TWI241913B - Use of PEG-IFN-alpha and ribavirin for the treatment of chronic hepatitis C - Google Patents
Use of PEG-IFN-alpha and ribavirin for the treatment of chronic hepatitis C Download PDFInfo
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
- A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
- A61K31/7056—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing five-membered rings with nitrogen as a ring hetero atom
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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- A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- A61K38/19—Cytokines; Lymphokines; Interferons
- A61K38/21—Interferons [IFN]
- A61K38/212—IFN-alpha
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
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- A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
- A61K47/62—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being a protein, peptide or polyamino acid
- A61K47/64—Drug-peptide, drug-protein or drug-polyamino acid conjugates, i.e. the modifying agent being a peptide, protein or polyamino acid which is covalently bonded or complexed to a therapeutically active agent
- A61K47/642—Drug-peptide, drug-protein or drug-polyamino acid conjugates, i.e. the modifying agent being a peptide, protein or polyamino acid which is covalently bonded or complexed to a therapeutically active agent the peptide or protein in the drug conjugate being a cytokine, e.g. IL2, chemokine, growth factors or interferons being the inactive part of the conjugate
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- A—HUMAN NECESSITIES
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
- A61P31/14—Antivirals for RNA viruses
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
Description
1241913 五、發明說明（1) 本發明係關於治療慢性C型肝炎感染，其利用有效量的 聚乙二醇-干擾素—α結合.物及三唑核苷治療C型肝炎。 干擾素（IFNs)是天然產生的蛋白質，具有抗病毒，抗複 製及免疫调印活性。已知人體中存在4種不同的干擾素種 類（Pestka et al. (1987) Ann. Rev· Biochem· 5 6， 727-777及Emanual & Pestka (1993) J. Biol· Chem. 2_68，1 2 56 5- 1 25 6 9 )。干擾素α家族代表主要由經刺激的 周邊血液中白血球（Pestka et al.， loc. cit· ;Havell et al. (1975) Proc. Natl. Acad. Sci. USA 72, 2185-2187 ；Cavalieri et al. (1977) Proc. Natl.
Acad· Sci· USA U, 3287-3291)，淋巴母細胞及肌母細 胞株（Familletti et al· (1981) Antimicrob· Agents·
Chemother. M， 5-9)所產生的干擾素。干擾素^的抗病 毒效果的達成不僅藉著直接影響病毒本身，並且藉著保護 目標細胞免受病毒的感染。干擾素對於癌症的腫瘤細胞可 產生效用，並且可影響該個體的免疫系統，例如，干擾素 可活化其巨噬細胞及天然殺手細胞，且強化多種具有免疫 重要性的組成分於細胞膜上的表現。干擾素_cDNA及其直 ，，現的製備方法，特別是在大腸桿菌中表現，已發表在 多篇文獻中。例如，自然_( 1 9 82 ) ，5〇3一5〇8，自然^^ ( 1 980 )，326 - 32 0，自然m(1981)，2〇一26，核酸研究爸 (1980) ’4057-4074 以及由歐洲專利申請Ν〇·32134，4398〇 及211148中均提及重組干擾素的製備。 在歐洲專利申請No· 7 0 78 55中提出以干擾素^及三唑核
1241913 發明說明（2) 不過，該方法並不是每 脊做為慢性C型肝炎的組合治療 一次都有效。 . ϋ =二醇-干擾素_ α結合物及三唑 干擾素…鋪做為組合治療更為有：…療比以 已知以干擾素-α而言，聚乙—臨 停留在u巾的_，ΛΛ 半生期及 提高生理活性。 &八、免‘生產性’降低清除性及 土 ：明因此提供使用聚乙二醇_干擾素1結合物及三唑 2 k造治療慢性C型肝炎感㈣的藥物。另彳，本發明 =治療經慢性C型肝炎感染的患者的方法，包括办予 C:/炎的聚乙二醇_干擾素1結合物及三唾㈣治療慢性 - ί ί :斤使用的名5司聚乙二醇-干擾素~ α結合物”包括 =自任：天然物料(如’白血球，肌母細胞，淋巴球)或 :二自天然物料的物料(如細胞株），或以重組纽技術 ^ 6、干擾素—α。干擾素α選殖的細節及其直接表現的 匕，，特別是在大腸桿菌中的表現，已是多篇文獻的主 曰。已知重組干擾素α的製備方式，例如，由Goeddel et a1· (198㈧自然Mi，316-320 及（1981)，自然_， 2 0 - 2 6 ’及歐洲專利中請案號3 2 1 3 4，4 3 9 8 0及2 1 1 1 4 8。干 擾素α有多種型式，如干擾素αί，干擾素^2 ;甚至其亞 型更包括’但不以此為限，干擾素α 2Α，干擾素α 2β，干 擾素a 2C及^擾素.α丨丨（又稱為干擾素α丨〗或ω —干擾 素）名3 干擾素α 也包括Amgen具一致性的干擾素
第5頁 1241913
α ’或是天然及/或重組的干擾素的混合物。以使用干 擾素α2Α為佳。歐洲專利申請案號43980及211148中敘述 了干擾素α2Α的製造。 將干擾素α與聚合物結合，如聚烷基二醇（經取代或未 經取代），例如，聚乙二醇，以生成聚乙二醇干擾素α結 合物。結合的方式可利用多種已知的結合子進行，特別是 歐洲專利申請案號05 1 0 3 56，5 938 6 8，及8 0 9 9 9 6中所描 述。聚合物的分子量，較佳為聚乙二醇聚合物，其範圍由 3 0 0至70. 〇〇〇道耳呑（dal ton)，同時可利用一種或多種的 聚合物’較佳為一種到三種的聚合物與干擾素^結合。較 佳的聚乙二醇干擾素α結合物，其式如下： 〇
II
R〇CH2CH2(〇CH2CH2)n—〇—〇—NH ROCH2CH2(OCH2CH2)rr2·~〇
其中R及R’是甲基，X是NH，且n及n，分別是，或均為42 〇 或 520。 在第11版默克指標（Merck Index)中，化合物No. 8199， 及描述三唑核苷，1 - yS - D -核苷呋喃糖基-1 Η - 1，2，4 -三唑 - 3 -羰化醯胺。其製造及調配如美國專利申請 No· 4. 21 1 · 771 。
第6頁 1241913 i五、發明說明（4)
