The REP 301 treatment protocol involved the treatment of patients with chronic hepatitis B / hepatitis D co-infection with two agents: REP 2139-Ca and pegylated interferon (peg-IFN). In this protocol, similar reduction/clearance of serum HBsAg and improved response to immunotherapy were observed in addition to clearance of serum HDV RNA. The REP 301 protocol was designed to include a 24 week follow-up period after treatment, however given the strong antiviral response against HBV and HDV infection in these patients, it is now important to extend the follow-up period in these patients to monitor over a longer period after treatment the safety and efficacy combined REP 2139-Ca / peg-IFN treatment in patients in the REP 301 protocol.

开始日期2016-08-01

申办/合作机构

Replicor, Inc.

NCT02565719 / Completed临床2期

An Open-label, Randomized, Active Controlled, Parallel Comparison Study of the Safety and Efficacy of REP 2139-Mg in Combination With Pegasys® and Viread® and REP 2165-Mg in Combination With Pegasys® and Viread® in Patients With HBeAg Negative Chronic Hepatitis B

NAPs have been previously shown to clear serum hepatitis B virus surface antigen (HBsAg) both preclinically (in duck HBV infected ducks) and in human patients. REP 2139-Ca mediated HBsAg clearance acts synergistically with immunotherapeutic agent pegylated interferon-alpha 2a to restore host immunological control of HBV infection. REP 2165 is a version of REP 2139 which has been shown preclinically to retain antiviral activity with lower accumulation in the liver.
Both REP 2139 and REP 2165 used in this protocol are formulated as magnesium chelate complexes, which improve their administration tolerability. This open label, randomized and controlled study will examine the safety and efficacy of REP 2139-Mg and REP 2165-Mg therapy in patients with HBeAg negative chronic hepatitis B when used in combination with tenofovir disoproxil fumarate and pegylated interferon alpha-2a.

开始日期2016-03-01

申办/合作机构

Replicor, Inc.

NCT02233075 / Completed临床2期

A Study of the Safety and Efficacy of Combination Treatment With REP 2139-Ca and Pegasys™ in Patients With Hepatitis B / Hepatitis D Co-infection

REP 2139-Ca is nucleic acid polymer. Nucleic acid polymers have been previously shown to clear serum hepatitis B virus surface antigen (HBsAg) both preclinically (in duck HBV infected ducks) and in human patients and to act synergistically with immunotherapeutic agents such as pegylated interferon-alpha 2a or thymosin alpha-1 to restore host immunological control of HBV infection.
HBsAg is an essential component of the hepatitis D virus (HDV), therefore the direct action of REP 2139-Ca in removing serum HBsAg and its synergistic effect with pegylated interferon-alpha 2a is expected to have a significant antiviral effect against HDV infection.
This study will examine the safety and efficacy of REP 2139-Ca therapy when used in combination with pegylated interferon alpha-2a in patients with HBV / HDV co-infection.
The primary hypothesis to be tested is that this combined dosing regimen is safe and well tolerated in patients with HBV / HDV co-infection which will be assessed by examining the number of patients with adverse events (including reported symptoms and laboratory abnormalities).
The secondary hypothesis to be tested is that this combined dosing regimen will have an antiviral effect against HBV / HDV co-infection in these patients which will be assessed by examining the following outcomes:
The number of patients with reductions in serum HBsAg.
The number of patients with reductions in serum HDAg and HDV RNA
The number of patients that experience a sustained antiviral response after treatment is stopped (reductions in serum HBV DNA and HDV RNA).
The secondary hypothesis to be tested is that this combination approach can have an effective

开始日期2014-09-01

申办/合作机构

Replicor, Inc.

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2023-09-01·Journal of clinical virology : the official publication of the Pan American Society for Clinical Virology

Novel fully automated prototype assays for specific detection of phosphorylated and non-phosphorylated Hepatitis B core antigens.

Article

作者: Geissler, Rene ; Patel, Megha ; Anderson, Mark ; Qiu, Xiaoxing ; Vaillant, Andrew ; Cloherty, Gavin

BACKGROUND:

Hepatitis B core antigen (HBcAg) has been proposed as a surrogate marker to reflect transcriptional activity of HBV covalently closed circular DNA (cccDNA) during active infections and may be a valuable tool to monitor the efficacy of antiviral therapies. However, HBcAg-specific immunoassays are unavailable, and current assays that measure hepatitis B core-related antigen (HBcrAg) cannot distinguish between HBcAg, HBeAg, and precore (PreC) proteins.

