Azvudine

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Azvudine
Azvudine.svg
Clinical data
Trade names捷倍安, 双新艾克
Other names2′-deoxy-2′-β-fluoro-4′-azidocytidine (FNC), RO-0622
Legal status
Legal status
  • US: Investigational drug
  • CN: Conditional use Rx
Pharmacokinetic data
Bioavailability83% (rat, dog)[1]
Metabolismliver (CYP3A)[2]
Elimination half-life4 hours (dog)[1]
Identifiers
  • 4-amino-1-[(2R,3S,4R,5R)-5-azido-3-fluoro-4-hydroxy-5-(hydroxymethyl)oxolan-2-yl]pyrimidin-2-one
CAS Number
PubChem CID
DrugBank
ChemSpider
UNII
ChEMBL
Chemical and physical data
FormulaC9H11FN6O4
Molar mass286.223 g·mol−1
3D model (JSmol)
  • C1=CN(C(=O)N=C1N)[C@H]2[C@H]([C@@H]([C@](O2)(CO)N=[N+]=[N-])O)F
  • InChI=1S/C9H11FN6O4/c10-5-6(18)9(3-17,14-15-12)20-7(5)16-2-1-4(11)13-8(16)19/h1-2,5-7,17-18H,3H2,(H2,11,13,19)/t5-,6-,7+,9+/m0/s1
  • Key:KTOLOIKYVCHRJW-XZMZPDFPSA-N

Azvudine is an antiviral drug which acts as a reverse transcriptase inhibitor.[3] It was discovered for the treatment of Hepatitis C[4] and has since been investigated for use against other viral diseases such as AIDS and COVID-19,[2][5] for which it was granted conditional approval in China.[6][7]

Azvudine was first discovered in 2007.[8] It costs 350 Chinese yuan per 7 days for COVID, As of November 2022.[9]

Medical uses[edit]

In July 2021, azvudine became conditionally approved in China for the following indication: "to treat high-viral-load cases of HIV-1, in combination with a nucleoside reverse-transcriptase inhibitor and a non-nucleoside reverse-transcriptase inhibitor". The approval text describes it as a dual reverse transcriptase and Vif inhibitor.[10]

In July 2022, azvudine received emergency conditional approval for COVID-19 in adults.[11]

Adverse effects[edit]

According to the manufacturer, phase II trials of FNC in combination with doravirine and tenofovir disoproxil fumarate in HIV patients found an adverse effect profile similar to, but milder, than lamivudine combined with the two drugs. Very common (> 10%) side effects include dizziness, elevated liver enzymes, vomiting, and elevated alkaline phosphatase. Common (> 1%) side effects include nausea, elevated blood lipids, fever, insomnia, tiredness, and diarrhea. Detailed numbers are provided by Geniune in the slides and the medication package insert.[12][13] A boxed warning is present at the beginning of the Chinese package insert, describing a risk of "decrease in absolute neutrophil count, increase in total bilirubin, increase in glutathione aminotransferase, and increase in blood glucose".[13]

The small (n=10) open-label pilot study for FNC used alone in COVID reported no adverse events.[14] No data is available from the later, larger phase III study for FNV in COVID.[citation needed]

Non-human models[edit]

Azvudine is found to be mutagenic in in vitro in the Ames test, CHL test, and in vitro in the mice micronucleus test.[15]

Azvudine is toxic to the reproductive system of rats and rabbit. The mimimum reproductive NOAEL found for males is 5.0 mg/kg/d and for females 0.5 mg/kg/d. It is excreted in rat breast milk; the NOAEL for rat pups is 1.5 mg/kg/d.[15]

Azvudine is mainly toxic to the immune system, bone marrow, and digestive system of model animals. The chronic NOAELs are 0.5 mg/kg/d (rat, 3 months), 0.3 mg/kg/d (rat, 26 weeks), and 0.1 mg/kg/d (beagle dog, 1 month and 39 weeks).[15] For comparison, the chronic human dose for HIV treatment is 0.05 mg/kg/d, using the reference 3 mg dose and an average Chinese body mass of 59.5 kg (2014).[citation needed]

