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本帖最后由 sir 于 2020-4-16 10:13 编辑
SAN FRANCISCO, April 15, 2020 (GLOBE NEWSWIRE) -- Vir Biotechnology, Inc. (NASDAQ: VIR) today announced additional interim data from the ongoing Phase 2 trial in patients and results from the Phase 1 trial in healthy volunteers of VIR-2218, an investigational small interfering ribonucleic acid (siRNA) that mediates RNA interference (RNAi) for the treatment of chronic hepatitis B virus (HBV) infection.
Interim results from the ongoing Phase 2 trial demonstrate that VIR-2218 results in a significant dose-dependent and durable reduction in hepatitis B surface antigen (HBsAg) through Week 24 in patients with chronic HBV who received two doses of VIR-2218, ranging from 20 mg to 200 mg. Similar HBsAg reductions were observed in both HBeAg- and HBeAg+ patients. In addition, VIR-2218 was generally well tolerated, with the majority of treatment emergent adverse events (AEs) reported as mild in severity, and no clinically significant alanine transaminase (ALT) elevations observed.
“The rapid and sustained dose-dependent knockdown of surface antigen observed in this trial with only 2 doses of VIR-2218 is impressive,” said Edward J. Gane, M.D., Professor of Medicine at the University of Auckland, New Zealand and Chief Hepatologist, Transplant Physician and Deputy Director of the New Zealand Liver Transplant Unit at Auckland City Hospital. “Notably, this response was seen in both the HBeAg- and HBeAg+ patient groups, demonstrating that this single siRNA can knock down HBsAg in patients regardless of the stage of their disease. Novel agents like VIR-2218 that reduce the high viral antigen burden associated with chronic HBV infection will likely become the cornerstone of future functional cure regimens.”
By targeting a conserved region of the HBV genome, VIR-2218 is designed to inhibit the production of all HBV proteins, including HBsAg. Suppression of HBV proteins, particularly HBsAg, is hypothesized to remove the inhibition of T and B cell activity directed against HBV. VIR-2218 was the first siRNA in the clinic to include Alnylam Pharmaceutical, Inc.’s (NASDAQ:ALNY) Enhanced Stabilization Chemistry-Plus (ESC+) technology to enhance stability and minimize off-target activity, which may result in an enhanced therapeutic index.
Dose-dependent HBsAg reductions in HBV patients
In the ongoing Phase 2 trial, virally suppressed patients on nucleos(t)ide reverse transcriptase inhibitor therapy (n=24) received two subcutaneous 20, 50, 100, or 200 mg doses of VIR-2218 on Day 1 and Day 29. At Week 24, the mean change in HBsAg observed with 20, 50, 100, and 200 mg was -0.76 log10, -0.93 log10, -1.23 log10, and -1.5 log10, respectively. Of note, all patients who received the 200 mg dose level achieved a ≥1 log10 reduction in HBsAg, with HBeAg- and HBeAg+ patients achieving similar mean declines. There has been no dose-related trend in the frequency of AEs observed during the trial, with the most common AE being headache (n=6; 25%). No patients discontinued the trial due to an AE.
ESC+ design suggests a potentially improved hepatic safety profile
The Alnylam ESC+ technology incorporated into VIR-2218 is designed to reduce off-target binding while maintaining on-target activity, which is hypothesized to result in an improved hepatic safety profile. In analyses of the in vitro, in vivo and Phase 1 clinical data, the ESC+ siRNA VIR-2218, when compared to the parent compound ALN-HBV, which is not an ESC+ siRNA, was shown to have:
Improved in vitro specificity by reducing off-target effects on host messenger RNA;
Decreased propensity to cause ALT elevations in a humanized liver chimeric mouse model; and
In a cross-study comparison of Phase 1 data, decreased propensity to cause ALT elevations in healthy volunteers at dose levels anticipated to be clinically relevant.
Information on the potential hepatic safety profile of all siRNAs is an important consideration in the HBV patient population, especially those with advanced liver disease.
“We are pleased that the data from our VIR-2218 Phase 1/2 clinical trial continue to support the potential of this molecule to be the backbone of a treatment regimen aimed at the functional cure of chronic HBV infection,” said Phil Pang, M.D., Ph.D., Chief Medical Officer of Vir. “Our next step will be to demonstrate whether knockdown of HbsAg can result in high rates of functional cure when VIR-2218 is given in combination with other agents, which is the goal of our next set of trials. We expect the first of those combination trials – combining VIR-2218 with a shortened course of pegylated interferon - to begin dosing patients in the second half of this year.”
Conference Call Information
Vir will discuss these results via a conference call today at 2:00 p.m. PT (5:00 p.m. ET). The call will include presentation by Dr. Gane, who is the lead investigator for the VIR-2218 trials.
Participant Toll-Free Dial-In Number: +1 (833) 727-9519
Participant International Dial-In Number: +1 (830) 213-7696
A live webcast of the presentation can be accessed under Events & Presentations in the Investors section of the Vir website at www.vir.bio and will be archived there following the presentation for 30 days.
