背景:Toll样受体7(TLR7)激动剂可增强免疫活性,并具有治疗慢性乙型肝炎病毒(HBV)感染的潜力。我们旨在评估RO7020531(也称为RG7854)的安全性和耐受性,TLR7激动剂RO7011785的前药,在健康志愿者和慢性HBV感染患者中。
方法:这是随机的,观察者盲,安慰剂对照,第一阶段研究分为两部分。第1部分在新西兰的一个地点完成,第2部分在保加利亚的12个地点完成,香港,意大利,新西兰,荷兰,台湾,泰国,和英国。在第1部分中,健康志愿者被随机分配(4:1)在八个剂量组中的一个剂量组中(3mg,10毫克,20毫克,40毫克,60mg,100毫克,140毫克,或170毫克)接受单一的RO7020531剂量或安慰剂或随机分配(4:1)在三个剂量组(100毫克,140毫克,或170毫克)每隔一天接受RO7020531或安慰剂,共13天。在第2部分,核苷或核苷酸类似物抑制慢性HBV感染的患者被随机分配(4:1)在队列1-3(150毫克,150毫克,或170mg)接受RO7020531或安慰剂和未接受治疗的慢性HBV感染患者在队列4中随机分配(3:1)接受150mgRO7020531或安慰剂。患者每隔一天治疗6周。研究药物在参与者禁食后口服给药。研究参与者和研究人员被掩盖治疗分配。主要结果是RO7020531的安全性和耐受性,通过不良事件的发生率和严重程度以及实验室的发生率来衡量,生命体征,心电图异常,并对所有接受至少一剂研究药物的参与者进行了分析.该试验已在ClinicalTrials.gov注册,NCT02956850,且研讨完成。
结果:在2016年12月12日至2021年3月21日之间,在第1部分中筛选了340名健康志愿者,其中80名被随机分配到单剂量递增剂量研究中(每个队列中有8名分配RO7020531,16名安慰剂),30名被随机分配到多剂量递增剂量研究中(每个队列中有8名分配RO7020531,6名安慰剂)。第2部分筛选了110例患者,其中30例随机分配到第1-3组(16例分配RO7020531150mg,八个分配的RO7020531170毫克,和6个分配的安慰剂)和20个在队列4中随机分配(15个分配的RO7020531和5个分配的安慰剂)。所有随机分配的参与者都接受了至少一个剂量的研究药物,并被纳入安全性分析。所有测试剂量的RO7020531是安全的,并且在健康志愿者和患者中具有可接受的耐受性。在整个研究人群中,最常见的与治疗相关的不良事件是头痛(160名参与者中的15[9%])。流感样疾病(160名参与者中有7名[4%]),和发热(160名参与者中有10名[6%])。大多数不良事件是轻度和短暂的。健康志愿者没有发生严重或严重的不良事件。在患者队列中,有1例严重不良事件(使用170mgRO7020531的流感样疾病)和1例严重不良事件(接受RO7020531的未接受治疗患者住院3天的中度流感样疾病).没有治疗相关的死亡。
结论:由于可接受的安全性和耐受性,RO7020531应继续开发用于治疗慢性HBV感染患者。
背景:FHoffmann-LaRoche.
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.