LO8: A PHASE 2 STUDY OF PEGINTERFERON LAMBDA, LONAFARNIB, AND RITONAVIR FOR 24 WEEKS: END-OF-STUDY RESULTS FROM THE LIFT HDV STUDY.Dr. Christopher Koh, MD, MHSc FAASLD1, Dr. Julian Hercun2, Farial Rahman3, Amy Huang4, Dr. Ben Da5, Ms. Pallavi Surana6, Dr. Devika Kapuria7, Dr. Yaron Rotman8, Dr. Anusha Vittal2, Dr. Christy Ann L Gilman2, Gil Ben-Yakov9, Dr. Chunwei Walter Lai4, Prof. Harel Dahari10, Dr. Jeffrey Glenn11and Dr. Theo Heller12, (1)Liver Disease Branch, National Institute of Diabetes Digestive and Kidney Diseases, National Institutes of Health, DHHS, (2)Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, (3)Niddk-Nih, (4)Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, (5)Icahn School of Medicine at Mount Sinai, (6)Liver Disease Branch, National Institute of Diabetes and Digestive and Kidney Diseases, (7)Liver Disease Branch, National Institutes of Health, (8)Liver and Energy Metabolism Section, National Institute of Diabetes and Digestive and Kidney Diseases, (9)Liver Disease Branch, Niddk, (10)Loyola University Chicago, (11)Div of Gastroenterologyand Hepatology, Stanford University Medical Center, (12)Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, DHHSBackground: Hepatitis Delta Virus (HDV) infection, the most aggressive form of human chronic viral hepatitis, is still without an approved FDA therapy. Separate clinical trials evaluating the prenylation inhibitor lonafarnib (LNF) boosted with ritonavir (RTV) and peginterferon lambda-1a (LMD) monotherapy have demonstrated anti-HDV activity. In a first-in-humans clinical trial, the Lambda InterFeron combination Therapy (LIFT) study evaluated the safety and antiviral effects of combination therapy with LMD/LNF/RTV in chronic HDV infected patients.Methods: In this phase 2 open-label study, 26 adult patients with chronic HDV and quantifiable HDV RNA in serum (lower limit of quantitation <40 IU/mL) were treated with subcutaneous LMD 180 mcg weekly and oral LNF 50 mg and RTV 100 mg twice daily for 24 weeks followed by 24 weeks of post-therapy follow-up. The primary therapeutic endpoint was a decrease of HDV RNA by >2 log from baseline at 24 weeks of therapy. Tenofovir or Entecavir was started prior to therapy. Serial assessments of safety parameters, liver tests, pharmacokinetics, histology, and virologic (HDV RNA, HBV DNA, and HBsAg) markers were obtained.Results: In this completed study, patients were 65% male, median age of 40 years and included Asian (54%), White (31%) and African (15%) subjects. Median baseline evaluations included: ALT (64 IU/mL), AST (47 IU/mL), Ishak Fibrosis (3), modified HAI inflammation (9), HBV DNA (<21 IU/mL) and log HDV RNA (4.7 IU/mL). During the study, 24 patients (92%) achieved a >2 log