TW202126304A - 使用核心蛋白異位調節劑治療hbv感染之方法 - Google Patents
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Abstract
本發明係關於治療人類病患之HBV感染之方法,其中該方法包括投與治療有效量之化合物(I)或其醫藥上可接受之鹽。
Description
本發明係關於治療人類病患之HBV感染之方法,其中該方法包括投與治療有效量之核心蛋白異位調節劑。
B型肝炎病毒(HBV)感染係全世界主要之公共衛生問題,大約30%之世界人口顯示當前或過去感染之血清學證據。儘管在1980年代初期引進一種安全且有效之針對該病毒之預防性疫苗,但據估計,全世界仍有超過2.57億慢性HBV攜帶者,其中很高比例將最終發展為肝硬化或肝細胞癌(HCC) (WHO Hepatitis B. Fact Sheet N°204)。在2010年全球疾病負擔研究(R Lozano等人,Lancet, 380 (2012), 2095-2128)中,HBV感染係世界上最重要之健康問題,且亦係第十大主要死因(每年780,000例死亡)。已顯示持續清除HBsAg可預防疾病進展及HBV並發症(包括肝硬化、肝衰竭及HCC)之發展。因此,就慢性B型肝炎(CHB)病患而言,認為HBsAg損失(功能性治癒)係最佳終點。將功能性治癒定義為在有限之治療過程完成後,血清中持續存在、無法偵測之HBsAg及HBV DNA,有或無血清轉化為抗HBs (Lok AS、Zoulim F、Dusheiko G等人,Hepatitis B cure: from discovery to regulatory approval. J Hepatol 2017;67:847-861)。
當前,存在兩種可用於治療CHB之治療類別:皮下投與干擾素-α (IFN-α)製劑(習知或PEG-IFN-α)及經口投與之核苷類似物(NUC),諸如替諾福韋(tenofovir)、恩替卡韋(entecavir)、阿德福韋(adefovir)、替比夫定(telbivudine)及拉米夫定(lamivudine)。兩種治療均無法達成高功能性治癒率(無論有或無血清轉化,均持續損失HBsAg)。另外,基於IFN之療法與許多副作用相關聯,而NUC通常需延長或可能終生之療法,及一些與病毒耐藥性之高風險相關聯。
最近,CpAM(核心蛋白異位調節劑)係經研發用於治療HBV感染病患。化合物(I)係藉由靶向HBV衣殼在人類中治療及/或預防之CpAM,其係揭示於WO2015132276中,結構係經下文顯示:
化合物(I)
已完成三項臨床研究(YP39364 (NCT02952924)之第1部分及第2部分、YP39406 (NCT03570658)及YP40218 (NCT03717064))以表徵化合物(I)在健康志願者及CHB病患中之安全性、耐受性、藥物動力學(PK)及藥效學(PD)。短期PD標誌物(HBV DNA及HBV RNA)在用化合物(I)治療四週期間顯示穩健之減少,然而在此期間未觀察到HBsAg之明顯減少。因此,對用化合物(I)治療之新穎方法存在未滿足之醫學需求,其可在有限之治療持續時間內及以極佳之耐受性達成更高之功能性治癒率。
在本發明中,研發化合物(I)單一療法及化合物(I)與其他抗HBV藥劑組合歷時12至144週之方法。化合物(I)在慢性B型肝炎病患中安全且耐受性良好。與當前NUC治療相比,本發明之當前有限治療方法最小化耐藥性之風險並減少NUC治療之不利影響(例如,腎損傷、骨密度損失及肌酸激酶升高之風險等)。
就效用而言,本發明之治療方法在病患中證實穩健之HBV DNA及HBV RNA減少。此外,化合物(I)與其他抗HBV藥劑組合之治療方法歷時12至144週導致明顯之B型肝炎表面抗原(HBsAg)減少或損失。另外,當前尚無針對免疫耐受病患(定義為高度複製(HBV DNA含量升高)及低發炎(ALT含量係正常或肝活檢無明顯發炎或纖維化徵象)之病患)之有效抗病毒治療。然而,用化合物(I)之本發明之治療方法亦可在此等病患中誘導穩健之HBV DNA及HBV RNA減少。
定義
術語「NUC」表示用作HBV療法之核苷類似物,包括(但不限於)拉米夫定、阿德福韋酯(adefovir dipivoxil)、恩替卡韋(ETV)、替比夫定、替諾福韋富馬酸替諾福韋酯(tenofovir disoproxil fumarate) (TDF)及替諾福韋阿拉芬醯胺(tenofovir alafenamide) (TAF)。
術語「HBsAg損失」表示定量HBsAg低於如藉由Elecsys®
HBsAg II (Roche)量測之定量臨限值(<0.05IU/mL)。
術語「禁食」表示一段時間內不進餐,其可為在下一餐之前或最後一餐之後的12小時內之任何時間。
術語「食物」表示任何種類之食物,包括(但不限於)高脂食物、輕食或標準食物。
術語「IFN-α」表示習知干擾素-α或聚乙二醇化干擾素-α (PEG-IFN-α)。IFN-α之實例包括(但不限於) Pegasys®
(Roche)及PEG-Intron®
(Schering公司)。
術語「皮下注射」或「SC」意謂藥物經由短針遞送至皮膚與肌肉間之病患組織層內,皮下劑量將在任何適當之位點,例如腹部或大腿上部投與。就多個劑量而言,應旋轉投與位點。
術語「靜脈內注射」或「IV」意謂使用針頭或管子將藥物直接遞送至病患之靜脈內。
