Spring Bank公布最近完成的2期慢性乙型肝炎实验和其他Inarigivir

StephenW

Spring Bank Announces Positive Results from the Recently Completed Phase 2 Chronic Hepatitis B ACHIEVE Trial and Additional Inarigivir Studies
Email Print Friendly Share
April 12, 2019 06:00 ET | Source: Spring Bank Pharmaceuticals, Inc.

Consistent reduction in HBV DNA demonstrated with higher inarigivir doses including in high viral burden HBeAg-positive patients

26% HBsAg responder population for all inarigivir doses showed mean HBsAg change of 0.8log10 with a range of 0.5log10 - 1.4log10

Inarigivir 400mg rapidly and uniformly increased activation markers of innate immunity without evidence of tolerance in a new inarigivir study in healthy volunteers

Favorable safety and tolerability profile observed across all doses studied

Conference call to be held today, April 12 at 8:00am EDT

HOPKINTON, Mass., April 12, 2019 (GLOBE NEWSWIRE) -- Spring Bank Pharmaceuticals, Inc. (Nasdaq: SBPH), a clinical-stage biopharmaceutical company developing novel therapeutics for the treatment of viral infections, inflammatory diseases and certain cancers, today announced at The International Liver Congress™ (ILC), the 2019 Annual Meeting of the European Association for the Study of the Liver (EASL) in Vienna, Austria, robust results from the recently completed inarigivir Phase 2 dose escalation ACHIEVE trial for patients with chronic hepatitis B virus (HBV). Spring Bank is developing inarigivir, an orally-administered hepatic-selective immunomodulator, as a potential backbone in a combinatorial treatment for chronic HBV with the goal to accelerate and substantially increase chronic HBV functional cure rates in a simple, safe and selective manner.

In an oral presentation during the General Session II Award Ceremony I at the ILC earlier today, Professor M.F. Yuen, Chief of Gastroenterology and Hepatology, University of Hong Kong, and Principal Investigator for the ACHIEVE trial, presented top-line results from all cohorts including the final 200mg dosing cohort. The data show that inarigivir continued to demonstrate a dose-dependent effect on HBV DNA and HBV RNA in the fourth cohort of the ACHIEVE trial over the 12-week dosing period. Inarigivir 200mg monotherapy dosing exhibited a mean decrease of 1.54log10 in HBV DNA with a range of 0.71log10 to 3.26log10 and a mean decrease of 1.14log10 in HBV RNA with a range of 0.08log10 to 4.88log10. Inarigivir 200mg monotherapy showed a uniform antiviral response (HBV DNA) in all patients, in particular the high viral burden HBeAg-positive patients who had not responded to the lower doses of inarigivir monotherapy in the earlier ACHIEVE cohorts. In addition, across all patients HBV DNA and HBV RNA responses strongly correlated with baseline HBsAg, baseline IP-10 and the decline of IP-10 at week 12, comparable to the clinical experience with interferon in chronic HBV.

Across all four dosing cohorts, 16 of the 62 (26%) evaluable patients treated with inarigivir had a 0.5log10 or greater reduction in HBsAg at week 12 or week 24 and were categorized as responders. The mean reduction of HBsAg in this responder population was 0.8log10 with a range of 0.5log10 to 1.4log10. Importantly, the HBsAg response to inarigivir in the ACHIEVE trial was genotype and host dependent.  Although the number of patients was small, the HBsAg response seen in Genotype A and D was excellent with 4 of 5 patients responding. Genotype B and C were the most common genotypes and 33% of genotype B responded compared to 10% of genotype C. It is important to note that 2 of the 3 genotype C patients that responded received 200mg inarigivir dose and belonged to the higher viral burden HBeAg-positive group. This amplified HBsAg response observed with inarigivir in genotype B compared to genotype C is comparable to the clinical experience of the immunomodulator interferon in the treatment of chronic HBV.

