RNA interference targeting ANGPTL3 for triglyceride and cholesterol lowering: phase 1 basket trial cohorts.

Elevated triglycerides and non-high-density lipoprotein cholesterol (HDL-C) are risk factors for atherosclerotic cardiovascular disease (ASCVD). ARO-ANG3 is an RNA interference therapy that targets angiopoietin-like protein 3 (ANGPTL3), a regulator of lipoprotein metabolism. This first-in-human, phase 1, randomized, placebo-controlled, open-label trial investigated single and repeat ARO-ANG3 doses in four cohorts of fifty-two healthy participants and one cohort of nine participants with hepatic steatosis, part of a basket trial. Safety (primary objective) and pharmacokinetics (in healthy participants) and pharmacodynamics (secondary objectives) of ARO-ANG3 were evaluated. ARO-ANG3 was generally well tolerated, with similar frequencies of treatment-emergent adverse events in active and placebo groups. Systemic absorption of ARO-ANG3 in healthy participants was rapid and sustained, with a mean Tmax of 6.0-10.5 h and clearance from plasma within 24-48 h after dosing with a mean t½ of 3.9-6.6 h. In healthy participants, ARO-ANG3 treatment reduced ANGPTL3 (mean -45% to -78%) 85 days after dose. Reductions in triglyceride (median -34% to -54%) and non-HDL-C (mean -18% to -29%) (exploratory endpoints) concentrations occurred with the three highest doses. These early-phase data support ANGPTL3 as a potential therapeutic target for ASCVD treatment. ClinicalTrials.gov identifier: NCT03747224.

A single, oral dose of the TLR7 agonist JNJ-64794964 induces transcriptomic and phenotypic changes in peripheral immune cells in healthy adults.

BACKGROUND: Chronic hepatitis B (CHB) is responsible for major disease burden worldwide. However, the number of available therapies is limited; cure remains an elusive goal. JNJ-64794964 (JNJ-4964) is an oral toll-like receptor-7 (TLR7) agonist being evaluated for the treatment of CHB. Here, we investigated the capacity of JNJ-4964 to induce transcriptomic and immune cell changes in peripheral blood in healthy volunteers. METHODS: Peripheral blood was collected in the JNJ-4964 first-in-human phase 1 trial at multiple time points to assess transcriptomics and changes in frequency and phenotype of peripheral-blood mononuclear cells. Correlation of changes to JNJ-4964 exposure (Cmax) and changes in cytokine levels (C-X-C motif chemokine ligand 10 [CXCL10] and interferon alpha [IFN-α]) were evaluated. RESULTS: Fifty-nine genes, mainly interferon-stimulated genes, were up-regulated between 6 hours and 5 days after JNJ-4964 administration. JNJ-4964 increased frequencies of CD69, CD134, CD137, and/or CD253-expressing natural killer (NK) cells, indicative of NK cell activation. These changes correlated with Cmax, increase of CXCL10, and induction of IFN-α and were observed at IFN-α levels that are associated with no/acceptable flu-like adverse events. JNJ-4964 administration resulted in increased frequencies of CD86-expressing B cells, indicative of B-cell activation. These changes were predominantly observed at high IFN-α levels, which are associated with flu-like adverse events. CONCLUSIONS: JNJ-4964 administration led to changes in transcriptional profiles and immune cell activation phenotype, particularly for NK cells and B cells. Together, these changes could represent a set of biomarkers for the characterization of the immune response in CHB patients receiving TLR7 agonists.

Population pharmacokinetic/pharmacodynamic models of JNJ-64794964, a toll-like receptor 7 agonist, in healthy adult participants.

BACKGROUND: JNJ-4964 is a TLR7 agonist, which, via a type I interferon (IFN)-dependent mechanism, may enhance host immunity suppressed by persistent exposure to hepatitis B antigens in chronic hepatitis B. METHODS: PK and PD data were pooled from 2 studies involving 90 participants (n = 74 JNJ-4964, dose range 0.2-1.8 mg; n = 16 placebo) in a fasted state. Food effects on PK were studied in 24 participants (1.2 or 1.25 mg). A population PK model and PK/PD models were developed to characterize the effect of JNJ-4964 plasma levels on the time course of IFN-α, IFN-γ-inducible protein 10 (IP-10 or CXCL10), IFN-stimulated gene 15 (ISG15), neopterin and lymphocytes following single and weekly dosing in healthy adults. Covariate effects, circadian rhythms and negative feedback were incorporated in the models. RESULTS: A 3-compartment linear PK model with transit absorption adequately described JNJ-4964 PK. Bioavailability was 44.2% in fed state relative to fasted conditions. Indirect response models with maximum effect (Emax) stimulation on production rate constant (kin) described IFN-α, IP-10, ISG15 and neopterin, while a precursor-dependent indirect response model with inhibitory effect described the transient lymphocyte reduction. Emax, EC50 and γ (steepness) estimates varied according to PD markers, with EC50 displaying substantial between-subject variability. Female and Asian race exhibited lower EC50, suggesting higher responsiveness. CONCLUSIONS: PK/PD models well characterized the time course of immune system markers in healthy adults. Our results supported sex and race as covariates on JNJ-4964 responsiveness, as well as circadian rhythms and negative feedback as homeostatic mechanisms that are relevant in TLR7-induced type I IFN responses.

