產品 | 藥物探索 | 臨床前試驗 | 臨床一期 | 臨床二期 | 臨床三期 | 藥證申請 | 上市銷售 |
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TMB-365 and TMB-380 雙抗體複方組合 | 藥物探索
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臨床前試驗
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臨床一期
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臨床二期
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臨床三期
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藥證申請
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上市銷售
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TMB-365/TMB-380 雙抗體複方組合
TMB-380是新一代抗HIV-1高效廣效型藥物中,屬於泛中和性單株抗體藥物。TMB-380是改良自同樣是泛中和性單株抗體的VRC07,而VRC07則是由HIV感染病患所產生並經體細胞突變基因重組之泛中和性單株抗體VRC01所衍生的。如同其親代及原生單株抗體VRC07和 VRC01的作用機制,TMB-380作用標靶是HIV-1病毒表面gp120套膜蛋白(Envelop Protein, ENV)與人類CD4受體(CD4 receptor)結合位點(CD4 binding site, CD4bs)。[1]
從VRC07和TMB-380既有的體外和體內研究得知,其病毒中和能力不僅能涵蓋約96%、跨不同亞型的HIV-1病毒株(cross-clade viruses),並且是五到八倍高效於原生抗體VRC01。在獼猴感染模式測試中,將抗體在感染前事先注射於動物體內,其能以低於VRC01五倍濃度保護動物免於感染發病。此外,由於具長效特性FcRn突變的導入,TMB-380的血中半衰期得以延長二到三倍。[1]
VRC605臨床研究計畫(計畫編號: NCT03015181)是單株抗體TMB-380 (VRC07-523LS)第一次在健康受試者身上進行預防感染之人體試驗,劑量包含1、5、20及40 mg/kg,給藥途徑包含靜脈輸注與皮下注射。 [2,3]
截至目前為止,試驗結果顯示TMB-380在不同劑量及不同注射途徑試驗情境下使用對人體是安全的,且人體之於藥物耐受狀況良好。研究也發現5 mg/kg皮下注射完成後,TMB-380血中濃度能迅速達到並高於10 μg/mL。而TMB-380血中半衰期估計為33±10天。因此,根據現有數據,泛中和性單株抗體藥物TMB-380已具備高效、廣效、長效型抗HIV藥物特質,理當可以勝任HIV-1預防與治療策略上領頭性候選藥物。
NCT02840474臨床試驗計畫是抗HIV-1單株抗體藥物VRC01LS與TMB-380 (VRC07-523LS)一對一在受試病人身上臨床表現比較的研究計畫。
已知的資料顯示,TMB-380與VRC01LS都具有良好的安全性與耐受性,在施打完VRC01LS或TMB-380任一單株抗體藥物後7天,少於半數的VRC01LS受試者有達到0.5 logs病毒載量減降(約為3倍病毒載量減降),但是,TMB-380受試者則是有遠大於 1.2 logs 病毒載量減降(約為16倍病毒載量減降)。[4,5]
中裕新藥與美國國家衛生研究院轄下國家過敏症和傳染病研究所(NIAID)簽訂TMB-380全球非獨家授權契約,搭配中裕新藥的抗體藥物發展出抗HIV的複方療法:TMB-365與TMB-380雙抗體複方組合(dual antibody combination)。
利用調整性試驗設計,針對使用抗病毒藥物組合治療且體內病毒量受到抑制的HIV-1感染者,評估在不同劑量下、每8週或每12週靜脈注射的TMB-365和TMB-380合併療法的安全性與有效性。
1.“VRC07-523 Info – Search Antibody Database” in HIV Databases operated by Triad national Security, LLC for National Nuclear Security Administration of US Department of Energy (DoE) and funded by US National Laboratory of Las Alamos, US National Institutes of Health (US-NIH), and US Department of Health and Human Services (US-HHS).
2. "VRC 605: A Phase 1 Dose-Escalation Study of the Saftey and Pharmacokinetics of a Human Monoclonal Antibody, VRC-HIVMAB075-00-AB (VRC07-523LS) Administered Intravenously or Subcutaneously to Healthy Adults." Conducted and funded by National Institutes of Health Clinical Center (NIH-CC), and National Institute of Allergy and Infectious Diseases (NIAID)
3. Martin R. Gaudinski et al., “A Phase I Dose-Escalation Study of Monoclonal Antibody VRC07-523LS in Healthy Adults.” Conference on Retroviruses and Opportunistic Infections” CROI 2018, Abstract Number: 1061 (Poster 022618).
4. “IAS 2019: FIRST TRIAL RESULTS OF NEW IMMUNE-MODULATING DRUGS PRESENTED IN MEXICO CITY.” - EATG REPORTED
5. Chen G et al. “Safety and virologic effect of the HIV-1 broadly neutralizing antibodies, VRC01LS or VRC07-523LS, administered to HIV-infected adults in a phase 1 clinical trial.” IAS2019 conference, Mexico City. Abstract WEAA0305LB. 2019.
6. Cohen YZ et al., “Safety, pharmacokinetics, and immunogenicity of the combination of the broadly neutralizing anti-HIV-1 antibodies 3BNC117 and 10-1074 in healthy adults: A randomized, phase 1 study.” PLOS ONE (2019)
7. Julio CC et al., “Neutralizing Activity of Broadly Neutralizing Anti-HIV-1 Antibodies against Primary African Isolates” J. Virol. (2021) 95: e01909-20
8. Wagh K et al., “Optimal Combinations of Broadly Neutralizing Antibodies for Prevention and Treatment of HIV-1 Clade C Infection” PLOS Pathogens (2016)
9. ViiV Healthcare Press and News Release: ViiV Healthcare to Present New Long-term Findings from Its Innovative 2-Drug and Long-Acting HIV Medicines Portfolio at CROI 2022. 07 FEB, 2022
10. ViiV Healthcare Press and News Release: ViiV Healthcare Announced US FDA Approval of CABENUVA (CABOTEGARVIR, RILPIVIRINE) for Use Every Two Months, Expanding the Label of The First and Only Complete Long Acting HIV Treatment. 01 FEB. 2022 01 FEB. 2022
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2019-10-012022
啟動TMB-365/TMB-380合併使用的臨床1b/2a試驗