The overall data from the ACHIEVE trial also revealed evidence of a significant shutdown of viral transcription by inarigivir in HBeAg-negative patients where HBV RNA was undetectable at week 12 in all patients treated with inarigivir at the 50mg, 100mg, and 200mg doses with a concomitant undetectable HBcrAg in the majority of these patients. At week 24, the HBV RNA and HBcrAg response was sustained with the switch to tenofovir disoproxil fumarate 300mg and associated with 18 of the 22 (82%) HBeAg-negative patients also having undetectable HBV DNA.

Inarigivir was shown to be well tolerated at all doses in the ACHIEVE trial. Treatment-emergent adverse events ranged from mild to moderate in severity, with no investigator determined interferon-like side effects. The percentage of treatment-emergent adverse effects reported in the ACHIEVE trial was similar between the active and placebo groups. In the fourth cohort, one Grade 3 event (hypertriglyceridemia) was observed, but was not sustained on retesting, and there was one serious adverse event (SAE) for knee pain hospitalization reported, but this patient was dosed with placebo. There were no other clinical or biochemical events above Grade 3 during the ACHIEVE trial.

“The data from the ACHIEVE trial demonstrate a clear dose dependent antiviral response on HBV DNA and HBV RNA with inarigivir treatment,” said Professor M.F. Yuen. “Importantly, inarigivir treatment of HBeAg- negative patients in this study suggests a rapid down-regulation of cccDNA transcription.” Professor Yuen continued, “The HBsAg response of a 0.5log10 or greater reduction in the inarigivir-treated patients is the best reported to date with an oral agent in the treatment of chronic HBV patients, with a similar genotype distribution of responders to that reported for interferon, the only approved immunomodulator treatment for chronic HBV.”

Additional inarigivir data announced highlighting immune-activation with the 400mg dose

Spring Bank also announced today the results from a healthy volunteer study that examined the potential for the use of the 400mg dose of inarigivir in chronic HBV patients. The results from this study revealed that inarigivir 400mg rapidly and uniformly increased activation markers of innate immunity on circulating peripheral monocytes and dendritic cells which was sustained over a ten-day period of dosing without evidence of tolerance. There was an associated activation of CD8+ t-cells and down-regulation of NK cells resulting in a potentially favorable adaptive immune profile for an antiviral response. The results from this study also demonstrated a lack of systemic cytokine activation secondary to the intra-hepatic targeting of inarigivir resulting in a favorable tolerability profile. These compelling immune-activation data for inarigivir, together with the dose-dependent effects on HBV DNA and HBV RNA and favorable tolerability profile observed up to 200mg daily in the ACHIEVE trial, serve as the basis for the recent launch of the Spring Bank global CATALYST trials in both treatment-naïve and virally-suppressed chronic HBV patients. The CATALYST trials will focus on the examination of the 400mg dose of inarigivir.

“The increasing antiviral response seen at the 200mg dose, especially in high viral burden patients, and the clear evidence of innate immune activation at the 400mg dose in healthy volunteers with good tolerability, has led Spring Bank to choose 400mg as the inarigivir dose to move forward into longer studies focused on HBV cure,” said Nezam Afdhal, M.D., D.Sc., chief medical officer of Spring Bank Pharmaceuticals. “We have developed a comprehensive strategic clinical trial program that takes into account both patient and viral heterogeneity that we anticipate will inform our Phase 3 strategy moving into 2020.”

EASL 2019 ILC Poster Presentation demonstrating antiviral activity of inarigivir in nucleoside- and capsid-resistant HBV variants

In a poster presentation at EASL 2019 ILC, Professor Stephen Locarnini, Head of Research & Molecular Development at the Victorian Infectious Diseases Reference Laboratory and Principal Investigator of the Virology Core for the ACHIEVE trial, described his in vitro study examining the antiviral activity of inarigivir in HBV clinical isolates consisting of capsid inhibitor (CpAM) and nucleoside (NUC) analog resistant variants. Looking forward to novel combinations with agents under investigation with differing mechanisms of action, Dr. Locarnini evaluated inarigivir in NUC- and CpAM-resistant clinical isolates from HBV patients. Professor Locarnini’s data indicate that inarigivir could be used as rescue or combination therapy for NUC/CpAM-resistant failures.

