Efficacy, safety, and pharmacokinetics of capsid assembly modulator linvencorvir plus standard of care in chronic hepatitis B patients.

BACKGROUND/AIMS: Four-week treatment of linvencorvir (RO7049389) was generally safe and well tolerated, and showed anti-viral activity in chronic hepatitis B (CHB) patients. This study evaluated the efficacy, safety, and pharmacokinetics of 48-week treatment with linvencorvir plus standard of care (SoC) in CHB patients. METHODS: This was a multicentre, non-randomized, non-controlled, open-label phase 2 study enrolling three cohorts: nucleos(t)ide analogue (NUC)-suppressed patients received linvencorvir plus NUC (Cohort A, n=32); treatment-naïve patients received linvencorvir plus NUC without (Cohort B, n=10) or with (Cohort C, n=30) pegylated interferon-α (Peg-IFN-α). Treatment duration was 48 weeks, followed by NUC alone for 24 weeks. RESULTS: 68 patients completed the study. No patient achieved functional cure (sustained HBsAg loss and unquantifiable HBV DNA). By Week 48, 89% of treatment-naïve patients (10/10 Cohort B; 24/28 Cohort C) reached unquantifiable HBV DNA. Unquantifiable HBV RNA was achieved in 92% of patients with quantifiable baseline HBV RNA (14/15 Cohort A, 8/8 Cohort B, 22/25 Cohort C) at Week 48 along with partially sustained HBV RNA responses in treatment-naïve patients during follow-up period. Pronounced reductions in HBeAg and HBcrAg were observed in treatment-naïve patients, while HBsAg decline was only observed in Cohort C. Most adverse events were grade 1-2, and no linvencorvir-related serious adverse events were reported. CONCLUSION: 48-week linvencorvir plus SoC was generally safe and well tolerated, and resulted in potent HBV DNA and RNA suppression. However, 48-week linvencorvir plus NUC with or without Peg-IFN did not result in the achievement of functional cure in any patient.

First-in-human randomized study of RNAi therapeutic RG6346 for chronic hepatitis B virus infection.

BACKGROUND & AIMS: RG6346 is an N-acetyl-D-galactosamine (GalNAc)-conjugated, double-stranded RNA interference agent targeting the HBV genome S-region. We investigated the safety, tolerability, pharmacokinetics, and pharmacodynamics of RG6346 in healthy volunteers and patients with chronic HBV infection (CHB). METHODS: This first-in-human, adaptive, randomized, double-blinded, phase I study recruited three groups of participants: Group A, 30 healthy volunteers received single-dose RG6346 at 0.1, 1.5, 3.0, 6.0, or 12.0 mg/kg, or placebo; Group B, nucleos(t)ide analogue-naïve participants with CHB received single-dose RG6346 at 3.0 mg/kg (n = 6) or placebo (n = 3); Group C, participants with nucleos(t)ide-suppressed CHB received four doses (every 28 days) of RG6346 at 1.5, 3.0, or 6.0 mg/kg (n = 4 in each cohort) or placebo (n = 6). RESULTS: RG6346 treatment for up to 4 months was safe and well tolerated. The most common adverse event was a mild injection site reaction. Several nucleos(t)ide-naïve participants exhibited self-resolving transaminase elevations with preserved liver function. By the end of RG6346 treatment in Group C (Day 112), the mean reduction from baseline in hepatitis B surface antigen (HBsAg) was 1.39, 1.80, and 1.64 log10 IU/ml in the 1.5, 3.0, and 6.0 mg/kg cohorts, respectively. Of the 12 participants in Group C, 11 (91.7%) achieved a ≥1 log10 IU/ml reduction in HBsAg (3 of 11 [27.3%] had the response sustained at conditional follow-up Day 448). No dose-response relationship was apparent between RG6346 and serum HBsAg levels. The RG6346-induced HBsAg response was independent of hepatitis B e antigen status. Moderate-to-marked sustained reductions of hepatitis B core-related antigen, HBV RNA, HBV DNA (in nucleos[t]ide analogue-naïve participants), and hepatitis B e antigen levels were observed. CONCLUSIONS: These favorable safety and pharmacodynamic data support the clinical development of RG6346 as the backbone of a finite antiviral treatment regimen, with the goal of sustained HBsAg loss (functional cure) in patients with CHB. CLINICAL TRIAL NUMBER: ClinicalTrials.gov NCT03772249. IMPACT AND IMPLICATIONS: Currently available therapies for chronic HBV infection are associated with low rates of functional cure and new, more efficacious treatments are needed. This first-in-human study of RG6346, an RNA interference therapy, showed a favorable safety profile as well as marked and durable reductions in hepatitis B surface antigen levels. These results support the continued development of RG6346 as the backbone of a finite treatment regimen targeting high functional cure rates and are important for HBV researchers and physicians.