術語「TLR激動劑」意謂一類鐸樣受體激動劑,其等可加強抗病毒細胞介素產生及天然殺手細胞、B細胞及T細胞之活化,及此等免疫反應可在達成CHB之功能性治癒(即,HBsAg損失)中發揮作用。TLR激動劑之實例包括(但不限於) TLR 7激動劑GS-9620 (Gilead Sciences Incs)、TLR 8激動劑GS-9688 (Gilead Sciences Incs)、TLR 7激動劑JNJ-64794964 (Janssen Research & Development LLC)及TLR9調節劑AIC649 (AiCuris Anti-infective Cures GmbH)。
術語「視黃酸誘導型基因I」或「RIG-1」表示針對許多RNA病毒啟動免疫反應之胞質病原體識別受體。RIG-I調節劑表示可通過視黃酸誘導型基因I (RIG-I)介導之HBV前基因組RNA之5'-ε區感知誘導III型及I型干擾素之分子。RIG-I調節劑之實例包括(但不限於)來自Spring Bank Pharmaceuticals之伊那吉韋(Inarigivir) (SB9200)。(Sato S、Li K、Kameyama T等人,The RNA sensor RIG-I dually functions as an innate sensor and direct antiviral factor for hepatitis B virus. Immunity 2015; 42: 123-32)。
術語「小干擾RNA」或「siRNA」表示小干擾核糖核酸,其係一類雙股RNA分子。siRNA靶向任何病毒轉錄本並藉由RISC/Ago2複合物誘導其降解,導致基因沉默。siRNA之實例包括(但不限於) ARB-1467 (Arbutus Biopharma)、ARO-HBV (Arrowhead Pharma)、AB-729 (Arbutus Biopharma)、DCR-HBVS (Dicerna)、Vir-2218 (Alnylam and Vir Biotech)、BB-103 (Benitec)及Lunar-HBV (Arcturus, USA with Janssen)。
術語「HBV LNA」表示含有靶向N-乙醯半乳糖胺(GalNAc)之鎖定核酸(LNA)之單股寡脫氧核糖核苷酸之分子,與來源於B型肝炎病毒(HBV)基因體之mRNA物種互補,旨在用於治療CHB感染。
術語「HBsAg抑制劑」表示可干擾HBsAg之組裝/釋放、產生或進入之分子。HBsAg抑制劑之實例包括(但不限於) REP 2139 (Replicor)及REP 2165 (Replicor),及Myrcludex B (MYR Pharma)。
術語「HBV治療性疫苗」或「HBV疫苗」表示可刺激或加強宿主免疫反應以恢復免疫控制,導致HBV複製之持續抑制及最終HBsAg損失之分子。HBV疫苗之實例包括(但不限於) ABX203 (Center for Genetic Engineering and Biotechnology)、INO-1800 (Inovio)、HB-110 (Ichor Medical Systems with Janssen)、TG1050 (Transgene)及HepTcell (Altimmune)。
術語「治療有效量」表示本發明之化合物或分子之量,當向個體投與時,(i)治療或預防特定疾病、病症或疾患,(ii)減輕、改善或消除該特定疾病、病症或疾患之一或多種症狀,或(iii)預防或延遲本文描述之特定疾病、病症或疾患之一或多種症狀之發作。該治療有效量將取決於化合物、治療中之疾病狀態、治療之疾病之嚴重程度、個體之年齡及相對健康、投與途徑及形式、主治醫師或獸醫之判斷及其他因素而變化。
術語「醫藥組合物」表示待向哺乳動物(例如,有需要人類)投與之包含治療有效量之活性醫藥成分及醫藥上可接受之賦形劑之混合物或溶液。
治療之組合物
另一實施例提供含有本發明之化合物及治療惰性載劑、稀釋劑或賦形劑之醫藥組合物或藥物,及使用本發明之化合物製備此等組合物及藥物之方法。在一項實例中,化合物(I)可藉由在周圍溫度下在適當pH及所需純度下與生理上可接受之載劑,即在採用之劑量及濃度下對接受者無毒之載劑混合以調配成蓋崙製劑之投與形式。該調配物之pH主要取決於化合物之特定用途及濃度,但較佳在約3至約8之範圍內任意變化。在一項實例中,在pH 5下將化合物(I)調配於乙酸鹽緩衝液中。在另一實施例中,該化合物(I)係無菌的。該化合物可(例如)作為固體或非晶型組合物、作為凍乾調配物或作為水溶液儲存。
組合物係以與良好醫學實務一致之方式調配、計量及投與。在此內文中考慮之因素包括治療中之特定疾患、治療中之特定哺乳動物、個別病患之臨床狀況、疾患之原因、藥劑之遞送位點、投與方法、投與之時間表及醫師已知的其他因素。待投與之化合物之「有效量」將由此等因素決定,及係有效用作CpAM所需之最小量,其可用於(但不限於)治療或預防感染B型肝炎病毒之病患。
本發明之化合物可藉由任何合適之方式投與,包括經口、局部(包括經頰及舌下)、直腸、陰道、經皮、非經腸、皮下、腹膜內、肺內、皮內、鞘內及硬膜外及鼻內,且視需要就局部治療而言,病灶內投與。非經腸輸注包括肌內、靜脈內、動脈內、腹膜內或皮下投與。
本發明之化合物可以任何便利之投與形式投與,例如錠劑、粉末、膠囊、溶液、分散液、懸浮液、糖漿、噴霧劑、栓劑、凝膠、乳液、貼劑等。此等組合物可含有醫藥製劑中習知的組分,例如稀釋劑、載劑、pH修飾劑、甜味劑、增積劑及其他活性劑。
