MLリソース：骨髄異形成症候群[MDS]
myelodysplastic syndrome
■個別製品収録●[1247]デシタビンdecitabine (Dacogen [MGI Pharma])ダコジェン
日本語版註）デシタビンdecitabine (Dacogen [MGI Pharma])ダコジェン
【別名】5-aza-2'-deoxycytydine 【開発元】SuperGen, Incが創製し、2004.9 MGI Pharma,Incに全世界の独占開発・製造販売権を供与。 [DBR_ID]
【化学名】4-amino-1-(2-deoxy-β-D-erythro-pentofuranosyl)-1,3,5-triazin-2(1H)-one
【承認】FDA申請=14-Nov-2005、FDA承認=May 2, 2006、米国発売=2006.5.26 ; 【製剤】Each 20 mL, single dose, glass vial contains 50 mg decitabine 【適応】(骨髄異形成症候群)myelodysplastic syndrome (MDS). 【用法用量】[初回サイクル]15mg/m2を３時間の静注、これを３日間８時間毎に繰り返す。 [以降サイクル]前記サイクルを６週毎に最低４サイクルを繰り返す 【作用】DNAメチル基転移酵素の阻害により腫瘍細胞成長阻害もしくはcytotoxicity 【特徴】 【製品情報】www.dacogen.com 【添付文書】Dacogen-PI 【EU】2005.11申請取下げ、再申請予定; MGIは北米以外の開発・販売権をCilag GmbH(J&J系)に再許諾。 【日本】未開発 【その他】前臨床試験でメラノーマ、大腸癌、卵巣癌に有効。AMLがP3、CMLはP2
●[1232]lenalidomide (Revlimid [Celgene])日本語版註）lenalidomide (Revlimid [Celgene])レナリドマイド(レブリミド)
【別名】CC-5013; CDC-501 【開発元】Celgene Corporation [DBR_ID]
【化学名】3-(4-amino-1,3-dihydro-1-oxo-2H-isoindol-2-yl)-2,6-piperidinedione ;C13H13N3O3; mw=259.3;CAS REG NR=191732-72-6
【承認】FDA申請=2005.4.7、FDA承認=Dec 27, 2005、発売=2006.; 【製剤】カプセル中5mgまたは10mg含有 【適応】(骨髄異形成症候群)for the treatment of patients with transfusion dependent anemia due to low or intermediate-1 risk myelodysplastic syndromes associated with a deletion 5 q cytogenetic abnormality with or without additional cytogenetic abnormalities. 【用法用量】１日10mgが初回推奨用量。 【作用】thalidomideアナログ。 【特徴】 【製品情報】www.revlimid.com 【添付文書】http://www.celgene.com/PDF/RevlimidPI.pdf 【EU】Revlimid [Celgene]申請=2005.8(MDS)、申請=2006.2(MM=多発性骨髄腫) 【日本】未開発 【その他】本剤の催奇形性等はRevAssist[SM] Risk Minimization Action Plan (RiskMAP)に沿って管理。本剤はこのRevAssistSM(患者・医師・看護婦・薬局を登録管理)を通じてのみ配布される。
●[1201]5-Azacytidine ５-アザシチジン azacitidine(Vidaza [Pharmion])日本語版註）5-Azacytidine ５-アザシチジン azacitidine(Vidaza [Pharmion])
【日本語版コメント1247】
【別名】NSC-102816;U-18496 【開発元】Pharmacia [DBR_ID]14511-422D
【化学名】4-amino-1-β-D-ribofuranosyl-s-triazin-2(1H)-one; CAS 320-67-2
【承認】FDA申請=2003.12.29、FDA承認=19-May-2004、米国発売=2004.7.1 ; 【製剤】皮下注射 1 vial中 【適応】Vidaza is indicated for treatment of patients with the following myelodysplastic syndrome(骨髄異形成症候群) subtypes: refractory anemia or refractory anemia with ringed sideroblasts (if accompanied by neutropenia or thrombocytopenia or requiring transfusions), refractory anemia with excess blasts, refractory anemia with excess blasts in transformation, and chronic myelomonocytic leukemia. 【用法用量】毎日75mg/m2を７日間皮下注射する。４週毎に行う。 【作用】メチル化阻害剤；骨髄中の異常なhematopoietic細胞への直接的な殺細胞作用およびDNAのメチル化阻害を引き起こすことにより、抗癌効果を発現すると考えられる。 【特徴】MDSの初の治療薬；a pyrimidine nucleoside analog of cytidine. 【製品情報】http://www.vidaza.com/ 【添付文書】Vidaza -Full Prescribing Information[pdf] 【提携】Pharmion社はPharmacia(Pfizer子会社)から2001年全世界権利をライセンス導入 【EU】2004.9 申請 【日本】未開発 【その他】
骨髄異形成症候群[MDS]は、最近、青島幸男元東京都知事の死因として注目された後天的な造血幹細胞異常による疾患。 国際的には2004年からazacitidine(Vidaza[Pharmion])、lenalidomide(REVLIMID[Celgene])、今回３番手のDecitabine(Dacogen[MGI])が発売された。 従来療法は補助的なものであったから、初の専用新薬azacitidineは2005年度売上高125.6百万ドルと商業的には成功を収めた。 それでも奏功率は低くて、最高レベルでも30%台であることから改良が望まれるが、３剤共日本での開発予定はない。 依然根治手段としては骨髄移植しかない。日本では、「骨髄異形成症候群」を適応症として認可されているのは、注射用エンドキサン50mg,100mg[塩野義製薬;シクロホスファミド]、スタラシドカプセル50,100[日本化薬;シタラビン オクホスファート]、グラン[麒麟麦酒株;フィルグラスチム]、ノイトロジン注50,100,250μg[中外製薬;レノグラスチム]のみ。
【日本語版コメント1232】
「骨髄異形成症候群」(MDS)という疾患が注目されている。
遺伝子・染色体の異常から骨髄が血液を造るという正常な働きをしなくなり、貧血、皮膚内出血等の症状を示す。 患者調査2002年度で、「D46骨髄異形成症候群」患者数は8千人(1999年度6千人)だが実際はもっと多いだろう。
- MDSは60才以上多く発症。 米国で1-3万人、EUで毎年3-4万人の新患者発生。 生存率はMDSタイプにより６か月から６年。 大半が出血と感染で死亡。 acute myelogenous leukemia (AML)(骨髄性白血病)への形質変換が患者の40%に生じる。
骨髄異形成症候群治療薬の開発はミニブーム状態で世界で２０製品が開発中。 承認第一号がazacitidine(Vidaza [Pharmion])-FDA2004.5認可。 今回2005.12承認のlenalidomide (Revlimid [Celgene])が２番手で、他に多発性骨髄腫などの適応追加で申請中。 第８回未承認薬使用問題検討会議(06.4.27)検討品目。
【日本語版コメント1201】
骨髄異形成症候群(MDS)は、造血幹細胞のクローン性異常による骨髄の機能異常を伴った骨髄異形成と血球減少によって特徴づけられる症候群。 原因はde novoで生ずる場合と化学療法あるいは放射線療法によって生ずる場合とがある。 多様な病態の集合体ともいうべき症候群で、輸血などの補助療法が中心となることも多く、標準的な治療法は確立していない。
- MDSは60才以上多く発症。 米国では1-3万人、EUで毎年3-4万人の新患者発生。 日本の患者数は8千人(患者装置2002)。 生存率はMDSタイプにより６か月から６年。 大半が出血と感染で死亡。 骨髄性白血病[AML]への形質変換が患者の40%に生じる。
今回取上げたのは、骨髄異形成症候群の適応を世界で初めてFDA承認された5-Azacytidine。 昨2004年7月米国発売以来、医療機関に広く受け入れられ、売上高も2004年度(半年)$47.1millin、2005年度$229-245millionを予定。【市場】■市場調査レポート ★ステークホルダー・オピニオン 骨髄異形成症候群 - 初の承認を受けて当ニッチ市場に関心が集まりそうです Datamonitor; 発行日: 2007年12月19日 骨髄異形成症候群は、造血幹細胞に異常が起きる疾患です。 2007年、主要7か国における発症数は3万6769件と予測され、最も多く見られる血液悪性疾患のひとつです。 現在唯一の治療法は造血幹細胞移植ですが、これが適している患者はごく一部に限られています。 患者の高齢、および合併症が原因で、造血幹細胞移植など強力な療法が不可能となる場合が多々あります。 このため、大半の患者は支持療法および低強度の療法で疾患管理を行っています。 Vidaza、Dacogen、およびRevlimidなどの低強度療法によって治療成果は改善されたもの の、高リスク骨髄異形成症候群患者の予後は依然不良です。 このため患者の生存および生活の質を向上させるような、より有効性が高く、毒性の低い 薬剤へのニーズが高まっています。 最近薬剤が承認されたのを受け、骨髄異形成症候群への関心が高まったものの今後かな りの研究開発努力が必要です。 第3相段階にはSchering-Plough社のSarasar (lonafarnib)の1剤があるのみです。 同薬は分子標的療法ですが、既存の療法に比べ大きな改善は期待できません。 ★ステークホルダーオピニオン： 造血幹細胞移植－さらなる研究開発が求められています Datamonitor; 発行日: 2009年4月10日 造血幹細胞移植(HSCT)は、幹細胞ソース、ドナーの特定および移植前処置の開発に支え られ、過去50年間で大きな進化を遂げてきました。 最近では、一部の血液悪性疾患の治療を含め、多様な適用があります。 しかし、その使用を拡大し患者の治療成果を向上するためには、さらなる研究が求められています。 HSCTの使用は、幹細胞ソースと移植前処置の開発に支えられ、過去数十年間で増加しつつ あります。しかし当治療の採用は依然十分ではなく、移植の対象となる患者の多くは 進行期にあり、治癒の可能性は高くありません。 骨髄非破壊的前処置(RIC)の開発がHSCTにおける重要な進展のひとつです。 現在行われているモノクローナル抗体および放射免疫療法の評価研究によって、前処置 の有効性と特異性の向上が実現する可能性もあります。 HSCT領域におけるアンメットニーズは、移植片対宿主病(GVHD)の効果的な管理です。 よりよい前臨床モデルの可用性、予後判定ツール、効果的な療法がR&Dの優先課題と考え られています。 モノクローナル抗体はGVHD治療に関与するかもしれませんが、その可能性を追究するた め、さらなる研究が必要です。 ■医療用医薬品の添付文書情報 /2011.10.11
($ Million) 2010 2009 2008 2007 2006 2005 2004 2003 備考 Vidaza[Celgene Corporation(旧Pharmion Corp)] 534.302(+38.0) 387.219(+87.3) 206.692 ? 142.2 125.6 47.1 - [azacitidine]骨髄異形成症候群(MDS)治療薬;発売2004.7.1 REVLIMID(R)[Celgene Corporation] 2,469.183(+44.7) 1,706.437(+28.8) 1,324.671(+71.2) 773.877(+141.4) 320.558 2.862(-) -- -- [lenalidomide]骨髄異形成症候群 Dacogen Inj[MGI Pharma,Inc] 189
(162億円)166
(154億円)170(+27) 134 36.102(-) - - - [decitabine]骨髄異形成症候群;米承認2006.5.2 ■骨髄異形成症候群治療薬 ３剤の比較 /2011.10.13
製品 組成 適応症 用法用量 備考 グラン注射液75,150,M300／グランシリンジ75,150,M300[協和発酵キリン] グラン注射液は1アンプル中にフィルグラスチム（遺伝子組換え）として(0.3mL)75μg(0.6mL)150μg (0.7mL)300μg;グランシリンジは1シリンジ中にフィルグラスチム（遺伝子組換え）として(0.3mL)75μg (0.6mL)150μg(0.7mL)300μg 1. 造血幹細胞の末梢血中への動員/2. 造血幹細胞移植時の好中球数の増加促進/3. がん化学療法による好中球減少症/4. ヒト免疫不全ウイルス（HIV）感染症の治療に支障を来す好中球減少症/5. 骨髄異形成症候群に伴う好中球減少症/6. 再生不良性貧血に伴う好中球減少症/7. 先天性・特発性好中球減少症 [5. 骨髄異形成症候群に伴う好中球減少症]通常、成人には好中球数が1,000/mm3未満のとき、フィルグラスチム（遺伝子組換え）100μg/m2を1日1回点滴静注する。ただし、好中球数が5,000/mm3以上に増加した場合は、症状を観察しながら減量、あるいは投与を中止する。 【メモ】一般臨床試験の結果、骨髄異形成症候群21例に対して漸増法により本剤50～400μg/m2（通常100μg/m2）を点滴静注した場合、20例に好中球数の増加効果及び17例中6例に骨髄所見の改善が認められた。 ノイトロジン注50μg,100μg,250μg[中外製薬] １バイアル中レノグラスチム(遺伝子組換え): 50,100,250μg 1. 造血幹細胞の末梢血中への動員/2. 造血幹細胞移植時の好中球数の増加促進/3. がん化学療法による好中球減少症/4. 骨髄異形成症候群に伴う好中球減少症/5. 再生不良性貧血に伴う好中球減少症/6. 先天性・特発性好中球減少症/7. ヒト免疫不全ウイルス（HIV）感染症の治療に支障を来す好中球減少症 /8. 免疫抑制療法（腎移植）に伴う好中球減少症 [4. 骨髄異形成症候群に伴う好中球減少症]通常、成人には好中球数1,000／mm3未満の状態を示した時点よりレノグラスチム（遺伝子組換え）として５μg／kgを１日１回静脈内投与する。ただし、好中球数が5,000／mm3以上に増加した場合は症状を観察しながら減量、あるいは投与を中止する。 【メモ】再生不良性貧血、骨髄異形成症候群等の各種好中球減少症患者を対象とした種々の試験において、好中球数は速やかに増加し、本剤投与期間中高いレベルで好中球数が維持された。 スタラシドカプセル５０,１００[日本化薬] 1カプセル中シタラビンオクホスファート水和物 51.5mg/103mg (無水物として) (50mg/100mg) １）成人急性非リンパ性白血病(強力な化学療法が対象となる症例にはその療法を優先する。) ２）骨髄異形成症候群(Myelodysplastic Syndrome) [骨髄異形成症候群(Myelodysplastic Syndrome) ]シタラビン オクホスファートとして、1日100～200mgを2～3週間連続経口投与し、2～3週間休薬する。これを繰り返す。なお、投与量は疾患、症状等により適宜増減する。本剤の投与時期は食後とし、1日1～3回に分けて服用する。 【メモ】本剤における臨床試験成績の概要は骨髄異形成症候群(MDS) 寛解率 28.9％ (13／45) ビダーザ注射用100mg [日本新薬] 1バイアル中アザシチジン100mg含有 骨髄異形成症候群 通常、成人にはアザシチジンとして75 mg/m2（体表面積）を1日1回7日間皮下投与又は10分かけて点滴静注し、3週間休薬する。これを1サイクルとし、投与を繰り返す。なお、患者の状態により適宜減量する。 【メモ】第III相比較試験（AZA-001試験）で主要評価項目である生存期間（中央値）は、CCR群（通常治療:シタラビン等179例）15.02ヵ月に対し、AZA群(本剤179例)24.46ヵ月であり9.44ヵ月の差が認められた（層別ログランク検定、p = 0.0001）。
国内臨床試験における副作用は、骨髄異形成症候群（MDS）患者53例中53例（100.0％）に認められた。主な副作用は、好中球減少症（発熱性好中球減少症を含む）47例（88.7％）、白血球減少症、血小板減少症 各45例（84.9％）、ヘモグロビン減少、便秘 各37例（69.8％）、注射部位反応（紅斑、発疹、そう痒感、硬結等）35例（66.0％）、赤血球減少症33例（62.3％）、ヘマトクリット減少29例（54.7％）、リンパ球減少症28例（52.8％）、倦怠感26例（49.1％）、発熱22例（41.5％）、ALT（GPT）増加20例（37.7％）、AST（GOT）増加、ALP増加 各18例（34.0％）、食欲不振、発疹、血中アルブミン減少 各17例（32.1％）であった。添付文書 - インタビューフォーム ; 申請資料概要 - [部会審議]審査報告書１ - [部会審議]審査報告書２～国内臨床第I/II相試験：NS17-P1/2(継続中)～１０名
レブラミドカプセル5mg [セルジーン株式会社] 1カプセル中レナリドミド5mg含有（レナリドミド水和物として5.174mg） 1)再発又は難治性の多発性骨髄腫 2)5番染色体長腕部欠失を伴う骨髄異形成症候群 [5番染色体長腕部欠失を伴う骨髄異形成症候群]通常、成人にはレナリドミドとして1日1回10mgを21日間連日経口投与した後、7日間休薬する。これを1サイクルとして投与を繰り返す。 【メモ】＜外国臨床試験成績:＞ 5番染色体長腕部欠失を伴う骨髄異形成症候群患者を対象とした外国第III相試験（MDS-004試験）を実施し、赤血球輸血依存からの離脱を評価した。その結果、プラセボ群の51例中3例（5.9％）、5mg群の46例中19例（41.3％）、10mg群の41例中23例（56.1％）が赤血球輸血依存からの離脱に成功した。5mg群、10mg群で赤血球輸血依存から離脱した患者の割合はプラセボ群での割合と比べて有意に高かった。
[副作用]5番染色体長腕部欠失を伴う骨髄異形成症候群患者を対象とした外国第III相臨床試験〔MDS-004試験（二重盲検期間2008年6月26日データカットオフ）〕の安全性評価症例において、10mg群69例中66例（95.7％）に副作用（臨床検査値異常を含む）が認められた。10mg群での主な副作用は、好中球減少症52例（75.4％）、血小板減少症33例（47.8％）、そう痒症18例（26.1％）、下痢13例（18.8％）、便秘9例（13.0％）、疲労7例（10.1％）であった。 骨髄異形成症候群患者では多発性骨髄腫患者より骨髄抑制が高い割合で認められた。添付文書 - インタビューフォーム ; 申請資料概要 - [部会審議]審査報告書 - [部会報告書]審査報告書(国内P1 )CC-5013-MM-017/-017PK試験：５施設15名(MM患者、薬物動態)
[] 【メモ】 略号 ITT, intent-to-treat; EE, efficacy evaluable; DS1, Dose Schedule 1 (2 weeks on/1 week off); DS2,Dose Schedule 2 (3 weeks on/1 week off); E, erythroid (anemia); EN, erythroid-neutrophil (anemia+ neutropenia); EP, erythroid-platelet (anemia + thrombocytopenia); NP, neutrophil-platelet(neutropenia + thrombocytopenia); E NP, erythroid-neutrophil-platelet (anemia + neutropenia +thrombocytopenia). DNA methyltransferase inhibitors (DMTIs) Hematologic Improvement-Erythroid (HI-E) , HI-Neutrophil (HI-N), HI-Platelet (HI-P) 【開発中の新薬】 ●開発中の新薬[＜情報提供：日本製薬工業協会＞] /2011.5.31 会社別開発中新薬一覧。 検索機能なし。６８社から情報提供
項目 Telintra
[Telik]ビダーザ注射用100mg
[日本新薬]レブラミドカプセル5mg
[セルジーン株式会社]製剤 Ezatiostat 1バイアル中アザシチジン100mg含有 1カプセル中レナリドミド5mg含有（レナリドミド水和物として5.174mg） 適応症 骨髄異形成症候群 骨髄異形成症候群 1)再発又は難治性の多発性骨髄腫 2)5番染色体長腕部欠失を伴う骨髄異形成症候群 用法用量 (Dose Schedule 1 (DS1) )初回Ezatiostat 3000mg/日(1500mg PO b.i.d.)x２週&１週休
(Dose Schedule 2 (DS2))初回Ezatiostat 2000mg/日(1000mg PO b.i.d.)x3週&１週休通常、成人にはアザシチジンとして75 mg/m2（体表面積）を1日1回7日間皮下投与又は10分かけて点滴静注し、3週間休薬する。これを1サイクルとし、投与を繰り返す。なお、患者の状態により適宜減量する。 [5番染色体長腕部欠失を伴う骨髄異形成症候群]通常、成人にはレナリドミドとして1日1回10mgを21日間連日経口投与した後、7日間休薬する。これを1サイクルとして投与を繰り返す。 作用機序 (Glutathione-S-transferase P1-1 (GSTP1-1)阻害剤)
GSTP1-1) is a negative regulator of Jun-N-terminal kinase (JNK), a kinase involved in cellular stress response, differentiation, and apoptosis. Ezatiostat causes myeloproliferation and differentiation of normal blood cell precursors and apoptosis of malignant cells by disrupting the GSTP1-1/JNK pathway.(DNAメチル化阻害剤)
DNA のメチル化により、DNA の構造を変えることなく遺伝子発現が抑制される。MDSでは多くの遺伝子がメチル化を受けており、脱メチル化により腫瘍性増殖の抑制がなされるものと期待された。また骨髄中の異常なhematopoietic細胞への直接的な殺細胞作用。 5-azacytidine はMDS のすべての病型において、白血化を遅らせ、生存期間を延長し、QOL を改善することが報告されている。(免疫調節剤)