Combination treatments including the small-interfering RNA JNJ-3989 induce rapid and sometimes prolonged viral responses in patients with CHB.

BACKGROUND & AIMS: RNA interference therapy has been shown to reduce hepatitis B surface antigen (HBsAg) levels in preclinical models, which could confer functional cure in patients with chronic hepatitis B. This phase IIa trial (ClinicalTrials.gov Identifier: NCT03365947) assessed the safety and efficacy of the small-interfering RNA JNJ-73763989 (JNJ-3989) plus a nucleos(t)ide analogue (NA), with/without the capsid assembly modulator JNJ-56136379 (JNJ-6379) in patients with chronic hepatitis B. METHODS: Treatment-naïve and NA-suppressed patients received 3 subcutaneous JNJ-3989 doses every week (QW; 100, 200, or 300 mg), 2 weeks (Q2W; 100 mg) or 4 weeks (Q4W; 25, 50, 100, 200, 300, or 400 mg), or JNJ-3989 Q4W (200 mg) plus oral JNJ-6379 250 mg daily for 12 weeks. Patients received NAs throughout. RESULTS: Eighty-four patients were recruited. All treatments were well tolerated, with all 5 serious adverse events considered unrelated to study drugs. JNJ-3989 100 to 400 mg Q4W resulted in HBsAg reductions ≥1 log10 IU/ml from baseline in 39/40 (97.5%) patients at the nadir. All patients receiving the triple combination (n = 12) had HBsAg reductions ≥1 log10 IU/ml from baseline at the nadir. HBsAg reductions were similar for HBeAg-positive (n = 21) and HBeAg-negative (n = 47) patients in all JNJ-3989 Q4W treatment arms, including the triple combination (n = 68). Smaller HBsAg reductions were seen with 25 mg (n = 8) and 50 mg (n = 8) than with 100 to 400 mg (n = 40). Shorter dosing intervals (QW [n = 12] and Q2W [n = 4]) did not improve response vs. Q4W dosing. HBsAg reductions ≥1 log10 IU/ml from baseline persisted in 38% of patients 336 days after the last JNJ-3989 dose. CONCLUSIONS: JNJ-3989 plus an NA, with/without JNJ-6379, was well tolerated and resulted in HBsAg reductions up to 336 days after the last JNJ-3989 Q4W dose. CLINICAL TRIAL NUMBER: NCT03365947. LAY SUMMARY: Hepatitis B virus affects people's livers and produces particles called hepatitis B surface antigen (HBsAg) that damage a person's liver and can help the virus infect a person for a long time, known as chronic hepatitis B (CHB). In this study, a new treatment called JNJ-3989 was assessed (in combination with normal treatment known as nucleos(t)ide analogues), for its safety and effectiveness in reducing the number of HBsAg particles in people with CHB. The results of this study showed that treatment with JNJ-3989 could be safe for people with CHB, lowered their HBsAg levels, and kept HBsAg levels lowered for 336 days in 38% of patients after receiving their last dose of JNJ-3989.

Plasma and breast milk pharmacokinetics of tenofovir alafenamide in mothers with chronic hepatitis B infection.