| 根據本發明，將聚乙二醇干擾素α結合物及三唑核苷以 |有效量施予受慢性C型肝炎·感染的患者，其可排除或至少 !減輕一種或多種慢性C型肝炎的症狀，包ALT增高，陽性抗 -HCV抗體測試，HCV-RNA陽性測試證明HCV存在，慢性肝病 的臨床紅斑出現，及肝細胞受損。 本發明之利用聚乙二醇-干擾素-α結合物施行組合治療 的劑量是不論體重，每週約為3 3至5 4 0微克，並且以每週 或每兩週施行一次。
用來施行本發明之三唑核脊的劑量是每天約為400至 1 2 0 0毫克，而且每週至少施行5天，較佳是每週7天。假設 患者的體重介於4 0至1 5 0公斤，則劑量給予的範圍則介於 每天，每公斤重施予1 0 - 3 0毫克。更詳細來說，三唑核苷 每天使用的劑量是8 0 0 - 1 2 0 0毫克。上述每天要使用的劑 量，可利用每天一次單一劑量的方式，或是分為每天兩次 或三次方式使用。較佳的，將三唑核苷分為每日兩次使 用。
根據本發明，將三唑核苷與聚乙二醇-干擾素-α結合物 一起使用，也就是說，當患者接受三唑核苷的同時，或是 在不同的時段，同時施予聚乙二醇-干擾素-α結合_。根 據本發明，在至少給予一劑的聚乙二醇-干擾素-α的同一 個週，需至少施予一日劑量的三唑核苷。更明確的說，在 同一個週中施予一劑或多劑聚乙二醇-干擾素-α時，須給 予大部份的三唑核苷。換句話說，當施予一劑或多劑聚乙 二醇-干擾素-α後的同一個週，需給予所有的，或是基本
第了頁 1241913 五、發明說明（5) ' _ ~~ ' ---—— -- 土 ：有的三唑核苷。目前，以口服方式使用聚乙二醇一干 擾* a結合物的有效性不、佳， ， 經腸道方式#用取r -萨工摄1 权住们万式疋以非 七抓命、飞使用承乙一知—干擾素—α結合物，以皮下注射 或肌肉 >主射為佳。二峻核驻 ^ 1土 一生^甘了利用膠囊或錠劊以口服使 j ^ =以非經腸道方式使用聚乙二醇_干擾素_ “結合 々畠=有，、他的方式，也可採用來使用上述兩種藥物，如 貝，皮下掩埋，栓劑，持久性釋放劑型， 口 劑型可奴（、吞# 寻 /、受〇茨 何型式了 k §的傳遞，而不破壞有效成份，可考慮使用任 由臨床試驗比較組合治療及單劑治及/
及三4姑社2 A 人丨促尔 U 的評作Μ、、且合治療訂定治療的有效性。組合治療有效性 三唑:^較前述干擾素—單劑治療及/或將干擾素-《及 及^甘做組合治療，對於減輕慢性^型肝炎感染的症狀 A = t用發生的頻率及嚴重性而定。將三群受慢性C型肝 组i木者做為評比。其中僅有一組或是所三群患者都接受 ，且5治療： 1 *從未經過治療的患者。 、已經過干擾素_ α及/或三唑核苷治療，或是經其他 Μ物治療，但又復發的患者。 3 ·—對於先前以干擾素-α及/或三唑核苷治療，或 /、他藥物治療沒有反應的患者。 、’二 組合治療有效性的決定係以前述的慢性肝炎症狀 的程度而定。 所減輕 範例
第8頁 1241913 五、發明說明（6) 醇化的干复素2A及三唑核苷與REBETR0NTm 玄1鱼療受慢性1_型肝炎t毒·感染（CHC)患者之第三相之任 1. ’多中心效性及支全試驗 本試驗的主要目的是比較聚乙二醇—干擾素—α 2A及三唑 (Schering/ICN品牌的三唑核苷）]對於治療(：][1(：的有效性及 安全性。使等數的患者（ 33 0位患者）接受聚乙二醇—干擾素 α2Α及二唑核苷或REBETRON達48週。使第三組患者（165 位患者）接受聚乙二醇-干擾素—α 2 Α加上安慰劑達4 8週。
單劑冶療的結果較聚乙二醇—干擾素—α 2 a的組合治療更具 有安全性及有效性。 干擾素A的劑量係將3 Mi 〇溶於〇· 5 ml的溶液中，並以每 週進行皮下（s c )注射二次的方式（^丨w)施行& 8週。 聚乙二醇-干擾素-α 2A的劑量是18〇微克，並以每週進 仃皮下（sc)注射一次的方式，與三唑核苷或安慰劑共組施 行48週。
依照體重的不同，三唑核苷及Rebet〇1的每天劑量是 1000¾克或1200毫克，分次使用。體重低於75公斤（ι65 磅）的患者每天接受1 0 0 0毫克（早上4〇〇毫克，且傍晚6〇〇毫 克），而體重南於75公斤（165磅）的患者每天接受12〇〇毫克 (早上600毫克，且傍晚600毫克）。 有效性的主要參數是在未治療的追縱階段中，其持續的 病毋反應[如以A Μ P L I C 0 RTM P C R測定無法測得之η c v _ r n A (靈 敏度$ 1 0 0複製/ m 1 )]及生化反應（血清中的常態a L τ濃
第9頁 1241913
度）。有反應的患者，在第68至72週中，血清裏呈 白主勺丙胺酸轉胺基酶（ALT)活性，但在第72週卻測不、到病吊 、在篩選的過程中，於基準線上，於第丨，2，4，6及第8 週砰估其安全性，並在4 8週的療程中，每4週測一次。 隨後24週的追蹤過程中持續評估安全性。安全性的呼估項 1包括副作用，重要的象徵，及實驗室試驗，錠劑量的調 整’以及未了安全及耐受性的原因，提前結束治療。