A phase I/II study of ARO-HSD, an RNA interference therapeutic, for the treatment of non-alcoholic steatohepatitis.

BACKGROUND & AIMS: Loss-of-function HSD17ß13 mutations protect against the development of chronic liver disease. HSD17ß13 inhibition represents a potential approach to treat liver diseases, such as non-alcoholic steatohepatitis (NASH). ARO-HSD is an RNA interference (RNAi) therapeutic designed to selectively reduce expression of HSD17ß13 mRNA in hepatocytes. In this study, we evaluated the effects of ARO-HSD in normal healthy volunteers (NHVs) and patients with confirmed or clinically suspected NASH. METHODS: The safety, tolerability, and pharmacodynamics of ARO-HSD were evaluated in 32 NHVs and 18 patients with confirmed/clinically suspected NASH. Double-blind NHV cohorts received single escalating doses of ARO-HSD (25, 50, 100, or 200 mg) or placebo subcutaneously on Day 1. Open-label patient cohorts received ARO-HSD (25, 100, or 200 mg) subcutaneously on Days 1 and 29. Liver biopsy was performed pre-dose and on Day 71 to evaluate expression levels of HSD17ß13 mRNA and protein. RESULTS: ARO-HSD treatment was well tolerated with no treatment-related serious adverse events or drug discontinuations. The most frequently reported treatment-emergent adverse events were mild injection site reactions, which were short in duration. Mean changes in hepatic HSD17ß13 mRNA from baseline to Day 71 were: -56.9% (25 mg), -85.5% (100 mg), and -93.4% (200 mg). The mean HSD17ß13 mRNA reduction was 78.6% (p <0.0001) across pooled cohorts. Hepatic HSD17ß13 protein levels were similarly reduced across doses. In patients, mean changes in alanine aminotransferase from baseline to Day 71 were -7.7% (25 mg), -39.3% (100 mg), and -42.3% (200 mg) (p <0.001 for pooled cohorts). CONCLUSIONS: ARO-HSD was well tolerated at doses ≤200 mg. This proof-of-concept study demonstrated that short-term treatment with ARO-HSD reduces hepatic HSD17ß13 mRNA and protein expression, which is accompanied by reductions in alanine aminotransferase. GOV NUMBER: NCT04202354. IMPACTS AND IMPLICATIONS: There is an unmet medical need for new therapies to treat alcohol-related and non-alcoholic liver disease. ARO-HSD is a small-interfering RNA designed to silence HSD17ß13 expression and hence to phenocopy the protective effect seen in individuals with HSD17ß13 loss-of-function. The reductions in HSD17ß13 expression and in transaminases seen with ARO-HSD administration represent an initial step towards clinical validation of HSD17ß13, a drug target with substantial genetic validation, as an important modulator of human liver disease.

A multicenter, randomized, open-label, 2-arm parallel study to compare the pharmacokinetics, safety and tolerability of AVT02 administered subcutaneously via prefilled syringe or autoinjector in healthy adults.

BACKGROUND: AVT02 is an adalimumab biosimilar, with bioequivalence previously established along with clinical similarity. This study assessed the pharmacokinetic (PK) similarity of a single dose of 100 mg/mL AVT02 administered via prefilled syringe (PFS) or autoinjector (AI). RESEARCH DESIGN AND METHODS: In this open-label, 2-arm, parallel-group study, healthy adults were randomized 1:1 to receive one 40 mg (100 mg/mL) dose of AVT02 subcutaneously via PFS (N = 102) or AI (N = 105). Primary PK parameters (Cmax, AUC0-t and AUC0-inf) were evaluated up to Day 64 of the study. Secondary PK parameters, safety, tolerability and immunogenicity were also assessed. RESULTS: The 90% CIs for the ratio of geometric least squares means were contained within the pre-specified 80-125% equivalence margins for the primary PK parameters, demonstrating bioequivalence of AVT02 when administered by PFS or AI. The incidence of treatment-emergent adverse events was comparable between the two groups, with a low frequency of injection site reactions observed. Immunogenicity profiles were also similar between the two groups. CONCLUSION: Bioequivalence was demonstrated for a single dose of AVT02 administered via PFS or AI. These results will help to increase availability of devices for patients, enabling treatment choice and flexibility.

