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Ruzotolimod (Toll‐like receptor 7 (TLR7) agonist, RG7854) is an oral, small molecule immuno‐modulator activating the TLR 7 and is being evaluated in patients with CHB. As with other TLR7 agonists, the study drug‐related adverse events of flu‐like symptoms have been reported in some participants during phase I studies with ruzotolimod. An exploratory analysis of the relationship between pharmacokinetic (PK)/pharmacodynamic (PD) and flu‐like symptoms was performed in participants from two phase I studies including both healthy volunteers and NUC‐suppressed CHB patients who received either single or multiple ascending doses of orally administered ruzotolimod. Linear and logistic regression were used to explore potential relationships between dose, flu‐like symptoms, PK, and PD. Generalized linear regression was performed to predict the probability of flu‐like symptoms of all intensities at different RO7011785 (the active metabolite of the double prodrug ruzotolimod) PK exposure. This analysis showed that single or multiple doses of ruzotolimod at ⩾100 mg, the immune PD (IFN‐α, neopterin, IP‐10, and the transcriptional expression of ISG15, OAS‐1, MX1, and TLR7) responses increase with the RO7011785 PK exposure, which increases linearly with the doses from 3 mg to 170 mg of ruzotolimod. The analysis also showed that the probability of flu‐like symptoms occurrence increases with PD responses (IFN‐α and IP‐10). Dose reduction of ruzotolimod can be an effective way to reduce the magnitude of PD response, thus reducing the probability of study drug‐related flu‐like symptoms occurrence at all intensity in the participants who are highly sensitive to PD activation and intolerant to flu‐like symptoms. [ABSTRACT FROM AUTHOR]

RO6870868 is an oral prodrug of the toll‐like receptor 7 (TLR7) specific agonist, RO6871765. TLR7 agonists augment host immune activity and are in development to treat hepatitis B infection. We evaluated the safety, tolerability, pharmacokinetics (PKs), and pharmacodynamics (PDs) of RO6870868 in a first‐in‐human, phase I, randomized, single ascending oral dose study in 60 healthy volunteers at 6 dose levels (200–2000 mg). Single oral doses were generally well‐tolerated with a predictable safety profile associated with dose‐dependent increases in systemic interferon. No serious adverse events (AEs) were reported and no subject withdrew from the study due to an AE. No clinically significant changes were observed in vital signs, electrocardiograms, or laboratory parameters. Following oral RO6870868 doses, plasma RO6871765 concentrations increased rapidly, exhibiting mean terminal half‐life ranging 2–6 h across all cohorts, with area under the plasma concentration versus time curve extrapolated to infinity (AUC0‐∞) increasing proportionally with dose. A pattern of dose and time‐dependent PD activity was demonstrated consistent with engagement of the TLR7 system. Single RO6870868 doses activated components of the TLR innate immune system in a dose‐dependent manner with adequate safety and tolerability. Single‐dose data in healthy volunteers are useful to evaluate safety, PK, and PD activity of TLR7 agonists and help to guide dose and regimen selection for further trials in patients with chronic hepatitis B. [ABSTRACT FROM AUTHOR]

Toll‐like receptor 7 (TLR7) agonists modulate broad spectrum immune activity and are evaluated in the treatment of human diseases, including cancer and chronic viral infection. RO7020531, an oral prodrug of a TLR7 agonist, is in clinical development as part of a curative regimen against chronic hepatitis B. We report the safety, tolerability, pharmacokinetics (PKs), and pharmacodynamics (PDs) of RO7020531 in healthy Chinese volunteers following single and multiple ascending doses (SAD and MAD). PK and PD samples were evaluated from four SAD cohorts and 3 MAD cohorts with 10 subjects each (8 active and 2 placebo). Safety and tolerability were monitored throughout the study. A total of 155 adverse events (AEs) were reported in 49 subjects. Fifty‐one AEs in 18 subjects were assessed as treatment‐related. Most of the AEs were mild; nine subjects experienced moderate AEs; there were no severe AEs. In two 150 mg MAD cohorts given every other day (q.o.d.), 7 of 20 subjects experienced pyrexia and were discontinued due to transient asymptomatic lymphopenia, which resolved 24–48 hours postdose. The PK of the active metabolite, RO7011785, increased linearly with dose from 40 mg to 170 mg. There was no PK accumulation following q.o.d. dosing. The PK profile is consistent with observations in white subjects in the global first‐in‐human study. SADs and MADs of RO7020531 resulted in dose‐dependent increases in TLR7 response markers at 100 mg or above. Flu‐like symptoms were associated with higher interferon‐α levels. RO7020531 was safe and acceptably tolerated in healthy Chinese volunteers with a multiple 150 mg q.o.d. dose regimen. [ABSTRACT FROM AUTHOR]

Background: Melanoma is a rare, deadly disease without effective treatment options in China. Vemurafenib is a selective inhibitor of oncogenic BRAFV600 kinase approved in more than 90 countries, based on results obtained primarily in Caucasian patients. Limited data are available regarding the efficacy and safety of vemurafenib in Asian patients.Methods: This phase I study investigated the pharmacokinetics, efficacy, and tolerability of vemurafenib (960 mg twice daily) in Chinese patients with BRAFV600 mutation-positive unresectable or metastatic melanoma. The study included two cohorts: a pharmacokinetic cohort (n = 20) and an expansion cohort (n = 26).Results: After 21 days of dosing, vemurafenib demonstrated marked accumulation and relatively constant steady-state exposure over the dosing period. Confirmed best overall response rate was 52.2% (95% CI 37.0-67.1%). Median progression-free survival was 8.3 months (95% CI 5.7-10.9%); median overall survival was 13.5 months (95% CI 12.2%-not estimable). The most common adverse events were dermatitis acneiform, arthralgia, diarrhea, blood cholesterol level increase, blood bilirubin level increase, melanocytic nevus, and alopecia. A total of nine grade 3 or 4 adverse events were reported in seven patients (15.2%).Conclusion: Overall, vemurafenib showed a favorable benefit-risk profile among Chinese patients. Pharmacokinetics, safety, and efficacy were generally consistent with those reported in Caucasian patients.Trial Registration: ClinicalTrials.gov identification: NCT01910181 . Registered 29 July 2013, prospectively registered. [ABSTRACT FROM AUTHOR]

Toll-like receptor 7 (TLR7) agonists augment immune activity and have potential for the treatment of chronic hepatitis B virus (HBV) infection. We aimed to assess the safety and tolerability of RO7020531 (also called RG7854), a prodrug of the TLR7 agonist RO7011785, in healthy volunteers and patients with chronic HBV infection. This randomised, observer-blind, placebo-controlled, phase 1 study was done in two parts. Part 1 was done at one site in New Zealand and part 2 was done at 12 sites in Bulgaria, Hong Kong, Italy, New Zealand, the Netherlands, Taiwan, Thailand, and the UK. In part 1, healthy volunteers were randomly assigned (4:1) within one of eight dose cohorts (3 mg, 10 mg, 20 mg, 40 mg, 60 mg, 100 mg, 140 mg, or 170 mg) to receive a single RO7020531 dose or placebo or randomly assigned (4:1) within one of three dose cohorts (100 mg, 140 mg, or 170 mg) to receive either RO7020531 or placebo every other day for 13 days. In part 2, nucleoside or nucleotide analogue-suppressed patients with chronic HBV infection were randomly assigned (4:1) within cohorts 1–3 (150 mg, 150 mg, or 170 mg) to receive either RO7020531 or placebo and treatment-naive patients with chronic HBV infection were randomly assigned (3:1) in cohort 4 to receive either 150 mg of RO7020531 or placebo. Patients were treated every other day for 6 weeks. Study medication was administered orally to participants after they had fasted. Study participants and investigational staff were masked to treatment allocation. The primary outcome was the safety and tolerability of RO7020531, as measured by the incidence and severity of adverse events and the incidence of laboratory, vital sign, and electrocardiogram abnormalities, and was analysed in all participants who received at least one dose of the study medication. This trial is registered with ClinicalTrials.gov , NCT02956850 , and the study is complete. Between Dec 12, 2016, and March 21, 2021, 340 healthy volunteers were screened in part 1, of whom 80 were randomly assigned in the single ascending dose study (eight assigned RO7020531 in each cohort and 16 assigned placebo) and 30 were randomly assigned in the multiple ascending dose study (eight assigned RO7020531 in each cohort and six assigned placebo), and 110 patients were screened in part 2, of whom 30 were randomly assigned in cohorts 1–3 (16 assigned RO7020531 150 mg, eight assigned RO7020531 170 mg, and six assigned placebo) and 20 were randomly assigned in cohort 4 (15 assigned RO7020531 and five assigned placebo). All randomly assigned participants received at least one dose of a study drug and were included in the safety analysis. All tested doses of RO7020531 were safe and had acceptable tolerability in healthy volunteers and patients. The most frequent treatment-related adverse events among the total study population were headache (15 [9%] of 160 participants), influenza-like illness (seven [4%] of 160 participants), and pyrexia (ten [6%] of 160 participants). Most adverse events were mild and transient. There were no severe or serious adverse events in healthy volunteers. In the patient cohorts, there was one severe adverse event (influenza-like illness with 170 mg of RO7020531) and one serious adverse event (moderate influenza-like illness with a 3-day hospitalisation in a treatment-naive patient receiving RO7020531). There were no treatment-related deaths. Due to acceptable safety and tolerability, RO7020531 should continue to be developed for the treatment of patients with chronic HBV infection. F Hoffmann-La Roche. [ABSTRACT FROM AUTHOR]