History[edit]

Azvudine was first found in literature in a patent filed by Chang Jun-biao of Zhengzhou University.[8] It received its current name in 2009, when researchers at Roche independently discovered it as a Hep C RNA polymerase inhibitor in vitro.[4] In the following years, Chinese scientists tested it in vitro for a number of targets, most importantly HBV (human and duck) and HTLV-1, two viruses with a reverse transcriptase.[16][17][18]

It was first proposed as an HIV treatment in 2011, when in vitro tests by the Chang group provided positive results.[19] In 2014, its oral pharmokinetics in rats was elucidated.[1] A phase II study (NCT04109183) was finished in March 2019 by Genuine Biotech. In August 2020, the Chang group found that the substance inhibits vif in vitro.[20] In the same month, China's drug regulator (NMPA) decided to fast-track the approval process, labelling it a first-in-class medication.[12] In July 2021, NMPA granted conditional approval for HIV-1.[7] It was included in the 2021 HIV treatment recommendnation by the Chinese Medical Association and Chinese CDC, published October that year.[12] Curiously, no full results of the trial have been made available for this study in any journal detailing the experiment design as of December 2022.[21] Parts of the results are shown on the drug monograph as well as a 2022 slides deck produced by Genuine for the NHSA available on the latter's website.[12]

FNC was found to inhibit some coronaviruses in vitro around 2020, leading to an interest for its use in COVID. An open-label pilot study on mild and moderate cases was performed in 2020, with mildly positive results.[14] A phase III trial was performed in 2022 in China. In July 2022, China's drug regulator granted conditional approval for it to be used to treat COVID-19, following a local phase III trial.[6] As of December 2022, no detailed description of the said trial has been published in any journal, but state media has been quoting some numbers from the developer: "40% clinical improvement in 7 days by FNC group, compared to 11% in control".[7] It is unclear how such improvement is defined.

Society and culture[edit]

Genuine owns two different tradenames for this medication: 双新艾克 (literally "dual new AIDS inhibitor") for HIV use[12] and 捷倍安 (literally "fast extra safe") for COVID use.[7] No generics are available.

Geniune holds one patent related to the drug: the original 2007 patent on the entire class of 2'-fluorine-4'-substituted nucleotides, purchased from the Zhengzhou University.[8] Two other Chinese patents on synthesizing the drug are found on Google Patents, but the owners do not appear connected to Geniune.[22] Roche held one 2002 patent, CNA028118480A (CN1516590A), over the broader class of 4'-substituted nucleotides. The patent was voided in 2019 after Riboscience, its new holder, stopeed paying fees.[23]

References[edit]