RNA Interference Therapy Targeting Apolipoprotein C-III in Hypertriglyceridemia.

APOC3-Targeting RNAi for HypertriglyceridemiaThis randomized controlled trial examined the safety and side effects of the small interfering RNA ARO-APOC3 in healthy volunteers and patients with hypertriglyceridemia and chylomicronemia. ARO-APOC3 was associated with few adverse events and no dose-limiting toxicities.

Safety, pharmacokinetics, and antiviral activity of the capsid inhibitor AB-506 from Phase 1 studies in healthy subjects and those with hepatitis B.

AB-506 is a potent, pan-genotypic small molecule capsid inhibitor that inhibits hepatitis B virus (HBV) pregenomic RNA encapsidation. We assessed the safety, pharmacokinetics, and antiviral activity of AB-506 in two randomized, double-blinded Phase 1 studies in healthy subjects (HS) and subjects with chronic HBV infection (CHB). Single ascending and multiple doses of AB-506 or placebo (30-1000 mg or 400 mg daily for 10 days) were assessed in HS. AB-506 or placebo was assessed at either 160 mg or 400 mg daily for 28 days in subjects with CHB. A second follow-up study examined AB-506 or placebo at 400 mg daily for 28 days in 14 Caucasian and 14 East-Asian HS. Twenty-eight days of AB-506 at 160 mg and 400 mg produced mean HBV-DNA declines from baseline of 2.1 log10 IU/ml and 2.8 log10 IU/ml, respectively. Four subjects with CHB (all Asian) had Grade 4 alanine aminotransferase (ALT) elevations (2 at each dose) as HBV DNA was declining; three events led to treatment discontinuation. In the second follow-up study, 2 Asian HS had serious transaminitis events leading to treatment and study termination. No subjects had bilirubin elevations or signs of hepatic decompensation. Conclusion: AB-506 demonstrated mean HBV-DNA declines of >2 log10 ; however, transient but severe ALT flares were observed in 4 Asian subjects with CHB. In the follow-up study in HS, 2 additional Asian HS had Grade 4 flares, suggesting that AB-506 hepatotoxicity contributed to the ALT elevations. The AB-506 development program was terminated because of these findings.

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.

Pharmacokinetics and pharmacodynamics of a proposed tocilizumab biosimilar MSB11456 versus both the US-licensed and EU-approved products: a randomized, double-blind trial.

BACKGROUND: Tocilizumab is a recombinant humanized monoclonal immunoglobulin G1 antibody against the interleukin-6 receptor (IL-6 R). MSB11456 is a proposed tocilizumab biosimilar. OBJECTIVES: To assess the pharmacokinetic and pharmacodynamic similarity of MSB11456 to both US-licensed and EU-approved tocilizumab. METHODS: Healthy adult volunteers (N = 685) received a single 162 mg subcutaneous injection of MSB11456, US-licensed tocilizumab, or EU-approved tocilizumab in this randomized, double-blind, parallel-group study. Blood samples were taken pre-dose and for up to 48 days post-dose. Primary endpoint pharmacokinetic parameters were analyzed using analysis of covariance. Secondary pharmacodynamic measures included serum-soluble IL-6 R and serum C-reactive protein. Safety data were analyzed descriptively. RESULTS: Pharmacokinetic equivalence (with all corresponding 90% confidence intervals for the geometric least squares mean ratios within the predefined 80.00% to 125.00% equivalence margin) was demonstrated between MSB11456 and both US-licensed and EU-approved tocilizumab, as well as between the reference products. Pharmacodynamic analyses demonstrated similarity of MSB11456 and both US-licensed and EU-approved tocilizumab, as well as between the reference products. Safety, tolerability, and immunogenicity were comparable between treatments. CONCLUSION: Pharmacokinetic and pharmacodynamic similarity of MSB11456, US-licensed tocilizumab, and EU-approved tocilizumab were demonstrated, and the three products had comparable immunogenicity and safety, supporting MSB11456 as a biosimilar to tocilizumab.

