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更新于：2025-04-20
Imdusiran
更新于：2025-04-20
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最高研发阶段临床2期 |
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最高研发阶段(中国)临床申请 |
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Sequence Code 453110990
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Sequence Code 453110991
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关联
9
项与 Imdusiran 相关的临床试验NCT06154278
Pilot Study to Evaluate Intrahepatic and Peripheral Responses to Small Interfering RNA, Imdusiran (AB-729), Among People With Chronic Hepatitis B
NCT06245291
A Phase 2a, Open-Label Multiple Dose Study Evaluating the Safety, Tolerability, and Pharmacodynamics of Imdusiran (AB-729) in Combination With Intermittent Dosing of Durvalumab, a PD-L1 Monoclonal Antibody, in Subjects With Chronic HBV Infection
ACTRN12622000317796
A Phase 2a, Randomized, Blinded, Multicenter Study Investigating a Combination of AB-729 and VTP-300 to evaluate their safety and reactogenicity in Virologically-Suppressed Chronic Hepatitis B Participants.
100 项与 Imdusiran 相关的临床结果
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100 项与 Imdusiran 相关的转化医学
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100 项与 Imdusiran 相关的专利（医药）
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3
项与 Imdusiran 相关的文献（医药）2024-10-11ACS Infectious Diseases
Control of Hepatitis B Virus with Imdusiran, a Small Interfering RNA Therapeutic
Article
作者: Cuconati, Andrea ; Paratala, Bhavna ; Thi, Emily P. ; Graves, Ingrid E. ; Ye, Xin ; McClintock, Kevin ; Rijnbrand, Rene ; Micolochick Steuer, Holly M. ; Espiritu, Christine ; Sofia, Michael J. ; Lee, Amy C. H. ; Harasym, Troy ; Jarosz, Agnes ; Snead, Nicholas M. ; Teng, Xiaowei ; Abbott, Cory ; Ardzinski, Andrzej ; Lam, Angela M.
Chronic hepatitis B is a global health concern with a high risk of end-stage liver disease. Current standard-of-care agents have low cure rates, and new therapies are needed. Small interfering RNAs (siRNAs) that target viral RNAs fulfill a gap not addressed by standard-of-care agents and may contribute to a functional cure. Here, we describe the preclinical characterization of imdusiran (AB-729), a novel, pan-genotypic siRNA therapeutic that effectively reduces HBsAg, viral antigens, and viral replication in chronic hepatitis B patients and is currently in Phase 2 clinical studies. In hepatitis B virus (HBV) cell-based systems, imdusiran possessed pan-genotypic nanomolar potency and retained activity against HBV target site polymorphisms. Imdusiran was active against nucleos(t)ide analogue- and capsid assembly modulator-resistant HBV isolates, and combination with standard-of-care agents was additive. In an HBV adeno-associated virus mouse model, HBsAg was reduced up to 3.7 log10 after a single imdusiran dose, with sustained suppression for 10 weeks. Imdusiran did not intrinsically stimulate cytokine release in healthy donor human whole blood, supportive of its mechanism of action as a direct acting RNA interference antiviral. Taken together, these data support imdusiran in combination treatment approaches toward chronic hepatitis B functional cure.
Hepatology communications
Measuring hepatitis B pgRNA stability using an updated automated HBV pgRNA assay with increased sensitivity
Article
作者: Anderson, Mark ; Thi, Emily P. ; Stec, Michael ; Mbanya, Dora ; Picchio, Gaston ; Cloherty, Gavin
Background::
HBV pregenomic RNA (pgRNA) is a circulating biomarker for covalently closed circular DNA activity in HBV-infected individuals and has been studied for treatment efficacy, disease staging, and off-therapy outcomes; however, data on the stability are scarce. Increasing HBV pgRNA assay sensitivity may improve its predictive value and provide additional insights at low viral levels.
Methods::
Modifications to a fully automated first (v1) generation HBV pgRNA assay improved sensitivity up to 15-fold over the previous assay. Flexible sample input volumes yielded lower limits of quantitation of 10 and 22 copies/mL for 0.6 and 0.2 mL assays, respectively. Results are standardized to secondary standards that are traceable to the WHO HBV DNA standard, and internal and external controls are included.
Results::
Comparison between v1 and modified v2 assays showed increased sensitivity from 152 copies/mL with v1 to 10 (0.6 mL) and 22 (0.2 mL) copies/mL with v2, respectively. Quantitated v2 results were indistinguishable from v1, indicating that comparisons can be made to previous studies. Single timepoint treatment-naive blood donors or longitudinal draws from patients with chronic hepatitis B on AB-729, an investigational siRNA therapy, showed improved detection and quantifiable pgRNA with v2 compared with v1. Stability testing demonstrated excellent HBV pgRNA plasma stability after 3 freeze-thaw cycles, for at least 7 days at 25–37 °C and at least 30 days at 4°C, with ≤0.25 Log U/mL decrease.
