VIR-2218在1/2期临床试验中证明剂量依赖性和持久性降低乙型肝

StephenW

VIR-2218 Demonstrates Dose-Dependent and Durable Reductions of Hepatitis B Surface Antigen in Phase 1/2 Trial

-- Company to host a conference call at 2:00 p.m. PT today

SAN FRANCISCO – April 15, 2020 - 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 -1.43 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.

StephenW

VIR-2218在1/2期临床试验中证明剂量依赖性和持久性降低乙型肝炎表面抗原

-公司将于下午2:00举行电话会议今日PT

旧金山-2020年4月15日-Vir Biotechnology，Inc.（纳斯达克股票代码：VIR）今天宣布了正在进行的患者2期试验的其他中期数据，以及VIR-2218（一项研究性小干扰）健康志愿者的1期试验的结果核糖核酸（siRNA）介导RNA干扰（RNAi），用于治疗慢性乙型肝炎病毒（HBV）感染。

正在进行的2期试验的中期结果表明，在接受了两剂VIR-2218的慢性HBV患者的第24周内，VIR-2218导致了乙型肝炎表面抗原（HBsAg）的剂量依赖性和持久性显着降低。 20 mg至200 mg。在HBeAg-和HBeAg +患者中观察到相似的HBsAg降低。此外，VIR-2218的耐受性一般良好，据报道大多数治疗的紧急不良事件（AE）严重程度较轻，并且未观察到临床上显着的丙氨酸转氨酶（ALT）升高。

新西兰奥克兰大学医学教授兼首席肝病学家爱德华·J·加恩博士说：“仅用2剂VIR-2218，在该试验中观察到的快速而持续的剂量依赖性表面抗原敲减效果令人印象深刻。”奥克兰市医院移植医师，新西兰肝脏移植科副主任。 “值得注意的是，这种反应在HBeAg-和HBeAg +患者组中均可见，表明这种单一的siRNA可以击垮患者的HBsAg，无论其疾病的阶段如何。减少与慢性HBV感染相关的高病毒抗原负担的VIR-2218等新型药物可能会成为未来功能性治疗方案的基石。”

通过靶向HBV基因组的保守区域，VIR-2218被设计为抑制所有HBV蛋白（包括HBsAg）的产生。假设抑制HBV蛋白，特别是HBsAg，可以消除针对HBV的T细胞和B细胞活性的抑制作用。 VIR-2218是临床上首个包含Alnylam Pharmaceutical，Inc.（NASDAQ：ALNY）增强稳定化化学加（ESC +）技术的siRNA，可增强稳定性并最大程度地降低脱靶活性，这可能会增强治疗效果指数。

HBV患者剂量依赖性HBsAg降低
在正在进行的2期试验中，接受核苷酸（t）逆转录酶抑制剂治疗（n = 24）的病毒抑制患者在第1天和第29天接受了两次皮下20、50、100或200 mg的VIR-2218剂量。在图24中，用20、50、100和200mg观察到的HBsAg的平均变化分别为-0.76log10，-0.93log10，-1.23log10和-1.43log10。值得注意的是，所有接受200 mg剂量水平的患者的HBsAg降低≥1 log10，而HBeAg-和HBeAg +患者的均值下降相似。在试验期间观察到的AE的频率没有剂量相关的趋势，最常见的AE是头痛（n = 6； 25％）。没有患者因不良事件而中止试验。

ESC +设计表明可能会改善肝脏的安全性

VIR-2218中包含的Alnylam ESC +技术旨在减少脱靶结合，同时保持脱靶活性，据推测可以改善肝的安全性。在体外，体内和1期临床数据分析中，与非ESC + siRNA的母体化合物ALN-HBV相比，ESC + siRNA VIR-2218具有：

     通过减少对宿主信使RNA的脱靶作用提高体外特异性；
     在人源化肝嵌合小鼠模型中引起ALT升高的倾向降低；和
     在第1阶段数据的交叉研究比较中，健康志愿者以预期与临床相关的剂量水平引起ALT升高的倾向降低。


在HBV患者人群中，尤其是那些患有晚期肝病的人群中，有关所有siRNA潜在肝安全性的信息是重要的考虑因素。

医学博士Phil Pang说：“我们很高兴我们的VIR-2218 1/2期临床试验数据继续支持该分子成为旨在有效治愈慢性HBV感染的治疗方案的基础的潜力。”博士，Vir首席医学官。 “我们的下一步将是证明，将VIR-2218与其他药物联合使用时，敲低HbsAg是否可导致高功能治愈率，这是我们下一轮试验的目标。我们希望这些联合试验中的第一个试验-将VIR-2218与缩短的聚乙二醇干扰素疗程相结合-将于今年下半年开始为患者给药。”

电话会议信息

Vir将于今天下午2:00通过电话会议讨论这些结果。 太平洋时间（美国东部时间下午5:00）。 此次电话会议将包括VIR-2218试验的首席研究员Gane博士的演讲。

参加者免费电话拨入号码：+1（833）727-9519

参加者国际拨入号码：+1（830）213-7696

演示文稿的实时网络广播可在Vir网站的“投资者”部分的“活动和演示文稿”下访问，网址为www.vir.bio，演示文稿保存30天后，将在此处进行存档。

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