新疗法开发中的多个乙肝目标

StephenW

Multiple Hep B Targets in Development for New Treatments         

Ingrid Hein

   

April 18, 2019

   
                          VIENNA — Three potential approaches to the treatment of hepatitis B, each targeting a different part of the virus, attracted attention here at the International Liver Congress 2019.
To achieve a cure, "many people believe that you will not have just one mechanism," said Markus Peck-Radosavljevic, MD, from Klinikum Klagenfurt in Austria.
Because the hepatitis B virus is a highly complex, "clever" virus, several approaches at the same time might be needed to eliminate it, he told Medscape Medical News.
Current treatment options control viral replication but do not eliminate it, he explained.

An initial phase 1b trial showed that ABI-H0731, a novel core protein inhibitor from Assembly Biosciences, reduced viral activity in patients with hepatitis B over a 28-day period when administered as a standalone treatment, and was well tolerated.
Now, interim results from two ongoing double-blind, placebo-controlled phase 2a clinical trials show that the addition of ABI-H0731 to standard care reduces hepatitis B RNA to undetectable levels in patients with chronic hepatitis B and stage F0 to F2 fibrosis.
Novel Core Protein Inhibitor In the first trial, the 73 participants already suppressed with nucleos(t)ide polymerase inhibitors — 47 who tested positive for the hepatitis B e-antigen and 26 who did not — were randomized to receive additional once-daily ABI-H0731 300 mg or placebo.
In the 64 patients who had completed week 12 assessments, reductions in hepatitis B RNA levels were significantly larger in the ABI-H0731 group than in the placebo group (2.34 vs 0.05 log10 IU/mL; P < .001). In patients who had completed week 24 assessment, those reductions followed a similar pattern (2.20 vs 0.15 log10 IU/mL; P = .012).
In addition, DNA viremia dropped below the limits of a highly sensitive PCR assay in the ABI-H0731 group but was persistent in the placebo.
In the second phase 2a study, 25 treatment-naive patients who tested positive for hepatitis B e-antigen were randomized to the combination of entecavir plus once-daily ABI-H0731 300 mg or to entecavir plus placebo.
Reductions in hepatitis B RNA levels were also larger in the ABI-H0731 group than in the placebo group (2.54 vs 0.61 log10 IU/mL; P < .005).