レナリドミドは、サイトカイン産生調節作用、造血器腫瘍細胞に対する増殖抑制作用、血管新生阻害作用を持つと考えられる。しかし、詳細な作用機序は解明されていない。有効性 第III相比較試験（AZA-001試験）で主要評価項目である生存期間（中央値）は、CCR群（通常治療:シタラビン等179例）15.02ヵ月に対し、AZA群(本剤179例)24.46ヵ月であり9.44ヵ月の差が認められた（層別ログランク検定、p = 0.0001）。 ＜外国臨床試験成績:＞ 5番染色体長腕部欠失を伴う骨髄異形成症候群患者を対象とした外国第III相試験（MDS-004試験）を実施し、赤血球輸血依存からの離脱を評価した。その結果、プラセボ群の51例中3例（5.9％）、5mg群の46例中19例（41.3％）、10mg群の41例中23例（56.1％）が赤血球輸血依存からの離脱に成功した。5mg群、10mg群で赤血球輸血依存から離脱した患者の割合はプラセボ群での割合と比べて有意に高かった。 安全性 8７例のうち主な副作用は、嘔吐55例（63％）、めまい38例（44％）、下痢32例（37％）、疲労17例（20）であった。 好中球減少症、血小板減少症、貧血など血液学的副作用は各１例すずつのみ 国内臨床試験における副作用は、骨髄異形成症候群（MDS）患者53例中53例（100.0％）に認められた。主な副作用は、好中球減少症（発熱性好中球減少症を含む）47例（88.7％）、白血球減少症、血小板減少症 各45例（84.9％）、ヘモグロビン減少、便秘 各37例（69.8％）、注射部位反応（紅斑、発疹、そう痒感、硬結等）35例（66.0％）、赤血球減少症33例（62.3％）、ヘマトクリット減少29例（54.7％）、リンパ球減少症28例（52.8％）、倦怠感26例（49.1％）、発熱22例（41.5％）、ALT（GPT）増加20例（37.7％）、AST（GOT）増加、ALP増加 各18例（34.0％）、食欲不振、発疹、血中アルブミン減少 各17例（32.1％）であった。 5番染色体長腕部欠失を伴う骨髄異形成症候群患者を対象とした外国第III相臨床試験〔MDS-004試験（二重盲検期間2008年6月26日データカットオフ）〕の安全性評価症例において、10mg群69例中66例（95.7％）に副作用（臨床検査値異常を含む）が認められた。10mg群での主な副作用は、好中球減少症52例（75.4％）、血小板減少症33例（47.8％）、そう痒症18例（26.1％）、下痢13例（18.8％）、便秘9例（13.0％）、疲労7例（10.1％）であった。 骨髄異形成症候群患者では多発性骨髄腫患者より骨髄抑制が高い割合で認められた。 備考 申請資料概要 - [部会審議]審査報告書１ - [部会審議]審査報告書２～国内臨床第I/II相試験：NS17-P1/2(継続中)～１０名 申請資料概要 - [部会審議]審査報告書 - [部会報告書]審査報告書(国内P1 )CC-5013-MM-017/-017PK試験：５施設15名(MM患者、薬物動態) ■開発パイプライン /2011.10.1 by R&D Insight
治験薬記号(一般名)
および剤型予定される効能又は効果、
対象疾患名および症状名開発段階 その他 国内 海外 (地域) Dacogen(E7373)(一般名デシタビン)[エーザイ] 【適応追加】急性骨髄性白血病（ＡＭＬ） 米第Ⅲ相 MGI Pharma 【適応追加】骨髄異形成症候群（ＭＤＳ）延命効果 米第Ⅲ相 【適応追加】ＭＤＳの５日間投与 米承認2010.3.11 【メモ】DNAメチル化阻害による細胞分化誘導作用を有し、すでに米国で骨髄異形成症候群（ＭＤＳ）で適応を取得。 【新適応症】急性骨髄性白血病(AML)への適応拡大(注射剤)。DNAメチル化阻害による細胞分化誘導作用を有し、骨髄異形成症候群(MDS)治療剤として、米MGIファーマ社が2006年5月米で承認取得し発売、2006年売上高は3600万ドル。国内ではMDS適応ではヤンセンファーマが開発。米では2006年8月にAML適応でもオーファンドラッグ指定された。2008年1月、エーザイはMGIファーマ社の買収手続きが完了したと発表、MGIファーマ社はエーザイの米国統括会社エーザイ・コーポレーション・オブ・ノースアメリカ(ECA)の100％子会社となった。2008年7月、エーザイはAMLの小児有用性についてPPSR(ProposedPediatric Study Request：小児適応用試験提案書)提出済みと発表。11th.EHA(欧血液学会)Abst0118(2006.6)●ニューカレント19(20)p25
DNAメチル化阻害剤 「DACOGEN®」注射剤の急性骨髄性白血病に対する第III相臨床試験結果がASCOで発表される[2011.6.7]～この試験は、485名の患者様を対象とした多施設、非盲検試験で、新たに診断された原発性および二次性AML高齢患者様における「Dacogen®」と、患者様選択療法（支持療法もしくは低用量cytarabine）を比較対照し、全生存期間（Overall Survival）を主要評価項目とした。 本試験で観察された有害事象は、すでに確立されている「Dacogen®」の安全性プロファイルと同等であり、両群の間に大きな差異は認められなかった。最も多く報告されたグレード3またはグレード4の有害事象は、血小板減少症（「Dacogen®」投与群：40％、患者様選択療法群：32％、cytarabine投与患者様：35％、支持療法患者様：14％）、貧血（34％、25％、27％、14％）、好中球減少（32%、42%、20%、3%）、発熱性好中球減少（32％、22％、25％、0％）。 この結果に基づき、「Dacogen®」は、高齢者AML患者様に対して一般に認められた標準療法と比較して、安全性に差異はなく、特に治療手段が限定的である当該患者群にとって臨床的に重要な全生存期間を延長する傾向が認められた旨が、本年度ASCO年次総会にて発表された。
【新適応症】骨髄異形成症候群(MDS)の延命効果への適応拡大(注射剤)。DNAメチル化阻害による細胞分化誘導作用を有し、MDS治療剤として、米MGIファーマ社が2006年5月米で承認取得し発売。国内ではMDSの適応ではヤンセンファーマが開発中。
【新適応症】骨髄異形成症候群(MDS)での5日間投与法への適応拡大(注射剤)。MDSは正常な血液細胞を産出する働きが阻害される疾患で死亡リスクもある。本剤はDNAメチル化阻害による細胞分化誘導作用を有し、MDS治療剤(1日3回3日間投与)として、米MGIファーマ社が2006年5月米で承認取得し発売、2006年売上高は3600万ドル。2008年1月、エーザイはMGIファーマ社の買収手続きが完了したと発表、MGIファーマ社はエーザイの米国統括会社エーザイ・コーポレーション・オブ・ノースアメリカ(ECA)の100％子会社となった。2008年7月1日、エーザイは2008度末までに米FDAに5日間投与法での適応追加申請する予定と発表、申請にはフェーズ2試験(Daco-020)データを使用する。Daco-020は原発性および二次性MDS患者99名を対象とした北米での多施設オープンラベル単一群フェーズ2で、5日間連日投与した結果、生存期間中央値は19.4カ月、1年生存率は66%、外来患者への投与における完全寛解率(国際ワーキンググループ2006年基準)は32%で、これまでに報告された外来患者における寛解率のデータと同様であった。安全性プロファイルも従来報告と同様であった。欧州がん研究・治療機構(EORTC)が実施したフェーズ3では、本剤投与群の延命率に統計学的な有意性は認められなかったが、奏効率についてはMDS患者対象として3日間連日投与スケジュールで行われた他の臨床試験と同様の結果が得られた。2008年7月、エーザイはMDS患者を対象とした5日間連日投与スケジュールによるフェーズ2(生存期間中央値19.4カ月、完全寛解率32%)の適応追加申請提出は2008年度中の予定と発表、申請には北米でのフェーズ2多施設オープン試験で得られたデータを使用する。現在3日間連日投与では承認を取得済みだが、治療法の幅を広げ処方拡大につなげる。日経産業新聞(2008.7.16)化学工業日報(2008.7.3)44th.ASCO:Abst7032(2008.5-6)●ニューカレント19(20)p25
JNJ30979754 (デシタビン) 注射剤[ヤンセンファーマ] 骨髄異形成症候群 第Ｉ/Ⅱ相 販売(米) 新有効成分 MLN8237 経口剤[武田薬品] 進行性非ホジキンリンパ腫、急性骨髄性白血病およびハイリスクの骨髄異形成症候群
(オーロラAキナーゼ阻害薬)米国第Ⅱ相開始09.3.3 自社品Millennium 【メモ】オーロラAキナーゼは、細胞分裂に重要な役割を果たすセリン・スレオニンキナーゼで、多くの癌細胞において遺伝子増幅や蛋白質の発現増強が認められています。 本薬は、選択性の非常に高い経口の低分子オーロラA キナーゼ阻害薬である。オーロラA キナーゼ、B キナーゼともに細胞の有糸分裂に重要な役割を果たすが、細胞内での分布や有糸分裂の過程における役割が異なることが知られている。またオーロラA キナーゼは、中心体および紡錘体極に存在するセリン・スレオニンキナーゼであり、有糸分裂時の紡錘体の形成に重要な役割を果たすことが知られている。 「ビダーザ®注射用100mg」（一般名：アザシチジン）NS-17;Vidaza[日本新薬株式会社] 血液癌/骨髄異形成症候群 発売2011.3.11
承認2011.1.21
申請09.12.9導入(米･ファーミオン社→セルジーン社)、自社開発;提携契約2006.11.21 【メモ】平成18年セルジーン社（米国）から導入した骨髄異形成症候群（MDS）治療剤で、米国で第一選択薬として用いられている。平成20年12月にセルジーン社がEUで承認取得。全てのMDSサブタイプに効果が認められ、白血病（AML）への転化を遅らせる。作用機序は、血液形成細胞DNAのメチル化阻害。国内ＰⅡ試験実施中。平成20年11月にオーファン指定。 Improved patient access scheme allows NICE to recommend azacitidine to treat myelodysplastic syndromes[2011.216]～ＮＩＣＥ 患者アクセス計画改善により「アザシチジン」を骨髄異形成症候群治療薬に推奨～ 英国国立医療技術評価機構（ＮＩＣＥ）は2月16日、セルジーンの「アザシチジン」（製品名：ビダーザ）に関し、リスク分類intermediate-2で高リスクの骨髄異形成症候群患者、 慢性骨髄単球性白血病、急性骨髄性白血病など造血幹細胞移植に適さない患者への治療オプションとして推奨するとのガイダンス草案を発出した。今回の推奨は、患者アクセス計画の一部としてアザシチジンの製品コストの値引き提案がされたことに基づくもの。ＮＩＣＥ医療技術評価センター所長のキャロル・ロングソン氏は「アザシチジンは骨髄異形成症候群治療薬として初めて承認された薬剤で、平均9ヵ月の患者延命効果が示されているが非常に高価であった。今回製造者であるセルジーンが患者アクセス計画に基づき製品の値引き提案を行ったことから、英国国民保健機関（NHS）での使用に費用対効果が認められるとして推奨することができた」としている。
●リスト除外品目～承認 レブラミドカプセル5mg(一般名レナリドミド水和物/lenalidomide)Revlimid[セルジーンKK] 再発・難治性多発性骨髄腫および骨髄異形成症候群 発売2010.7.20
承認2010.6.25【メモ】添付文書 - インタビューフォーム ＦＤＡ 「レブリミド」に二次発がん増加リスクの安全性通知/FDA Drug Safety Communication: Ongoing safety review of Revlimid (lenalidomide) and possible increased risk of developing new malignancies[2011.4.8]
～米国食品医薬品局（ＦＤＡ）は4月8日、骨髄異形成症候群や多発性骨髄腫治療薬として用いられるサリドマイド類縁化合物「レブリミド」（一般名：レナリドミド）に関し、米国内外で実施されたレブリミド長期間暴露後の評価を行った試験と比較臨床試験の予備データ結果により、レブリミド投与を受けていない患者に比べ、投与患者での急性骨髄性白血病やＢ細胞リンパ腫など二次発がんの発症率増加が認められたことから、安全性レビューを実施中であるとの安全性通知を発出した。
現時点でＦＤＡは、患者に対して医療提供者の処方通りのレブリミド使用を推奨しており、また医療提供者には同剤処方に際して慎重に検討するよう指示、レブリミド投与による新たながん発症リスクがある旨を患者に認識させるよう勧告している。フルダラ錠10mg(一般名 リン酸フルダラビン/Fludarabine phosphate)； SHT586[バイエル薬品] 【適応追加】 【適応】再発又は難治性の低悪性度B細胞性非ホジキンリンパ腫及びマントル細胞リンパ腫）
(慢性リンパ性白血病（CLL）治療薬として使用されているフルダラ(R)静注の経口剤。)発売2007.7.12
承認2007.1.26CLL治療薬として販売中 既フルダラ静注用;別名Fludara,SH-586;慢性リンパ性白血病[CLL]で英国はじめ10ヶ国で発売のフルダラ(R)静注の経口剤 【適応追加】貧血又は血小板減少症を伴う慢性リンパ性白血病 承認2009.11.6 販売中 【メモ】フルダラビンは、1969年に米国Southern Research Instituteで合成され、さらに1980年、水溶性を高めるためモノリン酸エステル化したリン酸フルダラビンが合成された。本邦では、リン酸フルダラビン注射剤が「貧血又は血小板減少症を伴う慢性リンパ性白血病」を効能・効果として1999年9月に承認された。海外では、低悪性度B細胞性非ホジキンリンパ腫に対しても有効性と安全性が確認されており、現在、リン酸フルダラビン注射剤は「慢性リンパ性白血病」の治療薬として本邦を含む99カ国以上で、「低悪性度B細胞性非ホジキンリンパ腫」の治療薬として29カ国以上で使用されている（2007年1月現在）。 一方、QOLの向上を目的として開発された経口剤（リン酸フルダラビン錠）は、「慢性リンパ性白血病」を適応として74カ国以上で販売されている（2007年1月現在）。本邦では、経口剤による低悪性度B細胞性非ホジキンリンパ腫の治療が望まれていたことから、治療歴を有する低悪性度B細胞性非ホジキンリンパ腫、マントル細胞リンパ腫を対象に2001年から第Ⅰ相試験を、2003年から第Ⅱ相試験を開始し、これらを評価資料としてリン酸フルダラビン錠の承認申請を行い、2007年1月、「再発又は難治性の低悪性度B細胞性非ホジキンリンパ腫、マントル細胞リンパ腫」を効能・効果として承認された。 from フルダラ錠10mg添付文書 - インタビューフォーム
フルダラ(R)静注用50mg(一般名 リン酸フルダラビン/Fludarabine phosphate)；SHL573[バイエル薬品] 貧血又は血小板減少症を伴う慢性リンパ性白血病(CLL) 発売2000.4.19
承認1999.9.29承認 発売時フルダラとして;別名Fludara：「フルダラ(R)静注用50mg」としては承認2005.2.9、発売2005.6.10 【適応追加】造血幹細胞移植の前処置薬。 承認2008.5.20 承認 【適応追加】再発又は難治性の低悪性度B細胞性非ホジキンリンパ腫及びマントル細胞リンパ腫 承認2009.11.6 承認 【メモ】リン酸フルダラビンは，プリン環にフッ素を導入したアデニンヌクレオシド誘導体である．アデニンにハロゲンを導入することで白血病細胞の増殖抑制効果が増強されることを発見した米国Southern Research Institute（SRI）のMontgomeryらによって1969年に合成され，1980年には水溶性を向上させたモノリン酸エステルとして改良された． リン酸フルダラビン注射剤は本邦において，「貧血又は血小板減少症を伴う慢性リンパ性白血病」を効能・効果として1999年9月に承認され，2000年4月より販売されている．海外では，低悪性度B細胞性非ホジキンリンパ腫に対しても有効性と安全性が確認されており，現在，リン酸フルダラビン注射剤は「慢性リンパ性白血病」の治療薬として本邦を含む99ヵ国以上で，「低悪性度B細胞性非ホジキンリンパ腫」の治療薬として世界29ヵ国以上で使用されている．
一方，QOLの向上を目的として開発された経口剤（リン酸フルダラビン錠）は，慢性リンパ性白血病を適応として世界74ヵ国以上で販売されている．また，本邦では，経口剤であるリン酸フルダラビン錠が2007年1月，「再発又は難治性の低悪性度B細胞性非ホジキンリンパ腫，マントル細胞リンパ腫」を効能・効果として承認され，同年7月より発売されている．
また，日本造血細胞移植学会の使用調査報告書によると，ミニ移植の臨床使用は急速に拡大しており，高齢者あるいは臓器障害を有する患者にも移植の機会を提供することのできる非常に有益な治療法となってきている． このことから，厚生科学研究費補助金ヒトゲノム・再生医療等研究事業としてリン酸フルダラビン及びアルキル化剤を移植前治療レジメンに用いた「骨髄非破壊的前処置療法を用いた同種造血幹細胞移植の開発.骨髄非破壊的前処置療法の有用性，ならびに急性GVHDの予防方法に関する検討」が実施され，平成11年2月1日付研第4号・医薬審第104号通知「適応外使用に係る医療用医薬品の取扱いについて」に基づく承認事項一部変更承認申請を行い，「急性骨髄性白血病，骨髄異形成症候群，慢性骨髄性白血病，慢性リンパ性白血病，悪性リンパ腫，多発性骨髄腫における同種造血幹細胞移植の前治療」を追加の効能・効果として，2008年5月に「フルダラ(R)静注用50mg」の承認を取得した． from フルダラ静注用50mg添付文書 - インタビューフォーム
★2005 Survey: Medicines in Development for Cancer[RhPMA;pdf,60p] ★Thalidomide 血管新生抑制効果や抗サイトカイン効果などを有するとされるThalidomide は、RA、RARS を中心とした低リスクMDS 患者の貧血の改善に効果があることが報告されているが、副 作用の強さが問題であった。 ★CC5013..(lenalidomide, Revlimid) Thalidomide の誘導体であるCC5013は、神経系の副作用を軽減するとともに薬理効果を強 めたもので、主にIPSS でLow もしくはInt-1 の患者に用いた試験では、60%以上の患者に 貧血の改善効果を認めたとされ、なかでも5q-症候群の患者では有効率が高く、染色体異常の消失を認めた例も報告されている。 WHO 分類で5q-症候群、RCMD、RCMD-RS に対す る第一選択薬になることが期待されている。 ★DNAメチル化阻害剤 DNA のメチル化により、DNA の構造を変えることなく遺伝子発現が抑制される。MDS では多くの遺伝子がメチル化を受けており、脱メチル化により腫瘍性増殖の抑制がなされ るものと期待された。5-azacytidine はMDS のすべての病型において、白血化を遅らせ、 生存期間を延長し、QOL を改善することが報告されている。 さらに、5-azacytidineの誘導体である5-aza-2'-deoxycytidine (Decitabine)はIPSS で Int-1、Int-2,.. High リスクの患者に5-azacytidine 以上の有効性が期待されている。 ★Farnesyl transferase 阻害剤 MDS ではras 遺伝子の異常が高率に見られることから、ras を標的とした薬剤である Farnesyl transferase 阻害剤の効果が期待された。最近のRAEB 患者を中心にした臨床試 験において、生存期間の延長効果が期待される結果が報告されており、今後の追試が 待たれる。 cf. Tipifarnib（Zarnestra） 【解説資料】 ●メルクマニュアル第18版日本語版 骨髄異形成症候群 ●[医療従事者向けがん情報] 骨髄異形成症候群[国立がんセンター] ●特集 難治性貧血 -分子病態と治療戦略-[最新医学61巻3号,2006] - 骨髄異形成症候群診療ガイドほか ●骨髄異形成症候群[財団法人国際医学情報センター：がん Info ] ●[難病情報センター]不応性貧血（骨髄異形成症候群） Cell Therapeutics, Inc. 10-K (Annual)[2005.3.4] -TRISENOX for Myelodysplastic Syndrome 【データ】 患者調査2008年度で、「D46 骨髄異形成症候群」患者数は9千人(2005年度9千人、2002年度8千人、1999年度6千人) - MDSは60才以上多く発症。 米国で1-3万人、EUで毎年3-4万人の新患者発生。 生存率 はMDSタイプにより６か月から６年。 大半が出血と感染で死亡。 acute myelogenous leukemia (AML)(骨髄性白血病)への形質変換が患者の40%に生じる。 【臨床ガイドライン】 ●National Guideline Clearinghouse - 米国 ●NICE - Clinical Guidelines by 英国NHS [National Health Service] NICE recommends new treatment for myelodysplastic syndromes[21 March 2011] ●不応性貧血(骨髄異形成症候群) 診断・治療指針[難病情報センター] ●「骨髄異形成症候群に対する画期的治療法に関する研究」 生労働科学研究費補助金 難治性疾患克服研究事業 主任研究者 獨協医科大学 三谷 絹子 - 本邦における診療のガイドライン「骨髄異形成症候群診療参照ガイド」[pdf,41p,2004.11.10] 【総説記事・文献】 ●第10回国際MDSシンポジウム～骨髄異形成症候群における診断と治療の最新動向(2009年5月6-9日、ギリシャ)8P [特集] 骨髄異型性症候群（MDS）の病態と治療の進歩 血液フロンティア 16/8 2006年8月号 [特集]骨髄異形成症候群（MDS）：病態の解明と最新の診療 血液・腫瘍科 53(2) Aug 2006 [特集]難治性貧血 －分子病態と治療戦略－ 最新医学 61(3) Mar 2006 [特集]骨髄不全症候群とその周辺疾患 内科 94(3) Sep 2004 【ニュース・トピックス】 The Need for Iron Chelation Therapy in Myelodysplastic Syndromes - 鉄キレート剤EXJADEがMDSの生存率を改善。 Iron Chelation for Myelodysplastic Syndromes Improves Survival Rate: Presented at ASH[2006.12.12] - 鉄キレート剤EXJADEがMDSの生存率を改善。 鉄キレート療法(ICT)投与群は４年生存率が80%、非投与群44%。 【リンク・リソース】 【主要サイト】 Aplastic Anemia & Myelodysplastic Syndromes International Foundation, Inc
製品名 開発会社 開発段階 作用 適応症 備考 Alisertib
(MLN 8237; MLN8237)Millennium Pharmaceuticals Phase-II Aurora kinase A inhibitors Myelodysplastic syndromes
Acute myeloid leukaemia
Non-Hodgkin's lymphoma
Ovarian cancer (Fourth-line treatment )*【メモ】Alisertib is an orally active, small molecule inhibitor of the aurora A kinase being developed by Millennium Pharmaceuticals (Takeda) for the treatment of solid tumours and haematological malignancies. The aurora family of protein kinases are involved in the regulation of cell growth and proliferation, particularly in chromosome segregation and cytokinesis. Aurora A and aurora B kinases are commonly overexpressed in tumours, making them potential targets for anticancer agents. Inhibition of aurora kinases may provide a promising way of delaying or even reversing the growth of cancer cells. Millennium is conducting clinical trials with alisertib in the US and EU in various cancer types including haematological malignancies, Non-Hodgkin's lymphoma, breast, ovarian and prostate cancers. In May 2008, Millennium Pharmaceuticals became a wholly-owned subsidiary of Takeda 1.
