Eiger 宣布在丁型肝炎病毒 (HDV) 的关键 3 期 D-LIVR 试验中，两

StephenW

Eiger 宣布在丁型肝炎病毒 (HDV) 的关键 3 期 D-LIVR 试验中，两种基于 Lonafarnib 的治疗在综合主要终点方面均取得了与安慰剂相比的统计显着性
Eiger BioPharmaceuticals (PRNewsFoto/Eiger BioPharmaceuticals, Inc.)

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艾格生物制药公司

2022 年 12 月 8 日，美国东部时间 08:00
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- Lonafarnib/ritonavir 的反应率为 10.1% (p=0.0044)
- Lonafarnib/ritonavir 与聚乙二醇干扰素 alfa 的组合反应率为 19.2% (p<0.0001)
- 聚乙二醇干扰素 alfa 比较组，包括效应贡献，响应率为 9.6%
- 组织学反应率改善的患者比例的关键次要终点在组合臂与安慰剂组中具有统计学意义

加利福尼亚州帕洛阿尔托，2022 年 12 月 8 日 /美通社/ -- Eiger BioPharmaceuticals, Inc.（纳斯达克代码：EIGR），一家商业阶段的生物制药公司，专注于开发针对丁型肝炎病毒 (HDV) 和其他严重疾病的创新疗法 疾病，今天公布了其具有里程碑意义的 3 期 D-LIVR 研究（N = 407）的第 48 周主要数据，该研究评估了 lonafarnib，一种一流的异戊烯化抑制剂，在慢性 HDV 患者的两种治疗方案中：lonafarnib 单独使用利托那韦（ 全口服）并与聚乙二醇干扰素 alfa 联合使用（联合）。 复合主要终点是与安慰剂相比，在 48 周治疗结束时 HDV RNA 下降≥2 log 和丙氨酸氨基转移酶 (ALT) 正常化。

第 48 周的顶线结果显示，两个治疗组在复合主要终点以及组分病毒学和生化反应方面均取得了优于安慰剂的统计学显着性。 与接受安慰剂的参与者 (1.9%) 相比，接受全口服治疗和联合治疗的研究参与者的综合反应分别为 10.1% (p=0.0044) 和 19.2% (p <0.0001)。 与接受安慰剂的参与者 (7.7%) 相比，接受全口服治疗和联合治疗的研究参与者的 ALT 正常化率分别提高了 24.7% (p=0.003) 和 34.4% (p<0.0001)，具有统计学意义。 聚乙二醇干扰素 alfa 比较组被纳入研究以显示效果的贡献。 全口服组的综合缓解率与聚乙二醇干扰素 α 组相当（10.1% 对 9.6%）。 联合治疗组的综合缓解率是聚乙二醇干扰素 α 治疗组的两倍（19.2% 对 9.6%）。

关键的次要组织学终点定义为组织学活性指数 (HAI) 改善≥2 分并且 Ishak 纤维化评分没有恶化，这是通过对在基线和第 48 周收集的成对肝活检 (n=229) 进行盲法评估确定的。这是 66 名患者中的 35 名 (53%, p=0.0139) 在联合治疗组中表现出统计学显着性，而接受安慰剂的 30 名患者中有 8 名 (27%) 表现出统计学意义。 与安慰剂组相比，全口服组的 107 名患者中有 35 名 (33%，p=0.61) 显示有反应。 聚乙二醇干扰素 α 比较组的反应是 26 名患者中的 10 名 (38%)。

正在收集剩余的次要终点，包括第 72 周（治疗后 24 周）的病毒学、生化和综合反应，预计将在 2023 年年中报告。

Eiger 总裁兼首席执行官 David Cory 表示：“我们要对参与这项控制良好、具有里程碑意义的研究的患者、研究人员和临床研究中心表示衷心的感谢。” “随着我们继续分析这些一线数据以充分了解基于 lonafarnib 的治疗慢性 HDV 的疗效和安全性概况，我们期待在下一季度与 FDA 举行 NDA 前会议，并看到完整的数据集，包括 24- 治疗后一周的数据。”

