OSPREY was a single-arm, open-label, phase 1b study that assessed whether reduction of viral antigens by the small-interfering RNA daplusiran/tomligisiran (DAP/TOM) could enhance HBV-specific T-cell and/or HBsAg responses to the DNA vaccine JNJ-64300535 (JNJ-0535) in participants with virologically suppressed, HBeAg-negative chronic hepatitis B. All participants received DAP/TOM (200 mg, Q4W) for 24 weeks and 4 doses of JNJ-0535 from Week (W)14 to W26. NA was given until W36 and continued to Follow-up W48, unless stopping criteria were met. Of 24 participants enrolled, 11 (45.8%) achieved the primary endpoint of ≥2 log10 HBsAg reduction at W36. JNJ-0535 vaccination enhanced core/polymerase-specific T-cell responses in 22% of participants by W28, and 39% during follow-up. Seven participants stopped NA based on W36 results and had more polyfunctional CD4 T-cells targeting ≥2 HBV antigens and a greater mean reduction in HBsAg at Follow-up W48 versus those who continued NA (2.42 log10 IU/mL vs 0.96 log10 IU/mL).

The role of T-cell-mediated immune responses is recognized as pivotal in achieving functional cure in chronic hepatitis B (CHB) patients. We aimed to assess safety and T-cell responses induced by JNJ-6430535 (JNJ-0535); a hepatitis B virus (HBV)-specific therapeutic DNA vaccine administered via electroporation-mediated intramuscular injection. JNJ-0535 comprises 2 plasmids, encoding HBV core and polymerase (pol) proteins, respectively. We describe the safety, tolerability, and immunogenicity results of JNJ-0535 from an open-label, single arm phase 1 study in healthy volunteers (HVs) (64300535HPB1003, NTC04736147) and a randomized, placebo controlled phase 1 study in CHB patients (64300535HPB1001, NTC03463369). HBV-specific T-cell responses were evaluated using enzyme-linked immunospot (ELISpot) and intracellular cytokine staining (ICS). We performed baseline single-cell RNA sequencing (scRNA-seq) to explore immune correlates associated with vaccine response in HVs, and baseline serum proteomics (Olink Explore® 3072) to explore differences in soluble immune markers between responders and non-responders in both HVs and CHB patients. JNJ-0535 was safe and well tolerated in both HVs and CHB patients. Compared to CHB patients, HVs showed a higher proportion of participants with vaccine-induced HBV-specific T-cell responses (92% versus 50%), a greater increase from baseline (24× [interquartile range=40×;9×] versus 4.8× [interquartile range=5×;6×]) and a broader response in terms of number of antigens. Serum proteomics revealed few differential circulating host biomarkers between CHB and HVs, but these could not be linked to differences in immunogenicity. In addition, whole-blood scRNA-seq was performed in HVs to explore differences between participants with a strong vaccine response and those with low or no response. Our research showed a decrease in vaccine-induced responses in CHB patients compared to HVs and may provide preliminary insights into immune-related biomarkers that could influence vaccine immunogenicity but require further confirmation in future larger studies. trial numbers: 64300535HPB1001 (NCT03463369) First posted: 18. April 2018; ULR: https://clinicaltrials.gov/study/NCT03463369?term=JNJ-64300535&rank=2 and 64300535HPB1003 (NCT04736147) First posted: 03. Feb. 2021; URL: https://clinicaltrials.gov/study/NCT04736147?term=JNJ-64300535&rank=1.