典型調配物係藉由混合本發明之化合物及載劑或賦形劑製備。合適之載劑及賦形劑係為熟習此項技術者熟知及詳細描述於例如 Ansel, Howard C.等人,Ansel’s Pharmaceutical Dosage Forms and Drug Delivery Systems
. Philadelphia: Lippincott, Williams & Wilkins, 2004;Gennaro, Alfonso R.等人,Remington: The Science and Practice of Pharmacy
. Philadelphia: Lippincott, Williams & Wilkins, 2000;及Rowe, Raymond C.Handbook of Pharmaceutical Excipients
. Chicago, Pharmaceutical Press, 2005中。該等調配物亦可包括一或多種緩衝劑、穩定劑、表面活性劑、濕潤劑、潤滑劑、乳化劑、懸浮劑、防腐劑、抗氧化劑、遮光劑、助流劑、加工助劑、著色劑、甜味劑、芳香劑、調味劑、稀釋劑,及其他已知添加劑,以提供藥物(即本發明之化合物或其醫藥組合物)之優質呈現或有助於藥物產品(即藥物)製造。
治療方法
本發明係關於(i)治療人類病患之HBV感染之方法,其包括向該病患投與含有化合物(I)之活性成分之醫藥組合物,以200 mg QD或BID至1000 mg QD或BID之量,在有或無其他抗HBV藥劑之情況下投與12至144週;其中化合物(I)為3-[(8aS)-7-[[(4S)-5-乙氧基羰基-4-(3-氟-2-甲基-苯基)-2-噻唑-2-基-1,4-二氫嘧啶-6-基]甲基]-3-側氧基-5,6,8,8a-四氫-1H-咪唑并[1,5-a]吡嗪-2-基]-15 2,2-二甲基-丙酸。
本發明之另一實施例係(ii)根據(i)之方法,其中化合物(I)係經口、SC或IV投與。
本發明之另一實施例係(iii)根據(i)或(ii)之方法,其中化合物(I)係經禁食或進食投與。
本發明之另一實施例係(iv)根據(i)至(iii)中任一項之方法,其中化合物(I)投與之量及頻率為200 mg QD或BID、400 mg QD或BID、600 mg QD或BID、800 mg QD或BID,或1000 mg QD或BID。
本發明之另一實施例係(v)根據(i)至(iv)中任一項之方法,其中化合物(I)係投與12週、24週、36週、48週、52週、60週、72週、84週、96週、104週、108週、120週、132週或144週。
本發明之另一實施例係(vi)根據(i)至(v)中任一項之方法,其中化合物(I)不與其他抗HBV藥劑一起投與。
本發明之另一實施例係(vii)根據(i)至(vi)中任一項之方法,其中化合物(I)係與一或兩種其他抗HBV藥劑一起投與,其中該其他抗HBV藥劑係獨立地選自NUC、IFN-α、TLR激動劑、RIG-I調節劑、siRNA、HBVLNA寡核苷酸、HBsAg抑制劑及HBV疫苗。其他抗HBV藥劑之治療方法可根據現有護理標准應用。
本發明之另一實施例係(viii)根據(i)至(vii)中任一項之方法,其中化合物(I)係與NUC一起投與;其中該NUC係選自ETV、TAF及TDF。
本發明之另一實施例係(ix)根據(i)至(viii)中任一項之方法,其中化合物(I)係投與48至96週,尤其48週、52週、60週、72週、84週或96週。
本發明之另一實施例係(x)根據(i)至(ix)中任一項之方法,其中化合物(I)係在600 mg QD下經由經口投與並用NUC禁食48週;其中NUC係選自ETV、TAF及TDF。
本發明之另一實施例係(xi)根據(i)至(x)中任一項之方法,其中化合物(I)係與NUC及IFN-α一起投與;其中NUC係選自ETV、TAF及TDF。
本發明之另一實施例係(xii)根據(i)至(xi)中任一項之方法,其中化合物(I)係投與48至96週,尤其48週、52週、60週、72週、84週或96週。
本發明之另一實施例係(xiii)根據(i)至(xii)中任一項之方法,其中化合物(I)係在600 mg QD下經由經口投與並用NUC及IFN-α禁食48週;其中NUC係選自ETV、TAF及TDF;其中該IFN-α係選自Pegasys®
及PEG-Intron®
。
本發明之另一實施例係(xiv)根據(i)至(xiii)中任一項之方法,其中化合物(I)係與NUC及TLR激動劑一起投與;其中該NUC係選自ETV、TAF及TDF;其中該TLR激動劑係選自GS-9620、GS-9688、JNJ-64794964及AIC649。
本發明之另一實施例係(xv)根據(i)至(xiv)中任一項之方法,其中化合物(I)係與NUC及RIG-I調節劑一起投與;其中該NUC係選自ETV、TAF及TDF。
本發明之另一實施例係(xvi)根據(i)至(xv)中任一項之方法,其中該RIG-I調節劑係伊那吉韋。
本發明之另一實施例係(xvii)根據(i)至(xvi)中任一項之方法,其中化合物(I)係投與12至48週,尤其12週、24週、36週或48週。
本發明之另一實施例係(xviii)根據(i)至(xvii)中任一項之方法,其中化合物(I)係與NUC及siRNA一起投與;其中該NUC係選自ETV、TAF及TDF。
本發明之另一實施例係(xix)根據(i)至(xviii)中任一項之方法,其中該siRNA係選自ARB-1467、ARO-HBV、AB-729、DCR-HBVS、Vir-2218、BB-103及Lunar-HBV。
