ࢯࣈࣜ࢔࣮ࢻ࢝ࣉࢭࣝ 100mg ࡟㛵ࡍࡿ㈨ᩱ ᮏ㈨ᩱ࡟グ㍕ࡉࢀࡓ᝟ሗ࡟ಀࡿᶒ฼ཬࡧෆᐜ࡟ࡘ࠸࡚ࡢ㈐௵ࡣࠊࣖࣥࢭࣥࣇ࢓࣮࣐ᰴᘧ ఍♫࡟ᖐᒓࡍࡿࡶࡢ࡛࠶ࡾࠊᙜヱ᝟ሗࢆᮏ⸆๣ࡢ㐺ṇ౑⏝௨እࡢႠ฼┠ⓗ࡟౑⏝ࡍࡿࡇ ࡜ࡣ࡛ࡁࡲࡏࢇࠋ ࣖࣥࢭࣥࣇ࢓࣮࣐ᰴᘧ఍♫ TMC435 1.5 ⿠ේ෶ߪ⊒⷗ߩ⚻✲෸߮㐿⊒ߩ⚻✲ ⋡ᰴ 1.5 ⿠ේ෶ߪ⊒⷗ߩ⚻✲෸߮㐿⊒ߩ⚻✲ ............................................................................................ 3 1.5.1 ⿠ේ෶ߪ⊒⷗ߩ⚻✲ ................................................................................................................ 3 1.5.2 ᧄ೷ߩኻ⽎∔ᖚ෸߮⥃ᐥ਄ߩ૏⟎ઃߌ ................................................................................ 3 1.5.2.1 C ဳᘟᕈ⢄Ἳߩ᭎ⷐ......................................................................................................... 3 1.5.2.2 C ဳᘟᕈ⢄Ἳߩᴦ≮ߩ⃻⁁ ............................................................................................. 3 1.5.3 㐿⊒ߩ⚻✲ ................................................................................................................................ 4 1.5.3.1 ຠ⾰ߦ㑐ߔࠆ⹜㛎ߩ᭎⇛ ................................................................................................ 4 1.5.3.2 㕖⥃ᐥ⹜㛎ߩ᭎⇛ ............................................................................................................ 