BACKGROUND: Antenatal antiviral therapy (AVT) is effective in preventing mother-to-child transmission (MTCT) in chronic hepatitis B (CHB); tenofovir disoproxil fumarate (TDF) is the preferred agent. Tenofovir alafenamide (TAF) is a prodrug of tenofovir (TFV) similar to TDF, with improved bone and renal safety. There are no data on TAF breast milk pharmacokinetics and exposure to breastfeeding infants in CHB. AIM: To assess the pharmacokinetics of TAF/TFV in breastfeeding women with CHB on TAF monotherapy. METHODS: Pregnant women with CHB requiring AVT commenced TAF 25 mg daily at third trimester or postpartum. Sample collection occurred while breastfeeding and taking TAF for minimum 4 weeks. Maternal blood, breast milk and infant urine samples were collected. Drug concentrations were measured by LCMS/MS analyses using validated methods. Non-compartmental analyses were performed to quantify the pharmacokinetic parameters. RESULTS: Eight women provided samples. In breast milk and plasma, median TAF half-life was 0.81 and 0.94 h, respectively, and Cmax 1.69 and 120.5 ng/ml, respectively. Median maternal breast milk to plasma (M/P) ratio of TAF was 0.029; for and TFV it was 2.809. The relative infant dose of TAF was 0.005% of maternal dose, well below safety threshold of 5-10%. TFV was detectable in three out of seven infant urine samples with median steady-state concentration of 5 ng/ml being 300-2500 times less than reported adult steady-state urine concentrations in those taking TAF and TDF, respectively. CONCLUSIONS: In this first pharmacokinetic study of TAF monotherapy in breastfeeding women with CHB, concentrations of TAF and TFV were low in breast milk with negligible infant exposure, supporting the use of TAF to prevent MTCT.

Therapeutic vaccine BRII-179 restores HBV-specific immune responses in patients with chronic HBV in a phase Ib/IIa study.

BACKGROUND & AIMS: Functional cure of chronic HBV infection (CHB) without life-long treatment requires the restoration of defective HBV-specific humoral and cellular immunity. Therapeutic vaccines based on the major structural and non-structural proteins have been tested in patients with CHB but have shown scarce immunogenicity. BRII-179, also known as VBI-2601, is a novel formulation comprised of all 3 HBV surface envelope proteins (Pre-S1, Pre-S2, and S). Safety, antiviral activity, and immunogenicity of BRII-179 admixed with co-adjuvant interferon (IFN)-α were assessed in patients with CHB. METHOD: This randomized, open-label, controlled phase Ib/IIa study included 2 dose levels, 20 µg BRII-179 (Part 1, n = 25) and 40 µg BRII-179 (Part 2, n = 24). Patients, virally suppressed under nucleos(t)ide analogue (NA) therapy were randomized 1:2:2 into 3 cohorts in Part 1 and 1:1 into 2 cohorts in Part 2 to receive 4 monthly intramuscular injections of BRII-179 admixed with/without 3 MIU IFN-α. Antibody and cellular responses to HBsAg, as well as evolution of circulating HBsAg were monitored. RESULTS: Both 20 µg and 40 µg BRII-179 with/without IFN-α were well tolerated with no severe adverse events. BRII-179 induced anti-HBs responses in >30% patients in all treatment cohorts, however, moderate anti-Pre-S1 or anti-Pre-S2 antibody responses were only observed in patients receiving BRII-179 with IFN-α. BRII-179 also restored S-, Pre-S1-, Pre-S2-specific IFN-γ-producing T-cells in the majority of treated patients. Overall, no notable reduction of HBsAg was observed after BRII-179 treatment. CONCLUSION: In patients with CHB under NA therapy, BRII-179 with/without IFN-α exhibited a good safety profile and induced HBV-specific B- and T-cell immune responses. These data support further clinical evaluation of BRII-179 in combination with other therapies. CLINICAL TRIAL NUMBER: ACTRN12619001210167. LAY SUMMARY: BRII-179 is a therapeutic vaccine designed to improve the immune response in patients with chronic hepatitis B. In this study, BRII-179 alone or with a low dose of interferon-α was safe, well tolerated, and induced enhanced HBV-specific antibody and T-cell responses in patients with chronic hepatitis B. However, BRII-179 treatment alone had minimal effect on patient's virological status. The potential of BRII-179 to achieve a functional cure in conjunction with other agents is being evaluated in the clinic.

Clinical Study of Single-Stranded Oligonucleotide RO7062931 in Healthy Volunteers and Patients With Chronic Hepatitis B.