OBJECTIVE:

Two fully automated assays were developed to specifically detect phosphorylated HBcAg (P-HBcAg, representing non-HBV DNA-containing particles) and non-phosphorylated HBcAg (representing HBV DNA-containing particles) circulating in HBV infected patients.

STUDY DESIGN:

P-HBcAg and HBcAg levels were analyzed in 124 single timepoint patients with active infections, in three longitudinal specimens from patients with acute HBV infections, and in four chronic hepatitis B (CHB) patients on-therapy (TDF - tenofovir disoproxil fumarate, pegIFN - pegylated interferon, NAPs - nucleic acids polymers).

RESULTS:

Analyzing acute infections revealed that P-HBcAg and HBcAg levels correlate more closely than HBcrAg to HBV DNA. During antiviral treatment of CHB patients, HBcAg correlates well with HBV DNA and indicates a therapeutic response to the treatment at the beginning of the therapy. In contrast, P-HBcAg tracks more closely to HBV RNA. Importantly, P-HBcAg is detectable several months after HBcAg became undetectable indicating that cccDNA is still transcriptionally active in hepatocytes.

CONCLUSIONS:

Overall, the ability to specifically distinguish between the various states of HBcAg (phosphorylated and non-phosphorylated) can provide additional insights for disease staging, drug development, and management of HBV therapies.

2023-03-01·Journal of hepatology

Bepirovirsen/GSK3389404: Antisense or TLR9 agonists?

Letter

作者: Vaillant, Andrew

A review.The present article emphasizes about the role of Bepirovirsen, GSK3389404 as TLR9 agonists in HBV infected patients.

2022-08-01·Hepatology communications2区 · 医学

HBsAg isoform dynamics during NAP‐based therapy of HBeAg‐negative chronic HBV and HBV/HDV infection

2区 · 医学

ArticleOA

作者: Anderson, Mark ; Placinta, Gheorghe ; Kuhns, Mary ; Vaillant, Andrew ; Jimbei, Pavlina ; Jucov, Alina ; Smesnoi, Valentina ; Cloherty, Gavin ; Musteata, Tatina ; Pântea, Victor ; Moscalu, Iurie ; Cojuhari, Lilia ; Cebotarescu, Valentin ; Dittmer, Ulf ; Gersch, Jeff ; Bazinet, Michel ; Iarovoi, Liviu ; Holzmayer, Vera

Abstract:

Nucleic acid polymers block the assembly of hepatitis B virus (HBV) subviral particles, effectively preventing hepatitis B surface antigen (HBsAg) replenishment in the circulation. Nucleic acid polymer (NAP)–based combination therapy of HBV infection or HBV/hepatitis D virus (HDV) co‐infection is accompanied by HBsAg clearance and seroconversion, HDV‐RNA clearance in co‐infection, and persistent functional cure of HBV (HBsAg < 0.05 IU/ml, HBV‐DNA target not dected, normal alanine aminotransferase) and persistent clearance of HDV RNA. An analysis of HBsAg isoform changes during quantitative HBsAg declines (qHBsAg), and subsequent treatment‐free follow‐up in the REP 301/REP 301‐LTF (HBV/HDV) and REP 401 (HBV) studies was conducted. HBsAg isoforms were analyzed from frozen serum samples using Abbott Research Use Only assays for HBsAg isoforms (large [L], medium [M], and total [T]). The relative change over time in small HBsAg relative to the other isoforms was inferred by the change in the ratio over time of T‐HBsAg to M‐HBsAg. HBsAg isoform declines followed qHBsAg declines in all participants. No HBsAg isoforms were detectable in any participants with functional cure. HBsAg declines > 2 log10 IU/ml from baseline were correlated with selective clearance of S‐HBsAg in 39 of 42 participants. Selective S‐HBsAg decline was absent in 9 of 10 participants with HBsAg decline < 2 log10 IU/ml from baseline. Mild qHBsAg rebound during follow‐up <10 IU/ml consisted mostly of S‐HBsAg and M‐HBsAg and not accompanied by significant covalently closed circular DNA activity. Conclusion: The faster observed declines in S‐HBsAg indicate the selective clearance of subviral particles from the circulation, consistent with previous mechanistic studies on NAPs. Trace HBsAg rebound in the absence of HBV DNA may reflect HBsAg derived from integrated HBV DNA and not rebound of viral infection.