5 1.5.3.3 ⥃ᐥ㐿⊒ߩ᭎⇛ ................................................................................................................ 6 1.5.4 ᧄ೷ߩ੍ᗐߐࠇࠆᴦ≮਄ߩ૏⟎ઃߌ .................................................................................. 11 JEDI_DEV00 \ 0900fde980400983 2.4 2013-08-19 13:38 1 TMC435 1.5 ⿠ේ෶ߪ⊒⷗ߩ⚻✲෸߮㐿⊒ߩ⚻✲ ⇛ภ৻ⷩ⴫ ⇛ภ෶ߪ⇛⒓ ൻቇฬ෶ߪ৻⥸ฬ ᭴ㅧᑼ ↱᧪ Monosodium O CH3 (cyclopropylsulfonyl)[(2R,3aR,10Z,11aS, O S O CH 12aR,14aR)-2-({7-methoxy-8-methyl-2-[4- O NNa 3 O (1-methylethyl)-1,3-thiazol-2-yl]quinolin- H N N H TMC435 4-yl}oxy)-5-methyl-4,14-dioxo- CH ਥ⮎ H 3 H O N 1,2,3,3a,4,5,6,7,8,9,11a,12,12a,13,14,14a- H hexadecahydrocyclopenta[c]cyclopropa[g] S CH3 [1,6]diazacyclotetradecine-12a- N O carbonyl]azanide CH3 ⇛ภ෶ߪ⇛⒓ ฬ⒓෸߮ౝኈ ALT alanine aminotransferase㧔ࠕ࡜࠾ࡦࠕࡒࡁ࠻࡜ࡦࠬࡈࠚ࡜࡯࠯㧕 AST aspartate aminotransferase㧔ࠕࠬࡄ࡜ࠡࡦ㉄ࠕࡒࡁ࠻࡜ࡦࠬࡈࠚ࡜࡯࠯㧕 BCOP bovine corneal opacity-permeability㧔࠙ࠪⷺ⤑ᷙỘ෸߮ㅘㆊᕈ㧕 CYP cytochrome P450㧔࠴࠻ࠢࡠ࡯ࡓ P450㧕 GCP Good Clinical Practice㧔ක⮎ຠߩ⥃ᐥ⹜㛎ߩታᣉߩၮḰ㧕 GLP Good Laboratory Practice㧔ක⮎ຠߩ቟ోᕈߦ㑐ߔࠆ㕖⥃ᐥ⹜㛎ߩታᣉߩၮḰ㧕 HCV hepatitis C virus㧔C ဳ⢄Ἳ࠙ࠗ࡞ࠬ㧕 HIV human immunodeficiency virus㧔ࡅ࠻఺∉ਇో࠙ࠗ࡞ࠬ㧕 The International Conference on Harmonisation of Technical Requirements for Registration ICH of Pharmaceuticals for Human Use㧔ᣣ☨ EU ක⮎ຠⷙ೙⺞๺࿖㓙ળ⼏㧕 IFN interferone㧔ࠗࡦ࠲࡯ࡈࠚࡠࡦ㧕 