Tocilizumab is a biologic drug that is used to treat autoimmune diseases, including rheumatoid arthritis. Biologic drugs are very important for the treatment of autoimmune diseases, but their costs limit accessibility. Therefore, the availability of biosimilars, which are biologics that are very similar in structure and function to an existing biologic drug, may provide a significant cost advantage for national healthcare programs and consumers. MSB11456 is a proposed tocilizumab biosimilar. Our study tested the pharmacokinetic and pharmacodynamic similarity of MSB11456 to the approved formulations of tocilizumab in the US and EU (US-licensed and EU-approved tocilizumab) in a large group of healthy adults. Volunteers received a single 162 mg subcutaneous injection of MSB11456, US-licensed tocilizumab, or EU-approved tocilizumab in this randomized, double-blind, parallel-group study. Blood samples were taken before and regularly after the injection, and safety was monitored. We showed that the pharmacokinetics and pharmacodynamics of MSB11456, US-licensed and EU-approved tocilizumab were sufficiently similar to claim equivalence between the three products. Safety and immunogenicity were also comparable between the three treatments. These findings suggest that MSB11456 can be considered as a biosimilar to tocilizumab. Biosimilars have improved price competition and led to a reduction in the net costs of biologics, so tocilizumab biosimilars can be expected to contribute to this and potentially improve access to the best available care.

A randomized, adaptive design, double-blind, 3-arm, parallel study assessing the pharmacokinetics and safety of AVT02, a high-concentration (100 mg/mL) Adalimumab biosimilar, in healthy adult subjects (ALVOPAD FIRST).

BACKGROUND: This study (ALVOPAD FIRST) assessed bioequivalence, safety, and immunogenicity of AVT02, an adalimumab biosimilar, compared with reference product adalimumab (EU- and US-approved Humira®). METHODS: Healthy subjects (N = 392) were randomized 1:1:1 to receive one 40 mg dose of AVT02, EU-reference product, or US-reference product subcutaneously. An interim analysis was planned when ~30 subjects per arm had completed the study, to optimize final sample size. The primary PK parameters were Cmax, AUC0-t, and AUC0-inf. Bioequivalence was demonstrated if the 90% confidence intervals (CI) for the ratio of geometric means for the primary pharmacokinetic (PK) parameters were all contained within the prespecified margins of 80% and 125%. Safety and immunogenicity were assessed until Day 64. RESULTS: The 90% CI for the ratio of geometric means for the primary PK parameters, based on Fisher's Combination test analysis, were all contained within the prespecified bioequivalence margins of 80% and 125%, supporting the demonstration of bioequivalence between AVT02 and both EU- and US-reference product. The safety and immunogenicity profiles were comparable across all three treatment arms. CONCLUSION: PK bioequivalence was supported between AVT02, US-licensed- and EU-approved-reference product adalimumab. Similar safety and immunogenicity were also demonstrated. TRIAL REGISTRATION: The trial is registered at ClinicalTrials.gov (CT.gov identifier: NCT03849313).

Safety, antiviral activity and pharmacokinetics of JNJ-64530440, a novel capsid assembly modulator, as 4 week monotherapy in treatment-naive patients with chronic hepatitis B virus infection.

OBJECTIVES: We investigated JNJ-64530440 (a hepatitis B virus capsid assembly modulator) safety, antiviral activity and pharmacokinetics in patients with chronic hepatitis B (CHB) (Phase 1b, NCT03439488). METHODS: Twenty treatment-naive, HBeAg-positive or -negative CHB patients were randomized 4|:|1 to JNJ-64530440 750 mg once or twice daily, or placebo for 28 days. RESULTS: All patients (mean age 43.8 years; 85% male; 70% White; 20% HBeAg positive) completed dosing/28 day follow-up. Mild-to-moderate treatment-emergent adverse events occurred in 3/4 (placebo), 6/8 (once-daily) and 4/8 (twice-daily) patients; mostly fatigue, increased alanine aminotransferase, decreased neutrophil count, and headache. Hepatitis B virus (HBV) DNA was substantially reduced; mean (range) changes from baseline at day 29 were: -3.2 (-2.4 to -3.9) (once-daily) and -3.3 (-2.6 to -4.1) (twice-daily) log10 IU/mL; placebo 0.1 (0.7 to -0.6) log10 IU/mL. HBV DNA levels were below the lower limit of quantification (LLOQ) in 5/8 (once-daily) and 3/8 (twice-daily) patients. For patients with detectable baseline HBV RNA, mean (SE) changes versus baseline in HBV RNA at day 29 were: -2.65 (0.81) (once-daily) and -2.94 (0.33) (twice-daily) log10 copies/mL. HBV RNA levels were 'target not detected' in 4/6 (once-daily) and 3/7 (twice-daily) patients. JNJ-64530440 pharmacokinetics in CHB patients were comparable with those in healthy volunteers. CONCLUSIONS: JNJ-64530440 750 mg once-daily or twice-daily for 28 days was well tolerated and achieved potent antiviral activity in CHB patients.