BACKGROUND This Phase I, two-part, first-in-human study assessed safety/tolerability and pharmacokinetics/pharmacodynamics of single-ascending doses (SAD) and multiple doses (MD) of the oral toll-like receptor-7 agonist, JNJ-64794964 (JNJ-4964) in healthy adults. METHODS In the SAD phase, participants received JNJ-4964 0.2 (N = 6), 0.6 (N = 6), 1.25 (N = 8) or 1.8 mg (N = 6) or placebo (N = 2/dose cohort) in a fasted state. Food effect was evaluated for the 1.25 mg cohort following ≥6 weeks washout. In the MD phase, participants received JNJ-4964 1.25 mg (N = 6) or placebo (N = 2) weekly (fasted) for 4 weeks. Participants were followed-up for 4 weeks. RESULTS No serious adverse events (AEs) occurred. 10/34 (SAD) and 5/8 (MD) participants reported mild-to-moderate (≤Grade 2), transient, reversible AEs possibly related to JNJ-4964. Five (SAD) participants had fever/flu-like AEs, coinciding with interferon-α serum levels ≥100 pg/mL and lymphopenia (<1 × 109/L), between 24-48 h after dosing and resolving approximately 96 h after dosing. One participant (MD) had an asymptomatic Grade 1 AE of retinal exudates (cotton wool spots) during follow-up, resolving 6 weeks after observation. JNJ-4964 exhibited dose-proportional pharmacokinetics, with rapid absorption (tmax 0.5-0.75 h) and distribution, and a long terminal half-life (150-591 h). Overall, no significant differences in JNJ-4964 pharmacokinetic parameters were observed in the fed versus fasted state. JNJ-4964 dose-dependently and transiently induced cytokines with potential anti-HBV activity, including interferon-α, IP-10, IL-1 RA, and/or MCP-1, and interferon-stimulated genes (ISG15, MX1, and OAS1) in serum. CONCLUSIONS In healthy adults, JNJ-4964 was generally well-tolerated, exhibited dose-proportional pharmacokinetics and induced cytokines/ISGs, with possible anti-HBV activity.

The combination of three direct-acting antiviral agents (AL-335, odalasvir, and simeprevir: JNJ-4178 regimen) for 6 or 8 weeks demonstrated good efficacy and safety in a phase IIa study in chronic hepatitis C virus (HCV) genotype (GT)-1-infected patients without cirrhosis and has now been evaluated in a larger phase IIb study, OMEGA-1. This multicenter, randomized, open-label study (NCT02765490) enrolled treatment-naïve and interferon (±ribavirin) treatment-experienced patients with HCV GT1, 2, 4, 5, or 6 infection. Patients with HCV GT3 infection and/or liver cirrhosis were excluded. Patients received AL-335 800 mg, odalasvir 25 mg, and simeprevir 75 mg once daily for 6 or 8 weeks. The primary endpoint was sustained virologic response 12 weeks after the end of treatment (SVR12). In total, 365 patients (GT1a, 29.3%; GT1b, 42.5%; GT2, 12.3%; GT4, 14.2%; GT5, 1.4%; GT6, 0%) were randomized to receive 6 weeks (n = 183) or 8 weeks (n = 182) of treatment. SVR12 rates after 6 weeks (98.9%) or 8 weeks (97.8%) of treatment were noninferior to a historical control (98%). Viral relapse occurred in 5 patients (1.4%; 4 with HCV GT2c; 1 with GT1a). With the exception of 4 patients in the 8-week group, including 3 patients with missing data at the SVR24 timepoint, all patients who achieved SVR12 also achieved SVR24. One GT1a-infected patient experienced late viral relapse after achieving SVR18. Most adverse events (AEs) were mild with no treatment-related serious AEs. All randomized patients completed treatment. Conclusion: In HCV-infected patients, 6 and 8 weeks of treatment with JNJ-4178 resulted in SVR12 rates of 98.9% and 97.8%, respectively, and was well tolerated.

Simeprevir is approved with pegylated interferon and ribavirin (PR) for chronic hepatitis C virus (HCV) genotype (GT) 1 and GT4 infection in the USA and the European Union.

This Phase 3, open-label, rollover study (NCT01323244) investigated the efficacy and safety of simeprevir plus peginterferon α-2a (PegIFNα-2a) and ribavirin (RBV) in a well-characterized population of HCV genotype 1 (GT1)-infected treatment-experienced patients.