Conclusion::
HBV pgRNA v2 assays with increased sensitivity and flexible input volumes demonstrated increased detection and quantitation of low viral titer samples. Highly sensitive HBV pgRNA assays may be useful in refining predictive treatment outcomes based on this marker. HBV pgRNA was stable under multiple conditions, which increases the reliability of this marker.
AIDS reviews4区 · 医学
Hepatitis B Gene Therapy Coming to Age.
4区 · 医学
Review
作者: Soriano, Vicente
The major pandemics caused by chronic viral infections is produced by HIV, hepatitis C virus (HCV), and hepatitis B virus (HBV), with estimates of 38, 70, and 250 million people worldwide, respectively (Fig. 1). During the last couple of years, the advent of direct oral antivirals has allowed pursuing global HCV eradication. In an unprecedented manner, these drugs cure more than 95% of hepatitis C patients when given for only 2-3 months. The enthusiasm on HCV has renewed the interest for curative strategies for both HIV and HBV. However, important biological differences between all three viruses may preclude envisioning a similar rapid success for either HIV or HBV than for HCV infection. As shown in figure 1, once infection of targeted cells has occurred, the viral genetic material only replicates in the cytosol for HCV whereas it enters the nucleus and integrates into the chromosomes as provirus for HIV or is converted in a circular covalently closed form (cccDNA) for HBV (Fig. 1). Blocking viral nucleic acid replication for a minimum lag of time allows definitive clearance of HCV infection, with degradation of residual cytoplasmic HCV-RNA strands. In contrast, blocking viral replication has only a transient effect on HIV or HBV, as mRNA expression resumes following treatment discontinuation, given the stability of the HIV provirus or the HBV cccDNA, respectively. The European Liver meeting took held in Paris on April 2018. A relatively large number of presentations addressed distinct new hepatitis B therapeutic strategies. Table 1 summarizes some of the molecules that have been investigated so far with more promising results, grouping them into distinct drug classes (Soriano et al. Exp Op Inv Drugs 2017;26:843-51), based on their distinct mechanism of action and targeted steps in the HBV life cycle (Fig. 2). Considering the pros and cons of novel HBV therapeutic candidates, it has become apparent new HBV gene therapies among the most attractive. Several advances have contributed to position gene therapy in front within the experimental HBV armamentarium. First, progresses in delivery systems, including the use of polymers and nanoformulations have allowed developing easier forms of administration that now are becoming subcutaneous and monthly. Second, the synthetic production of oligonucleotide formulations has reduced costs. Third, the specificity against HBV is higher than for other experimental agents, as immune modulators that enhance innate immunity, such as TLR agonists (i.e., GS-9620) or checkpoint inhibitors (i.e., nivolumab). Fourth, significant declines in serum hepatitis B surface antigen (HBsAg) are demonstrated during gene therapy, which have never been seen using the most potent polymerase inhibitors (i.e., tenofovir or entecavir). Finally, unanticipated significant reductions in cccDNA are seen with HBV gene therapy, most likely as prove of an indirect benefit of waning the immunosuppressive effect of large over amounts of HBsAg released by infected hepatocytes that contributes to T-cell exhaustion. In a pioneering study, Roche was the first to publish the potent effect of an oral small molecule that blocked HBV gene expression (Mueller et al. J Hepatol 2018;68:412-20). The drug belonged to the dihydroquinolizinone class, and directly or indirectly modified viral RNAs, promoting their degradation. This posttranscriptional silencing was accompanied by rapid drops in HBV-DNA and more importantly in serum HBsAg in the humanized mice. However, Roche decided to discontinue any further clinical development of the drug. Nowadays, two major groups of agents are being developed as HBV gene therapies. At this time, interference RNA (iRNA) molecules and nucleic acid polymers (NAPs) are the most promising. Overall, iRNA is double-stranded RNA molecules, 20 nucleotides long. One strand matches a segment of specific HBV mRNA and induces its degradation. Several iRNA molecules have entered into Phase II clinical trials (Flisiak et al. Exp Op Biol Ther, in press), including ARB-1467 and AB-729 (Arbutus), ARO-HBV (Arrowhead), ALN-HBV (Alnylam), and IONIS-HBVRx (Ionis). In most cases, they are tested as part of combination therapy with nucleos(t)ide analogs and/or peginterferon. NAPs are phosphorothioate 40 length oligonucleotides that no map any HBV sequence. However, they interact with a liver host target protein (apolipoprotein-like) and result in specific inhibition of HBV mRNAs. This is followed by rapid suppression of HBsAg release (Roehl et al. Mol Ther Nuc Acids 2017;8:1-12). In a pilot study with intravenous REP-2139, investigators from Replicor demonstrated strong reductions in HBV-DNA along with significant drops in HBsAg and seroconversion in some patients. More interestingly was the recognition of significant reductions in hepatic cccDNA, most likely a result of an indirect effect following the removal of large amounts of HBsAg from the bloodstream that contributes to impaired T-cell responses in chronic hepatitis B patients (Bazinet et al. EASL, Paris 2018; abstract FRI-343). An improved NAP, named REP-2165 and subcutaneous administration are currently being tested.