  1. ^ a b c Peng, Y; Cheng, T; Dong, L; Zhang, Y; Chen, X; Jiang, J; Zhang, J; Guo, X; Guo, M; Chang, J; Wang, Q (September 2014). "Quantification of 2'-deoxy-2'-β-fluoro-4'-azidocytidine in rat and dog plasma using liquid chromatography-quadrupole time-of-flight and liquid chromatography-triple quadrupole mass spectrometry: Application to bioavailability and pharmacokinetic studies". Journal of Pharmaceutical and Biomedical Analysis. 98: 379–86. doi:10.1016/j.jpba.2014.06.019. PMID 24999865.
  2. ^ a b Liu Y, Liu B, Zhang Y, Peng Y, Huang C, Wang N, et al. (July 2017). "Intestinal absorption mechanisms of 2'-deoxy-2'-β-fluoro-4'-azidocytidine, a cytidine analog for AIDS treatment, and its interaction with P-glycoprotein, multidrug resistance-associated protein 2 and breast cancer resistance protein". European Journal of Pharmaceutical Sciences. 105: 150–158. doi:10.1016/j.ejps.2017.05.009. PMID 28487144. S2CID 4252337.
  3. ^ Wang RR, Yang QH, Luo RH, Peng YM, Dai SX, Zhang XJ, et al. (2014). "Azvudine, a novel nucleoside reverse transcriptase inhibitor showed good drug combination features and better inhibition on drug-resistant strains than lamivudine in vitro". PLOS ONE. 9 (8): e105617. Bibcode:2014PLoSO...9j5617W. doi:10.1371/journal.pone.0105617. PMC 4140803. PMID 25144636.
  4. ^ a b Smith DB, Kalayanov G, Sund C, Winqvist A, Maltseva T, Leveque VJ, et al. (May 2009). "The design, synthesis, and antiviral activity of monofluoro and difluoro analogues of 4'-azidocytidine against hepatitis C virus replication: the discovery of 4'-azido-2'-deoxy-2'-fluorocytidine and 4'-azido-2'-dideoxy-2',2'-difluorocytidine". Journal of Medicinal Chemistry. 52 (9): 2971–8. doi:10.1021/jm801595c. PMID 19341305.
  5. ^ Harrison C (27 February 2020). "Coronavirus puts drug repurposing on the fast track". Nature Biotechnology. 38 (4): 379–381. doi:10.1038/d41587-020-00003-1. PMID 32205870.
  6. ^ a b Ye, Yvaine (2022-07-26). "China approves first homegrown COVID antiviral". Nature. doi:10.1038/d41586-022-02050-x. PMID 35883009. S2CID 251104078.
  7. ^ a b c d "首个国产抗新冠口服药附条件获批上市" [First domestic oral anti-Covid drug conditionally approved]. 新华网. 证券日报. 2022-07-26. Archived from the original on 2022-08-09. Retrieved 2022-07-26.
  8. ^ a b c Chang J, Bao X, Wang Q, Guo X, Wang W, Qi X. Preparation of 2′-fluoro-4′-substituted nucleoside analogs as antiviral agents. 20070807. Chinese Patent Application No: CN 2007-10137548. Chinese Patent No: CN 101177442A, 20080514.
  9. ^ Beijing Daily (repost) (19 November 2022). "新冠口服药阿兹夫定片线上开售,每瓶售价350元" [Oral COVID drug Azvudine tablet available online at 350 yuan/bottle]. Xinmin Evening News. Retrieved 28 December 2022.
  10. ^ "国家药监局附条件批准阿兹夫定片上市" [NMPA conditionally approvals azvudine tablets]. www.nmpa.gov.cn (in Chinese). 2021-07-21.
  11. ^ "国家药监局应急附条件批准河南真实生物科技有限公司阿兹夫定片增加新冠肺炎治疗适应症注册申请" [NMPA grants emergency conditional approval for additional indication registration of azvudine tablets (Hebei Genuine Biotech Co., Ltd.)]. www.nmpa.gov.cn. 2022-07-25.
  12. ^ a b c d e Genuine Biotech (July 11, 2022). "阿兹夫定片(双新艾克)" [Azvudine Tablets (Shuāngxīnàikè)]. NHSA.gov.cn. Archived from the original on 2022-09-06.
