Introduction Ulcerative colitis (UC) patients intolerant/refractory (IR) to anti-TNFs are difficult to treat. Several objective markers for clinical, endoscopic and histological response are currently being assessed in clinical trials The HICKORY open label induction (OLI) trial evaluated the safety and efficacy of etrolizumab in patients I/R to anti-TNF. Here we assessed patient reported outcomes (PRO), centrally read endoscopy and histology in this population.

Introduction HICKORY OLI evaluated the safety and efficacy of etrolizumab (etro) via independent, centrally-read endoscopy, patient (pt)-reported outcomes, and inflammatory biomarkers in pts who are IR to aTNFs. Methods Pts received etro 105 mg injected SC every 4 weeks (14 week induction). Mayo clinical subscores (MCS) based on endoscopic score (ES), and pt-reported rectal bleeding (RB) and stool frequency (SF) were assessed at baseline (BL) and week 14. Clinical response:≥3 point and 30% reduction of MCS from BL and ≥1 point decrease in RB or RB ≤1. Remission: MCS ≤2 with individual subscores≤1 and RB=0. Endoscopic improvement: ES ≤1. RB remission: RB=0; SF remission: SF ≤1 with≥1 point reduction from BL. The% decline from BL in RB and SF at week 14 was also calculated. Results HICKORY OLI enrolled 130 UC pts; 45% had previously failed >1 TNF antagonist. BL disease activity included MCS score, 9.4; median C-reactive protein (CRP), 6.6 (95% CI: 2.9, 14.5) g/dL; and median faecal calprotectin (FC), 1778 (95% CI: 898, 3452) mg/kg. At week 14, etro treatment was associated with clinical response in 50.8% of pts; remission in 12.3%; ES ≤1 in 23.9%; RB remission in 52.3%; and SF remission in 35.4%. 43.9% of pts had ≥1 point improvement from BL in the ES score, and improved ES scores were associated with increased rates of RB and SF remission. Among pts with ES=0, 100% reported RB ≤1, and 90% reported SF ≤1 (table 1). Pts who achieved either SF or RB remission or ES ≤1 also demonstrated >50% geometric mean reduction in CRP (BL ≥2.87 mg/L) and >70% geometric mean reduction in FC. Conclusions TNF antagonist-experienced pts with moderate-severe UC and high disease burden treated with open label etro for 14 weeks achieved clinically meaningful clinical response and remission and endoscopic improvement. Pts who had a decline in ES ≥1 achieved higher rates of RB and SF remission and greater reductions in inflammatory biomarkers. Recruitment to HICKORY continues in a randomised, placebo controlled induction cohort and a randomised maintenance phase is ongoing.

BACKGROUND Patients with ulcerative colitis (UC) who have experienced failure of anti-TNF therapy are a difficult-to-treat population with a notable unmet medical need. The OLI Cohort of the Hickory Study (NCT02100696) evaluates etrolizumab in patients intolerant/refractory to anti-TNFs.