旧金山，2020年4月15日（环球新闻社）--Vir生物技术公司（NASDAQ:Vir）今天宣布了正在进行的第2阶段患者试验的额外中期数据，以及Vir-2218健康志愿者的第1阶段试验的结果，这是一种研究性小干扰核糖核酸（siRNA），介导了慢性乙型肝炎病毒（HBV）感染的治疗。
正在进行的第2阶段试验的中期结果表明，在接受两剂VIR-2218（从20毫克到200毫克）的慢性乙型肝炎患者中，VIR-2218在24周内导致乙型肝炎表面抗原（HBsAg）的显著剂量依赖性和持久性降低。HBeAg-和HBeAg+患者的HBsAg水平也有相似的下降。此外，VIR-2218的耐受性一般良好，大多数治疗引起的不良事件（AEs）严重程度较轻，没有观察到临床上显著的丙氨酸转氨酶（ALT）升高。
新西兰奥克兰大学医学教授、首席肝脏病学家Edward J.Gane博士说：“在这项试验中，仅用2剂VIR-2218就观察到表面抗原的快速和持续的剂量依赖性敲除，令人印象深刻，奥克兰市医院移植医生兼新西兰肝脏移植科副主任。值得注意的是，这一反应在HBeAg-和HBeAg+患者组中都能看到，这一单一siRNA可降低患者的HBsAg，而不论其疾病的阶段如何。新型药物如VIR-2218可减轻慢性乙型肝炎病毒感染引起的高病毒抗原负担，可能成为未来功能治疗方案的基石。”
通过靶向HBV基因组的保守区域，VIR-2218被设计用来抑制包括HBsAg在内的所有HBV蛋白的产生。HBV蛋白的抑制，特别是HBsAg的抑制，被认为可以消除针对HBV的T和B细胞活性的抑制。VIR-2218是临床上第一个siRNA，它包括Alnylam制药公司（NASDAQ:ALNY）的增强稳定化学增强（ESC+）技术，以增强稳定性和尽量减少非靶向活性，从而提高治疗指数。
HBV患者HBsAg的剂量依赖性降低
在正在进行的第2阶段试验中，接受核苷逆转录酶抑制剂治疗的病毒抑制患者（n=24）在第1天和第29天接受了两次皮下注射20、50、100或200 mg剂量的VIR-2218。24周时，20、50、100和200mg的HBsAg平均变化分别为-0.76log10、-0.93log10、-1.23log10和-1.5log10。值得注意的是，所有接受200mg剂量水平治疗的患者的HBsAg下降≥1 log10，HBeAg-和HBeAg+患者的平均下降幅度相似。试验期间观察到的不良事件频率没有剂量相关趋势，最常见的不良事件是头痛（n=6；25%）。没有患者因不良事件而中止试验。
ESC+的设计表明有可能改善肝脏的安全性
结合到VIR-2218中的Alnylam ESC+技术被设计成在保持靶向活性的同时减少靶向结合，这被假设会导致肝脏安全性的改善。在对体外、体内和1期临床数据的分析中，当与不是ESC+siRNA的母体化合物ALN-HBV相比时，ESC+siRNA VIR-2218显示出：
通过减少宿主信使RNA的非靶向效应提高体外特异性；
在人源性肝嵌合体小鼠模型中降低导致ALT升高的倾向；以及
在对第一阶段数据的交叉研究比较中，在预期具有临床相关性的剂量水平下，健康志愿者导致ALT升高的倾向降低。
关于所有siRNAs的潜在肝脏安全性的信息是HBV患者群体中的一个重要考虑因素，尤其是那些晚期肝病患者。
“我们很高兴从我们的VIR-2218第1/2阶段临床试验的数据继续支持这个分子的潜力，成为一个治疗方案的骨干，旨在慢性乙型肝炎病毒感染的功能治疗，”Phil Pang，医学博士，VIR的首席医疗官说。“我们的下一步将是证明，当VIR-2218与其他药物联合使用时，HbsAg的敲除是否能导致高功能治愈率，这是我们下一系列试验的目标。我们预计，第一个联合试验——将VIR-2218与缩短的聚乙二醇干扰素疗程结合起来——将于今年下半年开始给患者用药。”
讨论：VIR-2218的安全性没问题，疗效也还可以，注射两次降低HBSAG 1.5log，ARO-HBV注射3次降低1.7log，从各个剂量组来看VIR-2218和ARO-HBV疗效是比较相似的。VIR-2218在今年会开展一项24周联合干扰素的临床试验，个人认为24周疗程时间有点短，48周可能会有更好的结果。VIR-2218／ARO-HBV 24-48周降低3log左右的HBSAG（HBSAG平均水平低于10IU），之后添加干扰素可能效果更好，王福生院士针对低于10IU人群使用干扰素后功能性治愈的比例大概80%左右。Replicor研究认为HBSAG低于1效果更好，但VIR-2218／ARO-HBV要实现4log的目标是很困难的，如果ARO-HBV+CAMp+NA 48周可以实现降低4-6log的话，那就可能不需要干扰素了，年底AASLD或者明年EASL会有初步的结果。
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发表于 2020-4-16 10:13