【Key Development Milestones】
Haematological malignancies: a phase I clinical trial (NCT00697346) is assessing the efficacy of alisertib in subjects with advanced haematological malignancies for whom there are limited standard treatment options. This trial will enrol approximately 97 patients from the Sarah Cannon Research Institute, USA 2.
A phase II clinical trial (NCT00830518) evaluated alisertib in adult patients with acute myelogenous leukaemia and high-grade myelodysplastic syndromes. This trial enrolled approximately 41 subjects from the US 3 4. Phase II development in the EU is also taking place.
Amifostine
(Ethiofos; Ethyol®; Gammaphos; NSC 296961; WR 2721; YM 08310)MedImmune Oncology(Licensee)/Southern Research Institute(Originator) Discontinued(II) Oxygen radical scavengers 【適応追加】Myelodysplastic syndromes 放射線防護剤として発売 【メモ】Amifostine, an organic thiophosphate with oxygen scavenging activity, is selectively protective against radiation, platinum and alkylating agent toxicities. Amifostine was originally developed by the Southern Research Institute in Birmingham, Alabama, USA. Sun Pharmaceutical launched the first US generic version of amifostine in March 2008 1.
【Company Agreements】
The originators of amifostine, the Southern Research Institute, licensed the agent to US Bioscience, which later became MedImmune Oncology. MedImmune Oncology has had exclusive US marketing rights to amifostine since 2001, when the rights were returned from ALZA (Johnson & Johnson). MedImmune Oncology plans to focus its efforts on developing different methods of administration of amifostine to reduce toxicities associated with chemotherapy and radiation therapy.
Eli Lilly has acquired the rights to market amifostine in Canada and Teva Pharmaceutical Industries has rights to market amifostine in Israel. In addition, Erkim has exclusive rights in Turkey and Ramco has exclusive rights in Egypt.
Scherico, an affiliate of Schering-Plough, acquired exclusive rights from US Bioscience to market amifostine in Europe, Latin America, the Far East, Australia, New Zealand, South Africa and certain Middle East countries. These marketing rights continued until December 31, 2003. At the end of this period, MedImmune Oncology was to co-promote amifostine with Scherico for a further 2 year period. Thereafter, MedImmune Oncology reacquired sole marketing rights, subject to an obligation to pay Scherico a royalty fee based on percentage of net sales, if any, from the European territories for a period of 3 years.
【Key Development Milestones】
Amifostine has been widely launched as a chemoprotectant and radioprotectant in patients receiving treatment for cancer. In addition to the amorphous formulation of amifostine, which is approved in the US and other countries, a crystalline formulation of amifostine has also been granted US marketing approval.
Myelodysplastic syndrome: amifostine was also undergoing clinical studies in Europe and the US for the treatment of myelodysplastic syndrome. MedImmune received orphan drug status for this indication in October 1999. However, no recent development for this indication has been reported.
Antithymocyte globulin
(Antithymocyte immunoglobulin; Polyclonal rabbit antithymocyte globulin; Rabbit antithymocyte globulin; Thymoglobulin®; Thymoglobuline®)sanofi pasteur(Originator)/Genzyme Corporation(Licensee) Phase-II Immunosuppressants 【適応追加】Myelodysplastic syndromes 腎移植、骨髄移植、肝臓移植、膵臓移植などで販売 【メモ】Antithymocyte globulin is a pasteurised rabbit polyclonal antibody specific for human thymocytes. Its main indication is for the prevention of organ rejection in kidney transplant recipients. Genzyme Corporation (a subsidiary of sanofi-aventis) markets antithymocyte globulin in the US as Thymoglobulin® and outside the US as Thymoglobuline®. The company is also conducting clinical development in liver transplant patients and myelodysplastic syndrome, and evaluating potential use of Thymoglobulin® in new-onset type 1 diabetes in the US. The compound was previously being developed by SangStat Medical Corporation. However, the company was acquired by Genzyme Corporation in September 2003. Genzyme became a subsidiary of sanofi-aventis in April 2011 1. 【Company agreements】 SangStat Medical Corporation acquired the exclusive rights to develop and market antithymocyte globulin in the US and Canada from Pasteur MAmrieux Connaught (now Aventis Pasteur) in 1993. Aventis Pasteur continues to have some involvement in quality control issues for the product. Pasteur MAmrieux Connaught was formerly a subsidiary of RhAxne-Poulenc. In December 1999, RhAxne-Poulenc merged with Hoechst to form Aventis and Pasteur MAmrieux Connaught underwent a name change to Aventis Pasteur. Aventis Pasteur is the distributor of Thymoglobuline® for most countries outside of North America, Europe and Japan. Genzyme is renegotiating distribution agreements with Aventis to allow direct contracts with distributors in countries in which Aventis has no direct presence such as Israel and Asia. In August 2004, Aventis merged with Sanofi-Synthelabo to form Sanofi-Aventis. In January 2005, Aventis Pasteur changed its name to sanofi pasteur. 【Key development milestones】
Thymoglobulin® is available in 56 countries worldwide, including Europe and the USA, for the treatment and prevention of acute organ transplant rejection. It has been marketed in the US since 1999 for the treatment of acute rejection in patients with renal transplant. In Canada, it has been marketed since 2003 for the prevention and treatment of acute rejection in renal transplant patients. Clinical trials are also being conducted to expand Thymoglobulin® in the US, with trials underway in living donor transplants, induction, and chronic immunosuppression. It is marketed in Europe for induction and treatment of rejection in solid organ transplants; prevention and treatment of graft-versus-host disease; and for the treatment of aplastic anaemia. These indications are also held in certain Asian and Latin American countries.
Myelodysplastic syndrome: antithymocyte globulin is in phase II development with Genzyme for the treatment of myelodysplastic syndrome.
A phase II trial in conjunction with the M. D. Anderson Cancer Center was initiated in May 2005 investigating antithymocyte globulin in combination with cyclosporine, methylprednisolone and G-CSF in patients with aplastic anaemia or myelodysplastic syndrome in the US (NCT00806598). Another phase II trial in myelodysplastic syndrome was terminated due to slow enrolment (NCT00542828).
SangStat has conducted phase II trials in patients with myelodysplastic syndrome. The FDA granted orphan drug designation to Thymoglobulin® for this indication in September 2000 4.
AR 67 Arno Therapeutics(Licensee)/University of Pittsburgh(Originator) Phase-II DNA topoisomerase I inhibitors Myelodysplastic syndromes
Glioblastoma【メモ】AR 67 is a third-generation camptothecin analogue being developed by Arno Therapeutics for the treatment of cancer. Camptothecins treat cancer by disrupting cell division through the inhibition of topoisomerase I, a critical enzyme used in DNA replication. These camptothecin compounds react with water and exist in two forms under physiological conditions, in a biologically active lactone form and an inactive, toxic carboxylate form. Preclinical studies and phase I data have confirmed that AR 67 maintains a greater proportion of drug in the active lactone form, compared with approved second-generation camptothecins such as topotecan and irinotecan, as well as showing increased stability and an improved pharmacokinetic profile. The potential for oral administration may increase patient compliance. AR 67 is in phase II development in the US, for the treatment of myelodysplastic syndromes and glioblastoma multiforme. 【Company Agreements】
AR 67 was discovered and patented by researchers at the University of Pittsburgh, USA. In October 2006, Arno Therapeutics entered into an exclusive, worldwide, royalty-bearing licence for the rights to commercialise technologies embodied by certain patents, patent applications and know-how relating to AR 67 for all therapeutic uses. Under the terms of the agreement, Arno paid a one-time cash payment of $US350,000 to the University of Pittsburgh and reimbursed the institution for past patent expenses. The University of Pittsburgh will be eligible for performance-based cash payments upon successful completion of clinical and regulatory milestones relating to AR 67, with the first milestone payment to be made on the filing of an NDA for AR 67.
The National Health Research Institutes (NHRI) of Taiwan licensed the Asian rights (including Japan) to AR 67, and assigned them to TTY Biopharm for development and commercialisation. In October 2003, TTY signed an agreement with TaiGen Biotechnology to jointly develop and market AR 67 for the treatment of cancer 1. Under the terms of the agreement, TaiGen was to conduct studies in animal disease models, pharmacokinetics, drug metabolism and toxicology, and TTY was to be responsible for formulation, GMP production of dosage forms and organisation of clinical trials. TaiGen and TTY had a plan in place to market the drug jointly in Asia; however, development in this territory appears to have ceased.
【Key Development Milestones 】
Myelodysplastic syndromes: in July 2009, Arno Therapeutics, in collaboration with the M.D. Anderson Cancer Center, initiated an open-label phase II trial of AR 67 in patients with myelodysplastic syndromes who have progressed following regimens containing hypomethylating agents (NCT00930540). The primary objective is response rate, with secondary objectives of evaluating safety, response duration, and disease-free survival 3 5. Enrolment of 25 patients was completed in April 2011.
ARRY 614 Array BioPharma Phase-I P38 mitogen-activated protein kinase inhibitors, TIE 2 receptor antagonists Myelodysplastic syndromes 【メモ】ARRY 614 is an orally active P38 and TIE2 inhibitor being developed by Array BioPharma for the treatment of cancer, including myelodysplastic syndromes. P38 is a kinase target that regulates the production of PGE2, as well as many pro-inflammatory cytokines such as TNF, IL-6 and IL-1. These cytokines can also act as cellular growth factors and are often up-regulated in certain cancers including prostate, ovarian and multiple myeloma. In addition, P38 may play a role in certain resistance mechanisms or metastatic progression in cancer. TIE2 plays an important role in angiogenesis and blood vessel growth which may lead to uncontrolled cell growth that characterises a number of cancer and chronic inflammatory diseases. ARRY 614 is in phase I development in the US. 【Key Development Milestones】
A phase Ib trial of ARRY 614 in 50 patients with myelodysplastic syndromes (MDS) is underway in the US (NCT00916227). The trial will determine the safety, maximum tolerated dose, pharmacokinetics and preliminary estimates of efficacy in this patient population 1 2. Array completed enrolment during the fourth quarter of FY 2011, and also tested a new formulation for improved drug exposure. The company will use a new formulation of AR 614 with reduced variability and improved exposure, as shown in a completed bioequivalence study 3 4.
Array BioPharma has completed a phase I single- and multiple-dose escalation trial of ARRY 614 in healthy volunteers. The study evaluated the safety and tolerability of the drug, as well as its inhibition of mechanism-related biomarkers. Results showed that ARRY 614 was well-tolerated and exhibited dose-dependent increases in exposure, as well as strong evidence of pharmacodynamic activity 5 1 2 6 7.
ARRY 614 inhibited angiogenesis, inflammation and tumour growth and demonstrated a low adverse event profile in preclinical models of arthritis and cancer 8 9.
Arsenic trioxide
(Trisenox®)Cephalon Phase-III
Phase-II
Phase-IIApoptosis stimulants Acute myeloid leukaemia
Multiple myeloma
Myelodysplastic syndromesALL,Acute promyelocytic leukaemiaで販売；日本新薬 【メモ】Arsenic trioxide is indicated in the US, EU, Japan and South Korea as an intravenously infused treatment for relapsed or refractory acute promyelocytic leukaemia. Rights to the product are currently owned by Cephalon. The compound is believed to work by multiple mechanisms of action including apoptosis induction of immature cancer cells, and by damaging or degrading the fusion protein PML-RAR-alpha that causes abnormal levels of immature white blood cells. Arsenic trioxide is also undergoing clinical testing for other haematological and solid cancers as both a single agent and in combination with other treatments. Studies are being conducted at the Memorial Sloan-Kettering Cancer Centre, New York, and the M.D. Anderson Cancer Centre, Houston, Texas, USA, as well as at a number of University centres in the USA. The number of patients diagnosed with acute promyelocytic leukaemia annually has been estimated at 500 to 700 in Japan and 250 in South Korea 1.
AS 101
(IVAX Q 101; IVX Q 101; Ossirene; Ossirene®; SAS; WAX 120337)IVAX Corporation(Licensee)/Bar-Ilan University(Originator) Phase-II
Phase-II
Phase-II
PreclinicalIntegrin alphaVbeta3 antagonists Human papillomavirus infections
Psoriasis
Thrombocytopenia
Myelodysplastic syndromes【メモ】AS 101 is a small molecule integrin αvβ3 inhibitor. It is being developed by BioMAS in Israel for the treatment of malignancies, neurological disorders, skin disorders, and chemotherapy-induced thrombocytopenia. It is an organotellurium compound which stimulates production of lymphokines and colony stimulating factors such as IL-1α, TNFα, IL-2 and γ-IFN. AS 101 is in phase II development in Israel for chemotherapy-induced thrombocytopenia and human papillomavirus infections. AS 101 was invented by two researchers, Albeck M and Sredni B, at the Bar-Ilan University in Israel. It was licensed to IVAX Corporation (now Teva Pharmaceuticals). The inventors of AS 101 founded BioMAS in 2000 to continue development of AS 101 and a related compound, SAS. SAS is a second generation tellurium compound with improved stability in aqueous solutions relative to AS 101.
Azacitidine
(5-azacitidine; 5-azacytidine; Aza C; Aza-C; Ladakamycin; NS 17; NS-17; NSC-102816; Vidaza®)Pharmion(Licensee)/Celgene Corporation(Licensee)/Pfizer(Originator) Marketed DNA methylation inhibitors 【適応追加】Myelodysplastic syndromes AML,CML等で販売 【メモ】Azacitidine is a DNA methyltransferase inhibitor that went through clinical trials in the 1980s without impressive outcomes. However, during that time the function of azacitidine as a methyltransferase inhibitor was unknown and the studies were not appropriately designed to maximise the effects of the drug. The potential of DNA methylation inhibition as a cancer treatment lies in the ability of the inhibitor to regulate expression of certain genes such as tumour suppressor genes, which are often silenced by methylation during tumour cell transformation. In theory, switching on or off deregulated genes could stop the uncontrolled proliferation or induce differentiation of tumour cells which may subsequently reverse the malignant phenotype. Azacitidine is being developed for myelodysplastic syndromes, other haematological malignancies and solid tumours.
Azacitidine was launched as a subcutaneous injection for the treatment of myelodysplastic syndromes (MDS) in the US in 2004, under the tradename Vidaza®. It was approved by the US FDA for the treatment of all five MDS subtypes (refractory anaemia; refractory anaemia with ringed sideroblasts; refractory anaemia with excess blasts; refractory anaemia with excess blasts in transformation; chronic myelomonocytic leukaemia). In January 2007, the FDA approved an sNDA filed by Pharmion (Celgene) to add intravenous use as an additional route of administration in the prescribing information for azacitidine. Additionally, the EMEA has approved the subcutaneous formulation in the EU for the treatment of higher-risk myelodysplastic syndromes, acute myeloid leukaemia (AML), and chronic myelomonocytic leukaemia. Canadian approval has also been granted for higher-risk myelodysplastic syndromes and a subset of AML patients who are not eligible for stem cell transplantation. Azacitidine has been approved in Japan for the treatment of MDS. An oral formulation of the drug is also in clinical development.