Background: Etrolizumab, an anti-β7 mAb targeting integrins α4β7 and αEβ7, showed significantly greater clinical remission at wk 10 vs placebo (PBO) in the phase 2 EUCALYPTUS trial. We assessed changes in symptoms and inflammatory biomarkers in aTNF refractory or intolerant (aTNF-IR) pts treated in a non-pivotal open-label induction (OLI) cohort of a phase 3 study. Methods: HICKORY is a multicentre, randomised, double-blind, PBO-controlled phase 3 study (NCT02100696) evaluating the safety and efficacy of etrolizumab during induction and maintenance in aTNF-IR pts with moderate-to-severe UC. The study includes a non-pivotal OLI cohort that treated 130 pts with etrolizumab 105 mg every 4 wk for 14 wk. Symptomatic improvement in this cohort was assessed based on the change in weekly mean rectal bleeding (RB) and stool frequency (SF) scores (each scored on a scale of 0–3), derived from pts' daily eDiary entries. SF remission was defined as a weekly mean score of ≤1 (rounded to the nearest integer) with ≥1 point reduction from baseline (BL). RB remission was defined as a weekly mean score of 0 (rounded to the nearest integer) with ≥0.5 point reduction from BL. Faecal calprotectin (FC) and C-reactive protein (CRP) were measured at BL and wk 14 or early termination. Changes in SF, RB, PRO score (SF + RB), FC and CRP were assessed descriptively. Results: Of 130 treated pts, 97% received all induction doses, 80% had a BL Mayo Clinic endoscopic score of 3, and 45% had received ≥2 prior aTNFs. RB remission rates improved from BL to wk 4 (∼30%) and 14 (∼50%). SF remission rates improved from BL to wk 4 (∼10%) and 14 (∼25%). PRO scores improved regardless of disease severity and irrespective of prior treatment with 1 or ≥2 aTNFs. The mean (± SE) decrease in PRO was 22% (±3%) at wk 4 and 36% (±3%) at wk 14; this decrease mirrored mean reductions in FC and CRP. Overall, FC and CRP levels decreased at wk 14 by a mean (95% CI) of 57% (42 to 69) and 33% (15 to 47), respectively. Mean decrease in CRP in pts with CRP levels >2.87 mg/L (ULN) at BL was 47%. Mean decreases in FC and CRP levels at wk 14 were greater in pts in SF remission (FC, 83%; CRP, 54%) and in pts in RB remission (FC, 69%; CRP, 49%). Etrolizumab demonstrated favourable safety and tolerability. Figure 1 Conclusions: aTNF-IR pts with moderate-to-severe UC reported symptom improvement as early as wk 4 during OLI treatment with etrolizumab. Clinically meaningful improvement in disease activity was observed in pt-reported SF and RB scores, serum CRP and FC by wk 14.

Most patients with chronic hepatitis C virus (HCV) genotype 1 infection who have had a previous null response (<2-log10 reduction in HCV RNA by treatment week 12) to peginterferon/ribavirin (PegIFN/RBV) do not achieve a sustained virological response (SVR) when re-treated with a first-generation HCV protease inhibitor (PI) administered in combination with PegIFN/RBV. We studied the incremental benefits associated with adding mericitabine (nucleoside analog inhibitor of HCV polymerase) to PI plus PegIFN alfa-2a/RBV-based therapy in two double-blind randomized multicenter phase 2 trials (with boceprevir in DYNAMO 1, and with telaprevir in DYNAMO 2). The primary endpoint in both trials was SVR, defined as HCV RNA <25 IU/mL 12 weeks after the end of treatment (SVR12). Overall, the addition of mericitabine to PI plus PegIFN alfa-2a/RBV therapy resulted in SVR12 rates of 60–70% in DYNAMO 1 and of 71–96% in DYNAMO 2. SVR12 rates were similar in patients infected with HCV genotype 1a and 1b in both trials. The placebo control arms in both studies were stopped because of high rates of virological failure. Numerically lower relapse rates were associated with longer treatment with mericitabine (24 versus 12 weeks), telaprevir-containing regimens, and regimens that included 48 weeks of PegIFN alfa-2a/RBV therapy. No mericitabine resistance mutations were identified in any patient in either trial. The addition of mericitabine did not add to the safety burden associated with either telaprevir or boceprevir-based regimens. These studies demonstrate increased SVR rates and reduced relapse rates in difficult-to-treat patients when a nucleoside polymerase inhibitor with intermediate antiviral potency is added to regimens containing a first-generation PI. Trial Registration: ClinicalTrials.gov NCT01482403 and ClinicalTrials.gov NCT01482390