—年齡在18歲或18歲以上，從未經過干擾素α2Α或三唑核 苷治療的CHC男性及女性患者組成試驗組。在丨2個月罹患^ CHC的情況下，患者必須有足量的hcv_rna，持續性不正“常 的ALT及肝臟的生檢結果。罹患其他肝臟的疾病，貧血， =人類後天免疫不全病毒（Η I V)感染，肝細胞癌，嚴重的 憂鬱症或其他精神病，心臟病，腎臟病，癲癇，或嚴重的 視網膜退化的患者不包括在試驗組中。 在進行試驗（4 8週）前，進行長達3 5天的篩選階段（由第 一次的篩選評估到第一次使用測試藥物的時間）。將符合 所有條件的患者任意的分配到三組治療的試驗組中。
、在試驗組的患者，若沒有顯現出第丨2週的反應[經定義 ^ ’相較於基準線，至少在HCV-RNA滴定度有1個對數值1〇 單位的下降，或是相較於基準線，至少其血清ALT下降 5 0% ]’則停止治療，並規類為非反應者。符合第丨2週反應 的患者’若是在第24週不展現測不到的HCV-RNA(<1 00複製 /ml)或是常態的alt，則停止治療。對於停止治療的患者
O:\58\58595.PTD
第10頁 1241913 五'發明說明（8) " 只追縱其安全性。所有符合第丨2週及第24週反應的患者， 則持續治療至48週。有效性的主要參數是治療完畢後的追 蹤階段（24週）之組合的病毒及生化反應（hcv — rna<1 〇〇複製 /ml及常態的ALT)。 " 目月ίι已知I n t r ο η A加上R e b e t ο 1組合治療之持續病毒反 應速率及估算出的以聚乙二醇—干擾素—α 2A單劑治療48週 後的持續病毒反應速率（以第丨丨相試驗所得的數據為基 準），以及聚乙二醇-干擾素—α2Α加上三唑核苷之持續病 毒反應速率的結果摘要如下： ο 夭口 及估再 治療組’ 的病每反 療時間 .應迷率 基因型1 (A & B) EOT ’基因型1 (A&B) EOF 基因型 非-1 EOT 基因型 非-1 EOF 組合. EOT. 組合 EOF N(對整體的比率) 2/3 1/3 1/： L Intron A 48週 9% 31% - 29% 16% Intron A plus Rebetol 48週 29% 659c 51% 41% 聚乙二醇-干擾素 48週 6〇i a ί29%/ 7〇i = (60%/ 62% ^(40?c/ 聚乙二醇-干擾素 +三唑核苷 :48週 (6i%r (46%)a 70% (70%)a (66%)a (539c)a ---- a :括旎中的百分以係以表中已知的反應速率管 的反應速率 估^出 EOT··治療後的病毒反應速率（清除病毒） E 0 F ·追縱後的病毒反應速率（清除病毒）
Claims (1)
1241913 _案號 88109246_年月日__ 六、申請專利範圍 其中R及R’是甲基，X是NH，且η及η’可以分別是或均 是4 2 0或是520。
O:\58\58595-940602.ptc 第14頁 1241913 案號088109246 #年么月 日 修正
O:\58\58595-940602.ptc 第12頁 1241913 口 94· 6,⑽ Wu 88109246_年月 臼 修正 々、申請專利範圍 1 · 一種用於治療慢性C型肝炎感染之具下式之聚乙二醇 干擾素-a 2 A結合物及三唑核苷之組合， Ο II -C —NH R〇CH2CH2(〇CH2CH2)n —〇 R，〇CH2CH2(〇CH2CH2)rV—〇-〇 _ 〇 .NH \G——X 一干擾素-沈2AII 〇 其中R及R’是曱基，X是NH，且η及η’可以分別是或均 是4 2 0或是5 2 0。 2 .根據申請專利範圍第1項的組合，其中聚乙二醇-干擾 素-α 2Α結合物的用量每星期約為33至5 4 0微克。 3 .根據申請專利範圍第1項的組合，其中三唑核苷的用 量是每天4 0 0至1 2 0 0毫克。 4. 一種具下式之聚乙二醇-干擾素-a 2 Α結合物及三唑核 苷之組合在製備用於治療慢性C型肝炎感染之藥物之用 途， 〇 ROCH2CH^(OCH2CPl2)n—〇—〇—NH ，闩2)4 / CH ROCH2CH.2(0CH2CH2)rf-0—C — NH 疗一X —干擾素-從 2A
O:\58\58595-940602.ptc 第13頁
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