【Company Agreements】
In March 2008, Pharmion was acquired and integrated into Celgene 1.
Pharmion in the US acquired global development and commercialisation rights to azacitidine from Pharmacia Corporation (now Pfizer) in June 2001. Under the terms of the agreement, Pharmion is obligated to pay Pharmacia a royalty of up to 20% on net sales of azacitidine. The licence has a term extending for the duration of either 10 years from the first commercial sale of the product in a particular country or until the expiry of the last valid patent claims in any given country, whichever occurs later.
Nippon Shinyaku acquired the exclusive commercialisation and development rights to azacitidine in Japan from Pharmion in November 2006. Nippon Shinyaku has the responsibility for funding and conducting any additional studies that may be required for approval in Japan 2.
Azacitidine - Mylan Bioniche Pharma Phase-I DNA methylation inhibitors Myelodysplastic syndromes 【メモ】 Belinostat
(CLN-9; PX 105684; PXD101)TopoTarget Discontinued(II)
Phase-II
Phase-II
Phase-IIHistone deacetylase inhibitors Myelodysplastic syndromes
Mesothelioma
Ovarian cancer
Peripheral T-cell lymphoma【メモ】TopoTarget is developing belinostat, a small molecule drug for the treatment of advanced cancer. Belinostat is a hydroxamate type inhibitor of class I and class II histone deacetylase (HDAC) enzymes. HDAC enzymes promote growth and proliferation of tumour cells, as they have a central role in repressing the transcription of tumour suppressor genes. HDAC inhibitors have been shown to enhance histone acetylation and to increase the expression of tumour suppressor genes in tumour cells. Belinostat has also been shown to sensitise tumour cells to overcome drug resistance, when used in combination with other anticancer agents. TopoTarget believes that belinostat is the sole compound in its class that can be administered orally and intravenously, including short and continuous infusion, which could be clinically and commercially advantageous in certain cancers. Intravenous and oral formulations of belinostat are in clinical development around the world, in a wide range of cancer types. 【Company Agreements】
In February 2010, Spectrum Pharmaceuticals and TopoTarget entered into a licensing agreement under which the former obtained rights to co-develop and commercialise belinostat in North America and India; Spectrum also secured an option to rights in China. Spectrum is required to make an upfront cash payment (of $30 million), potential milestone payments (up to $320 million), a common stock transfer (one million shares), based on the successful achievement of certain development, regulatory and commercial milestones, and royalty payments on net sales. Spectrum is responsible for 100% of development costs relating to the ongoing peripheral T-cell lymphoma trial and the CUP study. Future development costs will be shared by Spectrum and TopoTarget at a ratio of 70:30. This deal triggered TopoTarget to make a $US3 million payment to Celldex Therapeutics 1 2 3.
In June 2004, CuraGen Corporation (now Celldex Therapeutics) formed an agreement with TopoTarget to develop and commercialise belinostat for the treatment of solid and haematological cancers. In April 2008, CuraGen sold its ownership of belinostat to TopoTarget. Under the terms and conditions of the sale, CuraGen is eligible for 10% of any sublicense income 4 5.
In August 2004, CuraGen signed a Clinical Trials Agreement (CTA) with the National Cancer Institute (NCI) to sponsor several clinical trials of belinostat alone and in combination with chemotherapy, for the treatment of solid and haematological malignancies. CuraGen was to use the NCI's expertise to understand which patient populations will receive the greatest benefit from belinostat, when planning phase II trials 6.
【Key Development Milestone】
s In May 2005, TopoTarget signed a Cooperative Research and Development Agreement (CRADA) with the Division of Cancer Treatment and Diagnosis (DCTD) at the NCI, to conduct preclinical and clinical studies with belinostat. The aim of this agreement is to further elucidate the anticancer activity of belinostat and to use this information in the development of clinical trial protocols 7.
Haematological malignancies (acute leukaemia/myelodysplastic syndromes): in May 2010, patient dosing was initiated in an NCI-sponsored, phase I trial (NCT01075425) evaluating the safety and best dose of belinostat given in combination with bortezomib in patients with relapsed or refractory acute lymphocytic leukaemia (ALL), AML, chronic myelogenous leukaemia (CML) or myelodysplastic syndromes (MDS). The study will enrol approximately 24 patients to receive intravenous belinostat for 30 min on days 1-5 and 8-12 and intravenous bortezomib on days 1, 4, 8, and 11. Treatment repeats every 21 days for up to 12 courses based on an absence of disease progression or unacceptable toxicity. The duration of this trial is 2 years 29.
Cancer immunotherapies - BioSante
(CG 8123; GVAX Pancreas; GVAX® Leukemia; GVAX® Pancreatic; GVAX® Prostate)BioSante Pharmaceuticals(owner)/Cell Genesys(originator) Phase-III
Suspended(I)Granulocyte macrophage colony stimulating factor agonists Prostate cancer
Myelodysplastic syndromes【メモ】BioSante is developing GVAX® immunotherapies for the treatment of breast cancer, pancreatic cancer, prostate cancer, multiple myeloma, colorectal cancer, malignant melanoma and leukaemia. Originally developed by Cell Genesys, GVAX®immunotherapies are comprised of tumour cells that are genetically modified to secrete an immune-stimulating cytokine, called granulocyte-macrophage colony-stimulating factor (GM-CSF), which are then irradiated for safety. As these GVAX®immunotherapies consist of whole tumour cells, the immune system can be activated against multiple tumour cell antigens, potentially resulting in greater clinical benefit than if the immunotherapy consisted of only a single tumour cell antigen. The secretion of GM-CSF by the modified tumour cells is designed to enhance the immune response by recruiting and activating dendritic cells at the injection site, a critical step in the immune response. The anti-tumour immune response which occurs throughout the body following administration of a GVAX®product can potentially result in the destruction of tumour cells that persist or recur following surgery, radiation therapy or chemotherapy treatment. GVAX®cancer immunotherapies are administered intradermally on an outpatient basis. Clinical development is underway in the US for all indications except melanoma, which is in preclinical development. BioSante intends to seek development opportunities for GVAX immunotherapies including combinations with BioVantmV, BioSante's vaccine adjuvant, as well as opportunities to outlicense other former Cell Genesys technologies 1.
GVAX®consist of allogeneic, GM-CSF-secreting tumour cells, the use of allogeneic cells rather than autologous cells enables efficient, large-scale production of the immunotherapies. This also allows off-the-shelf usage, unlike similar products which require patient specific formulations.
【Company Agreements】
In July 2011, BioSante granted the Hussman Foundation in the US an exclusive global licence to its GVAX®melanoma vaccine. BioSante received an upfront payment of $US100 000, and under the terms of the licensing agreement, is eligible to up to $US39 million in milestone payments in addition to royalties on potential future sales. BioSante is also eligible to 15%-33% of any potential sublicense payments received by the Hussman Foundation, depending on the timing of any sublicensing agreements. The Hussman Foundation has also agreed to provide up to $US1 million to fund the development of the vaccine 2.
Aduro BioTech in-licensed GVAX®pancreatic cancer vaccine [GVAX®Pancreas] and GVAX®Prostate from BioSante Pharmaceuticals in April 2011, for use in combination with its Listeria monocytogenes-based vaccine platform; Aduro also has an option to licence additional GVAX®cancer vaccine indications for the combination therapies. Aduro will pay BioSante milestone and royalty payments after commercialisation 3.
GVAX®was originally being developed by Somatix, which was subsequently integrated into Cell Genesys. In October 2009, Cell Genesys was acquired and integrated into BioSante Pharmaceuticals 1.
In April 2008, Cell Genesys formed a global alliance with Takeda Pharmaceutical Company for the development and commercialisation of the GVAX®immunotherapy for prostate cancer. In exchange for exclusive worldwide commercial rights to the GVAX®immunotherapy for prostate cancer, Takeda paid Cell Genesys an upfront payment of $US50 million and was to pay additional milestone payments of up to $US270 million relating to regulatory approval and commercialisation for prostate cancer in the United States, European Union and Japan. However, this agreement was terminated in December 2008. Takeda returned all rights to Cell Genesys and made $US0.6 million as wind-down payments to Cell Genesys for the phasing-out of remaining clinical development activities 4 5 6.
In December 2000, Cell Genesys entered a technology licensing agreement with Xenogen Corporation (now Caliper Life Sciences). Under the agreement, Cell Genesys will have access to Caliper's proprietary real-time in vivo imaging technologies to develop cancer therapies. In August 2006, Caliper Life Sciences acquired Xenogen Corporation 7 8.
Cell Genesys had a worldwide collaboration agreement with the pharmaceutical division of Japan Tobacco for the development of selected product candidates from the company's GVAX®cancer programme. However, this agreement was terminated in October 2002 and Cell Genesys reacquired full commercial rights to the GVAX®lung cancer vaccines. Furthermore, in August 2003, Cell Genesys and Japan Tobacco reached an agreement regarding approximately $US16.8 million in clinical and patent-related milestone and wind down payments arising from the termination of their agreement in October 2002. Under the agreement, Japan Tobacco was to pay Cell Genesys approximately $US8.3 million in cash and waive $US8.5 million in future repayment obligations for capital expenditures associated with Cell Genesys' manufacturing facilities in Hayward, California and Memphis, Tennessee 9 10.
The original agreement between Cell Genesys and Japan Tobacco was signed in 1998 and modified in November 2001. What had previously been a worldwide 50/50 profit sharing agreement for GVAX®lung and prostate vaccines, was altered to a royalty arrangement on sales from the GVAX®lung cancer vaccine. In addition, under the terms of the new agreement, royalty payments were to be made on a certain form of the vaccine for other indications. As a result of the modifications, Japan Tobacco was to pay royalties on the lung cancer vaccine sales in Japan, Korea and Taiwan. Cell Genesys was also to make royalty payments to Japan Tobacco for lung cancer vaccine sales in North America and the all other countries not covered by Japan Tobacco.
Cancer vaccine PR1 - The Vaccine Company The Vaccine Company Phase-III
Phase-II
Phase-IIImmunostimulants Acute myeloid leukaemia
Chronic myeloid leukaemia
Myelodysplastic syndromes【メモ】The Vaccine Company in the US is developing a therapeutic PR1 peptide cancer vaccine for the treatment of certain leukaemias, including acute myeloid leukaemia (AML), chronic myeloid leukaemia (CML), and myelodysplastic syndrome (MDS). The vaccine is in a phase III clinical trial for AML, and phase II trials for CML and MDS. The vaccine is based on a fragment of a surface serine protease, proteinase 3, which is uniquely overexpressed on leukaemic myeloid cells. The fragment (PR1) is a nonapeptide which binds to major histocompatibility complex (MHC). This causes a conformation change which makes MHC susceptible to binding by a T cell receptor, leading to production of cytotoxic lymphocytes that are specific toward leukaemic myeloid cells.
Myelodysplastic syndrome (MDS): a US-based phase II clinical trial (NCT00513578) is ongoing for the treatment of MDS. Approximately 30 patients with low-risk or intermediate-risk myelodysplastic syndrome have been recruited into the study which will assess the vaccine mixed with montanide ISA-51 VG adjuvant and administered with GM-CSF.
Results from a phase I/II clinical trial showed that the median time to remission for patients with myeloid malignancies was three times longer in subjects who responded to the vaccine compared with non-responders 2.
CC 1088 Celgene Corporation Discontinued-II Type 4 cyclic nucleotide phosphodiesterase inhibitors Myelodysplastic syndromes 【メモ】CC 1088 is a small molecule inhibitor of tumour necrosis factor (TNF)-α overproduction. It is being developed as a potential anti-inflammatory and anti-cancer drug by Celgene in the USA. It is a member of the class of drugs known as SelCIDs™ (Selective Cytokine Inhibitory Drugs), and is the lead compound in this class. CC 1088, like other SelCIDs™ , reduces levels of TNF-α through a specific inhibitory effect on the enzyme phosphodiesterase type IV. CC 1088 is in clinical trials for the treatment of myelodysplastic syndromes.
Myelodysplastic syndromes: CC 1088 had been studied in a phase II clinical trial for the treatment of myelodysplastic syndromes, but appears to have been discontinued for this indication based on Celgene's R&D drug pipeline of August 2004 where the drug was not mentioned.
CC 11006 Celgene Corporation Phase-I Immunomodulators, Interleukin 1 beta inhibitors, Interleukin 10 stimulants, Tumour necrosis factor inhibitors Myelodysplastic syndromes 【メモ】Celgene is developing CC 11006, an immunomodulatory drug (IMiD®) as a treatment for inflammatory disorders, myelodysplastic syndromes, and amyotrophic lateral sclerosis (ALS). IMiD®s are small molecule, orally-active analogues of thalidomide that are designed to be more potent and safer than the parent compound. Celgene has stated that IMiD®s potently inhibit tumour necrosis factor-α and interleukin-1b and stimulate interleukin-10. In addition, IMiD®s enhance T cell proliferation and interleukin-2 production. CC 11006 is in a phase I open-label, dose-escalation study of CC 11006 in subjects with low- or intermediate-1 risk myelodysplastic syndromes. The trial is taking place in the US and is expected to enrol approximately 76 subjects.
Celgene has completed initial phase I trials of CC 11006 in patients with inflammatory disorders.
Preclinical trials in the US showed CC 11006 to be neuroprotective in a mouse model of familial amyotrophic lateral sclerosis (ALS).
Clofarabine
(Clofarex™; Clofaribine; Clolar®; Evoltra®; JC0707)Genzyme Corporation(Originator)/Southern Research Institute(Originator) Phase-II DNA synthesis inhibitors Myelodysplastic syndromes ALLで発売 【メモ】Clofarabine is a next-generation, purine nucleoside analogue originated by the Southern Research Institute. It is being developed by Genzyme Corporation (a subsidiary of sanofi-aventis) for the treatment of cancer. Clofarabine's nucleoside structure contains halogenated purine and ribose rings enabling it to inhibit DNA synthesis at two critical junctures: DNA polymerase α and RNA reductase. Clofarabine also directly disrupts mitochondrial membrane integrity, initiating apoptosis. Intravenous, oral and topical gel formulations are in development. In North and South America, the product is marketed as C lolar® and as Evoltra® elsewhere in the world, for the treatment of paediatric acute lymphoblastic leukaemia. Genzyme was acquired by sanofi-aventis in April 2011 1.
【Company Agreements】 Genzyme acquired the exclusive worldwide rights to clofarabine through its acquisition of Bioenvision in October 2007; Bioenvision had obtained these rights from the Southern Research Institute. Previously, Bioenvision had granted an exclusive sublicense to Genzyme to co-develop clofarabine for cancer indications in the US and Canada 2 3.
Mayne Pharma (a subsidiary of Hospira) has exclusive rights to market clofarabine for certain haematological malignancies in Australia and New Zealand. In February 2007, Mayne Pharma was acquired by Hospira 4 5.
【Key Development Milestones】
Myelodysplastic syndromes (MDS): a dose confirmation phase II trial (NCT00531232) is testing oral clofarabine in patients who failed or are intolerant to any available therapies for MDS 35.
Combretastatin A1 phosphate
(CA1; CA1P; Combrestatin A1 diphosphate; Combretastatin A1 di-phosphate; Combretastatin A1 diphosphate; OXi4503)OXiGENE(Licensee World)/Arizona State University(Originator) Phase-I/II Vascular disrupting agents Myelodysplastic syndromes 【メモ】OXiGENE is developing combretastatin A1 phosphate (OXi 4503), a second-generation, dual-mechanism vascular disrupting agent, as a treatment for solid and haematological tumours. As a synthetic prodrug of naturally occurring combretastatin A1, this agent is of particular interest as it exhibits not only vascular disrupting properties, but also appears to be metabolised in tumour tissue to a reactive cytotoxic ortho-quinone species, which directly kills tumour cells. Hence, combretastatin A1 phosphate not only causes extensive internal tumour necrosis, but has the potential to kill the rim of cells at the tumour periphery, an area responsible for the regrowth and vascularisation of the tumour. Clinical development for the treatment of solid tumours and haematological malignancies is underway. Dasatinib
(BMS 354825; BMS-354825; Sprycel®)Bristol-Myers Squibb Phase-III
Phase-II
Phase-II
Phase-II
Phase-IIBcr-abl tyrosine kinase inhibitors, EphA2 receptor antagonists, Platelet-derived growth factor beta receptor antagonists, Proto oncogene protein c-kit inhibitors, Src-Family kinase inhibitors 【適応追加】Prostate cancer
Myelodysplastic syndromes
Breast cancer
Non-small cell lung cancer
Pancreatic cancerALL,CMLで発売 【メモ】Dasatinib is an orally administered, small molecule tyrosine kinase inhibitor that is being developed by Bristol-Myers Squibb (BMS). It is able to bind to multiple conformations of the ABL kinase and at nanomolar concentrations dasatinib inhibits BCR-ABL, the SRC family, c-kit, EphA2, and PDGFRAc. By targeting these kinases, dasatinib inhibits the overproduction of leukaemia cells in the bone marrow of patients with chronic myelogenous leukaemia (CML) and Philadelphia chromosome-positive acute lymphoblastic leukaemia (Ph+ ALL). Dasatinib is approved as a second-line treatment for all phases of CML and as a second-line treatment for Ph+ ALL in a number of countries worldwide, including the US and EU. Dasatinib is also approved as a first line treatment for CML in the US, the EU, Canada and Japan. Bristol-Myers Squibb is supporting clinical trials with dasatinib, either alone or in combination with other therapeutics, for the treatment of various solid tumours. Phase I development for a liquid formulation is underway in the US. Company Agreements
In April 2009, BMS entered into a marketing collaboration for dasatinib, with Otsuka Pharmaceutical. From 2010, Otsuka will share in commercial expenses for the US, Europe and Japan, and will co-promote dasatinib with Bristol-Myers Squibb in the US, Japan and major EU markets. Otsuka will receive a collaboration fee from BMS on aggregate annual net sales of dasatinib, beginning in 2010, on a regressive tiering basis through to 2020 1 2. The companies commenced co-promotion activities in Japan in December 2010 3.
Key Development Milestones
Myelodysplastic syndromes (MDS): BMS is conducting a pilot phase II study evaluating the effect on dasatinib in 26 patients with MDS and excess marrow blasts in the US (NCT00624585). Enrolment of patients was completed in March 2010.
Decitabine
( 2'-Deoxy-5-azacytidine; Aza dC; DAC; Dacogen®; Dezocitidine; E 7373; E7373; NSC 127716))SuperGen Marketed DNA methylation inhibitors 【適応追加】Myelodysplastic syndromes CMS,MDSで発売 【メモ】Decitabine is an intravenously administered DNA methylation inhibitor being co-developed by Eisai and Janssen-Cilag for the treatment of haematological cancers, including myelodysplastic syndromes (MDS) and acute myeloid leukaemia (AML). It is a deoxycytidine and cytarabine derivative originated by SuperGen (now Astex Pharmaceuticals). The compound is available in the US for MDS and chronic myelomonocytic leukaemia and is undergoing regulatory review for AML. An MAA has been submitted in the EU for AML. Previously, an MAA was submitted in the EU for use of decitabine in MDS, however the application was withdrawn and development discontinued in that market. Decitabine has been shown to inhibit DNA methylation, leading to re-expression of suppressor genes and a resulting re-differentiation and maturation of the cancer cells back to normal. It has also been shown to restore sensitivity of tumours to drugs such as cisplatin by reversing drug resistance. It has demonstrated limited efficacy against solid tumours. However, the drug exhibits higher activity for the treatment of haematological malignancies.