Background and Aim: Chronic hepatitis C is an important public health problem in Asia. We evaluated the safety, efficacy, and pharmacokinetics of fixed-dose ritonavir-boosted danoprevir plus peginterferon alfa-2a/ribavirin in treatment-naive Asian patients with chronic hepatitis C virus (HCV) genotype (G) 1 infection.Methods: Treatment-naive G1 patients in Taiwan, Thailand, and Korea with serum HCV-RNA level >= 10(5) IU/mL received ritonavir-boosted danoprevir 125/100mg twice daily plus peginterferon alfa-2a/ribavirin for either 12 (noncirrhotic patients: Arm A, n = 34) or 24 weeks (cirrhotic patients: Arm B, n = 27) in this phase II open-label study. Sustained virologic response was defined as HCV-RNA < 25 IU/mL 12weeks after end of treatment (SVR12).Results: Similar SVR12 rates were achieved in Arms A (88.2%; 95% confidence interval, 73.4-95.3%) and B (88.9%; 71.9-96.2%). Most patients had G1b infection, among whom SVR12 rates in Arms A and B were 96.7% and 91.7%, respectively. The overall SVR12 rate was 94.0% in noncirrhotic Taiwanese patients (100% in the subset of G1b patients). No patients withdrew for safety reasons. Three (11%) cirrhotic patients (Arm B) experienced serious adverse events, none of which was considered to be related to treatment. No Grade 3/4 alanine aminotransferase elevations were reported. The pharmacokinetic properties of danoprevir were broadly overlapping in noncirrhotic and cirrhotic patients both on Days 1 and 14.Conclusions: Ritonavir-boosted danoprevir plus peginterferon alfa-2a/ribavirin produced sustained virologic response rates > 90% after 12 weeks' treatment in noncirrhotic and 24 weeks' treatment in cirrhotic Asian patients with G1b infection and was well tolerated. These regimens are well suited to countries where G1b predominates.

Effective and safe antiviral treatment regimens are needed for patients with chronic hepatitis C (CHC) and cirrhosis.

BACKGROUND/AIMS:PROGRESS randomized chronic hepatitis C genotype 1 patients with a baseline viral load ≥400,000 IU/mL weighing ≥85 kg to regimens of 180 μg/week for 48 weeks or 360 μg/week for 12 weeks followed by 180 μg/week for 36 weeks peginterferon alfa-2a plus ribavirin. This analysis explored pharmacokinetics and early viral kinetics (VK) and evaluates differences between groups.METHODOLOGY:Blood samples for pharmacokinetic and VK analyses were collected from 51 patients enrolled in the PROGRESS study.RESULTS:Mean peginterferon alfa-2a trough concentration at week 12 was 11.7±4.3 ng/mL for 180 μg and 23.4±11.3 ng/mL for 360 μg. Early VK profiles suggested a trend towards an enhanced viral decline in the 360 μg groups with a mean decrease in HCV RNA at 48 hours post first dose of 1.04 log10 (IU/mL) compared with 0.76 log10 (IU/mL) in the 180 μg groups. Mean beta slope increased with dose, ranging from 0.38±0.26 log10 IU/week at 180 μg to 0.52±0.32 log10 IU/week at 360 μg.CONCLUSIONS:Early viral de clines may be enhanced with the 360 μg dose. These data may suggest the utility of high-dose peginterfer on alfa-2a plus direct-acting antivirals (DAA) in select difficult-to-treat populations.

AIMS:The aim was to evaluate early viral kinetics in patients receiving mericitabine [hepatitis C virus (HCV) nucleoside polymerase inhibitor] with peginterferon alfa-2a (40KD) and ribavirin in two clinical trials (PROPEL and JUMP-C).METHODS:We examined rapid virological responses (RVRs; week 4 HCV RNA <15 IU ml(-1) ) and complete early virological responses (cEVR; week 12 HCV RNA <15 IU ml(-1) ) in HCV genotype 1/4-infected patients receiving mericitabine (500 or 1000 mg) or placebo twice daily plus peginterferon alfa-2a and ribavirin.RESULTS:Among IL28B rs12979860 CC genotype patients receiving 500 or 1000 mg mericitabine or placebo, respectively, RVR rates were 64.3% (95% confidence interval: 38.8-83.7%), 95.1% (83.9-98.7%) and 33.3% (20.2-49.7%), and cEVR rates were 100% (78.5-100%), 100% (91.4-100%) and 80.6% (65.0-90.3%). Among non-CC genotype patients, RVR rates were 26.5% (14.6-43.1%), 52.3% (43.0-61.3%) and 5.7% (2.2-13.8%), and cEVR rates were 76.5% (60.0-87.6%), 84.6% (76.6-90.1%) and 28.6% (19.3-40.1%), respectively. In multiple regression analysis, IL28B genotype (P < 0.0001), mericitabine dose (P < 0.0001) and bodyweight (P = 0.0009) were associated with first-phase (α) slope (change in log10 HCV RNA from baseline to week 1).CONCLUSIONS:Mericitabine-containing triple therapy reduces the impact of IL28B genotype on RVR and cEVR compared with peginterferon alfa-2a and ribavirin dual therapy. The IL28B genotype, mericitabine dose and bodyweight are the most important factors associated with the α slope, and there is no evidence of a pharmacokinetic drug-drug interaction between mericitabine and ribavirin.