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2024-09-12

·CPHI制药在线

乙肝治愈—ASO和siRNA药物孰高孰低？

关注并星标CPHI制药在线全球约有 3.54 亿人长期感染乙型肝炎病毒（hepatitis B virus，HBV），而全球肝病相关死亡的主要原因就是HBV 感染，每年约 80 万人死于 HBV 感染相关疾病，如不进行干预，预计到2035 年因HBV 感染导致的死亡人数将达到114 万的峰值。中国有超过 80% 的原发性肝癌与 HBV 感染相关。即使乙肝疫苗的有效应用大大减少了新发病例，但根据 2010 年-2022 年统计数据，全国乙肝每年新发人数仍然在 90 万～100 万。慢性乙型病毒性肝炎（chronic viral hepatitis B，CHB）是严重危害全球人民健康的重大公共卫生难题，有效彻底地治疗 CHB 对于目前存量巨大的 CHB 患者也仍具有十分重要地意义。 CHB 的治疗结局主要分为病毒学抑制、部分治愈、功能性治愈（临床治愈）及完全治愈。目前普遍认为共价闭合环状 DNA（covalently closedcircularDNA, cccDNA）及宿主基因组中整合的HBV DNA 是实现 CHB 治愈的最后突破点及难点。基于CHB 的治疗现状，治疗目标已不断趋向于临床治愈，完全治愈目前还很难实现。临床治愈（功能性/免疫学治愈）是指血清HBsAg消失，且在停止治疗后24周时使用常规检测方法检测不到HBsAg（检测下限0.05 IU/mL）且HBV DNA低于LLOQ（lower limit of quantification，最低可定量浓度），HBeAg阴转，伴或不伴HBsAg血清学转换（指HBsAg转阴且抗-HBs转阳），残留cccDNA可持续存在，肝脏炎症缓解和肝组织病理学改善，终末期肝病发生率显著降低。药物治疗后HBsAg转阴率和停药至少6个月(24周)后清除率是评价乙肝药物重要指标。核苷类药物（NA）虽然可以促进部分乙肝患者出现HBsAg 的丢失，但在大部分患者仍需要长期治疗，且由于 HBV DNA 的整合及 cccDNA 并未清除，肝癌的发生风险并未完全消除。聚乙二醇干扰素α（PEGylated interferon α, PegIFNα）HBsAg 清除和血清学转换发生率仅 3%～8%。PegIFNα单药治疗 CHB 患者的总体疗效仍差强人意。一项TDF 联用干扰素试验表明，9%的患者实现HBsAg 消失，显著高于单药治疗。在 NA 联合PegIFNα治疗的部分优势人群中（条件之一是HBsAg≤1500 IU/ml的低基线人群，包括NA经治优势人群、非活动性HBsAg携带状态人群以及慢乙肝儿童），临床治愈率可达到 30%～50%，如中国开展的珠峰项目结果。对于HBsAg>1500 IU/ml人群，PEG IFNα单药或联用NA难以实现治愈。疾病人群复杂、乙肝病人肝状态的异质性、不同个体药物响应差异大，乙肝新型治疗药物进展缓慢，乙肝功能治愈道阻且艰，机遇与挑战并存。针对乙肝治疗的很多在研新靶点药物临床进展受阻，纷纷遭弃或中止研发。ASO（反义寡核苷酸）和siRNA（小干扰RNA）药物被认为是能实现功能治愈的最有希望的药物，临床上也取得了一些可喜的结果，显示了研发活跃的积极状态。Bepirovirsen成为第一个且唯一一个进入临床三期实现功能治愈的新型乙肝药物。另外从近几年行业内关于ASO和siRNA抗乙肝药物一些事件可见端倪。 2021年12月13日，Arbutus宣布与齐鲁制药达成合作协议，齐鲁制药引进Arbutus的乙肝siRNA疗法AB-729的大中华区权益。因战略考虑，2023年10月31日强生公司将JNJ-3989（以前称为 ARO-HBV）全球权益转手给GSK，近日GSK启动了JNJ-3989和Bepirovirsen序贯治疗慢乙肝临床试验。 2024年05月7日，国家药监局网站公示腾盛博药的创新乙肝药物BRII-835 (即VIR-2218，小干扰RNA)拟获突破性治疗认定。VIR-2218是Alnylam、Vir Biotechnology和腾盛博药合作研发的靶向HBV基因组HBx区域的siRNA类乙肝新药 2024年7月3日，CDE官网公示，杭州浩博医药有限公司申报的AHB-137注射液拟纳入突破性治疗品种，用于治疗慢性乙型肝炎（简称：CHB）患者。 