“这项具有里程碑意义的研究结果突出了三个关键发现，”索罗卡大学医学中心胃肠病学和肝病科主任、D-LIVR 研究联合首席研究员 Ohad Etzion 医学博士说。 “首先，一小部分慢性 HDV 感染患者在治疗 48 周后可以通过全口服方案实现病毒学和生化改善。其次，lonafarnib 和 ritonavir 与聚乙二醇干扰素 alfa 结合显示出将反应率提高近一倍的潜力。和 第三，也许是最重要的是，基于这些数据，联合治疗可能会导致显着的组织学改善，这是普遍接受的改善患者未来临床结果的替代指标。我们期待这项研究的 24 周治疗后结果进行评估 慢性 HDV 感染的有限疗法的潜力。”
大多数治疗紧急不良事件 (TEAE) 的严重程度为轻度或中度。 与lonafarnib治疗相关的最常见的TEAE是胃肠道。 分别有 9% 和 8% 的患者停止了 lonafarnib 口服和联合治疗组的治疗，而聚乙二醇干扰素 α 和安慰剂组各有 2% 的患者停止治疗。 在罗那法尼治疗组中，分别有 8% 和 14% 的患者报告了严重的治疗中出现的不良事件，而聚乙二醇干扰素 α 组和安慰剂组的这一比例分别为 10% 和 4%。 研究中有两人死亡：一名接受聚乙二醇干扰素α治疗的患者死于药物治疗导致的失代偿性肝硬化。 lonafarnib/ritonavir 组的另一例死亡被认为与研究药物无关。
顶线数据摘要

响应率，% (n)

病毒学/生化终点


安慰剂

(n=52)


LNF + RTV

(n=178)


LNF + RTV + 阿尔法

(n=125)


阿尔法

(n=52)

复合端点


1.9%(1)


10.1% (18)

(p=0.0044)


19.2% (24)

(p<0.0001)


9.6%(5)

HDV RNA 下降≥2 对数


3.8%(2)


14.6% (26)

(p=0.0026)


32% (40)

(p<0.0001)


36.5%(19)

ALT标准化


7.7%(4)


24.7% (44)

(p=0.003)


34.4% (43)

(p<0.001)


11.5%(6)

组织学

端点


安慰剂

(n=30)


LNF + RTV

(n=107)


LNF + RTV + 阿尔法

(n=66)


阿尔法

(n=26)

HAI ≥ 2 点改善
分数和没有恶化
Ishak 纤维化评分


27%(8)


33% (35)

(p=0.61)


53% (35)

(p=0.0139)


38%(10)

LNF=lonafarnib； RTV=利托那韦； Alfa=聚乙二醇干扰素α； HAI=组织学活性指数

Eiger 计划与监管机构合作，从预计于 2023 年第一季度与 FDA 举行 NDA 前会议开始，讨论监管提交的途径。 完整的 D-LIVR 数据集，包括治疗后 24 周的分析，将包含在潜在的监管提交中。 Eiger 打算在未来的医学大会上展示 D-LIVR 研究结果，并在同行评审的期刊上发表。
关于 D-LIVR

D-LIVR（HDV 中的 Delta 肝脏改善和病毒学反应）是一项全球性、多中心、第 3 期研究，旨在评估两种基于 lonafarnib 的治疗方法：lonafarnib 的全口服组加利托那韦 (n=178) 和组合 在接受 48 周治疗后的 HDV 感染患者中，lonafarnib 组与利托那韦联合聚乙二醇干扰素 alfa (n=125) 加强治疗，每组与安慰剂组 (n=52) 进行比较。 该研究还包括聚乙二醇干扰素 alfa 比较组 (n=52)，仅用于证明效果的贡献。 不需要两个包含 lonafarnib 的臂来证明优于聚乙二醇干扰素 alfa。 该研究还包括 24 周的治疗后随访期。

主要终点是 48 周治疗结束时 HDV RNA ≥ 2 log 下降和 ALT 正常化的综合。 关键的病毒学和生化次要终点包括主要终点的组成部分。 关键的次要组织学终点定义为组织学活性指数（HAI）改善≥2 分，并且 Ishak 评分未使纤维化恶化。 盲法基线和第 48 周配对肝活检由单个中央阅读器读取。 其他次要终点包括在治疗后随访期间。 一个独立的数据安全监测委员会在整个试验过程中审查来自 D-LIVR 的安全数据，包括在治疗后随访阶段。