Clinical Development Phases I‐III Regulatory, Quality, Manufacturing

Mericitabine is a selective nucleoside analog inhibitor of the hepatitis C virus (HCV) NS5B RNA-dependent RNA polymerase, with activity across all HCV genotypes. Treatment-naive patients infected with HCV genotype 1 or 4 were randomized to 24 weeks of double-blind treatment with either mericitabine 1,000 mg (N = 81) or placebo (N = 85) twice-daily (BID) in combination with pegylated interferon alpha-2a (Peg-IFN-2a)/ribavirin (RBV). Patients randomized to mericitabine with HCV RNA <15 IU/mL from week 4 to 22 (extended rapid virologic response; eRVR) stopped all treatment at week 24; all other patients continued Peg-IFN-2a/RBV to complete 48 weeks of treatment. The primary efficacy endpoint was sustained virologic response (SVR; HCV RNA <15 IU/mL after 24 weeks of treatment-free follow-up). SVR was achieved in 56.8% (95% confidence interval [CI]: 45.9-67.0) of mericitabine-treated patients and 36.5% (95% CI: 27.0-47.1) of placebo-treated patients ( = 20.3%; 95% CI 5.5-35.2). SVR rates were higher in mericitabine- than placebo-treated patients when subdivided by IL28B genotype (CC, 77.8% versus 56.0%; non-CC, 44.1% versus 16.2%) and hepatic fibrosis (noncirrhotic, 63.3% versus 41.9%; cirrhotic, 38.1% versus 21.7%). Overall relapse rates were 27.7% and 32.0% in mericitabine- and placebo-treated patients, respectively. No evidence of NS5B S282T-variant virus or phenotypic resistance to mericitabine was observed in the one patient who experienced partial response. No S282T variants were detected in any baseline samples. The safety profile of mericitabine was similar to that of, and fewer patients in the mericitabine than in the placebo group discontinued treatment for safety reasons. Conclusion: A 24-week response-guided combination regimen of mericitabine 1,000 mg BID plus Peg-IFN-2a/RBV is well tolerated and more effective than a standard 48-week course of Peg-IFN-2a/RBV. (HEPATOLOGY 2013;58:514-523)

Mericitabine is a nucleoside analog polymerase inhibitor of hepatitis C virus (HCV). Treatment‐naïve HCV genotype 1 or 4 patients were randomized to double‐blind treatment with oral mericitabine at a dosage of 500 mg twice‐daily (BID) for 12 weeks (A), 1,000 mg BID for 8 (B) or 12 weeks (C and D), or placebo BID for 12 weeks (E). All patients received pegylated interferon alpha‐2a (Peg‐IFNα‐2a; 40 kD)/ribavirin (RBV) at standard doses for 24 or 48 weeks during and after mericitabine/placebo therapy. Patients in arms A‐C who maintained a virologic response (VR) (HCV RNA <15 IU/mL) from weeks 4 to 22 stopped all treatment at week 24; all other patients (arms A‐E) continued Peg‐IFNα‐2a/RBV to complete 48 weeks. The primary outcome was sustained VR (SVR) (HCV RNA <15 IU/mL after 24 weeks of untreated follow‐up; SVR‐24). VR rates were higher in arms A‐D than in arm E at weeks 4 and 12 overall, in patients with and without cirrhosis and in patients with CC and non‐CC IL28B genotypes. However, the overall SVR‐24 rate in arms D (50.6%) and E (placebo, 51.2%) was similar and those in the response‐guided therapy arms A, B, and C were lower (48.8%, 42.0%, and 32.9%, respectively). No viral breakthrough or mericitabine‐resistance mutations (S282T) were observed during mericitabine therapy. Conclusion: Treatment with mericitabine plus Peg‐IFNα‐2a/RBV for 8 or 12 weeks provided potent suppression of HCV RNA, was well tolerated, and did not select resistant variants, but did not increase SVR rates, compared to placebo. IFN‐free and IFN‐containing trials of mericitabine of longer treatment duration are ongoing. (HEPATOLOGY 2013;58:524–537)