Safety, pharmacokinetics, and antiviral activity of RO7049389, a core protein allosteric modulator, in patients with chronic hepatitis B virus infection: a multicentre, randomised, placebo-controlled, phase 1 trial.

BACKGROUND: RO7049389, a hepatitis B virus (HBV) core protein allosteric modulator being developed for the treatment of chronic HBV infection, was found to be safe and well tolerated in healthy participants (part 1 of this study). The objective of this proof-of-mechanism study (part 2) was to evaluate the safety, pharmacokinetics, and antiviral activity of RO7049389 in patients with chronic HBV infection. METHODS: This was a multicentre, randomised, placebo-controlled, phase 1 study. Patients with chronic HBV infection who were not currently on anti-HBV therapy were enrolled at 11 liver disease centres in Hong Kong, New Zealand, Singapore, Taiwan, and Thailand. Seven patients per dose cohort were randomly assigned (6:1) to receive oral administration of RO7049389 at 200 mg or 400 mg twice a day, or 200 mg, 600 mg, or 1000 mg once a day, for 4 weeks, or matching placebo. Randomisation was via interactive voice web response system-generated numbers, with study participants, investigators, and site personnel masked to treatment allocation. The primary endpoint of the study was safety of RO7049389 and its antiviral effect on HBV DNA concentration at the end of treatment, assessed in all patients who received at least one dose of study drug. This study is registered with ClinicalTrials.gov, number NCT02952924. FINDINGS: Between May 21, 2017, and April 3, 2019, 62 patients were screened for eligibility, and 37 eligible patients were enrolled in five dose cohorts sequentially. All adverse events were of mild or moderate intensity. Among the 31 patients who received RO7049389, the most common adverse events were headache (in five [16%] of 31 patients), increased alanine aminotransferase (ALT; five [16%]), increased aspartate aminotransferase (AST; four [13%]), upper respiratory tract infection (four [13%]), and diarrhoea (three [10%]). The most common moderate adverse events were ALT increase (three [10%]) and AST increase (two [6%]), and there were no serious adverse events. At the end of 4 weeks treatment, mean HBV DNA declines from baseline in RO7049389-treated patients were 2·44 log10 IU/mL (SD 0·98) in the 200 mg twice a day group, 3·33 log10 IU/mL (1·14) in the 400 mg twice a day group, 3·00 log10 IU/mL (0·54) in the 200 mg once a day group, 2·86 log10 IU/mL (0·79) in the 600 mg once a day group, and 3·19 log10 IU/mL (0·33) in the 1000 mg once a day group versus 0·34 log10 IU/mL (0·54) in the pooled placebo patients. INTERPRETATION: RO7049389 was safe and well tolerated and demonstrated antiviral activity over 4 weeks of treatment in patients with chronic HBV infection. These findings support further clinical development of RO7049389 as a component of novel combination treatment regimens for patients with chronic HBV infection. FUNDING: F Hoffmann-La Roche.

Safety, tolerability, pharmacokinetics, and pharmacodynamics of oral JNJ-64794964, a TLR-7 agonist, in healthy adults.

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.

Pharmacokinetics, safety and tolerability of single- and multiple-ascending doses of JNJ-64530440, a novel hepatitis B virus capsid assembly modulator, in healthy volunteers.

BACKGROUND: Pharmacokinetics and safety of JNJ-64530440, a hepatitis B virus capsid assembly modulator producing normal empty capsids (CAM-N), in healthy volunteers were evaluated. METHODS: This Phase I study (NCT03439488) was a double-blind, randomised, placebo-controlled study. Adults (n = 10/cohort, five Asian/five non-Asian), randomised 4:1, received single-ascending doses of oral JNJ-64530440 (first- and second-generation formulations) or placebo under fasted (50, 150, 300 and 900 mg) or fed (300, 750, 1,000, 2000 and 4000 mg) conditions. Multiple-ascending doses of 750 or 2000 mg once daily and 750 mg twice daily JNJ-64530440 (second-generation formulation) for 7 days were evaluated. Pharmacokinetic parameters were estimated from plasma concentrations. Safety was assessed throughout. RESULTS: Less than dose-proportional increases in maximum plasma concentrations (Cmax) and area under the plasma concentration-time curves (AUCs) were observed across the doses. Mean plasma half-lives ranged from 9.3 to 14.5 h. Cmax and AUC were ∼two fold higher under fed versus fasting conditions and slightly higher in Asians versus Caucasians. JNJ-64530440 doses ≥750 mg achieved plasma levels higher than protein-binding adjusted concentrations demonstrating in vitro antiviral activity. No serious adverse events (AEs), treatment discontinuations or dose-limiting toxicities were seen. AE frequency/severity did not increase with dose. CONCLUSIONS: Single (up to 4000 mg) and multiple doses (up to 2000 mg for 7 days) of JNJ-64530440 were well tolerated in healthy volunteers. Multiple doses ≥750 mg/day achieved plasma concentrations expected to have antiviral activity that may lower hepatitis B surface antigen. No clinically relevant differences in tolerability or pharmacokinetic parameters were seen between Asians versus Caucasians.