IL28B interleukin-28B㧔ࠗࡦ࠲࡯ࡠࠗࠠࡦ㧙28B㧕 LLNA local lymph node assay㧔ዪᚲ࡝ࡦࡄ▵⹜㛎㧕 PegIFN peginterferon㧔ࡍࠣࠗࡦ࠲࡯ࡈࠚࡠࡦ㧕 PegIFNĮ-2a peginterferon alfa-2a㧔ࡍࠣࠗࡦ࠲࡯ࡈࠚࡠࡦࠕ࡞ࡈࠔ-2a㧕 PegIFNĮ-2b peginterferon alfa-2b㧔ࡍࠣࠗࡦ࠲࡯ࡈࠚࡠࡦࠕ࡞ࡈࠔ-2b㧕 P-gp P-glycoprotein㧔P-♧ߚࠎ⊕⾰㧕 time interval between the start of the Q wave and the end of the T wave in cardiac electrical QT cycle㧔ᔃ㔚࿑ QT㧕 JEDI_DEV00 \ 0900fde980400983 2.4 2013-08-19 13:38 QTc QT interval corrected for heart rate㧔ᔃ㔚࿑ QT ⵬ᱜ୯㧕 RBV ribavirin㧔࡝ࡃࡆ࡝ࡦ㧕 RGT response-guided therapy RNA ribonucleic acid㧔࡝ࡏᩭ㉄㧕 SVR sustained virologic response㧔ᜬ⛯⊛࠙ࠗ࡞ࠬ㒶ᕈൻ㧕 㧨⥃ᐥ⹜㛎ߩ⹜㛎⇟ภߩᮡ⸥ߦߟ޿ߡ㧪 ⥃ᐥ⹜㛎ߩ⹜㛎⇟ภߪ㧘TMC435 ߩ㐿⊒ᤨᦼߦࠃߞߡᰴߩ 3 ㅢࠅߩᣇᴺߢઃਈߐࠇߚ㧔XXX ෸ ߮ XXXX ߪ㧘ߘࠇߙࠇ 3 ᩴ෸߮ 4 ᩴߩ࿕᦭ߩᢙሼ㧕ޕᧄ⾗ᢱߢߪ㧘ฦ⹜㛎⇟ภߪޟCXXXޠ෶ߪ ޟHPCXXXXޠߢ␜ߔޕ · TMC435350-TiDP16-CXXX㧔㐿⊒ೋᦼߩ⹜㛎ߦ૶↪㧕 · TMC435-TiDP16-CXXX · TMC435HPCXXXX㧔ᦨㄭߩ⹜㛎ߦ૶↪㧕 2 TMC435 1.5 ⿠ේ෶ߪ⊒⷗ߩ⚻✲෸߮㐿⊒ߩ⚻✲ 1.5 ⿠ේ෶ߪ⊒⷗ߩ⚻✲෸߮㐿⊒ߩ⚻✲ 1.5.1 ⿠ේ෶ߪ⊒⷗ߩ⚻✲ TMC435㧔ࠪࡔࡊ࡟ࡆ࡞࠽࠻࡝࠙ࡓ㧕ߪ㧘C ဳ⢄Ἳ࠙ࠗ࡞ࠬ㧔એਅ㧘HCV㧕ᗵᨴ∝ߦኻߔࠆᴦ ≮⮎ߣߒߡ㧘Medivir ␠෸߮ Tibotec Pharmaceuticals Ltd.㧔⃻ Janssen R&D Ireland㧕ߦࠃࠅ౒ห㐿 ⊒ߐࠇߚ╙ੑ਎ઍߩࡊࡠ࠹ࠕ࡯࠯㒖ኂ⮎ߢ޽ࠆޕTMC435 ߪᄢⅣ⁁᭴ㅧࠍ᦭ߒ㧘HCV ߩⶄ⵾ߦᔅ 㗇ߢ޽ࠆ NS3/4A ࠮࡝ࡦࡊࡠ࠹ࠕ࡯࠯ߣ㕖౒᦭⚿วߔࠆߎߣߦࠃࠅ․⇣⊛ߦߘߩᵴᕈࠍ㒖ኂߒߡ ᛫࠙ࠗ࡞ࠬ૞↪ࠍ␜ߔޕTMC435 ߩ᭴ㅧᑼࠍ࿑ 1.5-1 ߦ␜ߔޕ O CH O S O 3 CH O NNa 3 O H N N H CH3 H N H O H S CH3 N O CH3 ࿑ 1.5-1 TMC435 