Decitabine was initially being developed by Janssen-Cilag with MGI PHARMA. However, MGI PHARMA was acquired by Eisai in 2008 1.
SuperGen was renamed as Astex Pharmaceuticals in September 2011 2.
【Company Agreements】
The US launch of decitabine injection by MGI PHARMA (now Eisai) in May 2006 triggered a milestone payment from MGI PHARMA to SuperGen. In addition, SuperGen will earn a royalty on worldwide net sales starting at 20% and escalating to a maximum of 30% 3.
In July 2006, MGI PHARMA executed an agreement to sublicense decitabine to Janssen-Cilag, a Johnson & Johnson company, granting exclusive development and commercialisation rights in all territories outside North America. MGI retains all commercialisation rights and responsibility for all activities in the US, Canada and Mexico. Janssen-Cilag made an up-front and milestone payments to MGI, which it shared (50%) with SuperGen pursuant to the September 2004 licence agreement. Further, Janssen-Cilag is to pay MGI funds for research and development, and royalties from net sales in the areas licensed to Janssen-Cilag 4 5.
In September 2004, SuperGen executed a definitive agreement granting MGI Pharma exclusive worldwide rights to the development, manufacture, commercialization and distribution of decitabine.
【Key Development Milestones】
Myelodysplastic syndromes (MDS): decitabine injection (three-day dosing regimen) was launched in the USA for the treatment MDS in May 2006. It is indicated for previously treated and untreated MDS, de novo and secondary MDS of all French-American-British subtypes (refractory anaemia, refractory anaemia with ringed sideroblasts, refractory anaemia with excess blasts, refractory anaemia with excess blasts in transformation, and chronic myelomonocytic leukaemia) and intermediate-1, intermediate-2, and high-risk International Prognostic Scoring System groups 6.
DN 101
(Asentar™; Calcitriol - Novacea)Novacea Discontinued-III Vitamin D3 stimulants Myelodysplastic syndromes 【メモ】Novacea discontinued the development of DN 101, an oral, intermittent, high-dose formulation of calcitriol (the biologically active form of vitamin D) designed to enhance the efficiency of cytotoxic agents used for cancer therapy. Many tumour types contain vitamin D receptors and calcitriol is the most potent natural ligand or agonist of the calcitriol receptor (also known as the vitamin D3 receptor). Therefore, DN 101 induces arrest of cancer cell cycle at the G0/G1 phase and promotes apoptosis to ultimately inhibit proliferation of tumour cells. Clinical evaluation of DN 101 was underway in a variety of cancer types, including androgen-independent prostate cancer (AIPC) and non-small cell lung cancer. However, due to an imbalance of deaths in the DN 101-containing treatment arm in the phase III ASCENT-2 trial, the FDA placed a clinical hold on the IND for DN 101. The trial ended and enrolment in all ongoing and planned trials in all indications was suspended pending further analysis. Based on a response submitted by a Novacea, the FDA released the clinical hold on DN 0101 in September 2008, but required that any future clinical studies of DN 101 must include in the consent form an unambiguous statement of reduced survival in the ASCENT-2 trial and that any future consent form must not make reference to any survival benefits observed in earlier clinical trials involving DN 101 for the treatment of AIPC patients. However, Novacea has no plans to develop DN 101 further 1 2.
The company intended to initially seek approval for DN 101 in combination with docetaxel.
Novacea has entered into a definitive merger agreement with Transcept Pharmaceuticals, Inc. Closing of the transaction is subject to customary conditions, including obtaining the requisite shareholder approvals of both companies 1.
Schering-Plough terminated its licensing agreement for DN 101 in April 2008. All rights regarding DN 101 have been returned to Novacea. Previously, in May 2007, Schering-Plough Corporation entered into an worldwide licensing agreement with Novacea for the development and commericalisation of DN 101.
Erlotinib
(CP 358774; NSC 718781; OSI 774; R1415; RG 1415; RG1415; Tarceva®)OSI Pharmaceuticals[Originator]/Roche(Licensee World ) Phase-III
Phase-III
Phase-II
Phase-IIEpidermal growth factor receptor antagonists; Glutathione transferase inhibitors 【適応追加】Colorectal cancer
Liver cancer
Myelodysplastic syndromes
NeutropeniaNSCL,膵臓癌で発売 【メモ】Erlotinib is a once-a-day, orally active inhibitor of the epidermal growth factor receptor (EGFR) tyrosine kinase. This small molecule compound is one of a class of anticancer drugs that target the underlying molecular mechanisms involving oncogenes and tumour suppressor genes that play critical roles in the conversion of normal cells into a cancerous state. Erlotinib is being developed as an oral tablet by an alliance of companies, namely OSI Oncology (the cancer division of OSI Pharmaceuticals, which is now a subsidiary of Astellas), Genentech and Roche. The drug is widely launched in over 80 countries worldwide for the treatment of non-small cell lung cancer, and is launched in the US and EU and approved in Japan for the treatment of pancreatic cancer. Clinical development is proceeding in a range of cancers, including glioma and colorectal, head and neck, liver, squamous-cell skin, bladder and breast cancers, and cancer metastases. In June 2010, OSI Pharmaceuticals became a subsidiary of Astellas 1. Myelodysplastic syndromes (MDS): a phase II clinical trial was reinitiated in September 2010 at the H. Lee Moffitt Cancer Centre and Research Institute evaluating erlotinib in the treatment of MDS following suspension for an interim analysis (NCT00977548). The open-label trial completed enrolment of 35 patients in the US in February 2011 60. A phase I/II trial of erlotinib in 35 patients with higher-risk myelodysplastic syndromes is underway in France (NCT01085838). French researchers have conducted some preclinical investigations into the utility of using erlotinib as a treatment for haematological malignancies. The drug induced apoptosis in cancerous cells from patients with myelodysplastic syndromes and acute myeloid leukaemia, but exhibited no toxicity towards healthy bone marrow tissue 61. Ezatiostat
(Ezatiostat HCl; Ezatiostat hydrochloride; Telintra®; TLK 199; TLK-199; TLK199)Telik Phase-II Glutathione transferase inhibitors Myelodysplastic syndromes 【メモ】Ezatiostat is a glutathione S-transferase isozyme-specific inhibitor. Similar inhibitors exhibit beneficial effects on bone marrow biology. The in vivo effect of ezatiostat is similar to that of granulocyte colony-stimulating factor (G-CSF). Clinical data to date suggest that ezatiostat may act at a point in the bone marrow differentiation cycle that affects the subsequent development of all three major blood elements (white and red blood cells and platelets). Telik is conducting clinical trials of an oral (tablet) formulation for the treatment of myelodysplastic syndromes and severe chronic idiopathic neutropenia in the US. Telik is also conducting research programme on ezatiostat analogs to identify potential follow-on candidates [see separate profile] 1.
Telik, which owns the worldwide commercial rights to ezatiostat, intends to eventually seek a multinational partner to assist in completing clinical development of the agent.
【Company Agreements】 Telik reported, in its Form 10-Q (filed 7 May 2009), that clinical quantities of the active ingredient in its formulations of ezatiostat were sourced from a single supplier, Isochem, and the manufacture of ezatiostat tablets was being performed by Patheon.
【Key Development Milestones】
【 Oral formulation】
Myelodysplastic syndromes (MDS): in June 2011, Telik initiated a phase II trial of oral ezatiostat in patients with lenalidomide refractory or resistant, low to intermediate-1 risk, deletion 5q MDS. Ezatiostat will be administered for 21 days followed by a one week rest period in four week cycles. The primary outcome measure is the haematologic improvement-erythroid response rate as measured by transfusion reduction or independence. The trial will enrol 117 patients 2 3.In May 2008, Telik initiated a randomised, open label, dose comparing, parallel, phase II trial of ezatiostat in patients with low to intermediate-1 risk MDS (NCT00700206). The trial has completed enrolment of 87 patients in the US. Positive results from this trial were reported in June 2010 4 5 6 7. In June 2010, a case report published in the Journal of Hematology & Oncology described a patient in this trial who experienced a sustained haematologic response for over a year in all three blood cell lines, following an abbreviated course of oral ezatiostat 8.
A phase I/IIa, dose-ranging study of ezatiostat oral tablets in patients with MDS has been completed in the US (NCT00280631). The non-randomised, open-label trial evaluated the safety and efficacy of the formulation in this patient population. Telik believes the oral formulation may permit evaluation in additional haematological conditions characterised by low levels of more than one of the three blood cell lineages 9.
In January 2010, Telik initiated an open-label, multicenter phase I trial (NCT01062152) to evaluate the safety, tolerability and the maximum tolerated dose of ezatiostat tablets (in escalating doses) in combination with lenalidomide in patients with non-deletion (5q-) low to intermediate-1 risk MDS 10. The trial completed its recruitment of approximately 30 patients in August 2011 11.
Positive results from a phase I, dose-escalation study of ezatiostat oral tablets in 45 patients with MDS have been published. The study evaluated the safety, pharmacokinetics and preliminary efficacy of the tablet formulation of ezatiostat 12 13.
Severe chronic idiopathic neutropenia (SCIN): a phase II study began in April 2009, to determine the effect of ezatiostat in patients with SCIN (NCT00909584) 6 14. Approximately 20 patients are to be enrolled.
Chemotherapy-induced neutropenia: Ezatiostat was being investigated in a randomised phase II clinical trial in cancer patients at risk of chemotherapy-induced neutropenia (NCT00701870). The trial recruited 135 patients with non-small cell lung cancer who were treated with standard front-line combination chemotherapy 7. However, Telik discontinued this trial to focus resources on the development of ezatiostat tablets in MDS and haematological malignancies.
【IV formulation】
Myelodysplastic syndromes (MDS): phase II development of IV ezatiostat in patients with myelodysplastic syndrome (MDS) was completed. Results from a phase I/II, dose-escalation study supported further clinical development of the agent in MDS as well as in other haematological indications characterised by decreased blood cell production or chemotherapy-induced bone marrow suppression. The study evaluated the maximum tolerated dose and dose-limiting toxicities of the drug in patients with MDS 15 16 17 18. However, no further information has been published on the development of this formulation, therefore it is assumed to be discontinued.Financing information: Telik was awarded a Qualifying Therapeutic Discovery Project grant totalling $US1,222,396 under the Patient Protection and Affordable Care Act of 2010 (PPACA), to support the development of five projects, including this programme 19.
【Patent Information】 On 5 October 2000, Telik announced that it had been awarded a European Patent (EP 720 620) for "Glutathione Analogs and Paralog Panels Comprising Glutathione Mimics", covering ezatiostat. Compound patents for ezatiostat in the US and other territories will expire in 2014.
【Pharmacokinetics】
Clinical studies: in 45 patients in the phase I dose-escalation study of ezatiostat tablets, the drug was administered at ten dose levels taken daily for 7 days followed by two weeks of follow-up. The treatment was planned for up to six months (eights cycles) until MDS progression or unacceptable toxicity. In 39 patients evaluable for efficacy, there were dose-dependent increases in blood concentrations of the active metabolite of ezatiostat observed 12 13.
Preclinical studies: ezatiostat had tAA values of < 1 min and approximately 15 min in rodents and monkeys, respectively. The short tAA limits the intracellular drug concentrations that can be achieved, indicating that an improved formulation is required for efficacy 20.
【Adverse Events】
Oral (tablet) formulation Myelodysplastic syndromes (MDS)
Phase II: pooled data of 87 patients involved in a phase II study of ezatiostat tablets in patients with low to intermediate-1 risk myelodysplastic syndrome (MDS) have shown that the most common non-haematological adverse events (AEs) were Grade 1 and 2 gastrointestinal AEs, such as nausea (45% and 17%, respectively), diarrhoea (26% and 7%, respectively) and vomiting (30% and 12%, respectively). Grade 3 AEs were uncommon: nausea (1%), diarrhoea (3%) and vomiting (2%). Prior treatment with DNA methyltransferase inhibitors (DMTIs) was associated with an increased incidence of gastrointestinal AEs. Eighty-seven such patients were randomised; 11 drug-related serious adverse events occurred, but resolved without sequelae. After initial dose ranging in 14 patients, two dose levels were selected for further study: ezatiostat 3 g/day for 2 weeks followed by a 1-week rest period (n = 37), and ezatiostat 2 g/day for 3 weeks followed by a 1-week rest period (n = 36). Patients had received a median of three prior MDS therapies, including 34 patients (47%) with prior lenalidomide, and 28 patients (38%) with prior DNA methyltransferase inhibitors (DMTI) including azacitidine and decitabine 21 4.Phase I: in a phase I (NCT00280631) dose escalation study of 45 patients with MDS, oral ezatiostat tablets were generally well tolerated, with nausea (n = 25), diarrhoea (16) and vomiting (11) being the most common. Ezatiostat was administered once daily for one week prior to a 2-week washout period at ten dose levels (200, 400, 1000, 1400, 2000, 2400, 3000, 4000, 5000 and 6000mg). Throughout the study there were three cases of grade 4 anaemia (at doses of ezatiostat >3000mg). No grade 1, 2 or 3 haematological related adverse reactions were recorded 5 12.
Ezatiostat treatment was well tolerated at doses of 50-400 mg/m2 among 14 MDS patients in a dose escalation phase I/IIa trial. The drug was administered as a 60-minute IV infusion every day for 5 days every two weeks; the median number of such treatment cycles per patient was three. The most common adverse events were mild (grade 1- 2), including nausea (n = 3), headache (2), hypersensitivity reaction (2), vomiting (2), chest pain (2), back pain (1) and diarrhoea (1). Grade 3 bone pain (2), hypotension (1), nausea (1) and grade 4 interstitial pneumonia (1) were also reported. Use of 5@� inkｿline filters to eliminate liposomal aggregation led to a significant decrease in drugkｿrelated adverse events 17 22. Further interim results of the phase I/IIa trial in 25 MDS patients demonstrated that ezatiostat was well tolerated at doses of 50-600 mg/m2. Grade 4 back pain occurred in one patient. However the most common adverse events were mild (grade 1-2) and were flushing (6 patients), rigors (4), headache (3), nausea (3), pain in extremity (3), vomiting (2), and back pain (2) 23.
In 45 patients in the phase I dose-escalation study of ezatiostat tablets, the drug was administered at ten dose levels taken daily for 7 days followed by two weeks of follow-up. The treatment was planned for up to six months (eights cycles) until MDS progression or unacceptable toxicity. In 39 patients evaluable for efficacy, the drug was well tolerated with no dose-limiting toxicities observed. The most frequently reported adverse events were grade 1 and 2 nausea, diarrhoea and vomiting 12 13.
IV formulation
Animal toxicology: in animal studies, ezatiostat caused local irritation and/or necrosis when administered IV and injection site adhesions when administered IP or SC. These events may be a result of micro-crystal formation. Thrombi, possibly caused by localised vascular damage, were observed in the heart and lungs of some animals after IV administration of ezatiostat. When administered in combination with chemotherapy drugs, ezatiostat increased mortality by approximately 15%, relative to chemotherapy-only controls 20.【Pharmacodynamics】
Cancer Ezatiostat (50 @ol/L) enhanced the cytotoxicity of doxorubicin, daunorubicin, etoposide, vincristine and mitoxantrone in multidrug-resistant NIH3T3/MRP cells by factors of 1.3-7.4. It did not enhance the cytotoxicity of fluorouracil 24. Ezatiostat selectively inhibited glutathione S-transferase (GST) isozyme P1-1 at concentrations of < 0.5 @ol/L. Activity against isozymes M1, M2 and A1 was approximately 50-fold lower 20.
Haematological Disorders Ezatiostat (150 mg/kg PO) increased the number of CFU-GM/femur by > 200% in mice. In rats, TLK 199 (60-120 mg/kg IP) daily for 9 days after fluorouracil 150 mg/kg, significantly increased peripheral neutrophil and platelet numbers. Enhanced colony formation of human bone marrow cells was achieved with ezatiostat (0.1-10 @ol/L), compared with cytokine treatment 25.
【Therapeutic Trials】
Oral (tablet) formulation
Cancer Myelodysplastic syndromes (MDS)
Phase II: pooled data of 87 patients involved in a phase II study of ezatiostat tablets in patients with low to intermediate-1 risk, non-deletion 5q MDS have shown that the overall Hematologic Improvement - Erythroid (HI-E) rate was 22% (13 or 60 evaluable patients). Eighty-seven such patients were randomised. After initial dose ranging in 14 patients, two dose levels were selected for further study: ezatiostat 3 g/day for 2 weeks followed by a 1-week rest period (n = 37), and ezatiostat 2 g/day for 3 weeks followed by a 1-week rest period (n = 36). Patients had received a median of three prior MDS therapies, including 34 patients (47%) with prior lenalidomide, and 28 patients (38%) with prior DNA methyltransferase inhibitors (DMTI) including azacitadine and decitabine. At the time of this preliminary analysis, 8 patients remain on treatment for continuing clinical benefit. The median duration of HI-E response was 46 weeks (range 2-51 weeks). One patient continues in remission for >12 months following discontinuation of ezatiostat. Three cytogenetic complete responses were observed, including one in a patient with 45X,-Y[4], 46, XY [16] abnormal cytogenetics that converted to normal after 4 cycles of therapy. Of the four patients enrolled in the study with del 5q minus MDS, two had a complete cytogenetic response, including one who had failed prior lenalidomide therapy. Furthermore, ezatiostat continues to result in multilineage haematological improvements, as seen by a 15% Hematologic Improvement - Neutrophil (HI-N) rate in 3/20 patients, and a bilineage rate (i.e. HI-E + HI-N) of 11% in 2/19 patients. Results from a planned logistic regression analysis was used to evaluate all known prognostic characteristics in order to define patients who have an increased likelihood of HI-E response to ezatiostat. Prior treatment with DMTIs predicted a 5-fold decrease in the odds for a HI-E response to ezatiostat (p=0.023). Also, prior lenalidomide was shown to enhance HI-E response to ezatiostat 21 4.Phase I: in a phase I (NCT00280631), dose-escalation study of ezatiostat tablets in 45 patients with MDS, the drug was administered at ten dose levels (200, 400, 1000, 1400, 2000, 2400, 3000, 4000, 5000 and 6000mg) taken daily for 7 days followed by two weeks of follow-up. The treatment was planned for up to six months (eights cycles) until MDS progression or unacceptable toxicity. In 39 patients evaluable for efficacy, there were dose-dependent responses observed with majority occurring in patients receiving the higher dose levels. Neutrophil (HI-N) responses were observed in 21% (4/19) of patients with neutrophil cytopenias, platelet (HI-P) responses in 33% (7/21) of patients with platelet cytopenias, and erythroid (HI-E) responses in 21% (6/29) of patients with erythroid cytopenias. In this study, one patient had a complete cytogenetic response, one patient achieved platelet transfusion independence, and some patients achieved reduction in transfusion requirements or red blood cell transfusion independence 5 12 13.