2024年8月22日认证为"葛兰素史克（GSK）中国招聘官方平台"的微信视频号"GSK招聘"发布招聘信息，招聘医学联络官，推测将负责GSK重磅乙肝产品Bepirovirsen。Bepirovirsen作为唯一一款正在进行三期临床试验的功能性治愈药物备受期待，商业化已在紧锣密鼓进行。 2024年8月28日GSK宣布日本厚生劳动省（MHLW）已授予Bepirovirsen 治疗慢性乙型肝炎SENKU（原名 SAKIGAKE）指定。SENKU 指定根据创新水平、疾病严重程度和突出疗效授予的，目的是通过加快审查程序，让患者尽早获得治疗严重疾病和满足未满足医疗需求的创新药物。这是继今年早些时候FDA授予 Bepirovirsen 快速通道之后，Bepirovirsen 在2024年获得的第二个监管指定。针对乙肝功能治愈，ASO和siRNA药物孰高孰低是一个有意思的话题。本文对ASO和siRNA药物初步进行了比较分析，需要说明的是因为没有头对头比较的临床数据，只是拿各自的临床试验结果进行了比较，科学上可能欠妥。从作用机制比较，从药物设计理论上看，两者都是靶向HBV mRNA降解。siRNA 药物可抑制来自整合HBV DNA 和cccDNA 的HBsAg，而对cccDNA 或整合病毒DNA 无直接作用。siRNA 药物通常靶向于HBV 的s 基因片段转录物和x 基因片段转录物，同时抑制多个病毒基因，敲低从cccDNA 表达的所有病毒蛋白和pgRNA。siRNA 通过偶联N-乙酰半乳糖胺（GalNAc）靶向肝脏。ASO 是合成的单链寡核苷酸，与互补的HBV RNA转录物结合，形成ASO-RNA 复合物，其被核糖核酸酶H 切割。然而，临床结果表明，很多临床前的设想跟实际结果存在很大偏差，作用机制其实很复杂，还并不明确。尽管部分患者在Bepirovirsen治疗的24周内实现了HBV功能性治愈。但通过偶联GalNAc配体增强了肝细胞靶向性的ASO药物，如ALG-020572、RO7062931和GSK3389404等，都未能充分降低患者血清HBsAg的水平，显示GalNAc配体的肝靶向作用意义不大。Bepirovirsen可使部分患者实现停药后血清HBsAg持续消失，通过检测用药后患者不同组织的药物分布，结果显示只有少部分ASOs进入肝脏组织，最终进入肝细胞的则更少。北京大学医学部鲁凤民教授推测，考虑到参与临床试验的患者基线血清HBsAg水平并不高，那该ASO降低血清HBsAg的主要作用机制可能不是直接作用于感染肝细胞内的HBV转录本，而更可能是通过非特异地进入肝脏非实质细胞如库普弗细胞等，最终通过刺激和激活宿主免疫，攻击被感染的肝细胞，使得大多数患者的血清HBsAg下降，甚至小部分基线HBsAg水平不高的患者达到HBsAg阴转。而报导的临床试验中观察到的较高比例患者出现ALT水平异常升高的现象则在一定程度上支持上述推测。Replicor公司的Andrew Vaillant博士认为，由于 HBV 逆转录酶缺乏校对活性、cccDNA的快速更新和持续的免疫压力，HBV感染具有非常高的遗传可塑性（任何特定受试者中存在数千个准种），点突变会消除RNAi 或 ASO 靶向特定 mRNA切割的能力，RNAi 或 ASO药物治疗的理论基础尚不清楚。总之，RNAi 或 ASO药物的作用机制可能都还需要进一步证实。从单药效果比较，Bepirovirsen 的Ⅱb 期临床试验(B-Clear)显示，最高剂量(300mg)组的HBsAg 水平在治疗第24周显著下降，其中26%（NA经治组）和29%（初治组）在治疗结束时HBsAg转阴。停药24 周后，在Bepirovirsen 单药治疗组10%患者达到了主要终点，即HBsAg水平不可测，并且HBV DNA 水平低于20 IUomL-1；在基线HBsAg 水平低且未接受NA 治疗患者中，有25%达到主要终点，显示bepirovirsen 单药可以实现HBsAg转阴。而目前已公布临床结果的siRNA 药物虽然降低HBsAg效果显著，但单药治疗较少能实现HBsAg清除，JNJ-3989仅在联合PegIFNα后促进了患者的HBsAg清除。多种siRNA新药在联合PegIFNα后也都实现了更高的HBsAg清除率，目前大部分siRNA都在积极探索联合治疗策略。