the efficacy and safety of risankizumab, a humanised monoclonal antibody targeting the p19 subunit of interleukin-23 (IL-23), in patients with active ankylosing spondylitis (AS). Methods A total of 159 patients with biological-naïve AS, with active disease (Bath Ankylosing Spondylitis Disease Activity Index score of ≥4), were randomised (1:1:1:1) to risankizumab (18 mg single dose, 90 mg or 180 mg at day 1 and weeks 8, 16 and 24) or placebo over a 24-week blinded period. The primary outcome was a 40% improvement in Assessment in Spondylo Arthritis International Society (ASAS40) at week 12. Safety was assessed in patients who received at least one dose of study drug. Results At week 12, ASAS40 response rates were 25.5%, 20.5% and 15.0% in the 18 mg, 90 mg and 180 mg risankizumab groups, respectively, compared with 17.5% in the placebo group. The estimated difference in proportion between the 180 mg risankizumab and placebo groups (primary endpoint) was –2.5% (95% CI –21.8 to 17.0; p=0.42). Rates of adverse events were similar in all treatment groups. Conclusions Treatment with risankizumab did not meet the study primary endpoint and showed no evidence of clinically meaningful improvements compared with placebo in patients with active AS, suggesting that IL-23 may not be a relevant driver of disease pathogenesis and symptoms in AS. Trial registration number NCT02047110; Pre-results.

1185 CHARACTERIZATION OF HCV NS3 VARIANTS THAT EMERGED DURING VIROLOGIC BREAKTHROUGH AND RELAPSE FROM BI 201335 PHASE II SILEN-C2 STUDY IN PEGIFN/RBV TREATMENT-EXPERIENCED PATIENTS

ribavirin (TRIPLE) or with peginterferon alfa-2a (P) and ribavirin (R) (QUAD) in chronic HCV genotype 1 treatment-naive patients. Clinical virology analyses are presented from patients with viral breakthrough (vBT) in DUAL arms, which were terminated due to vBT. Methods: Patients were randomized to VX-222 100mg (n =18) or 400mg (n =29) bid with TVR 1125mg bid for 12 weeks. 79% (37/47) of patients were subtype 1a, 21% (10/47) were subtype 1b. Treatment arms were discontinued if vBT rate was >25% with 90% confidence and patients were offered 48 weeks of PR. HCVRNA levels were measured (Roche Taqman HCV assay version 2.0, LLOQ: 25 IU/mL). Population sequence analysis of NS3•4A and NS5B was performed at baseline, vBT, and follow-up time points. Results: All DUAL regimen patients had an initial decline in HCVRNA, with 72% having ≤LLOQ by Week 2. However, both DUAL arms were terminated due to vBT. Of 12 patients with vBT, 11 were subtype 1a and 1 was subtype 1b. Sequencing identified variants resistant to both TVR and VX-222 in all patients at time of vBT: NS3-V36A/L, R155I/T, A156S/T/V, V36A/M+R155K and NS5B-L419S, R422K, M423T. The most common profile was NS3-A156T+NS5BR422K (n =5). Eleven of 12 patients started PR in the extension phase (1 patient declined); HCVRNA levels became undetectable in 7/11 patients. Of 5 patients with detectable HCVRNA (including the patient who declined PR), 4 had only wild-type virus during followup (median time from end of TVR+VX-222 treatment = 24 weeks, range 6–31). Conclusions: The DUAL regimens of telaprevir+VX-222 resulted in rapid initial declines in HCVRNA but were associated with >25% on-treatment vBT. Patients with vBT had variants resistant to both drugs. Resistant variants were suppressed and HCVRNA levels became undetectable in the majority of patients who were subsequently treated with PR. In 4 of the 5 patients with viremia, resistance to both drugs was lost during follow-up, indicating poor fitness of dual-resistant variants. Additional antiviral pressure with PR in QUAD regimens resulted in viral suppression; no patients experienced vBT.

Su1053 Virological Response in Treatment-Naïve Patients With Chronic HCV Genotype-1 Infection Receiving Faldaprevir Plus Pegylated Interferon α-2A and Ribavirin Is Unaffected by Ribavirin Dose Reduction

Background: Optimal duration of interferon-free HCV treatment continues to be examined in clinical trials. The SOUND-C2 and -C3 studies assessed the efficacy and safety of 16, 24, 28 and 40 weeks (W) of the interferon-free combination of faldaprevir, deleobuvir ± ribavirin in treatment-naive patients infected with HCV genotype (GT)-1. Relapse was higher in HCV GT-1a-infected patients treated for 16W with this regimen compared with GT-1b. We examined the relationship between duration of undetectable HCV RNA and virological response in SOUND-C2 and -C3. Methods: Patients received faldaprevir 120 mg QD plus deleobuvir 600 mg BID or TID. A ribavirin-free arm was investigated in SOUND-C2. The relationship between duration of undetectable HCV RNA to the end of treatment and SVR12 was assessed. Results: SVR rates among patients with undetectable HCV RNA at the last ontreatment visit, based on duration of undetectable HCV RNA, are shown (Table). GT-1binfected patients may require less time at undetectable HCV RNA (8-12W) compared with GT-1a patients (>16W) in order to achieve SVR. Regression analysis indicated that duration of undetectable HCV RNA was significantly associated with SVR. Conclusions: Duration of undetectable HCV RNA to end of treatment with this two DAA regimen was associated with SVR. These data suggest that the optimal treatment duration in GT-1b-infected patients is between 8W and 12W plus the time required to reach undetectable HCV RNA. There were

P724 VIROLOGICAL RESPONSE IN TREATMENT-NAIVE PATIENTS WITH CHRONIC HCV GENOTYPE-1 INFECTION RECEIVING FALDAPREVIR PLUS PEGYLATED INTERFERON a-2a AND RIBAVIRIN IS UNAFFECTED BY RIBAVIRIN DOSE REDUCTION

Background: Optimal duration of interferon-free HCV treatment continues to be examined in clinical trials. The SOUND-C2 and -C3 studies assessed the efficacy and safety of 16, 24, 28 and 40 weeks (W) of the interferon-free combination of faldaprevir, deleobuvir ± ribavirin in treatment-naive patients infected with HCV genotype (GT)-1. Relapse was higher in HCV GT-1a-infected patients treated for 16W with this regimen compared with GT-1b. We examined the relationship between duration of undetectable HCV RNA and virological response in SOUND-C2 and -C3. Methods: Patients received faldaprevir 120 mg QD plus deleobuvir 600 mg BID or TID. A ribavirin-free arm was investigated in SOUND-C2. The relationship between duration of undetectable HCV RNA to the end of treatment and SVR12 was assessed. Results: SVR rates among patients with undetectable HCV RNA at the last ontreatment visit, based on duration of undetectable HCV RNA, are shown (Table). GT-1binfected patients may require less time at undetectable HCV RNA (8-12W) compared with GT-1a patients (>16W) in order to achieve SVR. Regression analysis indicated that duration of undetectable HCV RNA was significantly associated with SVR. Conclusions: Duration of undetectable HCV RNA to end of treatment with this two DAA regimen was associated with SVR. These data suggest that the optimal treatment duration in GT-1b-infected patients is between 8W and 12W plus the time required to reach undetectable HCV RNA. There were