decline and 20 patients (77%) achieved either undetectable HDV RNA levels or below the lower limit of quantification (BLOQ). By intention-to-treat analysis, at 24-weeks of therapy, the median HDV RNA decline from baseline was 3.23 log IU/mL (IQR:2.94-4.49, p<0.0001) with 9 patients (35%) achieving undetectable HDV RNA and 3 patients (11.5%) with HDV RNA BLOQ. Adverse events were mostly mild to moderate and included GI related side effects, weight loss, hyperbilirubinemia, and anemia. Therapy was dose reduced in3 patients and discontinued in 4 patients. After 24-weeks of follow-up, 3 patients (11.5%) maintained a durable response with undetectable HDV RNA and normal liver enzymes.Conclusion: Combination therapy with LMD/LNF/RTV was safe and tolerable for up to 6 months in most patients. Along with significant anti-HDV activity, this was the first demonstration of sustained anti-HDV response with this therapeutic regimen. Preliminary analysis supports continued exploration of this regimen and that increased duration of therapy may lead to increased response rates.作者: StephenW 时间: 2020-11-4 18:41
LO8：PEG干扰素Lambda，LONAFARNIB和RITONAVIR的第2阶段研究持续了24周：从LIFT HDV研究得出的研究最终结果。医学博士Christopher Koh，MHSc FAASLD1，Julian Hercun博士2，Farial Rahman3，Amy Huang4，Ben Da5，Pallavi Surana6，Devika Kapuria博士7，Yaron Rotman8博士，Anusha Vittal2博士，Christy Ann L Gilman2博士，Gil Ben-Yakov9，Chunwei Walter Lai博士4，Harel Dahari教授10，Jeffrey Glenn11博士和Theo Heller博士12，（1）美国国立卫生研究院（DHHS）国立卫生研究院糖尿病与肾脏病研究所肝病科2）国立卫生研究院国立糖尿病与消化及肾脏疾病研究所肝病科，（3）Niddk-Nih，（4）国立糖尿病及消化与肾脏病研究所肝病科，（5）伊坎学校西奈山医学研究所，（6）国立糖尿病与消化与肾病研究所肝病科，（7）国立卫生研究院肝病科，（8）国立糖尿病与消化研究所肝与能量代谢科和肾脏D疾病，（9）尼德克肝病科，（10）芝加哥洛约拉大学，（11）斯坦福大学医学中心胃肠病学和肝病科，（12）美国国立糖尿病与消化与肾病研究所，肝脏病科DHHS卫生部背景资料：肝炎三角洲病毒（HDV）感染是人类慢性病毒性肝炎中最具侵略性的形式，但仍未批准FDA治疗。单独的临床试验评估了利托那韦（RTV）和聚乙二醇干扰素lambda-1a（LMD）单一疗法加强的异戊二烯化抑制剂lonafarnib（LNF）的抗HDV活性。在一项人类首次临床试验中，Lambda InterFeron联合疗法（LIFT）研究评估了LMD / LNF / RTV联合疗法对慢性HDV感染患者的安全性和抗病毒作用。方法：在此2期开放标签研究中，对26名患有慢性HDV和可定量HDV RNA血清（定量下限<40 IU / mL）的成年患者，每周皮下注射LMD 180 mcg，每天两次口服LNF 50 mg和RTV 100 mg，治疗24周，随后24周治疗后的随访。主要治疗终点是治疗24周后，HDV RNA与基线相比减少了2 log以上。在治疗前开始使用替诺福韦或恩替卡韦。对安全性参数，肝试验，药代动力学，组织学和病毒学（HDV RNA，HBV DNA和HBsAg）标志物进行了连续评估。结果：在这项完成的研究中，患者为65％的男性，中位年龄为40岁，包括亚洲人（54％），白人（31％）和非洲人（15％）。中位基线评估包括：ALT（64 IU / mL），AST（47 IU / mL），Ishak纤维化（3），改良的HAI炎症（9），HBV DNA（<21 IU / mL）和log HDV RNA（4.7 IU） / mL）。在研究过程中，有24位患者（92％）的对数下降> 2，而20位患者（77％）的HDV RNA水平未检测到或低于定量下限（BLOQ）。通过意向性治疗分析，在治疗的24周内，HDV RNA相对于基线的中位数下降为3.23 log IU / mL（IQR：2.94-4.49，p <0.0001），其中9名患者（35％）达到了不可检测的HDV RNA 3例（11.5％）HDV RNA BLOQ。不良事件多为轻度至中度，包括胃肠道相关的副作用，体重减轻，高胆红素血症和贫血。 3例患者减少了治疗剂量，4例患者中止了治疗。随访24周后，有3例患者（11.5％）维持了持久的反应，未检测到HDV RNA和肝酶正常。结论：LMD / LNF / RTV联合疗法在大多数患者中安全且可耐受长达6个月。除了显着的抗HDV活性外，这是这种治疗方案对持续抗HDV应答的首次证明。初步分析支持继续探索该方案，延长治疗时间可能会导致缓解率增加。