本發明之另一實施例係(xx)根據(i)至(xix)中任一項之方法,其中化合物(I)係與NUC及HBV LNA寡核苷酸一起投與;其中該NUC係選自ETV、TAF及TDF;其中該HBV LNA寡核苷酸係化合物(II),其係WO2015/173208或WO2014/179627中揭示之化合物中之任何一者。
本發明之另一實施例係(xxi)根據(i)至(xx)中任一項之方法,其中化合物(I)係投與12至48週,尤其12週、24週、36週或48週。
本發明之另一實施例係(xxii)根據(i)至(xxi)中任一項之方法,其中化合物(I)係與NUC及HBsAg抑制劑一起投與;其中該NUC係選自ETV、TAF及TDF;其中該HBsAg抑制劑係選自REP 2139、REP 2165及Myrcludex B。
本發明之另一實施例係(xxiii)根據(i)至(xxii)中任一項之方法,其中化合物(I)係與另一抗HBV藥劑一起投與,其中該抗HBV藥劑係選自Pegasys®
、PEG-Intron®
、伊那吉韋、ARB-1467、ARO-HBV、AB-729、DCR-HBVS、Vir-2218、BB-103、Lunar-HBV、化合物(II)、REP 2139、REP 2165、Myrcludex B、GS-9620、GS-9688、JNJ-64794964、AIC649、ABX203、INO-1800、HB-110、TG1050及HepTcell。
實例
藉由參考下列實例將更充分地瞭解本發明。然而,其等不應解釋為限制本發明之範圍。
縮寫
AASLD: 美國肝研究協會
APASL: 亞太肝研究協會
BID: 一天兩次
CHB: 慢性B型肝炎
EASL: 歐洲肝研究協會
ETV: 恩替卡韋
NUC: 核苷類似物
HBeAg: B型肝炎e抗原
HBsAg: B型肝炎表面抗原
HBV: B型肝炎病毒
HCC: 肝細胞癌
PEG-IFN: 聚乙二醇化干擾素
QD: 一天一次
TAF: 替諾福韋阿拉芬醯胺
TDF: 替諾福韋富馬酸替諾福韋酯
WHO: 世界衛生組織
一般實驗條件研究群體:
感染HBV之病患(Terrault NA、Lok ASF、McMahon BJ等人,Update on prevention, diagnosis, and treatment of chronic hepatitis B: AASLD 2018 hepatitis B guidance. Hepatology. 2018; 67:1560-1599.European Association for the Study of the Liver. EASL 2017 Clinical Practice Guidelines on the management of hepatitis B virus infection. J Hepatol. 2017; 67:370-398.)。
化合物:
化合物(I):3-[(8aS)-7-[[(4S)-5-乙氧基羰基-4-(3-氟-2-甲基-苯基)-2-噻唑-2-基-1,4-二氫嘧啶-6-基]甲基]-3-側氧基-5,6,8,8a-四氫-1H-咪唑并[1,5-a]吡嗪-2-基]-15 2,2-二甲基-丙酸,其係具有下文顯示之結構之HBV CpAM:化合物(I)。
化合物(II):HBV LNA寡核苷酸,其係WO2015/173208或WO2014/179627中揭示之化合物中之任何一者。
伊那吉韋:由Spring Bank Pharmaceuticals研發之小分子二核苷酸經口活性HBV抗病毒藥,其具有直接作用及免疫調節活性,刺激宿主固有之抗病毒反應。其結合至胞質模式識別受體視黃酸誘導型基因(RIG-I)以增強RIG-1對HBV前基因組RNA之5'-ε區之結合。(Walsh R.、Hammond R.、Jackson K.等人,Effects of SB9200 (Inarigivir) therapy on immune responses in patients with chronic hepatitis B. Journal of Hepatology 2018; 68增刊1: S89-)。
REP 2139或REP 2165:由Replicor公司研發之核酸聚合物。它可經由進入後機制阻斷HBV亞病毒顆粒之組裝/釋放,容許自循環清除HBsAg來發揮作用。(Bazinet M.、Pântea V.、Placinta G.等人,Establishment of high rates of functional control and reversal of fibrosis following treatment of HBeAg negative chronic HBV infection with REP 2139-MG / REP 2165-MG, tenofovir disoproxil fumarate and pegylated interferon alpha-2a. Hepatology 2018; 68增刊1:234A-235A)。
GS-9620:由Gilead Sciences Incs研發之TLR 7激動劑之小分子。(Agarwal K.、Ahn S.H.、Elkhashab M., Safety and efficacy of vesatolimod (GS-9620) in patients with chronic hepatitis B who are not currently on antiviral treatment. Journal of Viral Hepatitis 2018; 25:1331-1340)。