从单药效果来看，ASO药物Bepirovirsen具有明显优势。从给药周期和频率比较，siRNA 比ASO具有更长的作用时间，所需给药频率更低。从治疗优势人群比较，优势人群是指治疗效果较好的人群，主要以基线血清HBsAg 水平区分，Bepirovirsen实现功能性治愈的主要是基线血清HBsAg> 100 IU/ml和< 3 000 IU/ml患者，对于基线血清HBsAg 水平大于3000的患者疗效并不好，相比之下，传统PegIFNα对于HBsAg> 1500 IU/ml患者疗效就不行了。 iRNA药物JNJ-3989或ARC-520治疗结束后平均随访52个月有31.2%的患者HBsAg < 100 IU/mL，发现基线HBsAg 水平和治疗后最大HBsAg降幅与随访结束时HBsAg < 100 IU/mL的患者比例独立相关。不过寻求对基线血清HBsAg更高水平患者的治愈是siRNA 和ASO药物共同的目标。从治疗给药后HBsAg清除率比较，每周300 mg Bepirovirsen治疗24周可使26%的NA经治和29%的初治慢乙肝患者获得HBsAg清除及HBV DNA阴转。 I/IIa期临床（AB-10-8002）结果显示在接受为期 4 周的 AHB-137 治疗后，12%(5/40）CHB受试者HBsAg 持续阴转（HBsAg 低于定量下限0.05 IU/mL)，其中 2 例发生血清学转换，HBsAg最大降幅发生在第29至第50天。 AB-729治疗24周后加用聚乙二醇干扰素α（PegIFNα）继续治疗24周可使28%的患者实现HBsAg清除（EASL2024大会摘要）。 II期研究显示JNJ-3989 + NA ± JNJ-6379可使HBsAg平均下降1.9-2.6 log，70% - 75%的患者HBsAg降至< 100 IU/mL，但几乎无患者实现HBsAg清除，联合JNJ-6379的三联疗法与二联疗法效果相似；而JNJ-3989 + NA ± JNJ-6379序贯联合PegIFNα在免疫耐受期患者中有19%（10/54）的患者出现至少一次的HBsAg清除。EASL2024大会摘要披露了有关JNJ-3989的最新研究数据，JNJ-3989（负荷剂量）+ NA + nivolumab可使HBsAg平均下降2 log10 IU/mL，约90%的患者HBsAg降至< 100 IU/mL，至停药随访24周70%-85%维持HBsAg < 100 IU/mL，无患者获HBsAg清除。在AASLD2022大会摘要中披露的II期数据显示，VIR-2218联合PEGIFNα治疗时间越长，HBsAg降幅越大，初始联合治疗48周可使30%的受试者实现HBsAg清除；VIR-2218联合VIR-3434可使约18%的受试者实现HBsAg清除。各个药物的更多联合治疗、更长期和更多样本的临床结果还需不断更新完善。从停药后HBsAg转阴率比较，siRNA、反义RNA类药物降低HBsAg水平的潜力已在多项临床研究中得到证实，但也都呈现出一个共性问题，即停药后存在HBsAg水平的反弹。如何避免停药后HBsAg的反弹，维持HBsAg清除的持久性是乙肝治愈必须考虑的问题。Bepirovirsen 的Ⅱb 期临床试验(B-Clear)显示，Bepirovirsen 单药治疗组中10%患者，Bepirovirsen 与NA 联合治疗组中9%患者，达到了主要终点，即停药24 周后HBsAg 水平不可测，并且HBV DNA 水平低于20 IUomL-1；在基线HBsAg 水平低且未接受NA 治疗患者中，有25%达到主要终点，而在接受NA 治疗患者中，有16%达到主要终点。Bepirovirsen序贯PegIFNα治疗可显著降低Bepirovirsen治疗的复发率，可能与PegIFNα有效激活体内免疫，促进HBsAb的产生，维持免疫应答的持久性有关；另外，相比Bepirovirsen治疗24周后序贯PegIFNα治疗的队列，更早序贯PegIFNα治疗的队列的复发率有极明显的降低（复发率58% vs. 0%），表明序贯PegIFNα的时间越早，越快激活患者的免疫应答可能获得更好的持久应答。 AB-729治疗24周后加用聚乙二醇干扰素α（PegIFNα）继续治疗24周并停药24周后 24%患者实现HBsAg清除；AB-729治疗24周后序贯VTP-300（乙肝治疗疫苗）共2剂在治疗结束时分别使95%、37%的受试者HBsAg < 100 IU/mL或< 10 IU/mL，停药24周后这一比例分别为80%和60%（EASL2024大会摘要）。 