IV formulation
Myelodysplastic syndromes (MDS)
Interim data from a dose escalation phase I/IIa study of IV ezatiostat showed that 9/16 (56%) evaluable MDS patients had clinically significant improvement in at least one of the three blood cell lineages (red cells, white cells, platelets). 3/9 such patients had improvement in all three cell lineages and bone marrow response, while 2/9 experienced improvement in two cell lineages. Three of these responding patients had reduced requirements for blood support. 5/16 (31%) patients had objective response as defined as Hematologic Improvement (HI) by MDS response criteria. Durability of response in both white blood cells and red blood cells in the longest observed cohort exceeds 4 months. All patients showed an increase in blood colony forming units measured in blood and bone marrow after ezatiostat administration. There was no evidence of stimulation of CD34 expressing cells. The drug was administered as a 60-minute IV infusion every day for 5 days every two weeks; the median number of such treatment cycles per patient was three 17 22 16.Further data from the phase I/IIa study demonstrated that of the 26 patients evaluable for efficacy 61.5% (16/26) had significant improvement in one or more blood cell lineages (red cells, white cells or platelets). Significant improvement has also been observed in all blood cell lineages and across all major MDS FAB subtypes (RA, RAEB, RAEB-t and RARS). Using IWG (International Working Group) MDS response criteria, haematologic improvement for neutrophils, platelets and erythrocyes was observed in 47% (8/17) of patients with white cell dysfunction, 35% (6/17) patients with platelet dysfunction and 33% (8/24) of patients with red blood cell dysfunction, respectively. Trilineage improvement was observed in 25% (3/12), and bilineage improvement in 21% (4/19) of patients, meeting IWG MDS objective response criteria for overall HI. Clinical responses were associated with decreased support requirements for red blood cells, platelets and growth factor and in some cases led to transfusion independence. Examination of bone marrow showed improvements in maturation, differentiation, M/E ratios and a decrease in dysplastic morphology 23 18.
Imatinib
(CGP 57148; CGP 57148B; CTI 571; CTI1571; Gleevec®; Glivec®; Imatinib mesylate; QTI 571; QTI571; STI 571; STI571)Novartis Marketed Bcr-abl tyrosine kinase inhibitors, Platelet-derived growth factor inhibitors, Platelet-derived growth factor receptor antagonists, Signal transduction pathway inhibitors 【適応追加】Myelodysplastic syndromes ALL,CML等で発売 【メモ】Novartis has developed imatinib, a Bcr-Abl protein tyrosine kinase inhibitor, that has been launched in various countries for the treatment of chronic myeloid leukaemia (CML), gastrointestinal stromal tumours, acute lymphoblastic leukaemia (ALL), dermatofibrosarcoma, eosinophilia, myelodysplastic syndromes and systemic mastocytosis. Imatinib selectively inhibits proliferation and induced apoptosis in Bcr-Abl positive cell lines, and in Philadelphia chromosome-positive CML and ALL cells. The agent is also an inhibitor of the tyrosine kinase receptors for platelet-derived growth factor (PDGF), stem cell factor (SCF) and c-Kit (or CD117). As such, imatinib inhibits proliferation and induces apoptosis in gastrointestinal stromal tumours which express an activating Kit mutation. Additionally, activation of the PDGF receptor or the Abl protein kinases has been implicated in the pathogenesis of myelodysplastic syndromes, eosinophilia and dermatofibrosarcoma. Imatinib inhibits signalling and proliferation of cells driven by abnormal activity of PDGF receptors and Abl kinase. Novartis markets imatinib as Glivec®film-coated tablets (100 and 400mg) or hard capsules (50 and 100mg). Novartis is also conducting clinical trials of imatinib for various other indications, including prostate cancer, pulmonary hypertension, acute myeloid leukaemia, polycythaemia vera, malignant melanoma, sarcoma, aggressive fibromatosis and scleroderma.
Myelodysplastic disorders: Novartis submitted marketing applications in the EU and the US for myelodysplastic syndrome/myeloproliferative diseases (MDS/MPD) in 2005. Approval was granted during 2006 17 18 1 16.
INNO 305 CytRx Corporation(Licensee)/Memorial Sloan-Kettering Cancer Center(originator) Phase-I Immunostimulants, Lyn protein-tyrosine kinase inhibitors Myelodysplastic syndromes
Acute myeloid leukaemia【メモ】INNO 305 is a peptide vaccine based on Wilms' tumor gene (WT1), being develped by CytRx Corporation as an immunotherapeutic for the treatment of cancer. WT1 is expressed at high levels not only in most types of leukemia but also in various types of solid tumors, including lung and breast cancer. INNO 305 is a heteroclitic peptide, that is able to stimulate both CD8 and CD4 T cells. The company believes that because of the ability of this peptide to activate both T cell subsets, it may be able to stimulate a more robust and ubiquitous immune response than WT1 peptides that stimulate only one subset of T cells. INNO 305 is in phase I clinical trials in the US. INNOVIVE Pharmaceuticals originally licensed the worldwide rights to INNO 305 from the Memorial Sloan-Kettering Cancer Center in the US. However, the company was acquired and merged into CytRx Corporation in September 2008 1.
【Key Development Milestones】 INNOVIVE Pharmaceuticals (now CytRx Corporation) initiated a phase I clinical trial of INNO 305 in October 2006. The trial is being conducted at the Memorial Sloan-Kettering Cancer Center in the US and is enrolling patients with acute myeloid leukaemia (AML), myelodysplastic syndromes (MDS), non-small cell lung cancer (NSCLC) and mesothelioma. The open label, fixed dose trial will evaluate the safety, tolerability, pharmacokinetics and preliminary efficacy of INNO 305. Preliminary results have been reported 2 3.
JNJ 26481585 Johnson & Johnson Pharmaceutical Research & Development Phase-I Histone deacetylase inhibitors Myelodysplastic syndromes
Leukaemia (Refractory metastatic disease)
Lymphoma (Refractory metastatic disease)【メモ】Johnson & Johnson Pharmaceutical Research and Development is developing JNJ 26481585, a second-generation pan-histone deacetylase (HDAC) inhibitor, for the oral treatment of cancer, particularly solid tumours and haematological malignancies. JNJ 26481585 is a broad spectrum hydroxamic acid derivative that interferes with expression of genes that control cancer cell proliferation, angiogenesis and metastasis. In preclinical animal models, no evidence of cardiac toxicity has been observed, suggesting a better therapeutic index for JNJ 26481585 compared with other HDAC inhibitors. Two phase I trials of JNJ 26481585 are underway in the UK and US, respectively. 【Key Development Milestones】 A phase II trial evaluating JNJ 26481585 in patients with previously treated stage Ib-IVa cutaneous T-cell lymphoma is being planned (NCT01389960). This open-label study will involve approximately 46 patients and will be conducted in the US 1.
A phase I trial was initiated by Johnson & Johnson in January 2009 to evaluate the maximum tolerated dose, pharmacokinetic properties and antitumour activity of JNJ 26481585 in patients with advanced or refractory leukaemia or myelodysplastic syndrome (NCT00676728). Oral capsules are administered once-daily in a continuous regimen with 21-day treatment cycles. The dose of JNJ 26481585 starts low and is increased in groups of two to six patients. Enrolment of 10 patients was completed in the US in June 2011 2.
Johnson & Johnson commenced an initial phase I trial of JNJ 26481585 in 50 patients with advanced or refractory solid tumours or lymphoma in August 2007 (NCT00677105). In addition to assessing the maximum tolerated dose, this trial will also determine how JNJ 26481585 and its metabolite, JNJ 26395018, are absorbed, broken down and eliminated after oral administration. The trial is being conducted in the UK in collaboration with Janssen Pharmaceutica NV, a Johnson & Johnson company.
Pharmacodynamic studies of numerous pyrimidyl-hydroxamic acid analogues resulted in the identification of JNJ 26481585 as a lead candidate from Johnson & Johnson's HDAC inhibitor programme. In contrast to R 306465, the company's first-generation HDAC inhibitor, JNJ 26481585 induced continuous (rather than transient) histone H3 acetylation in vivo, resulting in complete inhibition of tumour growth [see separate profile for R 306465]. Additionally, JNJ 26481585 has shown anti-tumour activity as a single agent in various preclinical models 3 4.
KW 2449 Kyowa Pharmaceutical Discontinued-I/II Aurora kinase inhibitors, Bcr-abl tyrosine kinase inhibitors, Fms-like tyrosine kinase 3 inhibitors Myelodysplastic syndromes
Acute myeloid leukaemia
Chronic myeloid leukaemia【メモ】Kyowa Hakko Kirin Pharma Inc. (a US subsidiary of Kyowa Hakko Kirin Co) is developing KW 2449, an orally administered multi-kinase inhibitor, for the treatment of cancer. The kinases inhibited by the drug include FMS-like tyrosine kinase 3 (FLT3), which is expressed in patients with acute myeloid leukaemia, Aurora kinases and Bcr-Abl tyrosine kinase. The target indications for KW 2449 include haematologic malignancies and solid tumours. KW 2449 was being investigated in a phase I/II trial in patients with acute myelogenous leukaemias (AML) in the US. However, the agent was listed as discontinued on the company's pipeline of 28 July 2010 based on portfolio re-assessment. Laromustine
(101M; Cloretazine®; Onrigin™; VNP 4010M; VNP40101M)Vion Pharmaceuticals(Licensee)/Yale University(originator) Suspended(I/II) Alkylating agents Myelodysplastic syndromes Acute myeloid leukaemiaで申請取下 【メモ】Laromustine is a small molecule sulfonyl hydrazine prodrug (SHP) that was being developed by Vion Pharmaceuticals for the treatment of cancer. It is one of a family of SHP alkylating agents which Vion licensed from Yale University. After entering the bloodstream, laromustine releases 90CE (1,2-bis[methylsulfonyl]-1-[2-chloroethyl]hydrazine), which subsequently chloroethylates the O6 position of guanine residues, ultimately resulting in DNA cross-linkage. Laromustine was the first candidate from this family of agents to enter clinical development for a variety of haematological malignancies such as acute myeloid leukaemia, and solid tumours including glioma. Laromustine had been filed for regulatory approval in the treatment of elderly patients with AML in the US. A complete response letter was received from the FDA, confirming that a new phase III trial would be required. Vion subsequently decided to file for bankruptcy and will seek to sell or merge the company and/or its key assets. In animal models it has shown broad antitumour activity against leukaemia, melanoma and lung and colon carcinomas. Laromustine appears to have good penetration across the blood-brain barrier and has activity against tumour cells resistant to standard alkylating agents.
【Company Agreements】 In December 2009, Vion filed a voluntary petition for relief, under Chapter 11 of the United States Bankruptcy Code, in the District of Delaware United States Bankruptcy Court. In February 2010, Vion filed a 'Chapter 11 Plan of Liquidation' and a related 'disclosure statement'. A hearing for the disclosure statement was scheduled for 1 March 2010, and a hearing for the Plan of Liquidation has been scheduled for 6 April 2010. Assuming Court approval, Vion anticipates that it will no longer be a reporting company under the amended Securities Exchange Act of 1934 1.
A manufacturing agreement between Vion and Ben Venue Laboratories was signed in December 2006 granting Ben Venue the rights to manufacture laromustine as the finished drug product 2.
Vion Pharmaceuticals extended its agreement with SAFC Pharma (a member of the Sigma-Aldrich Group) for the manufacture of the active pharmaceutical ingredient in laromustine. The amended contract extends the original supply agreement to 2009 3.
Lenalidomide
(CC 5013; CC-5013; CDC 5013; ENMD 0997; IMiD3; Revlimid®)Celgene Corporation Marketed Angiogenesis inhibitors, Immunomodulators, Interleukin 1 beta inhibitors, Interleukin 10 stimulants, Tumour necrosis factor inhibitors Myelodysplastic syndromes
Multiple myeloma【メモ】Lenalidomide is an immunomodulatory drug (IMiD®) and a structural analogue of thalidomide that has been designed and synthesised by Celgene. Lenalidomide is Celgene's lead IMiD® and is undergoing development as an anti-angiogenic, anticancer agent. The exact mechanisms of action of IMiDs® have not been fully elucidated but they are known inhibitors of tumour necrosis factor-α and interleukin-1β, and stimulate the anti-inflammatory cytokine interleukin-10. Lenalidomide is launched in the US, Canada and Japan, it has also been approved in Latin America, Malaysia, and Israel as a treatment for patients with myelodysplastic syndromes (MDS) associated with a deletion 5q cytogenetic abnormality. The compound is also launched in the US, UK, Germany, Switzerland, and France, and is approved in over 50 other countries including Canada and Latin America, in combination with dexamethasone, as a second-line treatment for multiple myeloma (MM). Lenalidomide is available in Australia, New Zealand and Japan, in combination with dexamethasone, for the treatment of patients with MM whose disease has progressed after one therapy. Clinical development is underway in multiple indications. Lintuzumab
(Anti-CD33 MAb; HuM 195; HuM195; SGN 33; SGN-33)PDL BioPharma Discontinued-II Cytokine synthesis inhibitors, Immunostimulants Myelodysplastic syndromes
Acute myeloid leukaemia【メモ】Seattle Genetics was developing lintuzumab, a humanised IgG1 antibody that targets CD33, for the treatment of cancer. Lintuzumab was licensed from PDL BioPharma (formerly Protein Design Labs & Eos) in April 2005. The two companies had been collaborating on the development of unconjugated and conjugated antibodies linked to synthetic, highly potent drugs. Intravenously administered lintuzumab was undergoing clinical development, as both a monotherapy and combination therapy, for acute myeloid leukaemia (AML) and myelodysplastic syndromes in the US. However, a phase IIb trial of lintuzumab in patients with AML did not meet its primary endpoint of extending overall survival and as a result of this, the company decided to discontinue development of lintuzumab in September 2010. Lintuzumab-gelonin conjugate
(Anti-CD-33 Immunotoxin Hum-195/rGel; Anti-CD33 monoclonal antibody M195-gelonin conjugate; Gelonin-lintuzumab conjugate; Hum-195/rGel; HuM195/rGel; Monoclonal antibody M195-gelonin conjugate)Targa Therapeutics Corporation(Licensee)/University of Texas M. D. Anderson Cancer Center(originator) Phase-I CD33 antigen inhibitors Myelodysplastic syndromes
Acute myeloid leukaemia
Chronic myeloid leukaemia【メモ】Lintuzumab-gelonin conjugate is an immunotoxin that recognises the CD33 antigen, being developed by Targa Therapeutics for the treatment of acute myeloid leukaemia (AML), chronic myeloid leukaemia (CML) and myelodysplastic syndromes (MDS). The CD33 antigen is expressed on the cell surface of more than 80% of leukaemia isolates from patients with myeloid leukaemia. Gelonin is an N-glycosidase that cleaves adenine from mammalian ribosomal RNA thereby ablating protein synthesis and resulting in cell death. A recombinant, de-glycosylated version of gelonin (rGel) has been expressed in bacteria and is biologically equipotent to the natural substance. It can be chemically conjugated or genetically fused to many targeting moieties, such as antibodies or growth factors, which become internalised into the cells to which they bind. Targa Therapeutics has initiated phase I clinical trials of lintuzumab-gelonin, in collaboration with the M.D. Anderson Cancer Centre in the US. Additionally, the company is also developing the conjugate for ex vivo purging of CD33-expressing leukaemic cells from peripheral blood stem cells prior to use in autologous transplantation. Lonafarnib
(MK 6336; MK-6336; Sarasar™; SCH 066336; SCH 66336)Schering-Plough Discontinued(III)I Farnesyl transferase inhibitors Myelodysplastic syndromes 【メモ】Lonafarnib (Sarasar™) is an orally active farnesyl transferase inhibitor that acts on cancer cells with mutated Ras proteins. Lonafarnib inhibits growth of tumour cells, but is not cytotoxic. Schering-Plough (now Merck & Co) is conducting clinical trials of lonafarnib in a capsule formulation for the treatment of progeria and various types of cancer. Myelodysplastic syndromes and chronic myelomonocytic leukaemia (CMML): a phase III trial (P02978; NCT00109538) of lonafarnib in the treatment of myelodysplastic syndromes and CMML was discontinued in the US, in October 2008.
In November 2009, Schering-Plough combined with Merck & Co. under the name Merck 1.
LOR 2040
(GTI 2040; GTI-2040)Lorus Therapeutics Phase-II DNA synthesis inhibitors, Ribonucleotide reductase inhibitors Myelodysplastic syndromes
Acute myeloid leukaemia
Breast cancer
Colorectal cancer
Prostate cancer
Renal cancer
Non-small cell lung cancer【メモ】LOR 2040, a 20-mer phosphorothioate oligonucleotide, targets the R2 component of the enzyme ribonucleotide reductase. It is the lead drug candidate in a series of antisense compounds being developed by GeneSense Technologies (a wholly owned subsidiary of Lorus Therapeutics). Ribonucleotide reductase is made up of two dimeric proteins called R1 and R2. It is required to catalyse a rate-limiting step in DNA synthesis, the reduction of ribonucleoside diphosphates to deoxyribonucleotides. While Lorus has developed LOR 2040 to target R2, it has also developed another agent GTI 2501 to target R1 [see separate profile]. LOR 2040 is in clinical development for acute myeloid leukaemia, myelodysplastic syndromes and solid tumours and in preclinical development for bladder cancer. Lorus Therapeutics is seeking co-development and commercialisation partners for LOR 2040 in the US, Europe and the rest of the world
MG 98
(HYB 101584; MG-98)MGI Pharma(Licensee)/MethylGene(originator) Discontinued-II DNA methylation inhibitors Myelodysplastic syndromes
Head and neck cancer
Renal cancer
Acute myeloid leukaemia【メモ】MG 98 is a second generation antisense oligonucleotide that selectively targets DNA methyltransferase 1 (DNMT1) mRNA. DNMT controls DNA methylation in the regulation of gene expression; however, in cancer, DNMT causes the hypermethylation of tumour suppressor genes thereby switching them off. By inhibiting the production of DNMT, the methylation of DNA is reversed and leads to re-expression of the tumour suppression genes. MG 98 was created by MethylGene Inc. who had out-licensed the North American development and commercialisation rights to MGI PHARMA (Eisai). It was undergoing phase II development in a variety of cancers. However, in March 2008 it was absent from MethylGene's pipeline therefore it is assumed that development has been discontinued. Another research programme is being developed by MGI Pharma and MethylGene that investigates small molecule inhibitors of DNMT, which have complementary activity to MG 98. Preclinical studies have shown that MG 98 combined with small molecule DNMT inhibitors have demonstrated synergistic activity [see separate profile for Research programme: DNA methyltransferase inhibitors - MGI Pharma].
ML 04 Milkhaus Laboratory Discontinued-II Undefined mechanism Myelodysplastic syndromes
Benign prostatic hyperplasia
Prostatitis【メモ】ML 04 [HP 4], a patented oral form of human chorionic gonadotropin (hCG), is under development with Milkhaus Laboratory in the USA for the treatment of benign prostatic hyperplasia (BPH) and prostatitis. ML 04 is believed to regulate genes affecting apoptosis and cell regulatory proteins, which restore control of cell growth. ML 04 is available for licensing.
It was in phase II clinical trials, however, its development apparently has been discontinued.Mocetinostat
(MG-0103; MGCD 0103; MGCD0103)Taiho Pharmaceutical(Licensee)/MethylGene(originator) Discontinued(II) Histone deacetylase inhibitors Myelodysplastic syndromes 【メモ】MethylGene is developing mocetinostat an orally administered, small-molecule histone deacetylase (HDAC) inhibitor, which is in clinical trials as a treatment for cancer. Mocetinostat is a non-hydroxymate compound that targets HDAC isoforms 1, 2, 3 and 11 in vivo. HDACs are responsible for the deacetylation of nuclear histones, and inhibition of HDAC results in a decreased interaction between chromatin and the acetylated histone tails. This results in the activation of a set of pre-programmed genes which leads to cell differentiation and/or apoptosis. Mocetinostat has demonstrated a broad spectrum of anticancer activity against many cancer types including prostate, breast, lung, colon and pancreatic human xenografts. Mocetinostat has also exhibited synergistic activity with other chemotherapeutics and may have potential in combination therapy. Mocetinostat is undergoing clinical trials for the treatment of solid tumours, lymphomas and haematological malignancies. In September 2009, the partial clinical hold on clinical trials evaluating mocetinostat was lifted following suspension by the FDA in August 2008 due to a suspected increased risk of serious pericardial adverse events. 【Company Agreements】 MethylGene and Pharmion Corporation (now Celgene) signed a license and collaboration agreement for the research, development and commercialisation of HDAC inhibitors, including mocetinostat, in January 2006. However, in October 2008, Celgene terminated its licensing agreement with MethylGene for HDAC inhibitors, including mocetinostat 1 2.
