Replicor 问题：'

StephenW

复制者的问题：'

在您的下一个临床试验中，您计划使用 pegIFN 和胸腺素 alpha 1。PegIFN 有潜在的副作用，而胸腺素 alpha 1 非常昂贵。您是否考虑过使用最新一代的 HBV 疫苗或治疗性疫苗，甚至 HBSag 单克隆抗体作为您的免疫调节剂？您的 NAP 皮下版本似乎需要很长时间才能开发出来，临床试验已宣布并推迟。研究团体、制药公司、政府或患者团体可以做些什么来帮助推动开发和临床试验更快地进行？

回复：
由于 NAP 具有新颖的生物化学和有效的抗病毒反应，科学/医学界花了很长时间才接受 NAP 作为合法的抗病毒技术。 NAP 现在已被广泛接受，我们迄今已使用我们之前的试验将药物产品转变为现在易于通过皮下注射 (SC) 自行给药的配方。仅在我们上一次使用 REP 2139-Mg 的试验（于 2020 年出版）中实现了这一点的证明。与许多其他公司一样，SARS CoV-2 大流行对我们启动新临床开发的能力产生了负面影响，但我们已经继续在法国的同情使用患者中使用 SC REP 2139-Mg 并取得了非常好的结果（http: //replicor.com/wp-content/uploads/2021/12/REP-2139-Mg-subcutaneous-compassionate-use-Hepdart2021-Poster-7.pdf）所以我们希望能够进行最后阶段 IIA在不久的将来使用 SC REP 2139 进行试验。 NAP 临床开发的延迟不是因为药物或我们的科学存在任何问题，而是由于其他不相关的问题。我们正在尽最大努力尽快为患者提供 REP 2139-Mg。

你关于免疫疗法的问题很好。实现功能性治愈有两个重要步骤：1）从血液中清除 SVP 和 2）从肝脏中去除 HBsAg 产生能力。使用 NAP (1) 很容易，但 (2) 更难。在所有患者中，HBsAg 也是由整合的 HBV DNA 产生的（它只能有效产生 HBsAg 和 SVP），这个 HBsAg 产生的储存库在整个 HBV 感染过程中逐渐增加。使这进一步复杂化的是 1000 种 HBV 准种的存在导致许多 HBV DNA 整合的准种产生许多 HBsAg 准种。最后一个复杂情况是，去除这种储存库的唯一方法是广泛的 HBsAg 特异性 T 细胞反应，能够或有效去除含有整合 HBV DNA 的细胞。

因此，让我们来看看各种免疫疗法在 HBV 功能性治愈方面的优缺点：

PegIFN - 强烈激活现有的 HBsAg 特异性 T 细胞库，但对 HBV 有轻微的副作用。

胸腺素 alpha 1 - 强烈激活 HBsAg 特异性 T 细胞，副作用可忽略不计（许多国家未批准）

HBV 疫苗 - 只有一种 HBsAg！ HBsAg 特异性 T 细胞的诱导不良。

治疗性 HBV 疫苗 - 刺激 T 细胞，但仅针对小范围的 HBsAg 准种，因为单一的 HBsAg 抗原株

HBsAg 单克隆抗体： - 对 T 细胞刺激没有影响，只有一种 HBsAg 菌株。

这就是为什么您没有看到任何 NAP 与这些药物的组合试验。好消息是，通过 NAP，我们能够将 pegIFN 的剂量从 180 微克减少到 90 微克，而不会影响抗病毒反应。

StephenW

Question to Replicor:'

In your next clinical trial, you plan to use pegIFN and thymosin alpha 1. PegIFN has potential side effects and Thymosin alpha 1 is very expensive. Have you considered using the latest generation of HBV vaccines or therapeutic vaccines, even HBSag monoclonal antibodies, as your immunomodulator? The subcutaneous version of your NAP seems to have taken a long time to develop, clinical trials were announced and postponed. Is there anything the research communities, pharmaceutical companies, governments or patient community can do to help push development and clinical trials to happen quicker?

Reply:
It took a long time to get the scientific / medical community to accept NAPs as a legitimate antiviral technology because of their novel biochemistry and potent antiviral responses. NAPs are now well accepted and we have used our previous trials to date to move the drug product to a formulation which is now easy to self administer via subcutaneous injection (SC). The proof of this was only achieved in our last trial with REP 2139-Mg (published in 2020). As for many other companies, the SARS CoV-2 pandemic has had a negative impact on our ability to initiate new clinical development but we have gone ahead to use SC REP 2139-Mg in compassionate use patients in France with very good results (http://replicor.com/wp-content/u ... rt2021-Poster-7.pdf) so we hope to be in a position to conduct the final phase IIA trial with SC REP 2139 in the very near future. The delay with the clinical development of NAPs is not because of any problems with the drug or with our science but is due to other unrelated issues. We are working as hard as we can to get REP 2139-Mg to patients as soon as possible.

Your question about immunotherapy is good one. There are two important steps in achieving functional cure: 1) clear SVP from the blood and 2) remove HBsAg producing capacity from the liver. With NAPs (1) is easy but (2) is more difficult. In all patients, HBsAg is also produced from integrated HBV DNA (which only efficiently produces HBsAg and SVP), this reservoir of HBsAg production gradually increases throughout HBV infection. Complicating this further is the presence of 1000’s of HBV quasispecies leading to many quasispeceis of HBV DNA integration producing many quasispecies of HBsAg. A final complication is that the only way to remove this reservoir is a broad HBsAg specific T-cell response capable or efficient removal of cells containing integrated HBV DNA.

So lets look at the pros and cons of the various immunotherapies in the context of HBV functional cure:

PegIFN - strong activation of existing pools of HBsAg specific T-cells but mild side effects in HBV.

Thymosin alpha 1 - strong activation of HBsAg specific T-cells with negligible side effects (not approved in many countries)

HBV vaccines - only one strain of HBsAg! poor induction of HBsAg specific T-cells.

Therapeutic HBV vaccines - stimulate T-cells but only to a small spectrum of HBsAg quasispecies because of a single strain of HBsAg antigen

HBsAg monoclonal antibodies: - not effect on T-cell stimulation, only one strain of HBsAg.

This is why you have not seen any combination trials of NAPs with these agents. The good news is that with NAPs we are able to reduce the dose of pegIFN from 180 to 90ug without affecting antiviral response.

StephenW

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