JNJ-3989 + NA ± JNJ-6379序贯联合PegIFNα治疗免疫耐受期患者，停药24周随访发现，HBsAg相比基线平均降幅为2.92 log10，13%患者实现HBsAg清除。JNJ-3989（负荷剂量）+ NA + nivolumab治疗后停药随访24周无患者获HBsAg清除。 EASL2023大会摘要公布显示VIR-2218 + PEG IFNα在停药后24周的HBsAg清除率为15%左右，其中治疗结束时anti-HBs水平> 500 mIU/mL的受试者100%维持HBsAg清除；而VIR-2218 + VIR-3434在停药后24周各队列的HBsAg 水平均逐渐反弹，无受试者维持HBsAg清除。总之，各个药物停药后药效持续性仍需大样本长期观察数据，目前的结果都是不全面的。综合来看，目前ASO药物Bepirovirsen占有一些优势，比如单药治疗HBsAg清除率和停药后HBsAg清除率，siRNA药物具有给药间隔周期长，用药依从性好的优势，不过通过与PegIFNα联合用药，siRNA药物也能获得一定的治疗HBsAg清除率和停药后HBsAg清除率。但是ASO和siRNA药物治疗效果都还很有限，机制仍不清晰，对于基线血清HBsAg 水平大于3000的患者治疗效果更加有限，而核苷类和PegIFNα仍是基石用药。筛选合适的生物标志物，进而选择合适的患者进行精准治疗非常重要。实现CHB 的功能性治愈非常具有挑战性，亟需研发靶向HBV感染复制周期不同阶段，及促进宿主抗HBV免疫的新型药物，以提高CHB的临床治愈。不同机制的CHB 治疗药物的合理联用是实现CHB 治愈的关键途径。参考资料 1. 朱校宇，吴桂娟，蓝竹，吴玉章，张记. 慢性乙型肝炎治疗新药研发进展. 中国新药与临床杂志，网络首发时间：2024-08-26 08:50:08 2. 李德瑶陆丹娟鲁凤民. 反义寡核苷酸治疗慢性乙型肝炎，相对确定的有限疗效与尚未明确的机制. 中华肝脏病杂志, 2023,31(2) : 192-197. 3. YUEN MF, LIM SG, PLESNIAK R, et al. Efficacy and safety of bepirovirsen in chronic hepatitis B infection[J]. N Engl J Med, 2022, 387(21): 1957-1968. 4. GANE E, LIM YS, KIM JB, et al. Evaluation of RNAi therapeutics VIR-2218 and ALN-HBV for chronic hepatitis B: Results from randomized clinical trials[J]. J Hepatol, 2023, 79(4): 924-932. 5. YUEN MF, ASSELAH T, JACOBSON IM, et al. Efficacy and safety of the siRNA JNJ-73763989 and the capsid assembly modulator JNJ-56136379 (bersacapavir) with nucleos(t)ide analogues for the treatment of chronic hepatitis B virus infection (REEF-1): a multicentre, double-blind, active-controlled, randomised, phase 2b trial[J]. Lancet Gastroenterol Hepatol, 2023, 8(9): 790-802. 作者简介：南海子，多年医药行业从业经历，先后从事过中药、化学药和生物药的研发及成果转化工作。 END 【智药研习社直播预告】来源：CPHI制药在线声明：本文仅代表作者观点，并不代表制药在线立场。本网站内容仅出于传递更多信息之目的。如需转载，请务必注明文章来源和作者。投稿邮箱：Kelly.Xiao@imsinoexpo.com ▼更多制药资讯，请关注CPHI制药在线▼ 点击阅读原文，进入智药研习社~