A Five-in-One First-in-Human Study To Assess Safety, Tolerability, and Pharmacokinetics of RO7049389, an Inhibitor of Hepatitis B Virus Capsid Assembly, after Single and Multiple Ascending Doses in Healthy Participants.

RO7049389, an inhibitor of hepatitis B virus (HBV) capsid assembly, is being developed for the treatment of patients with chronic HBV infection. The objectives of this first-in-human study are to assess the safety, tolerability, pharmacokinetics (PK), food effect, inhibitory effect on CYP3A, and effect on QT of RO7049389 in healthy participants. Five components, single-ascending-dose (SAD) cohorts, multiple-ascending-dose (MAD) cohorts, food effect assessment, drug-drug interaction assessment, and concentration-QT analysis were integrated in one study (five-in-one). Participants randomly received a single dose of 150 to 2,500 mg RO7049389 or placebo in SAD cohorts (n = 41), or multiple doses of 200 to 800 mg RO7049389 or placebo in MAD cohorts (n = 42). A single doses of 450 mg RO7049389 was administered under fasted and fed condition. The microdose of midazolam was administered before and after multiple dosing of RO7049389. Safety and tolerability were monitored throughout the study. Serial blood and urine samples were collected for the PK analysis. RO7049389 was safe and well tolerated in healthy participants. Absorption and elimination of RO7049389 occurred rapidly in plasma with minimal recovery in urine. Greater than dose-proportional increases in plasma exposure were observed. Exposure of RO7049389 (450 mg) increased by ∼2-fold when administered with a high-fat meal. The inhibition effect of RO7049389 on CYP3A was weak (<20%). No effect on QT interval was observed at up to a single dose of 2,500 mg. RO7049389 displayed a favorable safety, tolerability and PK profile suitable for further clinical development. (This trial was registered at ClinicalTrials.gov with the identifier NCT02952924.).

Development of an RNAi therapeutic for alpha-1-antitrypsin liver disease.

The autosomal codominant genetic disorder alpha-1 antitrypsin (AAT) deficiency (AATD) causes pulmonary and liver disease. Individuals homozygous for the mutant Z allele accumulate polymers of Z-AAT protein in hepatocytes, where AAT is primarily produced. This accumulation causes endoplasmic reticulum (ER) stress, oxidative stress, damage to mitochondria, and inflammation, leading to fibrosis, cirrhosis, and hepatocellular carcinoma. The magnitude of AAT reduction and duration of response from first-generation intravenously administered RNA interference (RNAi) therapeutic ARC-AAT and then with next-generation subcutaneously administered ARO-AAT were assessed by measuring AAT protein in serum of the PiZ transgenic mouse model and human volunteers. The impact of Z-AAT reduction by RNAi on liver disease phenotypes was evaluated in PiZ mice by measuring polymeric Z-AAT in the liver; expression of genes associated with fibrosis, autophagy, apoptosis, and redox regulation; inflammation; Z-AAT globule parameters; and tumor formation. Ultrastructure of the ER, mitochondria, and autophagosomes in hepatocytes was evaluated by electron microscopy. In mice, sustained RNAi treatment reduced hepatic Z-AAT polymer, restored ER and mitochondrial health, normalized expression of disease-associated genes, reduced inflammation, and prevented tumor formation. RNAi therapy holds promise for the treatment of patients with AATD-associated liver disease. ARO-AAT is currently in phase II/III clinical trials.

Immunogenicity and safety of a proposed pegfilgrastim biosimilar MSB11455 versus the reference pegfilgrastim Neulasta® in healthy subjects: A randomized, double-blind trial.