ߩ᭴ㅧᑼ 1.5.2 ᧄ೷ߩኻ⽎∔ᖚ෸߮⥃ᐥ਄ߩ૏⟎ઃߌ 1.5.2.1 C ဳᘟᕈ⢄Ἳߩ᭎ⷐ HCV ᗵᨴߪ㧘ో਎⇇ߢ⢄∔ᖚߩਥⷐߥේ࿃ߣߥߞߡ߅ࠅ㧘ߘߩᗵᨴ⠪ᢙߪ⚂ 1 ం 7000 ਁੱ㧘 ࿖ౝߢߪ 150 ਁੱએ਄ሽ࿷ߔࠆߣផቯߐࠇߡ޿ࠆ 1㧕ޕHCV ߦᗵᨴߔࠆߣኋਥ஥ߩ఺∉ᔕ╵ߦࠃ JEDI_DEV00 \ 0900fde980400983 2.4 2013-08-19 13:38 ࠅᕆᕈ⢄Ἳࠍ⊒∝ߒߚᓟ㧘ήᴦ≮ߩ႐ว 55㨪85%ߩᖚ⠪ߪ HCV ߇ឃ㒰ߐࠇߕᘟᕈ⢄Ἳ߳ߣ⒖ⴕ ߒ㧘⢄✢⛽ൻ߇✭ᓢߦㅴⴕߒ㧘20㨪25 ᐕߢ 5㨪20%ߩᖚ⠪ߪ⢄⎬ᄌߦ⥋ࠆޕ⢄⎬ᄌߪᦨ⚳⊛ߦ⢄ ਇో߿⢄⚦⢩≸ߦ⥋ࠆ㊀◊ߥォᏫࠍߚߤࠆ∔ᖚߢ޽ࠅ㧘⢄⎬ᄌ߆ࠄߩ⢄⚦⢩≸⊒∝₸ߪ᰷☨ߩᐕ 1㨪4%ߦᲧߒ࿖ౝߢߪᐕ 7%ߣ㜞޿ޕ߹ߚ㧘࿖ౝߢߩ⢄⚦⢩≸ߩᐕ㑆ᱫ੢⠪ߩ⚂ 80%߇ C ဳᘟᕈ ⢄Ἳ߆ࠄ⒖ⴕߒߚ߽ߩߣ⠨߃ࠄࠇߡ޿ࠆ 2㧕3㧕ޕC ဳᘟᕈ⢄Ἳߩ⥄ὼᴦ≹ߪᭂ߼ߡ⒘ߢ޽ࠅ㧘⢄ታ ⾰ౝߢߩ⢄⚦⢩ߩᄌᕈ෸߮უᱫᚲ⷗㧘ਗ߮ߦ㐷⣂ၞߦߪ࡝ࡦࡄ⃿ࠍਥ૕ߣߒߚἻ∝ᕈ⚦⢩ᶐẢߣ ✢⛽ൻ߇⃻ࠇ㧘ᜬ⛯⊛ߥ⢄ᯏ⢻⇣Ᏹࠍ๒ߔࠆޕ 1.5.2.2 C ဳᘟᕈ⢄Ἳߩᴦ≮ߩ⃻⁁ C ဳᘟᕈ⢄Ἳᴦ≮ߩਥߚࠆ⋡ᮡߪ㧘⢄Ἳߩᴉ㕒ൻߦࠃࠅ✢⛽ൻߩㅴⴕࠍᛥ߃㧘⢄⎬ᄌ෶ߪ⢄⚦ ⢩≸߳ߩㅴዷࠍ㒐ߋߎߣߢ޽ࠅ㧘ߘߩߚ߼ߦᦨ߽ലᨐ⊛ߥᴦ≮ߣߒߡ࠙ࠗ࡞ࠬឃ㒰߇㊀ⷐߣ⠨߃ ࠄࠇߡ߅ࠅ㧘․ߦ㧘㜞㦂⠪߿✢⛽ൻㅴዷ଀ࠍ฽߻㜞⊒߇ࠎ࡝ࠬࠢ⟲ߢߪ㧘ᣧᦼߦ᛫࠙ࠗ࡞ࠬ≮ᴺ ߇⠨ᘦߐࠇࠆߴ߈ߣߐࠇࠆ 1㧕ޕ ࿖ౝߦ߅޿ߡ㧘1992 ᐕߦࠗࡦ࠲࡯ࡈࠚࡠࡦ㧔એਅ㧘IFN㧕⵾೷߇࠙ࠗ࡞ࠬឃ㒰ࠍ⋡⊛ߣߒߚ C ဳᘟᕈ⢄Ἳߩᴦ≮⮎ߣߒߡ଻㒾ㆡ↪ߐࠇ㧘ߘߩᓟ࡝ࡃࡆ࡝ࡦ㧔એਅ㧘RBV㧕ߣߩ૬↪≮ᴺ߿ࡍࠣ 3 TMC435 1.5 ⿠ේ෶ߪ⊒⷗ߩ⚻✲෸߮㐿⊒ߩ⚻✲ ࠗࡦ࠲࡯ࡈࠚࡠࡦ㧔એਅ㧘PegIFN㧕⵾೷߇㐿⊒ߐࠇ㧘HCV Genotype ߦᔕߓߡᛩਈᦼ㑆߇ᦨㆡൻ ߐࠇߚޕ ߎࠇ߹ߢ㧘PegIFN ෸߮ RBV ߩ 2 ೷≮ᴺߪ㧘㔍ᴦᕈߩ Genotype 1 ဳߢ㜞࠙ࠗ࡞ࠬ㊂ߩᖚ⠪ߦኻ ߔࠆᮡḰ≮ᴺߢ޽ߞߚ߽ߩߩ㧘SVR24 ₸㧔ᛩਈ⚳ੌᤨ෸߮ᛩਈ⚳ੌᓟ 24 ㅳߩⴊẏਛ HCV RNA ߇㒶ᕈൻߒߚⵍ㛎⠪ߩഀว㧕ߪ 50%⒟ᐲߢ޽ߞߚ 4㧕ޕ߹ߚ㧘ਥߥ᦭ኂ੐⽎ߪ㧘⊒ᾲ㧘ୱᕃᗵ㧘 㗡∩╬ߩࠗࡦࡈ࡞ࠛࡦࠩ᭽∝⁁ߢ޽ࠅ㧘᦭ኂ੐⽎߿⥃ᐥᬌᩏ୯⇣Ᏹߩߚ߼ߦᄙߊߩᖚ⠪߇ᷫ㊂෶ ߪભ⮎ߦ⥋ࠅ㧘12㨪16%ߩᖚ⠪߇ᴦ≮ࠍਛᱛߒߚ 4㧕ޕᦝߦ㧘ᴦ≮ᦼ㑆߇ 48 ㅳ㑆㧔ലᨐਇචಽߥ ႐วߪ 72 ㅳ㑆߹ߢᑧ㐳㧕ߣ㐳ߊ㧘ᖚ⠪ߩᔃり߳ߩ⽶ᜂߪᄢ߈߆ߞߚޕߘߩߚ߼㧘ᴦ≮ലᨐߩะ ਄㧘቟ోᕈ෸߮ᔋኈᕈߩᡷༀ㧘ਗ߮ߦᴦ≮ᦼ㑆ߩ⍴❗߇⺖㗴ߢ޽ߞߚޕ߹ߚ㧘PegIFN ෸߮ RBV ߩ 2 ೷≮ᴺߢౣΆ෶ߪήലߢ޽ߞߚᖚ⠪ߦኻߒߡ㧘ᛩਈᦼ㑆ߩᑧ㐳߽฽߼ߚ PegIFN ෸߮ RBV ߦ ࠃࠆౣᴦ≮ᤨߩ SVR24 ₸ߪ㧘೨ᴦ≮ౣΆ଀ߢ 50%㧘೨ᴦ≮ήല଀ߢߪ 14%⒟ᐲߣߐࠇ 5㧕6㧕㧘․ ߦ೨ᴦ≮ήല଀ߦኻߔࠆ᦭ലߥ᛫࠙ࠗ࡞ࠬ≮ᴺߪታ⾰ߥ߆ߞߚޕ 2011 ᐕߦ NS3/4A ࠮࡝ࡦࡊࡠ࠹ࠕ࡯࠯㒖ኂ೷ߢ޽ࠆ࠹࡜ࡊ࡟ࡆ࡞߇࿖ౝߢᛚ⹺ߐࠇ㧘PegIFNĮ- 2b ෸߮ RBV ߣߩ 3 ೷૬↪≮ᴺ߇ዉ౉ߐࠇߚޕ࠹࡜ࡊ࡟ࡆ࡞ࠍട߃ߚ 3 ೷૬↪≮ᴺߦࠃࠅ㧘ᴦ≮ ലᨐߪะ਄ߒ㧘✚ᴦ≮ᦼ㑆߇ 24 ㅳ㑆ߦ⍴❗ߐࠇ㧘C ဳᘟᕈ⢄Ἳߩᴦ≮ߪᄢ᏷ߦᡷༀߐࠇߚ 7㧕8㧕ޕ ߒ߆ߒߥ߇ࠄ㧘㊀◊ߥ⊹⤏㓚ኂ߿⽺ⴊ╬ߩ೽૞↪ߩߚ߼㧘቟ోᕈ਄ߩ ᔨߦࠃࠆಣᣇ೙㒢߿೽૞ ↪߳ߩኻᔕߥߤ㧘ᣂߚߥ⺖㗴߽಴ߡ߈ߡ޿ࠆޕ߹ߚ㧘࠹࡜ࡊ࡟ࡆ࡞ߩ࿖ౝ⥃ᐥ⹜㛎ߢߪ 65 ᱦࠍ ⿥߃ࠆᖚ⠪ߪኻ⽎ߣߐࠇߡ߅ࠄߕ㧘ᣣᧄ⢄⤳ቇળߦࠃࠆޟC ဳ⢄Ἳᴦ≮ࠟࠗ࠼࡜ࠗࡦޠ1㧕ߦ߅޿ ߡ㧘࠹࡜ࡊ࡟ࡆ࡞㧘PegIFNĮ-2b ෸߮ RBV ߩ 3 ೷૬↪≮ᴺߪ Genotype 1 ဳ㜞࠙ࠗ࡞ࠬ㊂ߩ C ဳᘟ ᕈ⢄Ἳᖚ⠪ߩ߁ߜ㕖㜞㦂⠪ࠍၮᧄߦㆡᱜߥᖚ⠪ࠍ⷗ᭂ߼ߚ਄ߢ૶↪ߔࠆߎߣ߇ផᅑߐࠇߡ߅ࠅ㧘 㕖㜞㦂⠪ߦ߅޿ߡ߽㧘IL28B ㆮવሶᄙဳ㧔SNP rs8099917㧕߇ࡑࠗ࠽࡯ࠕ࡟࡞㧔TG ෶ߪ GG㧕ߢ HCV ࠦࠕ㗔ၞ 70 ⇟ࠕࡒࡁ㉄߇ᄌ⇣ဳߩᖚ⠪ߦኻߒߡߪផᅑߐࠇߡ޿ߥ޿ޕ 1.5.3 㐿⊒ߩ⚻✲ JEDI_DEV00 \ 0900fde980400983 2.4 2013-08-19 13:38 TMC435 ߩ㐿⊒ߩ⚻✲࿑ࠍ࿑ 1.5-2 ෸߮࿑ 1.5-3 ߦ␜ߔޕ 1.5.3.1 ຠ⾰ߦ㑐ߔࠆ⹜㛎ߩ᭎⇛ (1) ේ⮎ ේ⮎ߩ▤ℂߪࠪࡔࡊ࡟ࡆ࡞ߢⴕ߁ޕታ↢↥ߦ↪޿ࠆ⵾ㅧᣇᴺߢ⵾ㅧߒߚࠪࡔࡊ࡟ࡆ࡞ߪ㧘㐳ᦼ ଻ሽ⹜㛎㧔25°C/60%RH㧕෸߮ടㅦ⹜㛎㧔40°C/75%RH㧕ߦ߅޿ߡ㧘ߘࠇߙࠇ 18 ࠞ᦬㑆෸߮ 6 ࠞ ᦬㑆቟ቯߢ޽ߞߚޕ⧦㉃⹜㛎㧔50°C/3 ࠞ᦬㧕ߦ߅޿ߡࠪࡔࡊ࡟ࡆ࡞ߦ⚻ᤨ⊛ߥᄌൻߪ⹺߼ࠄࠇߥ ߆ߞߚ߽ߩߩ㧘⧦㉃⹜㛎㧔ᦑశ/ICH Q1B ߦḰ᜚㧕ߦ߅޿ߡᕈ⁁ߩᄌൻ㧘฽㊂ߩૐਅ෸߮ಽ⸃‛ ߩ↢ᚑ߇⹺߼ࠄࠇߚޕએ਄ߩ⚿ᨐߦၮߠ߈㧘ࠪࡔࡊ࡟ࡆ࡞ߩ࡝࠹ࠬ࠻ᦼ㑆ࠍ ࠞ᦬㧔ቶ᷷㧘ㆤ శ଻ሽ㧕ߦ⸳ቯߒߚޕ 4 TMC435 1.5 ⿠ේ෶ߪ⊒⷗ߩ⚻✲෸߮㐿⊒ߩ⚻✲ (2) ⵾೷ ᧄ೷ߪ㧘1 ࠞࡊ࠮࡞ਛߦࠪࡔࡊ࡟ࡆ࡞࠽࠻࡝࠙ࡓ 102.93 mg㧔ࠪࡔࡊ࡟ࡆ࡞ߣߒߡ 100 mg㧕ࠍ ฽᦭ߔࠆ⎬ࠞࡊ࠮࡞೷ߢ޽ࠆޕᧄ೷ߦᣂⷙᷝട೷ߪ૶↪ߒߡ޿ߥ޿ޕ ᧄ೷ߪ㧘㐳ᦼ଻ሽ⹜㛎㧔25°C/60%RH㧕෸߮ടㅦ⹜㛎㧔40°C/75%RH㧕ߦ߅޿ߡ㧘 ߩჇട߇ ⹺߼ࠄࠇߚ߽ߩߩ㧘ߘࠇߙࠇ 