BACKGROUND AND AIMS: RO7062931 is an N-acetylgalactosamine (GalNAc)-conjugated single-stranded locked nucleic acid oligonucleotide complementary to HBV RNA. GalNAc conjugation targets the liver through the asialoglycoprotein receptor (ASGPR). This two-part phase 1 study evaluated the safety, pharmacokinetics, and pharmacodynamics of RO7062931 in healthy volunteers and patients with chronic hepatitis B (CHB) who were virologically suppressed. APPROACH AND RESULTS: Part 1 was a single ascending dose study in healthy volunteers randomized to receive a single RO7062931 dose (0.1-4.0 mg/kg), or placebo. Part 2 was a multiple ascending dose study in patients with CHB randomized to receive RO7062931 at 0.5, 1.5, or 3.0 mg/kg or placebo every month for a total of 2 doses (Part 2a) or RO7062931 at 3.0 mg/kg every 2 weeks, 3.0 mg/kg every week (QW), or 4.0 mg/kg QW or placebo for a total of 3-5 doses (Part 2b). Sixty healthy volunteers and 59 patients received RO7062931 or placebo. The majority of adverse events (AEs) reported were mild in intensity. Common AEs included self-limiting injection site reactions and influenza-like illness. Supradose-proportional increases in RO7062931 plasma exposure and urinary excretion occurred at doses ≥3.0 mg/kg. In patients with CHB, RO7062931 resulted in dose-dependent and time-dependent reduction in HBsAg versus placebo. The greatest HBsAg declines from baseline were achieved with the 3.0 mg/kg QW dose regimen (mean nadir ~0.5 log10  IU/mL) independent of HBeAg status. CONCLUSIONS: RO7062931 is safe and well tolerated at doses up to 4.0 mg/kg QW. Supradose-proportional exposure at doses of 3.0-4.0 mg/kg was indicative of partial saturation of the ASGPR-mediated liver uptake system. Dose-dependent declines in HBsAg demonstrated target engagement with RO7062931.

HBsAg loss in a New Zealand community study with 28-year follow-up: rates, predictors and long-term outcomes.

BACKGROUND AND AIMS: HBsAg seroclearance is the most desired endpoint in chronic hepatitis B (CHB) but occurs uncommonly. Recent studies have shown baseline HBsAg levels to be predictive of HBsAg loss up to 10 years. We report the 28-year rates of HBsAg loss and outcomes in the Kawerau study cohort from New Zealand, and assess the predictive value of baseline HBsAg levels to predict long-term HBsAg loss. METHODS: The 1984 Kawerau community study identified 572 CHB patients, followed up for 28 years (41 % HBeAg-positive, median age 17 years, range 1-71 years). In 2012, surviving individuals attended a local clinic for an interview, blood tests and transient elastography. RESULTS: 384/218 (74 %) surviving individuals attended the clinic in 2012. Spontaneous HBsAg loss occurred in 145 (33 %) after 12,702 person-years of follow-up (1.14 per 100 person-years). Liver stiffness measurements were significantly lower if HBsAg loss occurred <50 years (mean 6.1 kPa) versus >50 years (mean 11.6 kPa), p = 0.0002. No HCC occurred following HBsAg loss (median follow-up 72 months). Predictors of HBsAg loss were older age and lower baseline HBsAg level (HR for HBsAg loss at 28 years 2.7 (95 % CI 1.7-4.2), 6.7 (95 % CI 3.9-11.4) and 9.4 (95 % CI 5.2-16.9), respectively, for HBsAg 1000-9999, 100-999 and <100 IU/mL compared to HBsAg >10,000 IU/mL at baseline, (p < 0.0001). Baseline HBsAg was a superior predictor of HBsAg loss compared to HBV DNA at all time-points: AUROC at 15 years: 0.87 (95 % CI 0.82-0.93) versus 0.73 (95 % CI 0.66-0.80) (p < 0.0001) and AUROC at 28 years: 0.74 (95 % CI 0.69-0.79) versus 0.67 (95 % CI 0.62-0.72) (p = 0.0007). The optimal cut-off HBsAg level to predict HBsAg seroclearance at 28 years is HBsAg <10,000 IU/mL (sensitivity 72 %, specificity 64 %, NPV 88 %). CONCLUSIONS: Rates of HBsAg loss in our community cohort were high, and occurred earlier than previously reported. Earlier HBsAg loss was associated with less severe liver fibrosis. Baseline HBsAg level was a good predictor of long-term HBsAg loss up to 28 years and superior to HBV DNA.