D-LIVR 在 22 个国家的 116 个临床试验点招募了 407 名患者，是一项具有里程碑意义的研究，它从控制良好的临床试验中生成最大的 HDV 患者数据来源，以更好地了解和描述这种破坏性疾病。

StephenW

Eiger Announces Both Lonafarnib-based Treatments in Pivotal Phase 3 D-LIVR Trial in Hepatitis Delta Virus (HDV) Achieved Statistical Significance Against Placebo in Composite Primary Endpoint
Eiger BioPharmaceuticals (PRNewsFoto/Eiger BioPharmaceuticals, Inc.)

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Dec 08, 2022, 08:00 ET
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-  Lonafarnib/ritonavir response rate of 10.1% (p=0.0044)
-  Lonafarnib/ritonavir in combination with peginterferon alfa response rate of 19.2% (p<0.0001)
-  Peginterferon alfa comparator arm, included for contribution of effect, response rate of 9.6%
-  Key secondary endpoint of proportion of patients with improvement in histological response rate demonstrated with statistical significance in combination arm vs placebo

PALO ALTO, Calif., Dec. 8, 2022 /PRNewswire/ -- Eiger BioPharmaceuticals, Inc. (Nasdaq: EIGR), a commercial-stage biopharmaceutical company focused on the development of innovative therapies for hepatitis delta virus (HDV) and other serious diseases, today announced topline primary Week 48 data from its landmark Phase 3 D-LIVR study (N=407) evaluating lonafarnib, a first-in-class prenylation inhibitor, in two regimens in patients with chronic HDV: lonafarnib boosted with ritonavir alone (all-oral) and in combination with peginterferon alfa (combination). The composite primary endpoint was a ≥2 log decline in HDV RNA and normalization of alanine aminotransferase (ALT) at the end of 48 weeks of treatment compared to placebo.

Topline Week 48 results showed that both treatment arms achieved statistical significance over placebo in the composite primary endpoint as well as the component virologic and biochemical responses. Study participants receiving the all-oral therapy and combination therapy showed a composite response of 10.1% (p=0.0044) and 19.2% (p <0.0001), respectively, compared to those receiving placebo (1.9%). Study participants receiving the all-oral therapy and combination therapy showed statistically significant improved rates of ALT normalization of 24.7% (p=0.003) and 34.4% (p<0.0001), respectively, compared to those receiving placebo (7.7%). A peginterferon alfa comparator arm was included in the study to show contribution of effect. The composite response rate in the all-oral arm was comparable to the peginterferon alfa arm (10.1% vs 9.6%). The composite response rate in the combination arm was twice that of the peginterferon alfa arm (19.2% vs 9.6%).

The key secondary histological endpoint was defined as ≥2-point improvement in histological activity index (HAI) and no worsening of Ishak fibrosis scoring as determined by blinded assessment of paired liver biopsies (n=229) collected at baseline and Week 48. This was demonstrated in 35 of 66 patients (53%, p=0.0139) with statistical significance in the combination arm versus 8 of 30 patients (27%) receiving placebo. Response was demonstrated in 35 of 107 patients (33%, p=0.61) in the all-oral arm versus placebo. Response in the peginterferon alfa comparator arm was 10 of 26 patients (38%).

Remaining secondary endpoints including virologic, biochemical, and composite responses at Week 72 (24-weeks post-treatment) are being collected and are expected to be reported mid-2023.

"We would like to extend our sincere gratitude to the patients, investigators, and clinical study sites for their participation in this well-controlled, landmark study," said David Cory, President and CEO, Eiger. "As we continue to analyze these topline data to fully understand the efficacy and safety profile of lonafarnib-based treatments in chronic HDV, we look forward to a pre-NDA meeting with FDA in the coming quarter and seeing the full dataset including the 24-week post-treatment data."