Hepatitis C virus (HCV)–infected patients with cirrhosis are historically a difficult‐to‐treat population and are at risk of hepatic decompensation. In the phase 2 COSMOS study that evaluated simeprevir (HCV NS3/4A protease inhibitor) + sofosbuvir (HCV nucleotide analogue NS5B polymerase inhibitor) ± ribavirin for 12 or 24 weeks in HCV genotype (GT)1–infected patients, high rates of sustained virologic response 12 weeks after planned end of treatment (SVR12) were achieved, including in patients with cirrhosis (METAVIR score F4). This phase 3, open‐label, single‐arm study (OPTIMIST‐2 [NCT02114151]) evaluated the efficacy and safety of 12 weeks of simeprevir + sofosbuvir in HCV GT1–infected treatment‐naive or treatment‐experienced patients with cirrhosis. Patients (aged 18‐70 years) with chronic HCV GT1 infection and documented presence of cirrhosis received oral simeprevir 150 mg once daily + sofosbuvir 400 mg once daily for 12 weeks. The primary efficacy endpoint of the study was the proportion of patients achieving SVR12 versus a composite historical control (SVR12 rate of 70%). Safety and patient‐reported outcomes were assessed. Overall, 103 patients received treatment. SVR12 with simeprevir + sofosbuvir (83%, 95% confidence interval 76%‐91%) met the primary objective of superiority versus the historical control (70%). SVR12 rates for treatment‐naive and treatment‐experienced patients were 88% (44/50) and 79% (42/53), respectively. Adverse events occurred in 72 (70%) patients, with most (64%) being grade 1 or 2. Serious adverse events (none considered related to study treatment) occurred in five (5%) patients, and three (3%) patients discontinued all study treatment due to adverse events. Patient‐reported outcomes improved from baseline to follow‐up week 12. Conclusion: Simeprevir + sofosbuvir for 12 weeks achieved superiority in SVR12 rates versus the historical control in treatment‐naive and treatment‐experienced HCV GT1‐infected patients with cirrhosis and was generally safe and well tolerated. (Hepatology 2016;64:360‐369)

SummarySimeprevir is a hepatitis C virus NS3/4A protease inhibitor. Hepatitis C virus baseline NS3/4A polymorphisms and emerging mutations were characterized in treatment‐naїve and treatment‐experienced genotype 4‐infected patients treated with simeprevir+peginterferon/ribavirin in the RESTORE study. Population sequencing of the NS3/4A region was performed and in vitro simeprevir activity against site‐directed mutants or chimeric replicons with patient‐derived NS3 protease sequences was assessed in a transient replicon assay. Simeprevir remained active against most (83/91 [91%]) baseline isolates tested in the chimeric replicon assay. Eight baseline isolates reduced simeprevir activity; these carried I132L or D168E substitutions reducing simeprevir median activity by 4.6‐ and 39‐fold, respectively. Six of these eight isolates were from patients achieving sustained virologic response. Baseline NS3 Q80K polymorphism was not observed in the genotype 4‐infected patients. Of the 107 simeprevir‐treated patients, 37 did not achieve sustained virologic response for any reason. Of the 32 patients who failed treatment and had sequencing information, 28 (88%) had emerging mutations at NS3 positions 80, 122, 155, 156 and/or 168 at time of failure, similar to those in genotype 1. Emerging mutations were mainly D168V and D168E alone or combined with mutations at position 80. In general, isolates obtained at time of failure displayed high‐level in vitro resistance to simeprevir (fold change ≥50) in a chimeric replicon assay with a median simeprevir fold change value of 440, consistent with observed mutations. In conclusion, emerging mutations in genotype 4 patients failing simeprevir+peginterferon/ribavirin treatment were similar to those in genotype 1 and conferred high‐level resistance to simeprevir.