Professor Locarnini stated, “The sensitivity of both NUC-resistant and CpAM-resistant strains to inarigivir and the lack of cross-resistance is beneficial for combination studies since inarigivir will cover both pre- existing resistant variants and prevent treatment-emergent resistance to both NUCs and CpAM inhibitors,” said Dr. Locarnini.

Inarigivir Clinical Development
Spring Bank has launched two Phase 2 global trials (CATALYST 1 and CATALYST 2) examining the administration of inarigivir 400mg as monotherapy and co-administered with a NUC in naïve and virally-suppressed chronic HBV patients. The CATALYST trials include multiple patient cohorts with dosing periods to include 12 weeks, 24 weeks, and 48 weeks. In addition, Gilead Sciences, Inc. is conducting a Phase 2 trial examining (i) the co-administration of inarigivir 50mg and tenofovir alafenamide 25mg (marketed by Gilead as Vemlidy®) in naïve chronic HBV patients, (ii) the co-administration of inarigivir 200mg and Vemlidy® in naïve chronic HBV patients and (iii) the administration of inarigivir 100mg in virally-suppressed patients who currently are and continue to be treated with a NUC.

Conference Call

Spring Bank will host a conference call and webcast at 8:00 am EDT today, Friday, April 12, 2019. The conference call may be accessed by dialing (877) 407-0789 for U.S. callers and (201) 689-8562 for international callers and providing the conference ID 13689400. Additionally, a live, listen-only webcast of the conference call can be accessed by visiting the Investors & Media section of the company’s website at www.springbankpharm.com or by clicking here.

A replay of the call may be accessed by visiting Spring Bank’s website.

Additional details, including presentation abstracts, can be found on the ILC website at https://ilc-congress.eu/. A copy of the presentation materials can be accessed by visiting the Presentations and Publications section of the Spring Bank Pharmaceuticals website.

StephenW

Spring Bank公布最近完成的2期慢性乙型肝炎实验和其他Inarigivir研究的阳性结果
电邮打印友好分享
2019年4月12日06:00 ET |资料来源：Spring Bank Pharmaceuticals，Inc。

使用较高的inarigivir剂量，包括高病毒负荷的HBeAg阳性患者，HBV DNA证据持续减少

所有inarigivir剂量的26％HBsAg应答人群显示平均HBsAg变化为0.8log10，范围为0.5log10  -  1.4log10

在健康志愿者的一项新的inarigivir研究中，Inarigivir 400mg快速均匀地增加了先天免疫的活化标志物而没有耐受性证据

在所研究的所有剂量中观察到有利的安全性和耐受性

电话会议将于美国东部时间4月12日上午8:00举行

马萨诸塞州霍普金顿，2019年4月12日（GLOBE NEWSWIRE） -  Spring Bank Pharmaceuticals，Inc。（纳斯达克股票代码：SBPH），一家临床阶段生物制药公司，开发用于治疗病毒感染，炎症性疾病和某些癌症的新疗法，国际肝病大会（ILC），奥地利维也纳欧洲肝脏研究协会（EASL）2019年会议宣布，最近完成的inarigivir 2期剂量递增ACHIEVE试验对慢性肝病患者的有力结果选择性inarigivir，一种口服给药的肝脏选择性免疫调节剂，作为慢性HBV组合治疗的潜在骨干，目的是以简单，安全和选择性的方式加速和显着增加慢性HBV功能治愈率。