siRNA寡核苷酸疫苗信使RNA核酸药物

2022-01-09

·新浪医药

Aligos乙肝药物失败股价暴跌67%

1月7日，美国生物技术公司Aligos宣布将终止其主打产品、降乙肝表面抗原（HBsAg）核酸药物ALG-010133的临床开发。这个决定是根据这个产品在一个叫做ALG-010133-101的一期临床结果，在预期有效剂量400毫克（肝暴露水平为EC90的3倍）几乎没有降HBsAg活性。据预测在最高可行剂量600毫克能降低90%（1 log）HBsAg的可能性也很低。ALGS虽然号称还有几个其它机理药物如ASO、siRNA、CAM I、CAM-2 、和PD-L1抑制剂，但ALG-010133是其支柱产品。自公布这个不幸消息后，ALGS已经暴跌近70%。 Aligos是由强生的几个抗病毒领域高管于2018年成立的公司，此前完成1亿美元A轮、1.25亿美元B轮、和IPO 1.5亿美元的融资。CEO Lawrence Blatt为首的这几个人以前是Intermune的主要成员，把一个结构超级简单的吡非尼酮打造成第一个上市的IPF药物、以83亿美元卖给罗氏。后来他们成立了Alios开发RSV药物，这个公司2014年也被杨森收购。ALG-010133是日本一个企业发现，曾有传言杨森也关注过这类产品、但2018年以37亿了收购了箭头的竞争产品RNAi，当时作为杨森抗病毒总监的Blatt不久退出杨森成立了Aligos。 Aligos的核心资产是乙肝组合疗法，但也有NASH、HCC等其它肝病产品。ALG-010133是一个抑制病毒S抗原转运的寡核苷酸聚合物（STOP），实际是加拿大公司Replicor的核酸聚合物（NAP）REP2165的类似物。这类药物是多聚A：C通过硫代磷酸链接，链长40个碱基左右。这类核酸药物与另一类很有前景的乙肝药物RNAi不同，并非与乙肝mRNA结合。STOP/NAP目前机理未知、现在的说法是抑制HBsAg的组装和释放，但作为核酸药物激活天然免疫系统可能也是重要机制之一。 Replicor是这个领域的开拓者，他们的几个药物在多个早期临床显示超强的降HBsAg能力。两年前在一个40人的二期临床中，与标准疗法联用24周有50%、48周有65%患者HBsAG下降到检测线一下（功能性治愈），而对照组周无人达到这个疗效。24周开始对照组也使用NAP、结果48周后55%达到功能性治愈。这个疗效不仅远优于现在的标准疗法，甚至显著好于被寄予厚望的RNAi和ASO。不过这类药物除了HBsAg几乎不改善任何其它治疗指标，单方对乙肝DNA、RNA、Dane颗粒水平都没影响。另外这类药物机理不清楚一直是个软肋，这可能是Replicor成立多年尚未被大药厂收购的原因。尽管Replicor的产品已经显示超强HBsAg能力，ALG-010133仅仅是对碱基进行了一些化学修饰、序列与Relicor产品几乎完全一样，但临床结果完全不同，因为机理不清楚导致优化方向不准确是个重要原因。虽然如果一个药物真正安全有效没人关心机理问题，但机理不清对厂家来说是个开发过程中的风险因素。对于原创厂家早期看到的疗效可能是物种特异或实验条件下的噪音，对于跟踪厂家则无法准确评价与原研产品的差异化程度。假如激活TLR是Replicor产品的疗效来源你优化抑制HBsAg组装就可能在临床试验中差很多。