12 ࠞ᦬㑆෸߮ 6 ࠞ᦬㑆቟ቯߢ޽ߞߚޕ⧦㉃⹜㛎㧔50°C/3 ࠞ᦬㧕ߦ ߅޿ߡ⚻ᤨ⊛ߥᄌൻߪ⹺߼ࠄࠇߥ߆ߞߚޕ⧦㉃⹜㛎㧔ᦑశ/ICH Q1B ߦḰ᜚㧕ߢߪ㧘ή൮ⵝຠߦ ߅޿ߡಽ⸃‛ߩࠊߕ߆ߥჇട෸߮฽㊂ߩૐਅ߇⹺߼ࠄࠇߚ߇㧘৻ᰴ൮ⵝຠߢߪ቟ቯߢ޽ߞߚޕએ ਄ߩ⚿ᨐߦၮߠ߈㧘ᧄ೷ߩ᦭ലᦼ㑆ࠍ 24 ࠞ᦬㧔ቶ᷷㧘ㆤశ଻ሽ㧕ߦ⸳ቯߒߚޕ 1.5.3.2 㕖⥃ᐥ⹜㛎ߩ᭎⇛ 1.5.3.2.1 ⮎ℂ⹜㛎 ലജࠍⵣઃߌࠆ⹜㛎ߣߒߡ㧘HCV NS3/4A ࡊࡠ࠹ࠕ࡯࠯ߦ⚿วߒߚࠪࡔࡊ࡟ࡆ࡞ߩ⚿᥏᭴ㅧࠍ ⸃ᨆߔࠆߣߣ߽ߦ㧘HCV NS3/4A ࡊࡠ࠹ࠕ࡯࠯ߦኻߔࠆ㉂⚛ቇ⊛㒖ኂ૞↪㧘࡟ࡊ࡝ࠦࡦ⚦⢩ࠍ↪ ޿ߚ᛫࠙ࠗ࡞ࠬ૞↪㧘ࡅ࠻෸߮േ‛⚦⢩ߦኻߔࠆ૞↪㧘HCV એᄖߩ࠙ࠗ࡞ࠬߦኻߔࠆ૞↪㧘 retinoic acid-inducible gene I ෸߮ toll-like receptor 3 ଐሽᕈ IFN ↥↢♽ߦኻߔࠆ૞↪㧘ઁߩ᛫ HCV ⮎෶ߪ᛫ࡅ࠻ ఺∉ਇో ࠙ࠗ࡞ࠬ㧔એਅ㧘HIV㧕⮎ߣߩ૬↪૞↪㧘ਗ߮ߦ⮎೷⠴ᕈߦ㑐ߔࠆᬌ⸛ ࠍⴕߞߚޕ೽ᰴ⊛⮎ℂ⹜㛎ߣߒߡ㧘ฦ⒳ฃኈ૕෸߮࠴ࡖࡀ࡞ߦኻߔࠆ in vitro ૞↪㧘ਗ߮ߦฦ⒳ ᯏ⢻෸߮⚵❱ߦኻߔࠆ in vitro ෸߮ in vivo ૞↪ࠍᬌ⸛ߒߚޕ቟ోᕈ⮎ℂ⹜㛎ߣߒߡ㧘ਛᨔ␹⚻♽㧘 ᔃⴊ▤♽㧘๭ๆ♽㧘⢗⣺▤♽㧘ⴊዊ᧼෸߮⿒ⴊ⃿ߦኻߔࠆ in vitro ෶ߪ in vivo ૞↪ࠍᬌ⸛ߒߚޕ 1.5.3.2.2 ⮎‛േᘒ⹜㛎 ๆ෼ߦ㑐ߔࠆ⹜㛎ߣߒߡ㧘⚦⢩⤑ㅘㆊᕈ㧘P-♧ߚࠎ⊕⾰㧔P-gp㧕ߦኻߔࠆᓇ㗀෸߮ⴊẏਛ⮎‛ JEDI_DEV00 \ 0900fde980400983 2.4 2013-08-19 13:38 േᘒߦߟ޿ߡᬌ⸛ߒߚޕಽᏓߦ㑐ߔࠆ⹜㛎ߣߒߡ㧘⚵❱ౝỚᐲ㧘ߚࠎ⊕⚿ว㧘ⴊ⃿⒖ⴕ㧘ਗ߮ߦ ⢝ఽ෸߮੃ఽ⒖ⴕߦߟ޿ߡᬌ⸛ߒߚޕઍ⻢ߦ㑐ߔࠆ⹜㛎ߣߒߡ㧘⢄⚦⢩෸߮⢄⚦⢩↹ಽࠍ↪޿ߚ ઍ⻢቟ቯᕈ㧘ⴊẏ㧘♮෸߮⢙᳝ਛઍ⻢‛㧘ઍ⻢㉂⚛㧘ਗ߮ߦ⢄⮎‛ઍ⻢㉂⚛♽߳ߩᓇ㗀ߦߟ޿ߡ ᬌ⸛ߒߚޕឃᴭߦ㑐ߔࠆ⹜㛎ߣߒߡ㧘ࡑࠬࡃ࡜ࡦࠬ෸߮⢙᳝ਛឃᴭߦߟ޿ߡᬌ⸛ߒߚޕ⮎‛േᘒ ቇ⊛⮎‛⋧੕૞↪ߦ㑐ߔࠆ⹜㛎ߣߒߡ㧘ᧄ೷ߣ૬↪ߐࠇࠆน⢻ᕈߩ޽ࠆ⮎‛ߩઍ⻢ߦ෸߷ߔᓇ㗀 ߦߟ޿ߡᬌ⸛ߒߚޕ߹ߚ㧘ࠪࡔࡊ࡟ࡆ࡞ߩઍ⻢ߦ㑐ਈߔࠆਥߥ࠴࠻ࠢࡠ࡯ࡓ P450㧔એਅ㧘 CYP㧕ಽሶ⒳ߪ CYP3A ߢ޽ࠆߎߣ߇␜ߐࠇߚߎߣ߆ࠄ㧘ߎߩ㒖ኂ೷ߣߒߡ⍮ࠄࠇߡ޿ࠆ࡝࠻࠽ ࡆ࡞ࠍ↪޿㧘ࠪࡔࡊ࡟ࡆ࡞ߩⴊẏਛ⮎‛േᘒߦ෸߷ߔᓇ㗀ߦߟ޿ߡ߽ᬌ⸛ߒߚޕᦝߦ㧘ᧄ೷ߩ⥃ ᐥ⹜㛎ߦ߅޿ߡ⹺߼ࠄࠇߚⴊẏਛࡆ࡝࡞ࡆࡦỚᐲ਄᣹ߩ⊒⃻ᯏᐨࠍ᣿ࠄ߆ߦߔࠆߚ߼ߦ㧘ߘߩઁ ߩ⮎‛േᘒ⹜㛎ߣߒߡ㧘ࡆ࡝࡞ࡆࡦߩࠣ࡞ࠢࡠࡦ㉄ᛴว㧘ਗ߮ߦ⢄ขࠅㄟߺ෸߮⢙᳝ਛឃᴭ࠻࡜ ࡦࠬࡐ࡯࠲࡯ߦ㑐ߔࠆᓇ㗀ߦߟ޿ߡᬌ⸛ߒߚޕ 1.5.3.2.3 Ქᕈ⹜㛎 ᕆᕈᲥᕈߪࡑ࠙ࠬ㧔ዊᩭ⹜㛎ߢ⹏ଔ㧕㧘࡜࠶࠻㧘ࠗ࠿෸߮ࠨ࡞ࠍ↪޿ߡ⹏ଔߒߚޕ෻ᓳᛩਈᲥ ᕈߪ㧘ᒝ೙⚻ญᛩਈᲥᕈ⹜㛎ࠍࡑ࠙ࠬ㧔3 ࠞ᦬㑆߹ߢ㧕㧘࡜࠶࠻㧔6 ࠞ᦬㑆߹ߢ㧕㧘ࠗ࠿㧔9 ࠞ᦬ 5 TMC435 1.5 ⿠ේ෶ߪ⊒⷗ߩ⚻✲෸߮㐿⊒ߩ⚻✲ 㑆߹ߢ㧕෸߮ࠨ࡞㧔1 ࠞ᦬㑆߹ߢ㧕ࠍ↪޿ߡᬌ⸛ߒ㧘ᷙ㙄ᛩਈᲥᕈ⹜㛎ࠍࡑ࠙ࠬ෸߮࡜࠶࠻㧔3 ࠞ᦬㑆߹ߢ㧕ࠍ↪޿ߡᬌ⸛ߒߚޕߔߴߡߩ⹜㛎ߢ࠻ࠠࠪࠦࠠࡀ࠹ࠖࠢࠬࠍ⹏ଔߒߚޕㆮવᲥᕈߪ㧘 in vitro ⹜㛎ߣߒߡ⚦⩶ࠍ↪޿ࠆᓳᏫ⓭ὼᄌ⇣⹜㛎෸߮ࡑ࠙ࠬ࡝ࡦࡈࠜ࡯ࡑ Tk ⹜㛎㧘in vivo ⹜㛎 ߣߒߡࡑ࠙ࠬዊᩭ⹜㛎ߢ⹏ଔߒߚޕ↢ᱺ⊒↢Ქᕈߪ㧘࡜࠶࠻ฃ⢝⢻෸߮⌕ᐥ߹ߢߩೋᦼ⢦⊒↢ߦ 㑐ߔࠆ⹜㛎㧘ࡑ࠙ࠬ෸߮࡜࠶࠻⢦࡮⢝ఽ⊒↢ߦ㑐ߔࠆ⹜㛎㧘࡜࠶࠻಴↢೨෸߮಴↢ᓟߩ⊒↢ਗ߮ ߦᲣ૕ߩᯏ⢻ߦ㑐ߔࠆ⹜㛎ߢ⹏ଔߒߚޕ߹ߚ㧘in vitro ߢ࠙ࠪⷺ⤑ᷙỘ෸߮ㅘㆊᕈ㧔BCOP㧕⹜㛎㧘 శᲥᕈ⹜㛎෸߮⚦⢩Ქᕈ⹜㛎㧘in vivo ߢࡑ࠙ࠬዪᚲ࡝ࡦࡄ▵⹜㛎㧔LLNA㧕㧘࠙ࠨࠡ⊹⤏৻ᰴೝ ỗᕈ⹜㛎෸߮࡜࠶࠻ߦ߅ߌࠆᛩਈน⢻ߥᦨᄢ㊂ߩᬌ⸛⹜㛎ࠍታᣉߒߚޕᦝߦ㧘5 ⒳㘃ߩਇ⚐‛ߦ ߟ޿ߡᲥᕈࠍ⹏ଔߒߚޕਥⷐߥ⹜㛎ߪ GLP ߦḰ᜚ߒߡታᣉߒߚޕ 1.5.3.3 ⥃ᐥ㐿⊒ߩ᭎⇛ C ဳᘟᕈ⢄Ἳߦኻߔࠆ TMC435 ߩ⥃ᐥ㐿⊒ߪ㧘ᶏᄖߢߪ Tibotec Pharmaceuticals Ltd.㧔⃻ Janssen R&D Ireland㧕߇ 20 ᐕࠃࠅ㐿ᆎߒߚޕ࿖ౝߢߪ㧘ࡗࡦ࠮ࡦࡈࠔ࡯ࡑᩣᑼળ␠߇ 20 ᐕ ࠃࠅ╙ II ⋧⹜㛎ࠍ㐿ᆎߒߚޕ⥃ᐥ㐿⊒ߩ᭎⇛ࠍએਅߦ␜ߔޕߥ߅㧘TMC435 ߩ↪㊂ߪࠪࡔࡊ࡟ࡆ ࡞ߣߒߡߩ↪㊂ߢ޽ࠆޕ ߹ߚ㧘޿ߕࠇߩ⥃ᐥ⹜㛎߽㧘ࡋ࡞ࠪࡦࠠት⸒ߩ୶ℂේೣ㧘ᣣ☨ EU ක⮎ຠⷙ೙⺞๺࿖㓙ળ⼏ 㧔ICH㧕ߢวᗧߐࠇߚޟක⮎ຠߩ⥃ᐥ⹜㛎ߩታᣉߩၮḰ㧔GCP㧕ޠ㧘ㆡ↪ߐࠇࠆⷙ೙ⷐઙ෸߮ߘ ࠇߙࠇߩᴦ㛎ታᣉ⸘↹ᦠߦೣߞߡታᣉ࡮ႎ๔ߒߚޕ 1.5.3.3.1 ╙ I ⋧⹜㛎 ᶏᄖߦ߅޿ߡ㧘ੱߢߩ቟ోᕈ෸߮ᔋኈᕈࠍᦨೋߦᬌ⸛ߔࠆ╙ I ⋧⹜㛎ߣߒߡ C101 ⹜㛎ࠍታᣉ ߒߚޕᧄ⹜㛎߆ࠄ㧘ஜᐽᚑੱߦኻߔࠆ TMC435 50㨪600 mg ߩන࿁ᛩਈ෸߮ 100㨪400 mg 1 ᣣ 1 ࿁ ߣ 200 mg 1 ᣣ 2 ࿁ߩ 5 ᣣ㑆෻ᓳᛩਈ㧘ਗ߮ߦ C ဳᘟᕈ⢄Ἳᖚ⠪ߦኻߔࠆ TMC435 200 mg 1 ᣣ 1 JEDI_DEV00 \ 0900fde980400983 2.4 2013-08-19 13:38 ࿁ߩ 5 ᣣ㑆෻ᓳᛩਈߪ㧘߅߅߻ߨ቟ోߢ޽ࠅ㧘ᔋኈᕈߪ⦟ᅢߢ޽ࠆߎߣ߇⏕⹺ߐࠇߚޕ ࿖ౝߢߩ C ဳᘟᕈ⢄Ἳᖚ⠪ࠍኻ⽎ߣߒߚ⥃ᐥ⹜㛎ታᣉߦవ┙ߜ㧘ᶏᄖ࿷૑ߩᣣᧄੱஜᐽᚑੱࠍ ኻ⽎ߣߒߡ╙ I ⋧⹜㛎㧔C109 ⹜㛎㧕ࠍ☨࿖ߢታᣉߒ㧘C101 ⹜㛎ᚑ❣ߣᲧセߒߚޕߘߩ⚿ᨐ㧘ᣣ ᧄੱஜᐽᚑੱߢߪᄖ࿖ੱஜᐽᚑੱߦᲧߴߡ TMC435 ߩหߓᛩਈ㊂ߦኻߒߡ߿߿㜞޿ᦑ㔺㊂߇ᓧࠄ ࠇࠆ௑ะ߇␜ߐࠇߚޕ ߘߩઁߩᣣᧄੱஜᐽᚑੱࠍኻ⽎ߣߒߚ╙ I ⋧⹜㛎ߣߒߡ㧘⋧ኻ⊛ࡃࠗࠝࠕࡌࠗ࡜ࡆ࡝࠹ࠖ⹜㛎 㧔HPC1003 ⹜㛎㧕෸߮㘩੐ߩᓇ㗀ࠍᬌ⸛ߔࠆ⹜㛎㧔HPC1007 ⹜㛎㧕ࠍታᣉߒߚޕ߹ߚᶏᄖߢ㧘 QT/QTc ߦኻߔࠆᓇ㗀ࠍᬌ⸛ߔࠆ⹜㛎㧔C117 ⹜㛎㧕ࠍታᣉߒ㧘ߘߩઁ㧘⋧ኻ⊛ࡃࠗࠝࠕࡌࠗ࡜ࡆ ࡝࠹ࠖ⹜㛎㧔3 ⹜㛎㧕㧘㘩੐ߩᓇ㗀ࠍᬌ⸛ߔࠆ⹜㛎㧔2 ⹜㛎㧕㧘ࡑࠬࡃ࡜ࡦࠬ⹜㛎㧔1 ⹜㛎㧕㧘․ ᱶᖚ⠪㧔⢄ᯏ⢻㓚ኂᖚ⠪෸߮⣢ᯏ⢻㓚ኂᖚ⠪㧕ߩ⮎‛േᘒࠍᬌ⸛ߔࠆ⹜㛎㧔ฦ 1 ⹜㛎㧕㧘⮎‛േ ᘒቇ⊛⮎‛⋧੕૞↪⹜㛎㧔12 ⹜㛎㧕෸߮శ቟ోᕈ⹜㛎㧔1 ⹜㛎㧕ࠍታᣉߒߚޕ 6 TMC435 1.5 ⿠ේ෶ߪ⊒⷗ߩ⚻✲෸߮㐿⊒ߩ⚻✲ 1.5.3.3.2 ╙ II ⋧⹜㛎 ᶏᄖߦ߅޿ߡ㧘Genotype 1 ဳ C ဳᘟᕈ⢄Ἳߩೋ࿁ᴦ≮ᖚ⠪෸߮ᣢᴦ≮ᖚ⠪ࠍኻ⽎ߦ㧘TMC435 න೷ᛩਈߒߚߣ߈ਗ߮ߦ PegIFNĮ-2a ෸߮ RBV ߣ૬↪ᛩਈߒߚߣ߈ߩ᛫࠙ࠗ࡞ࠬലᨐߦ߅ߌࠆ↪ ㊂ଐሽᕈ෸߮቟ోᕈࠍᬌ⸛ߔࠆ⋡⊛ߢ㧘Proof-of-Principle ⹜㛎㧔C201 ⹜㛎㧕ࠍ⸘↹ߒߚޕೋ࿁ᴦ ≮଀ߦኻߒ㧘TMC435 ࠍන೷ߢ 7 ᣣ㑆ᛩਈᓟ㧘PegIFNĮ-2a ෸߮ RBV ߣߩ 3 ೷૬↪ߢ 21 ᣣ㑆ᛩਈ ߔࠆߎߣߣߒߚޕ߹ߚ㧘ೋ࿁ᴦ≮଀෸߮ᣢᴦ≮଀ߦኻߒߡ㧘TMC435 ࠍ PegIFNĮ-2a ෸߮ RBV ߣ ߩ 3 ೷૬↪ߢ 28 ᣣ㑆ᛩਈߒߚޕߘߩ⚿ᨐ㧘ೋ࿁ᴦ≮଀ߦ߅ߌࠆ 3 ೷૬↪ᛩਈߢߪ㧘ᛩਈ 7 ᣣ⋡ ߩ HCV RNA ㊂ߩࡌ࡯ࠬ࡜ࠗࡦ߆ࠄߩᷫዋ㊂߇ TMC435 න೷ᛩਈࠃࠅᄢ߈ߊ㧘ᛩਈ 4 ㅳߩ HCV RNA ㊂ߩࡌ࡯ࠬ࡜ࠗࡦ߆ࠄߩᷫዋ㊂ߪ TMC435 75 mg ෸߮ 200 mg ᛩਈߢ߶߷ห⒟ᐲߢ޽ߞߚޕ ৻ᣇ㧘ᣢᴦ≮଀ߦ߅޿ߡ㧘ᛩਈ 4 ㅳߩ HCV RNA ㊂ߩࡌ࡯ࠬ࡜ࠗࡦ߆ࠄߩᷫዋ㊂ߪ㧘TMC435 150 mg ෸߮ 200 mg ᛩਈߦᲧߴߡ 75 mg ᛩਈߢዊߐ߆ߞߚޕ߹ߚ㧘TMC435 ߩ↪㊂෸߮ᦑ㔺㊂ߦ ଐሽߒߚⴊਛࡆ࡝࡞ࡆࡦ୯ߩ਄᣹߇ߺࠄࠇ㧘200 mg ᛩਈߢࠃࠅ㗼⪺ߢ޽ߞߚޕ ⛯޿ߡ㧘࿖ౝߦ߅ߌࠆᦨೋߩ⥃ᐥ⹜㛎ߣߒߡ㧘Genotype 1 ဳ㜞࠙ࠗ࡞ࠬ㊂ߩ C ဳᘟᕈ⢄Ἳߩೋ ࿁ᴦ≮ᖚ⠪ࠍኻ⽎ߦ㧘TMC435 ࠍ PegIFNĮ-2a ෸߮ RBV ߣ૬↪ߒߚߣ߈ߩ᦭ലᕈ෸߮቟ోᕈࠍᬌ ⸛ߔࠆ⋡⊛ߢ╙ II ⋧⹜㛎㧔C215 ⹜㛎㧕ࠍ㧘㕖⋤ᬌ⹜㛎ߣߒߡ⸘↹ߒߚޕTMC435 ߩ↪ᴺ࡮↪㊂