在今天早些时候在ILC举行的第二届大会颁奖典礼上的口头报告中，香港大学消化内科和肝病学系主任，以及ACHIEVE试验的首席研究员MF Yuen教授介绍了所有队列的最佳结果，包括最终显示200mg给药队列。数据显示，在12周给药期间，在ACHIEVE试验的第四组中，inarigivir继续表现出对HBV DNA和HBV RNA的剂量依赖性作用。 Inarigivir 200mg单药治疗显示HBV DNA平均下降1.54log10，范围为0.71log10至3.26log10，HBV RNA平均下降1.14log10，范围为0.08log10至4.88log10。 Inarigivir 200mg单药治疗显示所有患者均匀的抗病毒反应（HBV DNA），尤其是HBeAg阳性患者的高病毒负荷，这些患者在较早的ACHIEVE队列中对较低剂量的inarigivir单药治疗没有反应。此外，在所有患者中，HBV DNA和HBV RNA反应与基线HBsAg，基线IP-10和第12周IP-10下降强烈相关，与慢性HBV中干扰素的临床经验相当。

该应答者群体中HBsAg的平均降低是重要的，ACHIEVE试验中对于inarigivir的HBsAg应答是基因型和宿主依赖性的。虽然患者数量很少，但基因型A和D中的HBsAg反应非常好，4基因型B和C是最常见的基因型，33％的基因型B反应相比10％的基因型C.重要的是要注意响应的3个基因型C患者中的2个接受200mg inarigivir剂量并且属于与基因型C相比在基因型B中用inarigivir观察到的放大的HBsAg应答与在慢性HBV治疗Nt中的免疫调节剂干扰素的临床经验相当。

来自ACHIEVE试验的总体数据还揭示了HBeAg阴性患者中使用inarigivir显着关闭病毒转录的证据，其中所有患者在第12周检测不到HBV RNA，50mg，100mg和200mg剂量使用inarigivir治疗。伴随在第24周，HBV RNA和HBcrAg反应持续转换为替诺福韦地索普西富马酸300mg，并且与22名（82％）HBeAg阴性患者中的18名相关，其中也检测不到HBV DNA。
在ACHIEVE试验中，Inarigivir在所有剂量下均表现出良好的耐受性。治疗引起的不良事件的严重程度从轻度到中度，没有研究者确定干扰素样副作用。在ACHIEVE试验中报告的治疗引起的不良反应的百分比在活性组和安慰剂组之间是相似的。在第四个队列中，观察到一个3级事件（高甘油三酯血症），但在重新测试时没有持续，并且报告了膝关节疼痛住院治疗的一个严重不良事件（SAE），但该患者服用安慰剂。在ACHIEVE试验期间，没有其他临床或生化事件超过3级。

“来自ACHIEVE试验的数据显示，对于HBV DNA和HBV RNA的明确剂量依赖性抗病毒应答与inarigivir治疗，”M.F.教授说。玄。 “重要的是，本研究中对HBeAg阴性患者进行的inarigivir治疗表明cccDNA转录的快速下调。”Yuen教授继续说道，“对于inarigivir治疗患者，0.5log10或更高的HBsAg反应是最好的报告。口服药物治疗慢性HBV患者的日期，与干扰素报告的应答者的基因型分布相似，是唯一批准用于治疗慢性HBV的免疫调节剂。“

额外的inarigivir数据宣布强调400mg剂量的免疫激活

Spring Bank今天还公布了一项健康志愿者研究的结果，该研究调查了在慢性HBV患者中使用400mg剂量的inarigivir的可能性。该研究的结果显示，inarigivir 400mg快速且均匀地增加了对循环外周单核细胞和树突细胞的先天免疫活化标记，其在给药的10天期间持续而没有耐受性证据。存在相关的CD8 + t细胞活化和NK细胞的下调，导致抗病毒应答的潜在有利的适应性免疫谱。该研究的结果还表明缺乏继发于inarigivir的肝内靶向的全身性细胞因子活化，导致有利的耐受性特征。这些引人注目的inarigivir免疫激活数据，以及对HBV DNA和HBV RNA的剂量依赖性影响以及在ACHIEVE试验中观察到的每日200mg的良好耐受性特征，是最近推出Spring Bank全球CATALYST的基础。在初治和病毒抑制的慢性HBV患者中均进行了试验。 CATALYST试验将重点研究400mg剂量的inarigivir。