GS-9688:由Gilead Scientices Incs.研發之有效且選擇性TLR 8激動劑之小分子。(Khanam A.、Yoon J.A.、Poonia B.等人,GS-9688, a toll-like receptor 8 agonist induces innate and adaptive antiviral immune response in chronic hepatitis B patients. Hepatology 2018;68增刊1:329A-330A)。
JNJ-64794964:經口鐸樣受體7激動劑,旨在治療慢性HBV,其當前由Janssen Research & Development LLC.研發。(Ed Gane、Mina Pastagia、An De Creus等人,A Phase 1, Double-Blind, Randomised, Placebo-Controlled, First-in-Human Study of the Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of oral JNJ-64794964, a Toll-like Receptor-7 Agonist, in Healthy Adults. Journal of Hepatology 2019; 70 e141-e382: FRI-1988)。
AIC649:經不活化之羊副痘病毒(parapoxvirus ovis)顆粒製劑,已顯示其直接處理宿主免疫防禦之抗原呈遞細胞臂,導致經調節之細胞介素釋放及T細胞反應之活化。AIC649係由AiCuris Anti-infective Cures GmbH研發。(Ibironke Addy、Alen Jambrecina、Thomas Berg等人,First in Human, single ascending dose clinical trial of AIC649 in patients with chronic hepatitis. Journal of Hepatology 2019; 70 e141-e382: FRI-199)。
Myrcludex B:由MYR Pharma擁有之抗HBV分子,其可結合並不活化肝細胞表面蛋白牛磺膽酸鈉共轉運多肽,將HBV誤導至非生產途徑,並藉此防止該細胞感染。(http://myr-pharma.com/science/ about-myrcludex-b)。
DCR-HBVS:Dicerna Pharmaceuticals, Inc.研發之研究藥物。此研究藥物包含單一GalXC分子,其靶向HBsAg基因序列區內之HBV信使RNA。
HBV疫苗:ABX203 (Center for Genetic Engineering and Biotechnology)、INO-1800 (Inovio)、HB-110 (Ichor Medical Systems with Janssen)、TG1050 (Transgene)或HepTcell (Altimmune)。
一般方法:
為探索化合物(I)對HBsAg損失或減少之影響,遵循表1中列舉之劑量方案投與化合物(I)。主要量測為治療後24週之定量HBsAg減少或HBsAg損失(< 0.05 IU/mL,藉由Elecsys®
HBsAg II (Roche)®
量測)。
研究設計:
下表1中總結化合物(I)選擇之劑量及用於本發明中之時間表:
表1:化合物(I)之劑量方案
研究編號 | 劑量 | 投與途徑/頻率 | 飲食要求 | 組合策略 | 化合物(I)之治療持續時間 |
1 | 600 mg | 經口,QD | 禁食 | 化合物(I)與NUC (ETV、TAF或TDF)組合 | 48週 |
2 | 600 mg | 經口,QD | 禁食 | 化合物(I)與NUC (ETV、TAF或TDF)組合 | 52週、60週、72週、84週或96週 |
3 | 600 mg | 經口,QD | 禁食 | 化合物(I)與NUC (ETV、TAF或TDF)及IFN-α (Pegasys® 或PEG-Intron® )組合 | 48週 |
4 | 600 mg | 經口,QD | 禁食 | 化合物(I)與NUC (ETV、TAF或TDF)及IFN-α (Pegasys® 或PEG-Intron® )組合 | 52週、60週、72週、84週或96週 |
5 | 200 mg或400 mg或600 mg或800 mg或1000 mg | 經口,QD/BID; SC,QD/BID;或 IV,QD/BID | 禁食或進食 | 化合物(I)單一療法 | 12至144週(例如,12週、24週、36週、48週、52週、60週、72週、84週、96週、104週、108週、120週、132週或144週) |
6 | 200 mg或400 mg或600 mg或800 mg或1000 mg | 經口,QD/BID; SC,QD/BID;或 IV,QD/BID | 禁食或進食 | 化合物(I)與NUC (ETV、TAF或TDF)組合 | 12至144週(例如,12週、24週、36週、48週、52週、60週、72週、84週、96週、104週、108週、120週、132週或144週) |