并购寡核苷酸信使RNA免疫疗法IPO

2021-04-09

·GlobeNewswire

Hepatitis B Virus Infection - Global Drug Forecast and Market Analysis to 2029

New York, April 09, 2021 (GLOBE NEWSWIRE) -- Reportlinker.com announces the release of the report "Hepatitis B Virus Infection - Global Drug Forecast and Market Analysis to 2029" - For most patients, CHB is a lifelong disease that cannot be cured, with only a very small number of patients entering remission each year.Patients with CHB have a 20% risk of developing life-threatening liver disease, such as cirrhosis and hepatocellular carcinoma (HCC) as a result of their condition.Guidelines by the American Association of the Study of Liver Diseases (AASLD) and the European Association for the Study of Liver (EASL) have recommended CHB to be treated with nucleotide analogs (NA).Gilead Sciences and Bristol Myers Squibb (BMS) are the major players within the CHB market with their nucleotide analogs Viread (TDF, Gilead), Vemlidy (TAF, Gilead) and Baraclude (entecavir, BMS).However, generic versions of TDF and entecavir dominate the 9MM.The CHB treatment pipeline is predominantly in early stages.Gilead’s TLR-8 agonist selgantolimod, J&J’s capsid assembly modulator JNJ-6379, and antisense nucleotide JNJ-3898 could significantly impact the CHB market across the 9MM.Also Replicor, Assembly Biosciences, and Ionis Pharmaceuticals are developing CHB therapies. A major unmet for CHB treatment remains the potential to achieve functional cure.Key Highlights- During the 10-year forecast period, there are six major pipeline products that are on track to launch, driving a forecast growth in the 9MM from $3.8B in 2019 to $5.2B in 2029, which represents a CAGR of 3.1%.- To combat the unmet need of a functional cure, companies such as Gilead, J&J, Replicor, Ionis, and Assembly Biosciences are developing pipeline products with novel mechanism of action, with the potential of being used as a combination therapy either with current nucleotide analogs or with emerging products.- The pipeline products are expected to launch in the second half of the forecast period in 2029. Antisense nucleotides are expected to gain a market share of 14.7% and sales of $761M in the 9MM by 2029. However, capsid assembly modulators from J&J and a toll-like receptor 8 agonist from Gilead are expected to compete with antisense nucleotides for market shares in the 9MM by the end of the forecast period.Key Questions Answered- How will the CHB market landscape in the 9MM (US, France, Germany, Italy, Spain, UK, Japan, Brazil, China) change from 2019-2029?- What are the most promising late-stage pipeline products for CHB treatment?- How do the clinical and commercial attributes of late-stage pipeline products compare with one another, and against existing CHB treatment options?- What are the remaining unmet needs in CHB treatment?- What drivers and barriers will affect CHB treatment sales in the 9MM over the forecast period?Scope- Overview of CHB, including epidemiology, etiology, pathophysiology, symptoms, diagnosis, and current management strategies.- Topline CHB treatment market revenue from 2019-2029. Annual cost of therapy and major pipeline product sales in this forecast period are included.- Key topics covered include current CHB treatment, unmet needs and opportunities, and the drivers and barriers affecting CHB treatment sales in the 9MM.- Pipeline analysis: comprehensive data split across different phases, emerging novel trends under development, synopses of innovative early-stage projects, and detailed analysis of late-stage pipeline products.- Analysis of the current and future market competition in the global CHB treatment market. Insightful review of the key industry drivers, constraints, and challenges. Each trend is independently researched to provide qualitative analysis of its implications.Reasons to BuyThe report will enable you to -- Develop and design your in-licensing and out-licensing strategies through a review of pipeline products and technologies, and by identifying the companies with the most robust pipeline.- Develop business strategies by understanding the trends shaping and driving the global Hepatitis B Virus Infection market.- Drive revenues by understanding the key trends, innovative products and technologies, market segments, and companies likely to impact the Hepatitis B Virus Infection market in the future.- Formulate effective sales and marketing strategies by understanding the competitive landscape and by analyzing the performance of various competitors.- Identify emerging players with potentially strong product portfolios and create effective counter-strategies to gain a competitive advantage.- Organize your sales and marketing efforts by identifying the market categories and segments that present maximum opportunities for consolidations, investments, and strategic partnerships.Read the full report: ReportlinkerReportLinker is an award-winning market research solution. Reportlinker finds and organizes the latest industry data so you get all the market research you need - instantly, in one place.__________________________

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2024年12月23日管线快照

管线布局中药物为当前组织机构及其子机构作为药物机构进行统计，早期临床1期并入临床1期，临床1/2期并入临床2期，临床2/3期并入临床3期

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药物(靶点)	适应症	全球最高研发状态

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