“在200mg剂量下观察到的抗病毒反应增加，特别是在高病毒负荷患者中，以及400mg剂量的先天免疫激活的明确证据表明健康志愿者具有良好的耐受性，导致Spring Bank选择400mg作为inarigivir剂量移动转向更长期的研究，专注于HBV治疗，“Spring Bank Pharmaceuticals首席医疗官Nezam Afdhal博士说。 “我们已经制定了一项全面的战略性临床试验计划，该计划考虑了患者和病毒的异质性，我们预计这将会推动我们的第3阶段战略进入2020年。”

EASL 2019 ILC海报展示了inarigivir在核苷和衣壳抗性HBV变异体中的抗病毒活性

在EASL 2019 ILC的海报展示中，维多利亚传染病参考实验室研究与分子发展负责人兼ACHIEVE试验病毒学核心首席研究员Stephen Locarnini教授描述了他的体外研究，检测了inarigivir的抗病毒活性。 HBV临床分离株由衣壳抑制剂（CpAM）和核苷（NUC）类似物抗性变体组成。期待与正在研究的具有不同作用机制的药物的新型组合，Locarnini博士评估了来自HBV患者的NUC-和CpAM-抗性临床分离株中的inarigivir。 Locarnini教授的数据表明，inarigivir可用作NUC / CpAM抗性失败的挽救或联合治疗。

Locarnini教授表示，“NUC抗性和CpAM抗性菌株对inarigivir的敏感性和缺乏交叉耐药性对于联合研究是有益的，因为inarigivir将涵盖预先存在的抗性变体并防止对两种NUC的治疗紧急抗性和CpAM抑制剂，“Locarnini博士说。
Inarigivir临床开发
Spring Bank已经启动了两项全球2期试验（CATALYST 1和CATALYST 2），检查了inarigivir 400mg作为单药治疗的用药情况，并在幼稚和病毒抑制的慢性HBV患者中与NUC共同给药。 CATALYST试验包括多个患者队列，给药期包括12周，24周和48周。此外，Gilead Sciences，Inc。正在进行第2阶段试验，检查（i）在初治慢性HBV患者中共同给予奥利韦韦50mg和替诺福韦艾拉酚胺25mg（由Gilead以Vemlidy®销售），（ii）共同给药在原发性慢性HBV患者中使用inarigivir 200mg和Vemlidy，以及（iii）在目前并且继续用NUC治疗的病毒抑制患者中给予inarigivir 100mg。

电话会议

Spring Bank将于美国东部时间今天上午8点（2019年4月12日星期五）举行电话会议和网络直播。电话会议可通过拨打（877）407-0789拨打美国呼叫者和（201）689-8562拨打国际电话此外，您可以访问公司网站www.springbankpharm.com的投资者和媒体部分或点击此处访问电话会议的实时，只收听的网络直播。

可以通过访问Spring Bank的网站访问电话会议的重播。

其他详细信息，包括演示文稿摘要，可在ILC网站https://ilc-congress.eu/上找到。可以通过访问Spring Bank Pharmaceuticals网站的演示文稿和出版物部分访问演示材料的副本。

天上飞鱼

“We have developed a comprehensive strategic clinical trial program that takes into account both patient and viral heterogeneity that we anticipate will inform our Phase 3 strategy moving into 2020.”
估计明年进入三期

fuke

类似于干扰素，表抗下降不明显。只能作为辅助用药

天上飞鱼

回复 fuke 的帖子

这是目前进展最快的一个免疫调节药物，相比干扰素，它是口服用药，副作用禁忌症少。这家公司打算和arohbv或者核心抑制剂联用，看看会不会大幅提高临床治愈率，目前看还是很有希望的

齐欢畅

天上飞鱼 发表于 2019-4-13 18:11
回复 fuke 的帖子

这是目前进展最快的一个免疫调节药物，相比干扰素，它是口服用药，副作用禁忌症少。这家 ...

newchinabok