7 | 200 mg或400 mg或600 mg或800 mg或1000 mg | 經口,QD/BID; SC,QD/BID;或 IV,QD/BID | 禁食或進食 | 化合物(I)與IFN-α (Pegasys® 或PEG-Intron® )組合 | 12至144週(例如,12週、24週、36週、48週、52週、60週、72週、84週、96週、104週、108週、120週、132週或144週) |
8 | 200 mg或400 mg或600 mg或800 mg或1000 mg | 經口,QD/BID; SC,QD/BID;或 IV,QD/BID | 禁食或進食 | 化合物(I)與NUC (ETV、TAF或TDF)及TLR激動劑組合 | 12至144週(例如,12週、24週、36週、48週、52週、60週、72週、84週、96週、104週、108週、120週、132週或144週) |
9 | 200 mg或400 mg或600 mg或800 mg或1000 mg | 經口,QD/BID; SC,QD/BID;或 IV,QD/BID | 禁食或進食 | 化合物(I)與NUC (ETV、TAF或TDF)及GS-9688組合 | 12至144週(例如,12週、24週、36週、48週、52週、60週、72週、84週、96週、104週、108週、120週、132週或144週) |
10 | 200 mg或400 mg或600 mg或800 mg或1000 mg | 經口,QD/BID; SC,QD/BID;或 IV,QD/BID | 禁食或進食 | 化合物(I)與NUC (ETV、TAF或TDF)及GS-9620組合 | 12至144週(例如,12週、24週、36週、48週、52週、60週、72週、84週、96週、104週、108週、120週、132週或144週) |
11 | 200 mg或400 mg或600 mg或800 mg或1000 mg | 經口,QD/BID; SC,QD/BID;或 IV,QD/BID | 禁食或進食 | 化合物(I)與NUC (ETV、TAF或TDF)及JNJ-64794964組合 | 12至144週(例如,12週、24週、36週、48週、52週、60週、72週、84週、96週、104週、108週、120週、132週或144週) |
12 | 200 mg或400 mg或600 mg或800 mg或1000 mg | 經口,QD/BID; SC,QD/BID;或 IV,QD/BID | 禁食或進食 | 化合物(I)與NUC (ETV、TAF或TDF)及AIC649組合 | 12至144週(例如,12週、24週、36週、48週、52週、60週、72週、84週、96週、104週、108週、120週、132週或144週) |
13 | 200 mg或400 mg或600 mg或800 mg或1000 mg | 經口,QD/BID; SC,QD/BID;或 IV,QD/BID | 禁食或進食 | 化合物(I)與NUC (ETV、TAF或TDF)及RIG-Ι調節劑組合 | 12至144週(例如,12週、24週、36週、48週、52週、60週、72週、84週、96週、104週、108週、120週、132週或144週) |
14 | 200 mg或400 mg或600 mg或800 mg或1000 mg | 經口,QD/BID; SC,QD/BID;或 IV,QD/BID | 禁食或進食 | 化合物(I)與NUC (ETV、TAF或TDF)及伊那吉韋(Inarigivir)組合 | 12至144週(例如,12週、24週、36週、48週、52週、60週、72週、84週、96週、104週、108週、120週、132週或144週) |
15 | 200 mg或400 mg或600 mg或800 mg或1000 mg | 經口,QD/BID; SC,QD/BID;或 IV,QD/BID | 禁食或進食 | 化合物(I)與NUC (ETV、TAF或TDF)及siRNA組合 | 12至144週(例如,12週、24週、36週、48週、52週、60週、72週、84週、96週、104週、108週、120週、132週或144週) |
16 | 200 mg或400 mg或600 mg或800 mg或1000 mg | 經口,QD/BID; SC,QD/BID;或 IV,QD/BID | 禁食或進食 | 化合物(I)與NUC (ETV、TAF或TDF)及化合物(II)組合 | 12至144週(例如,12週、24週、36週、48週、52週、60週、72週、84週、96週、104週、108週、120週、132週或144週) |
17 | 200 mg或400 mg或600 mg或800 mg或1000 mg | 經口,QD/BID | 禁食或進食 | 化合物(I)與NUC (ETV、TAF或TDF)及化合物(II)組合 | 12至48週(例如,12週、24週、36週或48週) |
18 | 200 mg或400 mg或600 mg或800 mg或1000 mg | 經口,QD/BID; SC,QD/BID;或 IV,QD/BID | 禁食或進食 | 化合物(I)與NUC (ETV、TAF或TDF)及DCR-HBVS組合 | 12至144週(例如,12週、24週、36週、48週、52週、60週、72週、84週、96週、104週、108週、120週、132週或144週) |