Endoscopic Therapy for Treatment of Staple Line Leaks Post-Laparoscopic Sleeve Gastrectomy (LSG): Experience from a Large Bariatric Surgery Centre in New Zealand.

BACKGROUND: Laparoscopic sleeve gastrectomy (LSG) is one of the most commonly performed bariatric procedures for treatment of morbid obesity. Despite its popularity, it is not without risks, the most serious of which is the staple line leak. Staple line leaks are difficult to manage and require significant resources in the form of surgical, radiological and endoscopic interventions; long hospital and intensive care stay and significant morbidity. International experience is slowly emerging, but there are still no clear guidelines regarding optimal management of leaks. This study aims to describe the experience of endoscopic management of these leaks by the authors and the development of a customised stent for this condition. METHODS: Middlemore Hospital is the largest bariatric surgery centre in New Zealand. Since June 2007, a total of 21 patients have received endotherapy for post-LSG leak management. Treatment included the deployment of primary self-expanding metal stents (SEMS) across the leak site, combined with complementary endoscopic modalities. Persistent leaks were treated with follow-up stenting. This study aimed to evaluate the effectiveness of post-LSG staple line leak management at Middlemore Hospital. RESULTS: A total of 20/21 (95 %) patients now have resolved leaks following a mean of 75 days of treatment (median 47, range 9-187). The mean number of endoscopic procedures required was five. Inpatient stay and average duration till leak resolution has been notably reduced since the addition of customised stents. Clinically significant stent migration occurred in 19 % of primary stents. CONCLUSION: The use of SEMS in conjunction with complementary endotherapy has shown to be both safe and effective in treating sleeve leaks; however, migration is the limiting factor for optimal management. Recent improvements in stent design, such as the one proposed in this paper, show promise in addressing this problem. Earlier use of SEMS seems to reduce the time till closure as well as the total hospital stay, as is apparent from our data.

Serological and clinical outcomes of horizontally transmitted chronic hepatitis B infection in New Zealand Maori: results from a 28-year follow-up study.

BACKGROUND: Chronic hepatitis B infection is endemic in New Zealand and has high prevalence in New Zealand Maori. Previous longitudinal studies in populations with predominantly vertically acquired chronic hepatitis B have shown low spontaneous hepatitis B surface-antigen (HBsAg) seroclearance rates: 0.5-1.4% annually (mean age of clearance 48 years). We report the 28-year follow-up data on clinical and serological outcomes in indigenous New Zealand Maori with early horizontally acquired HBV. METHODS: In 1984, community seroprevalence study identified 572 HBsAg-positive individuals, followed for 28 years. Liver-related mortality and hepatocellular carcinoma (HCC) incidence were compared between these 572 HBV carriers and 1140 HBsAg-negative matched case-controls. Surviving HBsAg-positive individuals have been followed up in 2012 with clinical assessment, blood tests and liver transient elastography. Rates of hepatitis B e-antigen (HBeAg) and HBsAg seroconversion were determined. RESULTS: After total 13 187.4 person-years follow-up, 15 HBsAg-positive patients have developed HCC compared with none of the HBsAg-negative controls (p<0.001). 12 HBsAg-positive patients died from liver-related causes compared with none in the controls (p<0.001). Spontaneous HBeAg-seroconversion occurred in 91% of HBeAg-positive patients. Spontaneous HBsAg loss occurred in 33% overall (annual clearance rate 1.34%), with higher rates at older ages (1.05% in patients<20 years at entry vs 4.3% per annum >40 years at entry, p<0.0001). Median ages of HBeAg loss and HBsAg loss were 23 years (range 6-66 years) and 40 years (range 4-80 years), respectively. CONCLUSIONS: Horizontally transmitted HBV in Maori is similarly associated with increased risk of liver-related mortality and HCC compared with Chinese, although absolute incidence rates are lower. The rates of HBeAg and HBsAg loss are high, and occur at an earlier age than previously reported.