这项已发表的分析描述了 Aligos 在评估 NAP 的抗病毒活性时使用的基于转染的组织培养系统中固有的许多伪影。这些伪影是 LNA 修饰的 NAP 的明显功效的体外观察与其在人类中的不活动之间的脱节的基础。 Replicor 之前在与已验证体内活性的 NAP 化合物的几次独立合作中确定了转染不适合用于 HBV 的体外 NAP 分析。
Replicor 的 CSO Andrew Vaillant 博士评论说：“我们在 20 年前首次描述了 LNA 修饰的 NAP，例如 ALG-10133 - 由于缺乏抗病毒作用而终止 ALG-10133 证明了为什么 Replicor 很早就放弃了这种 NAP 修饰在 NAP 开发过程中。 LNA 修饰对 NAP 功能的抑制是由于其对寡核苷酸灵活性的抑制作用在该领域中众所周知的十多年。自 2006 年以来，在 Replicor 的 20 多篇出版物中，寡核苷酸的灵活性是 NAP 活性的一个关键特征。Aligos 公开提供的体外和临床前数据中存在 ALG-10133 失败的早期信号。
Vaillant 博士继续强调，Replicor 对 NAP 的所有体外和体内研究都是由多个独立的专家学术实验室进行的。在其所有临床试验中观察到的 NAP 活性也已通过独立专家测试实验室的验证。
Replicor announces post-mortem analysis of ALG-10133 failure
MONTREAL, March 30th, 2022 – Replicor Inc., a privately held biopharmaceutical company targeting functional cure for patients with chronic hepatitis B and D infection, announced the publication of its post-mortem analysis of the LNA-modified NAPs following the termination of their development by Aligos Therapeutics in the journal Molecular Therapy Nucleic Acids (see here). At dosing which yields 4-7 log10 reduction of HBsAg with Replicor’s NAPs REP 2055, REP 2139 and REP 2165, the LNA-modified analog of REP 2165 (ALG-10133) failed to show any meaningful HBsAg response in human patients (see here).
This published analysis describes the many artifacts inherent in the transfection-based tissue culture systems used by Aligos in their assessment of the antiviral activity of NAPs. These artifacts underly the disconnect between in vitro observations of apparent efficacy of LNA-modified NAPs and their inactivity in humans. The unsuitability of transfection for in vitro NAP analysis in HBV was previously established by Replicor in several independent collaborations with NAP compounds having validated in vivo activity.
Dr. Andrew Vaillant, CSO, Replicor commented, “We first described LNA-modified NAPs such as ALG-10133 twenty years ago - the termination of ALG-10133 for lack of antiviral effect demonstrates why this modification of NAPs was discarded by Replicor very early on in the NAP development process. The inhibition of NAP function by the LNA-modification is caused by its inhibition of oligonucleotide flexibility well known in the field for more than a decade. Oligonucleotide flexibility is a key feature of NAP activity well documented in more than 20 publications by Replicor since 2006. Early signals of the failure of ALG-10133 were present in the in vitro and pre-clinical data publicly presented by Aligos.”
Dr. Vaillant went on to emphasize that all of Replicor’s in vitro and in vivo studies on NAPs were conducted with multiple independent expert academic labs. The activity of NAPs observed in all its clinical trials has also been validated with independent expert test laboratories.
About Replicor
Replicor is a privately held biopharmaceutical company with the most advanced animal and human clinical data in the development of the cure for HBV and HDV. The company is dedicated to accelerating the development of an effective treatment for patients with HBV and HBV/HDV co-infection. For further information about Replicor please visit our website at www.replicor.com.