19 | 200 mg或400 mg或600 mg或800 mg或1000 mg | 經口,QD/BID; SC,QD/BID;或 IV,QD/BID | 禁食或進食 | 化合物(I)與NUC (ETV、TAF或TDF)及HBsAg抑制劑(REP 2139或REP 2165)組合 | 12至144週(例如,12週、24週、36週、48週、52週、60週、72週、84週、96週、104週、108週、120週、132週或144週) |
20 | 200 mg或400 mg或600 mg或800 mg或1000 mg | 經口,QD/BID; SC,QD/BID;或 IV,QD/BID | 禁食或進食 | 化合物(I)與NUC (ETV、TAF或TDF)及Myrcludex B組合 | 12至144週(例如,12週、24週、36週、48週、52週、60週、72週、84週、96週、104週、108週、120週、132週或144週) |
21 | 200 mg或400 mg或600 mg或800 mg或1000 mg | 經口,QD/BID; SC,QD/BID;或 IV,QD/BID | 禁食或進食 | 化合物(I)與RIG-Ι調節劑組合 | 12至144週(例如,12週、24週、36週、48週、52週、60週、72週、84週、96週、104週、108週、120週、132週或144週) |
22 | 200 mg或400 mg或600 mg或800 mg或1000 mg | 經口,QD/BID; SC,QD/BID;或 IV,QD/BID | 禁食或進食 | 化合物(I)與伊那吉韋組合 | 12至144週(例如,12週、24週、36週、48週、52週、60週、72週、84週、96週、104週、108週、120週、132週或144週) |
23 | 200 mg或400 mg或600 mg或800 mg或1000 mg | 經口,QD/BID; SC,QD/BID;或 IV,QD/BID | 禁食或進食 | 化合物(I)與siRNA組合 | 12至144週(例如,12週、24週、36週、48週、52週、60週、72週、84週、96週、104週、108週、120週、132週或144週) |
24 | 200 mg或400 mg或600 mg或800 mg或1000 mg | 經口,QD/BID; SC,QD/BID;或 IV,QD/BID | 禁食或進食 | 化合物(I)與化合物(II)組合 | 12至144週(例如,12週、24週、36週、48週、52週、60週、72週、84週、96週、104週、108週、120週、132週或144週) |
25 | 200 mg或400 mg或600 mg或800 mg或1000 mg | 經口,QD/BID; SC,QD/BID;或 IV,QD/BID | 禁食或進食 | 化合物(I)與DCR-HBVS組合 | 12至144週(例如,12週、24週、36週、48週、52週、60週、72週、84週、96週、104週、108週、120週、132週或144週) |
26 | 200 mg或400 mg或600 mg或800 mg或1000 mg | 經口,QD/BID; SC,QD/BID;或 IV,QD/BID | 禁食或進食 | 化合物(I)與REP 2139或REP 2165組合 | 12至144週(例如,12週、24週、36週、48週、52週、60週、72週、84週、96週、104週、108週、120週、132週或144週) |
27 | 200 mg或400 mg或600 mg或800 mg或1000 mg | 經口,QD/BID; SC,QD/BID;或 IV,QD/BID | 禁食或進食 | 化合物(I)與Myrcludex B組合 | 12至144週(例如,12週、24週、36週、48週、52週、60週、72週、84週、96週、104週、108週、120週、132週或144週) |
28 | 200 mg或400 mg或600 mg或800 mg或1000 mg | 經口,QD/BID; SC,QD/BID;或 IV,QD/BID | 禁食或進食 | 化合物(I)與TLR激動劑組合 | 12至144週(例如,12週、24週、36週、48週、52週、60週、72週、84週、96週、104週、108週、120週、132週或144週) |
29 | 200 mg或400 mg或600 mg或800 mg或1000 mg | 經口,QD/BID; SC,QD/BID;或 IV,QD/BID | 禁食或進食 | 化合物(I)與GS-9688組合 | 12至144週(例如,12週、24週、36週、48週、52週、60週、72週、84週、96週、104週、108週、120週、132週或144週) |
30 | 200 mg或400 mg或600 mg或800 mg或1000 mg | 經口,QD/BID; SC,QD/BID;或 IV,QD/BID | 禁食或進食 | 化合物(I)與GS-9620組合 | 12至144週(例如,12週、24週、36週、48週、52週、60週、72週、84週、96週、104週、108週、120週、132週或144週) |
31 | 200 mg或400 mg或600 mg或800 mg或1000 mg | 經口,QD/BID; SC,QD/BID;或 IV,QD/BID | 禁食或進食 | 化合物(I)與JNJ-64794964組合 | 12至144週(例如,12週、24週、36週、48週、52週、60週、72週、84週、96週、104週、108週、120週、132週或144週) |