BACKGROUND:Hepatitis C virus (HCV) infection is a leading cause of liver cirrhosis and subsequent hepatocellular carcinoma. HCV genotype 4 is found widely in the Middle East, Egypt and Africa, and has also spread into Europe. There are limited data available regarding the use of direct-acting antiviral agents in HCV genotype 4-infected patients with cirrhosis. AIM:To evaluate in the phase III, open-label, single-arm PLUTO study the efficacy and safety of 12 weeks of simeprevir (HCV NS3/4A protease inhibitor) plus sofosbuvir (HCV nucleotide-analogue NS5B polymerase inhibitor) in treatment-naïve and (peg)interferon ± ribavirin-experienced HCV genotype 4-infected patients, with or without compensated cirrhosis. METHODS:Adult patients with chronic HCV genotype 4 infection received simeprevir 150 mg once-daily and sofosbuvir 400 mg once-daily for 12 weeks. The primary efficacy endpoint was sustained virologic response 12 weeks after the end of treatment (SVR12). Safety was also assessed. RESULTS:Forty patients received treatment; the majority were male (73%) and treatment-experienced (68%). Overall, 7/40 (18%) patients had compensated cirrhosis. All patients achieved SVR12 [100% (Clopper-Pearson 95% confidence interval: 91-100%)]. Adverse events, all Grade 1 or 2, were reported in 20/40 (50%) patients. No serious adverse events were reported and no patients discontinued study treatment. Grade 3 treatment-emergent laboratory abnormalities were noted in 2/40 (5%) patients. CONCLUSIONS:Treatment with simeprevir plus sofosbuvir for 12 weeks resulted in SVR12 rates of 100% in treatment-naïve and -experienced patients with HCV genotype 4 infection with or without compensated cirrhosis, and was well tolerated. [NCT02250807].

Effective antiviral therapy is essential for achieving sustained virological response (SVR) in hepatitis C virus (HCV)‐infected patients. The phase 2 COSMOS study reported high SVR rates in treatment‐naive and prior null‐responder HCV genotype (GT) 1‐infected patients receiving simeprevir+sofosbuvir±ribavirin for 12 or 24 weeks. OPTIMIST‐1 (NCT02114177) was a multicenter, randomized, open‐label study assessing the efficacy and safety of 12 and 8 weeks of simeprevir+sofosbuvir in HCV GT1‐infected treatment‐naive and treatment‐experienced patients without cirrhosis. Patients were randomly assigned (1:1; stratified by HCV GT/subtype and presence or absence of NS3 Q80K polymorphism [GT1b, GT1a with Q80K, GT1a without Q80K]), prior HCV treatment history, and IL28B GT [CC, non‐CC]) to simeprevir 150 mg once daily+sofosbuvir 400 mg once daily for 12 or 8 weeks. The primary efficacy endpoint was SVR rate 12 weeks after end of treatment (SVR12). Superiority in SVR12 was assessed for simeprevir+sofosbuvir at 12 and 8 weeks versus a composite historical control SVR rate. Enrolled were 310 patients, who were randomized and received treatment (n = 155 in each arm). SVR12 with simeprevir+sofosbuvir for 12 weeks (97% [150/155; 95% confidence interval 94%‐100%]) was superior to the historical control (87%). SVR12 with simeprevir+sofosbuvir for 8 weeks (83% [128/155; 95% confidence interval 76‐89%]) was not superior to the historical control (83%). The most frequent adverse events were nausea, headache, and fatigue (12‐week arm: 15% [23/155], 14% [22/155], and 12% [19/155]; 8‐week arm: 9% [14/155], 17% [26/155], and 15% [23/155], respectively). No patients discontinued treatment due to an adverse event. One (1%, 12‐week arm) and three (2%, 8‐week arm) patients experienced a serious adverse event (all unrelated to study treatment). Conclusion: Simeprevir+sofosbuvir for 12 weeks is highly effective in the treatment of HCV GT1‐infected patients without cirrhosis, including those with Q80K. (Hepatology 2016;64:370‐380)