MSB11455 is a proposed biosimilar to the currently licensed reference pegfilgrastim (Neulasta® ). This study was designed primarily to compare the immunogenicity of MSB11455 and Neulasta® . As secondary objectives, the safety and tolerability of MSB11455 and Neulasta® were also compared. Healthy adult subjects were randomized to either MSB11455 or Neulasta® , stratified by antipolyethylene glycol (PEG) antibody status at screening and study site. Subjects received a single subcutaneous dose of MSB11455 or Neulasta® (both 6 mg/0.6 mL) on day 1 of each of two study periods (same product in both periods), separated by a washout of 28-35 days. Immunogenicity samples were taken predose and up to day 84 post-first dose. Noninferiority was confirmed if the upper limit of the exact one-sided adjusted 95% confidence interval (CI) for the difference in antidrug antibody (ADA)-positive rates was < 10%. Safety was assessed throughout the study. Overall, 336 subjects were randomized and treated (N = 168 in each group). Noninferiority of MSB11455 over Neulasta® was demonstrated for immunogenicity; the difference in confirmed treatment-induced ADA-positive rate between MSB11455 and Neulasta® was -0.6% (upper limit of the exact one-sided adjusted 95% CI: 6.25%). ADAs were mostly directed against the PEG moiety of pegfilgrastim. No filgrastim-specific neutralizing antibodies were detected in either treatment group. Safety and tolerability were as expected for pegfilgrastim, and comparable between treatments. This study supports and strengthens the available evidence for the biosimilarity of MSB11455 to Neulasta® .

Long-term Benefits of Sustained Virologic Response for Patient-Reported Outcomes in Patients With Chronic Hepatitis C Virus Infection.

BACKGROUND & AIMS: Patients with hepatitis C virus (HCV) infections who achieve a sustained virologic response (SVR) to treatment have improved patient-reported outcomes (PROs). We compared post-treatment PRO scores between patients with chronic HCV infection who did and did not achieve an SVR to treatment. METHODS: Patients who completed treatment in clinical trials were enrolled in 2 registries, depending on the treatment outcome (NCT01457755, NCT01457768), from 2016 to 2017 in 17 countries in North America, Europe, and the Asia-Pacific region. PRO scores (scale, 0-100) were collected at pretreatment (baseline); the last day of treatment; the post-treatment week 12 follow-up visit (in patients with SVR only); the registry baseline; and on registry weeks 12, 24, 36, 48, and 96 (the non-SVR registry) or every 24 weeks until week 96 (SVR registry), using the Short Form-36 (SF-36) instrument. RESULTS: Our analysis included 4234 patients with an SVR and 242 without an SVR from whom pretreatment PRO data were available (mean age, 54 ± 10 y; 63% male; 65% enrolled in the United States; 17% with cirrhosis; 12% with human immunodeficiency virus co-infection). Upon registry enrollment, patients with an SVR had significant increases in all PRO scores compared with pretreatment baseline levels (all P < .05). Patients without an SVR had mean reductions of 9.2 points or less in PRO scores while followed up on the registry (P < .05 for 4-8 of 8 PRO domains measured by the SF-36). In contrast, patients with an SVR had sustained increases in PRO scores (mean increase, ≤7.0 points) while on the registry. In multivariate analysis, achieving an SVR was associated independently with superior scores in all SF-36 domains at all registry time points (ß, +4.8 to +15.9 points, all P ≤ .01). CONCLUSIONS: In a follow-up analysis of participants in clinical trials, we found that those with an SVR to treatment for HCV infection had significant increases in well-being, based on PRO scores. Patients without an SVR had decreasing PRO scores over the follow-up period.

Safety, pharmacokinetics, and antiviral effects of ABI-H0731, a hepatitis B virus core inhibitor: a randomised, placebo-controlled phase 1 trial.