In five of six patients who received a nucleos(t)ide polymerase inhibitor plus ABI-H0731, viral DNA was eliminated over a period of 8 to 16 weeks, said Jacob Lalezari, MD, from Quest Clinical Research in San Francisco. And in the sixth patient, the virus was close to eliminated at week 24.
The results come down to the level of sensitivity of the assay. "It's not a true zero, but it's below detection," he said, adding that "this has obviously never been shown before."
This gives us a sense of what the time frame for a cure might look like, he explained. "Patients coming in fully suppressed are still taking anywhere from 2 to 6 months to get this virus closer to a true zero, but at least there's a significant reduction in the DNA."
Three patients experienced a rash that cleared, but there were no other adverse events.
Final results after the two trials are completed are expected to be even better, Lalezari said.
CAR T-Cell Modification Another treatment approach presented at the meeting involves stimulating T-cells extracted from an infected patient, modifying them to express chimeric antigen receptors (CAR) or T-cell receptors that specifically target the hepatitis B virus, and then returning them to the body.
"We introduce the receptors and they are able to find infected cells, bind to them, and destroy them," said Karin Wisskirchen, PhD, from the Institute of Virology at the Technical University of Munich.
"We think we can cure the patient this way because the T-cells resemble T-cells detected in patients who are able to clear hepatitis B infection on their own by attacking infected cells and thereby eliminating covalently closed circular [ccc]DNA," she explained.
In 2017, the US Food and Drug Administration (FDA) approved two CAR T-cell therapies, as reported by Medscape Medical News: tisagenlecleucel (Kymriah, Novartis), for relapsed or refractory acute lymphoblastic leukemia for young patients; and axicabtagene ciloleucel (Yescarta, Kite Pharma), for adults with relapsed or refractory diffuse large B-cell lymphoma and primary mediastinal large B-cell lymphoma after two or more lines of systemic therapy.
"This therapy has huge implications; it really is a major breakthrough in medicine," said Wisskirchen. "We know it works. We see the impact on leukemia. Children who did not have any chance are now running around happily; it's amazing."
"This is the ultimate personalized medicine," Peck-Radosavljevic told Medscape Medical News.
When cells are engineered for specific patients and then infused back to that patient, "the success has been incredible," he said, although he added that this strategy is way too expensive.
Eventually, it might become possible to treat more than one patient at a time. "It could become cheaper if you find a way to generate cells that can be injected into several patients," Wisskirchen said.
Her team is working with researchers in Germany and China to perform the first human clinical trial of a CAR T-cell hepatitis B therapy.
Another study, led by Lu Gao, MD, from the Roche Innovation Center in Shanghai, looked at ccc_R08, a novel cccDNA destabilizer, to treat hepatitis B infection in a mouse model.
cccDNA Destabilizer After twice-daily treatment for 2 weeks, levels of hepatitis B DNA, pregenome (pg)RNA, hepatitis B surface antigen, and hepatitis B antigen were all significantly reduced in mice that had been transduced with circular DNA to replicate the hepatitis B virus, after the establishment of a cccDNA-like molecule.
Levels of cccDNA molecules in the livers of the mice fell below the lower limit of quantification.
When evaluating ccc_R08 in human hepatocytes infected with hepatitis B, cccDNA reductions had no effect on mitochondrial DNA or toxicity, Gao told the audience.
This is the first time in the history of this research that it has been demonstrated that something like this is feasible, she said.
"Our compound is very effective. I hope we only need a short-term treatment for this complicated mechanism," she added.
However, the current destabilizer does not completely eradicate the infection, and that means it can replicate, Gao acknowledged. "If you have just one copy, it could come back. Molecule target identification is still underway."
Peck-Radosavljevic reports receiving grants from Gilead and MSD, and honoraria for consulting and lectures from AbbVie, Boehringer Ingelheim, Bristol-Myers Squibb, Gilead, Janssen, and MSD. Lalezari is a consultant for Assembly Biosciences. Wisskirchen has disclosed no relevant financial relationships. Gao is an employee of the Roche R&D Center ( China ) Ltd.
International Liver Congress (ILC) 2019: Abstract LBO-06, presented April 13, 2019; abstracts FRI-155 and PS-074, presented April 12, 2019.

StephenW

新疗法开发中的多个乙肝目标

英格丽德海因

2019年4月18日
   
维也纳 - 治疗乙型肝炎的三种潜在方法，每种方法针对病毒的不同部分，引起了2019年国际肝病大会的关注。

为了实现治愈，“许多人认为你不会只有一种机制，”来自奥地利Klinikum Klagenfurt的医学博士Markus Peck-Radosavljevic说。

他告诉Medscape医学新闻，由于乙型肝炎病毒是一种高度复杂的“聪明”病毒，可能需要同时采取几种方法来消除它。

他解释说，目前的治疗方案可以控制病毒复制但不能消除它。

初始阶段1b试验表明，来自Assembly Biosciences的新型核心蛋白抑制剂ABI-H0731在作为独立治疗给药的28天期间降低了乙型肝炎患者的病毒活性，并且耐受性良好。

现在，两项正在进行的双盲，安慰剂对照2a期临床试验的中期结果表明，在标准治疗中加入ABI-H0731可将慢性乙型肝炎和F0期至F2期纤维化患者的乙型肝炎RNA降低至不可检测的水平。
新型核心蛋白抑制剂

在第一项试验中，73名参与者已经被核苷（t）ide聚合酶抑制剂抑制 - 其中47名检测出乙型肝炎e抗原呈阳性而26名未检测到 - 被随机接受额外每日一次的ABI-H0731 300 mg或安慰剂。

在完成第12周评估的64名患者中，ABI-H0731组中乙型肝炎RNA水平的降低显着大于安慰剂组（2.34对0.05 log10 IU / mL; P <.001）。在完成第24周评估的患者中，这些减少遵循类似的模式（2.20对0.15 log10 IU / mL; P = .012）。

此外，DNA病毒血症降至ABI-H0731组中高灵敏度PCR测定的极限以下，但在安慰剂中持续存在。

在第二阶段2a研究中，25名未接受过乙型肝炎e抗原阳性检测的初治患者被随机分为恩替卡韦加每日一次ABI-H0731 300 mg或恩替卡韦加安慰剂组合。

ABI-H0731组中乙型肝炎RNA水平的降低也大于安慰剂组（2.54 vs 0.61 log10 IU / mL; P <.005）。

来自旧金山Quest Clinical Research的医学博士Jacob Lalezari表示，在接受核苷酸（t）ide聚合酶抑制剂加ABI-H0731的6名患者中，有5名病毒DNA在8至16周内被消除。在第六名患者中，病毒在第24周接近消失。