In October 2003, MethylGene entered into a licence and research collaboration with Taiho Pharmaceutical for the HDAC inhibitor programme, including mocetinostat. Taiho will provide MethylGene with research funding support for eight scientists for a minimum of two years as well as fund preclinical and clinical development costs in North America for an HDAC inhibitor in cancer. Under the terms of the agreement, MethylGene will receive an upfront licence fee, equity investment and research payment of $US3.75 million. In addition, MethylGene may attain milestone payments based on successful development, regulatory approval, and commercialisation of an HDAC oncology product, totaling up to $US16.25 million. MethylGene will receive royalties based on sales of an HDAC oncology product in Japan, Korea, Taiwan, and China. Taiho is responsible for development of the HDAC oncology product in their territories. MethylGene retains commercialisation rights in the rest of the world 3.
Obatoclax
(CEP-41601; CEP41601; GX 15-070; GX15-070; GX15-070MS; Obatoclax mesylate)Gemin X Biotechnologies/Cephalon(親会社) Discontinued(II) Apoptosis stimulants, Autophagy stimulants, Proto-oncogene protein c-bcl-2 inhibitors Myelodysplastic syndromes 【メモ】Cephalon is developing obatoclax, a small-molecule pan inhibitor of the Bcl-2 protein family, as a treatment for a wide range of haematological and solid tumours. Obatoclax induces apoptosis in cancer cells without damaging normal cells by inhibiting members of the Bcl-2 protein family. When overexpressed in cancer cells, Bcl-2 proteins arrest apoptosis by blocking Bax and Bak, two key elements of the cell-death pathway. The overexpression of Bcl-2 proteins has been observed in a wide range of cancers, including those of the lymph, breast, lung, prostate and colon. In vitro data indicated that obatoclax possesses a dual mechanism of action to induce both apoptosis (programmed) and autophagy-dependent (controlled) cancer cell death. Intravenous obatoclax is in phase II clinical development for the first-line treatment of small cell lung cancer, in combination with carboplatin and etoposide. Cephalon took over the development of obatoclax after Gemin X became its wholly-owned subsidiary in April 2011.
Gemin X completed phase II trials of obatoclax in myelofibrosis and myelodysplastic syndromes, and the drug was granted orphan drug status in the US for the treatment of both indications 10 11. However, it appears that the company has discontinued development in these indications.
Omacetaxine mepesuccinate
(CGX 635; CGX-635; CXS 635; CXS-635; HHT; Homoharringtonine; NCI 141633; Omapro™)ChemGenex Pharmaceuticals Preregistration
Phase-IIApoptosis stimulants, Cyclin D inhibitors, MCL1 protein inhibitors, Protein synthesis inhibitors, Proto-oncogene protein c-myc modulators Chronic myeloid leukaemia
Myelodysplastic syndromes【メモ】 Omacetaxine mepesuccinate is the first in the family of cetaxine drugs. The drug candidate is a small molecule alkaloid derived from the Chinese evergreen tree, Cephalotaxus harringtonia. The agent induces apoptosis by inhibition of protein synthesis, particularly Mcl-1, cyclin-D1 and c-Myc. It is being developed by Chemgenex and Stragen for the treatment of chronic and acute myeloid leukaemia (CML and AML), solid tumours, myelodysplastic syndrome (MDS) and other haematological malignancies. Omacetaxine mepesuccinate acts independently of tyrosine kinase inhibitors (TKIs), and may therefore have a therapeutic advantage for patients who have developed resistance to TKIs. Omacetaxine mepesuccinate was initially filed for approval in the US and EU as a single-agent treatment for patients with CML who have the T315I point mutation. However, ChemGenex later decided to seek approval for to treatment of adults with CML who have failed treated with at least two tyrosine kinase inhibitors regardless of mutation status. The drug has also been investigated in clinical studies for other leukaemias including AML and MDS. The natural extract of omacetaxine mepesuccinate was originally undergoing clinical evaluation by researchers at the US National Cancer Institute (NCI).
【Company Agreements】 ChemGenex and Cephalon signed a convertible note subscription agreement in October 2010. Cephalon will provide up to $A15 million to ChemGenex in return for a note that is convertible. ChemGenex operations will be supported by this funding, including clinical activities to complete a NDA submission to the US FDA for omacetaxine for the treatment of patients with CML who have failed two or more tyrosine kinase inhibitors. Cephalon also entered into two option agreements with two of ChemGenex's major shareholders, under which Cephalon has the right to acquire up to 19.9% of ChemGenex's outstanding shares 1.
In December 2009, ChemGenex granted Hospira an exclusive license to develop and commercialise omacetaxine mepesuccinate in Europe, the Middle East and parts of Africa. Under the terms of the agreement, Hospira will make an initial payment of l�11.1 million, with the potential for up to an additional l�74.1 million, in development and commercialisation milestone payments. Upon commercialisation, Hospira will pay ChemGenex a royalty on sales in those territories. ChemGenex will complete registration of the product in its initial indication (chronic myeloid leukaemia) with the EMEA, while Hospira and ChemGenex will collaborate to explore future applications in various haematological malignancies. Hospira will be responsible for commercialising the product in the licensed territories 2.
In June 2008, Stragen Pharma transferred the ownership of intellectual property and commercial rights relating to omacetaxine mepesuccinate, to ChemGenex, giving ChemGenex full control of the compound. The new agreement will remove the need for an IP royalty on manufacturing and will significantly reduce the cost of goods. Similarly, the new agreement removes the need for a European joint venture, allowing ChemGenex to control European development and access all profits from sales of omacetaxine in Europe, including compassionate use sales of the drug. Stragen will remain ChemGenex's supplier of omacetaxine, and will become a significant shareholder 3 4.
In June 2004, AGT Biosciences merged with ChemGenex Therapeutics to form ChemGenex Pharmaceuticals.
Myelodysplastic syndromes (MDS): ChemGenex is conducting a phase II open-label study (CGX-635-MDS-201) to evaluate the efficacy and safety of IV omacetaxine mepesuccinate as a treatment for patients with MDS. This study is being conducted in collaboration with the University of Texas M. D. Anderson Cancer Centre.
Orphan drug designation was granted to omacetaxine mepesuccinate for the treatment of MDS in January 2009 25.
Oxaliplatin
(1 OHP; 1670 RB; Dacotin®; Dacplat®; Eloxatin®; Elplat®; L OHP; NSC 266046; Oxalatoplatin; Oxalatoplatinum; PR 54780; RP 54780; SR 96669)/Nagoya University(originator) Phase-I/II DNA cross linking agents, DNA synthesis inhibitors 【適応追加】Myelodysplastic syndromes 大腸癌で発売 【メモ】Oxaliplatin is a non-nephrotoxic third generation platinum complex that acts as a DNA cross linking agent and as a DNA synthesis inhibitor. Its antitumour effectiveness is similar to that of cisplatin and it causes minimal haematological toxicity. The drug has been launched in over 60 countries as an infusion formulation for the treatment of colorectal cancer. An injectable formulation of the compound has also been launched in the US for the treatment of colorectal cancer. In addition, phase II and phase III trials of the drug are proceeding in various other cancer indications. Several generic equivalents were available in the US for colorectal cancer 1. The companies had rights to market the generic equivalents until 30 June 2010. Activities for some companies will resume on 9 August 2012.
【Company Agreements】
Oxaliplatin was discovered in 1976 by researchers at Nagoya University in Japan and was subsequently acquired by Debiopharm in 1989. In 1996, Debiopharm licensed oxaliplatin to Sanofi Winthrop (now sanofi-aventis) worldwide, excluding Japan, India, Argentina, Paraguay and Uruguay. Sanofi Winthrop's parent company, Sanofi merged with SynthAmlabo to form Sanofi-SynthAmlabo; in August 2004, Sanofi-SynthAmlabo merged with Aventis to form sanofi-aventis.
Debiopharm has a patent and know-how agreement for oxaliplatin with sanofi-aventis that is set to expire in the year 2016. The terms of this agreement allow both companies to share development costs on improvements to the existing formulations of oxaliplatin as well as new indications and new methods of use. Debiopharm is entitled to royalties on sales of oxaliplatin in the markets for which sanofi-aventis has rights.
Oxaliplatin has been licensed to Pfizer in Argentina, Uruguay and Paraguay. In India, the compound is licensed to Dr Reddy's Laboratories.
Oxaliplatin has been licensed to Yakult Honsha for colorectal cancer in Japan. In August 2004, Yakult Honsha announced it had signed an agreement with Taiho Pharmaceutical to co-promote oxalitplatin but this agreement was revoked in April 2005 2 3.
In April 1999, Sanofi and Eli Lilly announced that they had formed a joint venture to develop and market oxaliplatin for colorectal cancer in the US. In October 2000, Sanofi-Synthelabo purchased Eli Lilly's share of Sanofi Lilly Oncology and thereby recovered full rights to oxaliplatin in the US. Sanofi-aventis (formerly Sanofi-SynthAmlabo) and Eli Lilly will continue their collaboration for development of oxaliplatin in Europe.
【Key Development Milestones】
Acute myeloid leukaemia and myelodysplastic syndromes: in June 2011, a non-randomised, open-label phase I/II trial of oxaliplatin in combination with fludarabine and cytarabine was terminated due to lack of support by sanofi-aventis (NCT00480987). The non-randomised, single-group, open-label study had enrolled 27 patients in the US with acute myeloid leukaemia or high-risk myelodysplastic syndromes. The aim of the study was to determine the highest tolerable dose of oxaliplatin combined with fludarabine plus cytarabine that can be administered to patients 14.
Panobinostat
(DACi - Novartis; LBH 589; LBH589; LBH589A; LBH589B; NVP-LBH-589; NVP-LBH589)Novartis Phase-III
Phase-IIHistone deacetylase inhibitors Multiple myeloma
Myelodysplastic syndromes【メモ】Novartis is developing oral and intravenous formulations of panobinostat, a histone deacetylase inhibitor (HDAC inhibitor), for the treatment of cancer. HDACs have important roles in maintaining chromatin structure and in regulating gene expression, particularly that of tumour suppressor genes, and thus represent valid targets in the search for cancer therapeutics. Both oral and intravenous formulations of panobinostat are in various stages of clinical development for a range of haematological and solid tumours. In its pipeline dated January 2011, Novartis indicated that it plans to file for approval of panobinostat for the treatment of multiple myeloma in 2013 and for haematological tumours on or after 2015 1.
Myelodysplastic syndromes: Novartis is conducting phase II trials of panobinostat in patients with myelodysplastic syndromes (NCT01034657, NCT00946647) in the US and Germany. An additional phase II trial in this indication was restarted in May 2011 following suspension in July 2010 due to the outcomes of an interim analysis of the data (NCT00594230).
Rigosertib
(Estybon™; ON 01910; ON 01910.Na; ON-01910; ON-01910.Na)Onconova Therapeutics Phase-III 1 Phosphatidylinositol 3 kinase inhibitors, Angiogenesis inhibitors, Apoptosis stimulants, Polo-like kinase 1 inhibitors, Proto oncogene protein c-akt inhibitors Myelodysplastic syndromes 日本はシンバイオが導入 【メモ】Onconova Therapeutics is developing rigosertib, a small molecule, non-ATP competitive Polo-like kinase 1 (Plk1) inhibitor and proto-oncogene protein c-akt inhibitor that attacks key checkpoints of the cell cycle, and inhibits angiogenic activity. A phase III trial of an intravenous formulation is underway in the treatment of myelodysplastic syndromes (MDS). This formulation is also in phase II/III development for pancreatic cancer, and phase II development for acute myeloid leukaemia, chronic lymphocytic leukaemia, lymphoma, ovarian cancer and solid tumours. An oral formulation is in phase I trials in the treatment of MDS and solid tumours. Onconova Therapeutics has stated that the lead indication for rigosertib is MDS. Rigosertib is a benzyl styryl sulfone that simultaneously attacks tumour cells in the G1/S and mitotic phases, when cell division occurs, and induces cellular apoptosis. Normal cells are arrested at the G1 checkpoint and are therefore prevented from entering the S and M phases where the compound causes toxicity. These cells resume the normal cell cycle after drug levels decline by normal clearance from the body. Rigosertib has demonstrated potent antiangiogenic effects in preclinical studies, without harming the normal growth of endothelial cells and formation of new blood vessels.
Onconova Therapeutics believes that rigosertib will be most useful in combination regimens, as it lacks haematological, neurological or serious gastrointestinal toxicities. The company has claimed that rigosertib combines well with five different classes of cancer therapeutics, including taxanes, topoisomerase inhibitors, DNA-directed drugs, signal transduction modulators and receptor antagonists.
In July 2011, Onconova granted SymBio Pharmaceuticals an exclusive license to develop and market rigosertib for the treatment of MDS in Japan and Korea. Under the terms of the agreement, Onconova will receive an upfront payment in addition to development and marketing milestones plus sales royalties 1.
Myelodysplastic syndrome (MDS): in November 2010, Onconova initiated a randomised, open-label phase III trial to assess the efficacy and safety of intravenous rigosertib plus best supportive care in MDS patients with excess blasts who have failed azacitidine or decitabine treatment (ONTIME; NCT01241500). The control group will receive best supportive care only. Enrolment is underway in the US and Europe. The trial is being conducted under a Special Protocol Assessment, in collaboration with the Leukaemia and Lymphoma Society in the US, which is contributing funding. Onconova anticipates FDA approval for single-agent rigosertib in high-risk MDS in 2012 1 2 3 4.
In September 2009, rigosertib was granted orphan drug designation by the US FDA for the treatment of MDS.
A phase II clinical trial is taking place with rigosertib (48-hour continuous intravenous infusion) in the US in patients with MDS (NCT00906334). The trial enrolled approximately 14 patients with trisomy 8 or classified as intermediate-2 or high-risk who were not responding to current therapy. The single-arm trial is expected to be completed in September 2011 5.
Patient enrolment has been also completed in a phase II trial investigating the efficacy of rigosertib in patients with medium to high-risk MDS and trisomy 8 (NCT01326377). The trial enrolled 14 patients in the US 6.
Romiplostim
(AMG 531; AMG-531; Nplate®; Romiplate®)Kirin-Amgen Discontinued(II) Thrombopoietin receptor agonists 【適応追加】Myelodysplastic syndromes Immune thrombocytopenic purpuraで発売 【メモ】Romiplostim is a thrombopoietin receptor agonist that was developed by Kirin-Amgen, a joint venture company. Romiplostim is launched in the US and Japan, approved in the EU, Australia, Canada and Russia, and is awaiting approval in Switzerland, South Korea, Singapore, Hong Kong and Malaysia for the treatment of chronic immune thrombocytopenic purpura (ITP) in adults. Phase II trials with romiplostim in chemotherapy-induced thrombocytopenia are ongoing in the US. Amgen discontinued phase II development of romiplostim for the treatment of myelodysplastic syndromes in the US and Europe in April 2011 1. Romiplostim is an engineered Fc-peptide fusion protein (termed as peptibody) that binds and activates the thrombopoietin (TPO) receptor (Mpl), a mechanism analogous to endogenous TPO. Stimulation of the TPO receptor is necessary for growth and maturation of bone marrow cells, and plays an important role in sustaining platelet counts. Unlike most current treatments for chronic ITP, which prevent platelet destruction, romiplostim works by actually increasing platelet production.
Myelodysplastic syndromes (MDS): Amgen discontinued development of romiplostim for the treatment of MDS in April 2011 1.
Rubitecan
(-NC; 9-Nitro-20(S)-camptothecin; 9-Nitro-camptothecin; 9-Nitrocamptothecin; Partaject Orathecin; Partaject rubitecan; RFS 2000; RFS2000)SuperGen(Licensee)/The Stehlin Foundation for Cancer Research(originator) Discontinued-III DNA topoisomerase I inhibitors Pancreatic cancer
Myelodysplastic syndromes【メモ】Rubitecan is a topoisomerase I inhibitor extracted from the bark and leaves of the Camptotheca acuminata tree which is native to China. Rubitecan is an oral compound that was being developed for the treatment of pancreatic cancer and other solid tumours by SuperGen. One of the major benefits of rubitecan is that is can be administered in an outpatient setting, so patients can be treated in their homes.
Rubitecan was isolated by the Stehlin Foundation in the US. SuperGen is no longer actively developing the drug.At the BIO-2004 conference, SuperGen announced it was seeking a partner for rubitecan for territories outside the US.
【Company Agreements】
SuperGen acquired exclusive worldwide rights to rubitecan from the Stehlin Foundation in 1997 except in Mexico, Canada, Spain, Japan, the UK, France, Italy and Germany. SuperGen also received approval from the FDA to use its own-manufactured rubitecan in clinical trials.
In December 1999, SuperGen and Abbott signed a worldwide sales and marketing agreement for rubitecan. Under the terms of the agreement, Abbott had exclusive distribution and promotion rights for rubitecan outside the US, and co-promotion rights with SuperGen within the US. In return, Abbott made an initial equity investment in SuperGen. SuperGen and Abbott Laboratories ended their collaboration agreement in February 2002 by mutual consent with SuperGen stating that the dissolution of the agreement was based on commercial motivation rather than anything to do with rubitecan's safety or efficacy. Abbott no longer has rights or obligations to purchase shares of SuperGen stock or an option to purchase up to 49% of the company. For its part, SuperGen will no longer receive milestone payments worth up to $US57 million.
【Key Development Milestones】
Phase II studies are also underway in haematological malignancies including myelodysplastic syndrome (preleukaemia) and chronic myelomonocytic leukaemia.
Sapacitabine
(CS 682; CS682; CYC 682; CYC682)Daiichi Sankyo Company(originator)/Cyclacel Pharmaceuticals(Licensee World) Phase-III
Phase-IIDNA-directed DNA polymerase inhibitors Acute myeloid leukaemia
Myelodysplastic syndromes【メモ】Sapacitabine is an orally available, small-molecule nucleoside analogue of 2'-cyano-2'-deoxyarabinofuranosylcytosine (CNDAC) that is being developed by Cyclacel for the treatment of solid and haematological tumours. The compound was originally developed by researchers at Sankyo (later Daiichi Sankyo), Kanazawa University and Hokkaido University in Japan. Sapacitabine appears to have a dual mechanism of action: it interferes with DNA synthesis by causing single strand breaks and induces cell cycle arrest at the G2 phase. The compound may have potential in tumours with a low cytidine deaminase to deoxycytidine kinase ratio, and preclinical data also suggests that sapacitabine is complementary to and potentially synergistic with CYC 202 [see separate profile]. Clinical trials of sapacitabine capsules in the treatment of acute myeloid leukaemia, myelodysplastic syndromes and non-small cell lung cancer are underway in the US. The product was also being investigated for the treatment of cutaneous T-cell lymphoma. However, no recent development has been reported.
Sapacitabine is a palmitoyl derivative of CNDAC. According to Cyclacel, the presence of the fatty acid group reduces inactivation of the nucleoside analogue by deamination 1. CNDAC is the major metabolite of sapacitabine and induces DNA damage that is repaired by the homologous recombination pathway. Patients with cancers that have defects in the homologous recombination pathway (such as triple negative breast cancer, ovarian cancer or B-cell chronic lymphocytic leukaemia) may therefore benefit from treatment with sapacitabine as monotherapy or in combination with agents interfering with DNA repair or agents that target components of the homologous recombination pathway such as poly(ADP-ribose) polymerase (PARP) or ataxia telangiectasia mutated protein (ATM) 2.