  13. ^ a b "阿兹夫定片说明书" [Azvudine Tablets, Monograph] (PDF). WUXU DATA. Retrieved 2023-01-03.{{cite web}}: CS1 maint: url-status (link)
  14. ^ a b Ren, Z; Luo, H; Yu, Z; Song, J; Liang, L; Wang, L; Wang, H; Cui, G; Liu, Y; Wang, J; Li, Q; Zeng, Z; Yang, S; Pei, G; Zhu, Y; Song, W; Yu, W; Song, C; Dong, L; Hu, C; Du, J; Chang, J (October 2020). "A Randomized, Open-Label, Controlled Clinical Trial of Azvudine Tablets in the Treatment of Mild and Common COVID-19, a Pilot Study". Advanced Science. 7 (19): e2001435. doi:10.1002/advs.202001435. PMC 7404576. PMID 35403380.
  15. ^ a b c Drug Review Center (China) (June 30, 2022). "阿兹夫定片 (CXHS2000016-17) 申请上市技术审评报告" [Azvudine tabs (CHXS2000016-17) request for marketing technical review report] (PDF). WUXU DATA. Retrieved 2023-01-03.{{cite web}}: CS1 maint: url-status (link)
  16. ^ Wang, Q.; Liu, X.; Wang, Q.; Zhang, Y.; Jiang, J.; Guo, X.; Fan, Q.; Zheng, L.; Yu, X.; Wang, N.; Pan, Z.; Song, C.; Qi, W.; Chang, J. (2011). "FNC, a novel nucleoside analogue inhibits cell proliferation and tumor growth in a variety of human cancer cells". Biochemical Pharmacology. 81 (7): 848–855. doi:10.1016/j.bcp.2011.01.001. PMID 21219886.
  17. ^ Zheng, L.; Wang, Q.; Yang, X.; Guo, X.; Chen, L.; Tao, L.; Dong, L.; Li, Y.; An, H.; Yu, X.; Wang, Q.; Chang, J. (2012). "Antiviral activity of FNC, 2'-deoxy-2'-β-fluoro-4'-azidocytidine, against human and duck HBV replication". Antiviral Therapy. 17 (4): 679–687. doi:10.3851/IMP2094. PMID 22452880. S2CID 25576607.
  18. ^ Zhou, Y.; Zhang, Y.; Yang, X.; Zhao, J.; Zheng, L.; Sun, C.; Jiang, J.; Yang, Q.; Wang, Q.; Chang, J. (2012). "Novel nucleoside analogue FNC is effective against both wild-type and lamivudine-resistant HBV clinical isolates". Antiviral Therapy. 17 (8): 1593–1599. doi:10.3851/IMP2292. PMID 22910281. S2CID 29382902.
  19. ^ Wang, Q; Hu, W; Wang, S; Pan, Z; Tao, L; Guo, X; Qian, K; Chen, CH; Lee, KH; Chang, J (September 2011). "Synthesis of new 2'-deoxy-2'-fluoro-4'-azido nucleoside analogues as potent anti-HIV agents". European Journal of Medicinal Chemistry. 46 (9): 4178–83. doi:10.1016/j.ejmech.2011.06.020. PMC 3164908. PMID 21745701.
  20. ^ Sun, L; Peng, Y; Yu, W; Zhang, Y; Liang, L; Song, C; Hou, J; Qiao, Y; Wang, Q; Chen, J; Wu, M; Zhang, D; Li, E; Han, Z; Zhao, Q; Jin, X; Zhang, B; Huang, Z; Chai, J; Wang, JH; Chang, J (13 August 2020). "Mechanistic Insight into Antiretroviral Potency of 2'-Deoxy-2'-β-fluoro-4'-azidocytidine (FNC) with a Long-Lasting Effect on HIV-1 Prevention". Journal of Medicinal Chemistry. 63 (15): 8554–8566. doi:10.1021/acs.jmedchem.0c00940. PMID 32678592. S2CID 220631451.
  21. ^ Li, Guangdi; Wang, Yali; De Clercq, Erik (April 2022). "Approved HIV reverse transcriptase inhibitors in the past decade". Acta Pharmaceutica Sinica B. 12 (4): 1567–1590. doi:10.1016/j.apsb.2021.11.009. PMC 9279714. PMID 35847492.
  22. ^ Google Patents Search, "阿兹夫定" (with quotes), CN114149475A, CN111892636A.
  23. ^ Guokr.com (10 August 2022). "真实生物的真实面目". Huxiu.com. Retrieved 30 December 2022.