32 | 200 mg或400 mg或600 mg或800 mg或1000 mg | 經口,QD/BID; SC,QD/BID;或 IV,QD/BID | 禁食或進食 | 化合物(I)與AIC649組合 | 12至144週(例如,12週、24週、36週、48週、52週、60週、72週、84週、96週、104週、108週、120週、132週或144週) |
33 | 200 mg或400 mg或600 mg或800 mg或1000 mg | 經口,QD/BID; SC,QD/BID;或 IV,QD/BID | 禁食或進食 | 化合物(I)與治療性HBV疫苗組合 | 12至144週(例如,12週、24週、36週、48週、52週、60週、72週、84週、96週、104週、108週、120週、132週或144週) |
Claims (23)
- 一種醫藥組合物之用途,該醫藥組合物含有化合物(I)之活性成分,其用於製備用於治療人類病患之HBV感染之藥物,其中化合物(I)之量為200 mg QD或BID至1000 mg QD或BID在有或無其他抗HBV藥劑之情況下歷時12至144週;及其中化合物(I)為3-[(8aS)-7-[[(4S)-5-乙氧基羰基-4-(3-氟-2-甲基-苯基)-2-噻唑-2-基-1,4-二氫嘧啶-6-基]甲基]-3-側氧基(oxo)-5,6,8,8a-四氫-1H-咪唑并[1,5-a]吡嗪-2-基]-15 2,2-二甲基-丙酸。
- 如請求項1之用途,其中化合物(I)係經口、SC或IV投與。
- 如請求項2之用途,其中化合物(I)係經禁食或進食投與。
- 如請求項1至3中任一項之用途,其中化合物(I)投與之量及頻率為200 mg QD或BID、400 mg QD或BID、600 mg QD或BID、800 mg QD或BID,或1000 mg QD或BID。
- 如請求項1至3中任一項之用途,其中化合物(I)係投與12週、24週、36週、48週、52週、60週、72週、84週、96週、104週、108週、120週、132週或144週。
- 如請求項5之用途,其中化合物(I)不與其他抗HBV藥劑一起投與。
- 如請求項5之用途,其中化合物(I)係與一或兩種其他抗HBV藥劑一起投與,其中該其他抗HBV藥劑係獨立地選自NUC、IFN-α、TLR激動劑、RIG-I調節劑、siRNA、HBV LNA寡核苷酸、HBsAg抑制劑及HBV疫苗。
- 如請求項7之用途,其中化合物(I)係與NUC一起投與;其中該NUC係選自ETV、TAF及TDF。
- 如請求項8之用途,其中化合物(I)係投與48至96週,尤其48週、52週、60週、72週、84週或96週。
- 如請求項8之用途,其中化合物(I)係以600 mg QD經口投與並用NUC禁食48週;其中NUC係選自ETV、TAF及TDF。
- 如請求項7之用途,其中化合物(I)係與NUC及IFN-α一起投與;其中該NUC係選自ETV、TAF及TDF。
- 如請求項12之用途,其中化合物(I)係投與48至96週,尤其48週、52週、60週、72週、84週或96週。
- 如請求項11之用途,其中化合物(I)係以600 mg QD經口投與,並用NUC及IFN-α禁食48週;其中該NUC係選自ETV、TAF及TDF;其中該IFN-α係選自Pegasys® 及PEG-Intron® 。
- 如請求項7之用途,其中化合物(I)係與NUC及TLR激動劑一起投與;其中該NUC係選自ETV、TAF及TDF;其中該TLR激動劑係選自GS-9620、GS-9688、JNJ-64794964及AIC649。
- 如請求項7之用途,其中化合物(I)係與NUC及RIG-I調節劑一起投與;其中該NUC係選自ETV、TAF及TDF。
- 如請求項15之用途,其中該RIG-I調節劑係伊那吉韋(Inarigivir)。
- 如請求項16之用途,其中化合物(I)係投與12至48週,尤其12週、24週、36週或48週。
- 如請求項7之用途,其中化合物(I)係與NUC及siRNA一起投與;其中該NUC係選自ETV、TAF及TDF。
- 如請求項18之用途,其中該siRNA係選自ARB-1467、ARO-HBV、AB-729、DCR-HBVS、Vir-2218、BB-103及Lunar-HBV。
- 如請求項7之用途,其中化合物(I)係與NUC及HBV LNA寡核苷酸一起投與;其中該NUC係選自ETV、TAF及TDF;其中該HBV LNA寡核苷酸係化合物(II)。
- 如請求項20之用途,其中化合物(I)係投與12至48週,尤其12週、24週、36週或48週。
- 如請求項7之用途,其中化合物(I)係與NUC及HBsAg抑制劑一起投與;其中該NUC係選自ETV、TAF及TDF;其中該HBsAg抑制劑係選自REP 2139、REP 2165及Myrcludex B。
- 如請求項7之用途,其中化合物(I)係與另一抗HBV藥劑一起投與,其中該抗HBV藥劑係選自Pegasys® 、PEG-Intron® 、伊那吉韋、ARB-1467、ARO-HBV、AB-729、DCR-HBVS、Vir-2218、BB-103、Lunar-HBV、化合物(II)、REP 2139、REP 2165、Myrcludex B、GS-9620、GS-9688、JNJ-64794964、AIC649、ABX203、INO-1800、HB-110、TG1050及HepTcell。
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