BACKGROUND: Therapies with novel mechanisms of action against hepatitis B virus (HBV) infection are being explored with the goal of achieving a functional cure (sustained off-treatment response) without requiring lifelong therapy. We aimed to evaluate the pharmacokinetics, safety, and antiviral activity of ABI-H0731, an investigational inhibitor of the HBV core protein. METHODS: This phase 1, randomised, placebo-controlled study was done in two parts. In part 1, healthy adults without hepatitis B aged 18-65 years at one clinical research centre in New Zealand (eight participants per dose cohort) were randomly assigned (3:1) to receive single oral doses of ABI-H0731 (100, 300, 600, or 1000 mg) or matching placebo, or once-daily or twice-daily doses of ABI-H0731 800 mg or matching placebo for 7 days. In part 2, adults aged 18-65 years at clinical research centres in New Zealand, Australia, the UK, Hong Kong, Taiwan, and South Korea with chronic HBV (12 participants per dose cohort) were randomly assigned (5:1) to receive ABI-H0731 (100, 200, 300, or 400 mg) or matching placebo once daily for 28 days. In part 2, participants were required to have HBeAg-positive or HBeAg-negative chronic HBV infection, with serum HBV DNA concentrations of at least 2 × 104 IU/mL (HBeAg-positive) or 2 × 103 IU/mL (HBeAg-negative) and serum alanine aminotransferase concentrations less than seven times the upper limit of normal. Both parts used simple randomisation, with study participants, site personnel, and study monitors masked to treatment assignments. The primary study objective was dose-related safety and tolerability of ABI-H0731 in healthy volunteers and in participants with chronic HBV infection, assessed in all treated participants. Key secondary assessments included pharmacokinetic analyses and virological responses. This study is registered with ClinicalTrials.gov, identifier NCT02908191 and is completed. FINDINGS: 48 [61%] of 79 healthy volunteers were enrolled in the single-ascending or multiple-ascending dose phase of part 1 between Nov 16, 2016, and Jan, 27, 2017. 38 [55%] of 69 HBV-infected participants were enrolled in part 2 between June 15, 2017, and March 15, 2018. All adverse events were non-specific and of mild or moderate intensity apart from a single HBV-infected participant given the 400 mg dose who developed a severe (grade 3) maculopapular rash and terminated treatment. Overall, the most frequent adverse events of any grade among the 74 participants who received ABI-H0731 were headache (11 [15%]), influenza-like illness (seven [9%]), and dizziness (six [8%]); the most frequent adverse events considered treatment-related were rash (four [5%]) and dizziness (three [4%]). In part 1, ABI-H0731 reached maximum plasma concentrations (Tmax) in 2·50-4·17 h; the mean plasma half-life (t1/2) was 23·5-28·4 h. In part 2, mean maximum HBV DNA declines from baseline were 1·7 log10 IU/mL in the 100 mg dose cohort, 2·1 log10 IU/mL in the 200 mg dose cohort, and 2·8 log10 IU/mL in the 300 mg dose cohort. Across dose cohorts, serum HBV RNA declines correlated with HBV DNA declines. INTERPRETATION: No pattern of treatment-emergent adverse events was observed at ABI-H0731 doses up to 300 mg in individuals with chronic hepatitis B. ABI-H0731 was rapidly absorbed and exhibited a plasma half-life supportive of once-daily dosing. Dose-dependent decreases in serum HBV DNA and RNA concentrations are consistent with the proposed mechanism of action. FUNDING: Assembly Biosciences.

Anti-PD-1 blockade with nivolumab with and without therapeutic vaccination for virally suppressed chronic hepatitis B: A pilot study.

BACKGROUND & AIMS: To evaluate the hypothesis that increasing T cell frequency and activity may provide durable control of hepatitis B virus (HBV), we administered nivolumab, a programmed death receptor 1 (PD-1) inhibitor, with or without GS-4774, an HBV therapeutic vaccine, in virally suppressed patients with HBV e antigen (HBeAg)-negative chronic HBV. METHODS: In a phase Ib study, patients received either a single dose of nivolumab at 0.1 mg/kg (n = 2) or 0.3 mg/kg (n = 12), or 40 yeast units of GS-4774 at baseline and week 4 and 0.3 mg/kg of nivolumab at week 4 (n = 10). The primary efficacy endpoint was mean change in HBV surface antigen (HBsAg) 12 weeks after nivolumab. Safety and immunologic changes were assessed through week 24. RESULTS: There were no grade 3 or 4 adverse events or serious adverse events. All assessed patients retained T cell PD-1 receptor occupancy 6-12 weeks post-infusion, with a mean total across 0.1 and 0.3 mg/kg cohorts of 76% (95% CI 75-77), and no significant differences were observed between cohorts (p = 0.839). Patients receiving 0.3 mg/kg nivolumab without and with GS-4774 had mean declines of -0.30 (95% CI -0.46 to -0.14) and -0.16 (95% CI -0.33 to 0.01) log10 IU/ml, respectively. Patients showed significant HBsAg declines from baseline (p = 0.035) with 3 patients experiencing declines of >0.5 log10 by the end of study. One patient, whose HBsAg went from baseline 1,173 IU/ml to undetectable at week 20, experienced an alanine aminotransferase flare (grade 3) at week 4 that resolved by week 8 and was accompanied by a significant increase in peripheral HBsAg-specific T cells at week 24. CONCLUSIONS: In virally suppressed HBeAg-negative patients, checkpoint blockade was well-tolerated and led to HBsAg decline in most patients and sustained HBsAg loss in 1 patient. LAY SUMMARY: Chronic hepatitis B virus infection (CHB) is characterized by a dysfunctional immune response. In patients with CHB, inhibitory receptors, such as programmed death receptor 1 (PD-1) are overexpressed on T cells, leading to an ineffective immune response in the liver. Herein, we show that the PD-1 inhibitor, nivolumab, is safe and effective for the treatment of virally suppressed patients with CHB. Australian New Zealand Clinical Trials Registry (http://www.anzctr.org.au/) number: ACTRN12615001133527.