结果归结为测定的灵敏度水平。 “这不是一个真正的零，但它低于检测，”他说，并补充说“这显然以前从未显示过。”

他解释说，这让我们了解治愈的时间框架是什么样的。 “完全被抑制的患者仍然需要2到6个月才能使这种病毒接近真正的零，但至少DNA的显着减少。”
3名患者出现皮疹，但没有其他不良事件。

Lalezari说，两项试验完成后的最终结果预计会更好。
CAR T细胞修饰

在会议上提出的另一种治疗方法包括刺激从感染患者中提取的T细胞，修饰它们以表达特异性靶向乙型肝炎病毒的嵌合抗原受体（CAR）或T细胞受体，然后将它们返回体内。

慕尼黑工业大学病毒学研究所的Karin Wisskirchen博士说：“我们引入这些受体，它们能够找到受感染的细胞，与它们结合并破坏它们。”

“我们认为我们可以通过这种方式治愈患者，因为T细胞类似于能够通过攻击感染细胞从而消除共价闭合的圆形[ccc] DNA而能够自行清除乙型肝炎感染的患者中检测到的T细胞，”她解释。

2017年，美国食品和药物管理局（FDA）批准了两项CAR T细胞疗法，据Medscape医学新闻报道：tisagenlecleucel（Kymriah，Novartis），针对年轻患者的复发或难治性急性淋巴细胞白血病;和axicabtagene ciloleucel（Yescarta，Kite Pharma），对于患有复发或难治性弥漫性大B细胞淋巴瘤和原发性纵隔大B细胞淋巴瘤的成人，经过两次或更多次全身治疗。

“这种疗法具有重大意义;它确实是医学上的重大突破，”Wisskirchen说。 “我们知道它有效。我们看到了对白血病的影响。没有任何机会的孩子现在快乐地跑来跑去;这太棒了。”

“这是最终的个性化医疗，”Peck-Radosavljevic告诉Medscape医学新闻。

当细胞被设计用于特定患者然后再输回给患者时，“成功是令人难以置信的，”他说，尽管他补充说这种策略太昂贵了。

最终，有可能一次治疗多个患者。 “如果你找到一种方法来产生可以注射到几个病人身上的细胞，它可能会变得更便宜，”Wisskirchen说。

她的团队正与德国和中国的研究人员合作，开展第一项CAR T细胞乙型肝炎治疗的人体临床试验。

另一项由上海罗氏创新中心医学博士Lu Gao领导的一项研究，研究了ccc_R08，一种新型cccDNA去稳定剂，用于治疗小鼠模型中的乙型肝炎感染。
cccDNA去稳定剂

在每天两次治疗2周后，用环状DNA转导以复制乙型肝炎病毒的小鼠中乙型肝炎DNA，前基因组（pg）RNA，乙型肝炎表面抗原和乙型肝炎抗原的水平均显着降低，在建立cccDNA样分子后。

小鼠肝脏中cccDNA分子的水平低于定量的下限。

高智晟告诉观众，当评估感染乙型肝炎的人肝细胞中的ccc_R08时，cccDNA的减少对线粒体DNA或毒性没有影响。

她说，这是本研究史上第一次证明这样的事情是可行的。

“我们的化合物非常有效。我希望我们只需要对这种复杂的机制进行短期治疗，”她补充说。

然而，目前的不稳定因素并没有完全根除感染，这意味着它可以复制，高承认。 “如果你只有一份，它可能会回来。分子目标识别仍在进行中。”

Peck-Radosavljevic报告接受了Gilead和MSD的资助，以及来自AbbVie，Boehringer Ingelheim，Bristol-Myers Squibb，Gilead，Janssen和MSD的咨询和讲座酬金。 Lalezari是Assembly Biosciences的顾问。 Wisskirchen没有透露任何相关的财务关系。高是罗氏研发中心（中国）有限公司的员工。

国际肝脏大会（ILC）2019年：摘要LBO-06，于2019年4月13日提交;摘要FRI-155和PS-074，于2019年4月12日提交。

StephenW

https://www.medscape.com/viewarticle/911978