"The results of this landmark study highlight three key findings," said Ohad Etzion, MD, Director, Department of Gastroenterology and Liver Diseases at Soroka University Medical Center and D-LIVR study co-lead investigator. "First, a small subset of patients with chronic HDV infection may achieve virologic and biochemical improvements with an all-oral regimen after 48 weeks of treatment. Second, combining lonafarnib and ritonavir with peginterferon alfa demonstrated the potential to nearly double the response rate. And third, and perhaps most importantly, based on these data, combination treatment may lead to significant histologic improvement, a generally accepted surrogate for improved future clinical outcomes for patients. We look forward to the 24-week post-treatment results of this study for assessment of the potential for finite therapy for chronic HDV infection."
The majority of treatment emergent adverse events (TEAEs) were mild or moderate in severity. The most frequent TEAEs associated with lonafarnib treatment were gastrointestinal. Nine percent and 8% of patients discontinued treatment from the lonafarnib oral and combination therapy arms, respectively, compared to 2% of patients in each of the peginterferon alfa and placebo groups. In the lonafarnib treatment groups, 8% and 14% of patients, respectively, reported serious treatment-emergent adverse events, compared with 10% in the peginterferon alfa group and 4% in the placebo group. There were two deaths in the study: one patient treated with peginterferon alfa died due to decompensated cirrhosis that was attributed to drug therapy. The other death in the lonafarnib/ritonavir arm was deemed unrelated to study drug.
Summary of Topline Data

Response Rate, % (n)

Virological/Biochemical Endpoints
       

Placebo

(n=52)
       

LNF + RTV

(n=178)
       

LNF + RTV + Alfa

(n=125)
       

Alfa

(n=52)

Composite Endpoint
       

1.9 %(1)
       

10.1% (18)

(p=0.0044)
       

19.2% (24)

(p<0.0001)
       

9.6 %(5)

≥2 Log Decline in HDV RNA
       

3.8 %(2)
       

14.6% (26)

(p=0.0026)
       

32% (40)

(p<0.0001)
       

36.5 %(19)

ALT Normalization
       

7.7 %(4)
       

24.7% (44)

(p=0.003)
       

34.4% (43)

(p<0.001)
       

11.5 %(6)

Histological

Endpoint
       

Placebo

(n=30)
       

LNF + RTV

(n=107)
       

LNF + RTV + Alfa

(n=66)
       

Alfa

(n=26)

≥2-Point Improvement in HAI
Score and No Worsening in
Ishak Fibrosis Score
       

27 %(8)
       

33% (35)

(p=0.61)
       

53% (35)

(p=0.0139)
       

38 %(10)

LNF=lonafarnib; RTV=ritonavir; Alfa=peginterferon alfa; HAI=histological activity index

Eiger plans to engage with regulatory agencies, beginning with a pre-NDA meeting with FDA anticipated in Q1 2023, to discuss pathways for regulatory submissions. The full D-LIVR dataset, including analyses of the 24-week post-treatment period, would be included in potential regulatory submissions. Eiger intends to present D-LIVR study results at a future medical congress and publish in a peer-reviewed journal.
ABOUT  D-LIVR

D-LIVR (Delta Liver Improvement and Virologic Response in HDV) is a global, multi-center, Phase 3 study to evaluate two lonafarnib-based treatments: an all-oral arm of lonafarnib boosted with ritonavir (n=178) and a combination arm of lonafarnib boosted with ritonavir combined with peginterferon alfa (n=125), with each arm compared to a placebo arm (n=52), in HDV-infected patients after 48 weeks of treatment. The study also includes a peginterferon alfa comparator arm (n=52) used to demonstrate contribution of effect only. The two lonafarnib containing arms are not required to demonstrate superiority over peginterferon alfa. The study also includes a 24-week post-treatment follow up period.

The primary endpoint is a composite of a ≥2 log decline in HDV RNA and ALT normalization at end of 48 weeks of treatment. Key virological and biochemical secondary endpoints include the components of the primary endpoint. The key secondary histological endpoint is defined as ≥2-point improvement in histological activity index (HAI) and no worsening of fibrosis by Ishak score. Blinded baseline and Week 48 paired liver biopsies were read by a single, central reader. Additional secondary endpoints were included in the post-treatment follow up period. An independent data safety monitoring board reviews the safety data from D-LIVR throughout the conduct of the trial, including during the post-treatment follow-up phase.

With 407 patients enrolled across 116 clinical trial sites in 22 countries, D-LIVR is a landmark study generating the single largest source of HDV patient data from a well-controlled clinical trial to better understand and characterize this devastating disease.

StephenW

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