研发状态
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| 适应症 | 最高研发状态 | 国家/地区 | 公司 | 日期 |
|---|---|---|---|---|
| 慢性乙型肝炎 | 临床2期 | 澳大利亚 | 2021-05-07 | |
| 慢性乙型肝炎 | 临床2期 | 保加利亚 | 2021-05-07 | |
| 慢性乙型肝炎 | 临床2期 | 加拿大 | 2021-05-07 | |
| 慢性乙型肝炎 | 临床2期 | 新西兰 | 2021-05-07 | |
| 乙型肝炎 | 临床申请 | 中国 | 2022-05-10 | |
| 乙型肝炎 | 临床申请 | 中国 | 2022-05-10 |
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临床结果
临床结果
适应症
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临床2期 | 22 | 糧遞夢鏇齋醖鬱網遞獵(獵壓廠蓋願鹹廠鹽夢蓋) = 艱齋觸襯夢夢齋遞鬱網 窪淵壓襯鹽選鹹範獵鑰 (積積網鑰遞繭觸壓壓憲 ) | 积极 | 2024-11-15 | |||
临床2期 | 43 | (A1: 24 wks IFN + 2 imdusiran doses + NA) | 艱獵鏇鹹顧遞憲鏇鬱獵(遞鑰鹹衊範窪範廠衊願) = 蓋醖鏇鬱製窪積網艱簾 鹽構鹹顧鹽網網淵醖遞 (選觸顧鑰積蓋醖觸壓膚 ) 更多 | 积极 | 2024-06-01 | ||
(A2: 24 wks IFN + NA) | 艱獵鏇鹹顧遞憲鏇鬱獵(遞鑰鹹衊範窪範廠衊願) = 獵醖窪範遞鑰構餘鏇鏇 鹽構鹹顧鹽網網淵醖遞 (選觸顧鑰積蓋醖觸壓膚 ) 更多 | ||||||
临床2期 | 40 | imdusilan+VTP-300 | 鹽艱顧製簾襯顧鹹淵蓋(觸遞膚構願艱鬱鑰製襯) = There were no serious adverse events, Grade 3 or 4 adverse events or treatment discontinuations. 製餘膚襯窪簾廠憲觸繭 (鑰衊鹽壓淵願簾鹹淵鹽 ) 更多 | 积极 | 2023-11-09 | ||
imdusilan+placebo | |||||||
临床2期 | HBV RNA transcripts | HBV DNA | hepatitis B surface antigen (HBsAg) | - | 窪廠觸範觸壓鹽顧範壓(製製鹽願積憲艱範顧網) = 衊蓋願鹽願醖膚憲壓鑰 壓糧鑰憲糧醖窪鹹醖範 (餘憲鏇獵艱製憲築積襯 ) | 积极 | 2022-06-25 | ||
Control GalNAc siRNA | 窪廠觸範觸壓鹽顧範壓(製製鹽願積憲艱範顧網) = 壓淵築觸鹹製顧網鬱遞 壓糧鑰憲糧醖窪鹹醖範 (餘憲鏇獵艱製憲築積襯 ) | ||||||
临床2期 | 27 | 鏇鹽鹽觸淵遞窪積艱鬱(膚齋壓淵襯廠構夢範獵) = 膚糧糧範鹹鏇膚淵簾膚 艱獵壓觸鏇夢鹹網顧鹹 (製願襯顧顧蓋積糧鏇網 ) | 积极 | 2022-06-22 | |||
N/A | 慢性乙型肝炎 HBsAg | - | 淵糧顧鑰獵壓鹹夢膚鹽(糧構積糧夢餘簾鏇糧鏇) = 膚窪範糧醖網壓鹽壓壓 襯襯衊獵鹽醖夢網範製 (憲衊範積襯窪簾顧壓鏇 ) 更多 | - | 2021-06-23 |
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