【Company Agreements】
Cyclacel Limited (a wholly-owned subsidiary of Cyclacel Pharmaceuticals) and Daiichi-Sankyo have amended their original September 2003 exclusive licensing agreement relating to sapacitabine. Pursuant to this amendment (effective since 11 July 2011), Daiichi Sankyo irrevocably waived a termination right requiring Cyclacel to obtain regulatory approval to market sapacitabine in at least one country by September 2011, and has released Cyclacel from all claims and liabilities arising under such a provision. In addition, royalties due to Daiichi Sankyo on future net sales of sapacitabine have been increased by a percentage of 1.25 -1.50% depending on the level of net sales of sapacitabine. Under the original agreement, Cyclacel was granted exclusive rights to sapacitabine in nearly all world territories. Sankyo received an upfront payment and was entitled to receive milestones and royalties. In addition, Sankyo retained a right for first negotiation to market the compound in Japan 3 4 5 6.
Daiichi Pharmaceutical merged with Sankyo to form Daiichi Sankyo Inc. in April 2006 7.
【Key Development Milestones】
Acute myeloid leukaemia (AML): in January 2011, Cyclacel Pharmaceuticals initiated the phase III SEAMLESS trial of sapacitabine oral capsules as a front-line treatment for elderly patients with newly diagnosed acute myeloid leukaemia (AML) who are not candidates for intensive induction chemotherapy (NCT01303796). The two-part study has completed enrolment for the lead-in stage of the trial, which preceeds the randomised portion of the study. The second part of the study will commence pending the decision of the Drug Safety Monitoring Board's review of the lead-in data. The study is being conducted under a Special Protocol Assessment (SPA) agreement that Cyclacel reached with the US FDA in September 2010. The study will compare sapacitabine, administered in alternating cycles with decitabine, with either agent alone. The primary endpoint is overall survival. The trial will enrol 470 patients in the US 8 9 10 11.
Cyclacel initiated a phase I/II trial of sapacitabine in elderly patients with newly diagnosed AML in September 2010. This open-label study will evaluate the efficacy of sapacitabine administered in combination with decitabine in approximately 40 patients (NCT01211457) 12. Interim results have been reported 13.
Myelodysplastic syndromes (MDS): Cyclacel plans to initiate discussions with the FDA regarding potential registration pathways in MDS patients refractory to hypomethylating agents 10 14.
Cyclacel has designed a phase II trial (CYC682-06; NCT00590187) to evaluate the one-year survival rate of three dosing schedules of sapacitabine in elderly patients with AML who are previously untreated or in first relapse, in the US. Secondary objectives are to determine the number of complete responses or complete responses without blood count recovery, duration of response, transfusion requirements, number of hospitalised days, and safety. In September 2008, Cyclacel amended the protocol to include a cohort of 60 MDS patients who have been previously treated with hypomethylating agents; this was based on encouraging safety and efficacy data from AML patients. In order to confirm the tolerability of two of the sapacitabine dosing schedules, 45 more patients with acute myeloid leukaemia (AML) were also enrolled in early 2009. A total of 105 AML patients and 60 MDS patients have been recruited. Results have been reported 15 16 17 18.
In July 2009, Cyclacel raised $US5.9 million to support the clinical development of sapacitabine in haematological malignancies 19.
Sapacitabine received orphan drug status from the EMEA in May 2008 for the treatment of AML and MDS 20. The US FDA granted orphan drug designation to sapacitabine for the treatment of both AML and MDS in July 2010 21.
A phase I trial (CYC682-05-04; NCT00380653) of sapacitabine in patients with relapsed and refractory acute myelogenous leukaemia (AML) or myelodysplastic syndromes has been completed in the US. The aim of the trial was to determine the maximum tolerable dose of the drug. Patients received sapacitabine twice daily for seven days every 21 days, or three days per week for two weeks every 21 days. Final study results have been released. The trial has determined the recommended phase II dose at 325mg twice-daily 22 23 24 25.
Cutaneous T-cell lymphoma (CTCL): a phase II trial (CYC682-06-05; NCT00476554) of sapacitabine in patients with advanced cutaneous T-cell lymphoma began in the US in May 2007. The primary objective of the study is to evaluate tolerability and response rate of 50mg and 100mg regimens (both twice a day for three days per week for two weeks in a three week cycle) in approximately 32 patients with progressive, recurrent, or persistent CTCL on or following two systemic therapies. Secondary objectives are to assess response duration, time to response, time to progression and relief of pruritus or itching. Interim results from this trial showed that both regimens were well tolerated, with no grade 2 toxicities, therefore, the protocol is being amended to increase dosing to 100mg and 200mg, respectively, using the same schedule as that used previously 26 27. However, the trial was terminated in October 2009 due to slow accrual and financial resource limitation.
Non-small cell lung cancer (NSCLC): in January 2009, Cyclacel initiated a phase II study of sapacitabine in patients with NSCLC, in the US (CYC682-08; NCT00885963). The open-label, single arm, multicenter trial will enrol 60 patients who have had one prior chemotherapy. The primary objective will be to evaluate the rates of response and stable disease, and secondary objectives are to assess safety, progression-free survival, duration of response, duration of stable disease, one year survival and overall survival. The trial will begin with a lead-in phase for dose escalation, during which a recommended dose will be determined for the second stage. This trial builds on the observation of stable disease of nﾝ4 months experienced by heavily pretreated patients with NSCLC who participated in two phase I trials of sapacitabine 28 3 29.
Solid tumours: during the second quarter of 2009, Cyclacel initiated a phase I clinical trial of sapacitabine in combination with seliciclib, another compound developed by Cyclacel, in patients with advanced cancers 30 31.
Cyclacel completed two phase I trials of sapacitabine, including a phase I monotherapy study in patients with advanced solid tumours. Promising interim results were presented 32.
Sankyo previously conducted two phase I trials of sapacitabine in 88 patients with solid tumours in the US, and then suspended development, according to a statement in its 2002 annual report.
【Patent Information】
Cyclacel has filed patent applications claiming polymorphic forms of sapacitabine and methods for its preparation and use as well as related know-how and materials. Issued patents for sapacitabine cover the US, EU, Japan, and 20 other countries and expire between 2012 and 2014. The issued patents for polymorphic forms cover the US, EU, Japan and six other countries, with patents pending in a further seven countries; these expire in 2022.
SB 939 S*BIO[シンガポール] Phase-II Histone deacetylase inhibitors Myelodysplastic syndromes
Acute myeloid leukaemia【メモ】S*BIO, a privately held biotech company based in Singapore, is developing SB 939, an orally active, small molecule, hydroxamic-acid based inhibitor of the enzyme histone deacetylase (HDAC), for the treatment of solid tumours and haematological malignancies. HDACs play a crucial role in the regulation of pro-apoptotic factors and proteins involved in cell cycle progression and differentiation. SB 939 is believed to have potential to bring more therapeutic benefits than other HDAC inhibitors being developed worldwide, due to its high potency, superior oral availability, and good tolerability. Phase I combination trials of SB 939 in patients with advanced solid tumours, haematological malignancies and myelodysplastic syndrome are underway in the US and Singapore. Phase II trials in recurrent or metastatic sarcoma and in recurrent or metastatic prostate cancer are underway in Canada. SB 939 is phase II development for the treatment of myelofibrosis in the US. S*BIO is interested in collaborative and licensing opportunities for SB 939.
Myelodysplastic syndrome: S*BIO reported in its pipeline in October 2010 that a phase II trial of SB 939 had been initiated in myelodysplastic syndrome. Additionally, the company reported on its website that phase II trials began in 2007.
SGI 110 Astex Pharmaceuticals[旧SuperGen] Phase-I/II DNA methylation inhibitors Myelodysplastic syndromes
Acute myeloid leukaemia【メモ】Astex Pharmaceuticals (formerly SuperGen) is developing SGI 110, a small molecule DNA methyltransferase 1 (DNMT1) inhibitor for the treatment of haematological cancers, including myelodysplastic syndromes (MDS) and acute myeloid leukaemia (AML), and solid tumours. DNA methyltransferase enzymes silence unnecessary genes. However, this machinery can be taken over during the process of tumourigenesis, resulting in hypermethylation and the inactivation of tumour suppressor genes. SuperGen has used its proprietary CLIMB process to develop a small molecule inhibitor of DNMT1 that can reverse this hypermethylation process. SGI 110 is in phase I/II development in the US. SGI 110 is a dinucleotide containing decitabine (5-aza-2'-deoxycytidine) with superior activity to the parent compound due to increased stability. Decitabine is a potent DNA methylation inhibitor which is approved in the US for the treatment of myelodysplastic syndromes. However, decitabine is vulnerable to degradation by hydrolytic cleavage and deamination.
SGI 110 emerged as a clinical candidate from SuperGen's programme for DNA methylation inhibitors. Another DNMT1 inhibitor (SGI 1036) was in preclinical development for the treatment of AML, but appears to be superseded by SGI 101.
SuperGen was renamed as Astex Pharmaceuticals in September 2011.
SL 401
(DT388IL3; DTIL3)Texas A&M University(Originator)/Stemline Therapeutics(Licensee) Phase-I/II Interleukin 3 receptor antagonists Myelodysplastic syndromes
Acute myeloid leukaemia【メモ】SL 401 is a recombinant fusion protein being developed by Stemline Therapeutics as a treatment for leukaemia, including acute myeloid leukemia (AML) and chronic myeloid leukaemia (CML). The agent consists of the first 388 amino acid residues of diphtheria toxin (DT388) fused to human interleukin-3 (IL-3). SL 401 targets the IL-3 receptor which is overexpressed on multiple haematological cancer cells, including leukaemia and leukaemia cancer stem cells. SL 401 is under phase I/II development for AML and myelodysplastic syndromes (MDS) in the US and Canada; preclinical studies are underway for tyrosine kinase inhibitor-resistant CML in the US. Stemline Therapeutics in-licensed the exclusive worldwide rights to SL 401, in March 2007, from the Scott & White Cancer Research Institute/Texas A&M Health Science Center College of Medicine 1. SL 401 was called DT388IL3 before it was in-licensed to Stemline.
Sorafenib
(BAY 43-9006; BAY 439006; BAY43-9006; Nexavar®)Onyx Pharmaceuticals(originator)/Bayer(Licensee) Phase-I/II Angiogenesis inhibitors, Fms-like tyrosine kinase 3 inhibitors, Mitogen-activated protein kinase inhibitors, Platelet-derived growth factor beta receptor antagonists, Proto oncogene protein c ret inhibitors, Proto oncogene protein c-kit inhibitors, Raf kinase inhibitors, Vascular endothelial growth factor receptor 3 antagonists, Vascular endothelial growth factor receptor-2 antagonists 【適応追加】Myelodysplastic syndromes 腎癌、肝臓癌で発売 【メモ】Sorafenib is an orally administered, small-molecule compound that inhibits tumour cell growth and proliferation and tumour angiogenesis. It is being developed by Onyx Pharmaceuticals and Bayer Corporation as a treatment for a variety of cancers. Sorafenib has been approved as Nexavar®in more than 90 countries for the treatment of patients with hepatocellular carcinoma and in more than 95 countries for the treatment of patients with advanced renal cell carcinoma. In addition, sorafenib is in clinical development for the treatment of a variety of other cancers, including multiple myeloma, gastric, non-small cell lung, ovarian, breast, prostate and colorectal cancers. Multiple intracellular kinases, including C-Raf and B-Raf, are blocked by sorafenib; this leads to inhibition of the Raf/MEK/Map kinase signalling cascade (this cascade ultimately triggers cell proliferation). Sorafenib also inhibits cell-surface kinases such as c-kit, FLT-3, VEGFR-2, VEGFR-3, PDGFR-Ac, and c-ret, several of which are thought to be involved in tumour angiogenesis. In addition, the drug has shown radiosensitising effects in multiple cancer cell lines and preclinical data have indicated that modulation of the MAPK/ERK pathway increases apoptosis induced by radiation in a prostate cancer cell line 1.
Sorafenib is the lead compound from a collaboration between Onyx and Bayer to discover and identify compounds that target the Ras/Raf/MEK/Map kinase pathway. Mutations of proteins in this pathway have been found to contribute to a large portion of all human cancers.
Acute myeloid leukaemia (AML): Bayer is conducting a phase II clinical trial to evaluate the efficacy of sorafenib in combination with standard chemotherapy in patients between 18 and 60 yeaars of age (NCT00893373). This trial will enrol approximately 276 subjects from Germany, and is being conducted in collaboration with the University Hospital Carl Gustav Carus in Dresden. Additionally, a phase I/II study is being conducted by Bayer and the M.D. Anderson Cancer Centre, to assess sorafenib in combination with idarubicin and cytarabine for the treatment of AML and myelodysplastic syndromes (NCT00542971).
Talmapimod
(SCIO-469)Scios Preclinical P38 mitogen-activated protein kinase inhibitors Myelodysplastic syndromes 【メモ】Myelodysplastic syndromes: in March 2005, Scios initiated a randomised, open-label, modified dose-ascension phase I/II trial (NCT00744432) of talmapimod in the treatment of myelodysplastic syndromes. The study was completed in 2007, and no recent development has been reported. Treosulfan
(CB 2562; CB 40067; CCRIS 2781; Dihydroxybusulphan; HSDB 6963; NSC 39069; Ovastat®)Medac Phase-III Alkylating agents 【適応追加】Myelodysplastic syndromes 卵巣癌で発売 【メモ】Treosulfan is a bifunctional alkylating cytostatic with a broad anti-tumour spectrum and high activity in vitro and in vivo. Intravenous and oral formulations of treosulfan were launched by Medac in Germany in 1992 and 1982, respectively, as a therapy for ovarian cancer. Treosulfan was since launched in the UK, Denmark and the Netherlands for the treatment of ovarian cancer, in oral and intravenous formulations. Intravenous treosulfan has been launched in Russia, Ukraine and Belarus for the treatment of ovarian cancer. Treosulfan is in phase III development for the treatment of malignant melanoma, and in phase II development as a conditioning agent in patients with haematological cancers undergoing haematopoietic stem cell transplantation. AltaRex had a North American licensing option for treosulfan, which it declined in April 1998 due to the company becoming highly focused on immunotherapy.
In collaboration with the OHSU Knight Cancer Institute and the National Cancer Institute, Medac conducted a phase II trial (NCT00253513) of a reduced-intensity conditioning regimen of intravenous treosulfan and fludarabine prior to allogeneic haematopoietic stem cell transplantation in patients with acute myeloid leukemia, acute lymphoblastic leukemia or myelodysplastic syndromes. The open-label, uncontrolled trial enrolled 62 patients in the US and was completed in October 2009.
In October 2009, Medac completed an open-label, uncontrolled phase II trial (NCT01062490) to evaluate the safety and efficacy of intravenous treosulfan-based conditioning prior to allogeneic haematopoietic stem cell transplantation in patients with myelodysplastic syndromes. Treosulfan was administered in combination with fludarabine in 45 patients in Finland.
UCN 01 Kyowa Hakko Discontinued-II 3 phosphoinositide dependent protein kinase 1 inhibitors, Checkpoint kinase 1 inhibitors, Phosphotransferase inhibitors, Protein kinase C inhibitors Myelodysplastic syndromes 【メモ】UCN 01 is a staurosporine analogue, originated by Kyowa Hakko Kogyo, and isolated from the culture broth of Streptomyces sp. The agent was in development with licensee Keryx Biopharmaceuticals as a treatment for cancer. UCN 01 disrupts the cell-cycle by inhibiting the transition from G1 to S phase causing apoptosis. It selectively inhibits protein kinase C and has the capacity to inhibit other kinases that are involved in cell-cycle progression and apoptosis, including checkpoint kinase 1 (Chk1), 3-phosphoinositide-dependent protein kinase (PDK1), and cyclin-dependent kinase 2 (CDK2). UCN 01 has demonstrated in vitro synergistic activity with agents that affect the PI3-K pathway, such as perifosine and mTOR inhibitors. Industry involvement in the programme has ceased, and R&D Insight is no longer tracking development of this agent. However, the US National Cancer Institute is conducting clinical trials of UCN 01 in the USA. The family of drugs called staurosporine analogs have demonstrated an ability to inhibit multiple kinases involved in cell-cycle progression and apoptosis, including Chk-1 (Checkpoint kinase 1 inhibitors) and PDK1 (3-phosphoinositide dependent protein kinase 1 inibitors).
Keryx Biopharmaceuticals terminated is licensing agreement with Kyowa Hakko Kogyo for UCN 01 in April 2008. The termination was part of a strategic restructuring plan by Keryx to reduces its cash burn rate, following poor results from a phase III trial of sulodexide [see separate profile for sulodexide] 1. The agreement was originally signed in September 2006, and granted Keryx Biopharmaceuticals an exclusive license to develop and commercialise UCN 01 on a worldwide basis, excluding in Japan. Keryx paid an upfront fee and will pay milestone payments and royalties on sales to Kyowa.
Vorinostat
(MK 0683; MK0683; SAHA; Suberanilohydroxamic acid; Suberoylanilide hydroxamic acid; Zolinza®; Zolinza™)Aton Pharma(Licensee)/Columbia University(originator), Phase-II Histone deacetylase inhibitors, T lymphocyte stimulants 【適応追加】Myelodysplastic syndromes 皮膚T細胞リンパ腫で発売(日、米) 【メモ】Vorinostat is a cyto-differentiating agent that was originated by Columbia University and the Memorial Sloan-Kettering Cancer Center as a cancer therapeutic. Vorinostat is a histone deacetylase (HDAC) inhibitor that has demonstrated potential for the treatment and prevention of cancer; it has been launched in the US and is approved in Canada and Japan for the treatment of cutaneous T cell lymphoma (CTCL). Clinical development in a number of other cancer indications, including non-small cell lung cancer (NSCLC), is ongoing. Columbia University and the Memorial Sloan-Kettering Cancer Center have exclusively licensed the patents to vorinostat to Aton Pharma (a subsidiary of Princeton Pharma Holdings) and hold an equity position in the company.
In October 2006, Princeton Pharma Holdings LLC acquired 100% of the outstanding stock of Aton Pharma Inc., a subsidiary of Merck & Co. Inc.
In June 2011, MSD K.K. and Taiho Pharmaceutical entered into a distribution agreement for vorinostat in CTCL in Japan. Taiho will promote and distribute the drug while MSD will be the marketing authorisation holder.
Myelodysplastic syndromes (MDS): Merck is conducting a phase II trial (NCT00486720) assessing the safety, tolerability, and efficacy of vorinostat in 80 patients with lower risk MDS. This trial is being conducted in the US.
Merck is conducting a phase I trial (NCT00479232) of vorinostat administered either concurrently or sequentially with decitabine in approximately 80 patients with newly-diagnosed acute myeloid leukaemia or myelodysplastic syndromes. This trial is being conducted in the US. Interim results have been reported 7.
In May 2006, a phase I study of vorinostat and idarubicin in patients with relapsed or refractory acute myeloid leukaemia (AML) or MDS was initiated. Patients were randomised to receive oral vorinostat three times daily on days 1-14 and IV idarubicin over 15 minutes once daily on days 1-3. Treatment was repeated every 21 days for 6 courses in the absence of disease progression or unacceptable toxicity. This study was run by the NCI and the M.D. Anderson Cancer Center; a total of 40 patients were to be accrued in the study. Later, in April 2008, development progressed to phase II (NCT00656617), with vorinostat, idarubicin and cytarabine administered to approximately 105 patients with AML and high-risk MDS. Merck & Co. and the M.D. Anderson Cancer Center are sponsoring the phase II trial.
Vorinostat is also being assessed in a phase I/II trial (NCT00776503) in combination with low dose cytarabine for the treatment of MDS in France.
WT 4869 Chugai Pharmaceutical/Dainippon Sumitomo Pharma Phase-I/II Immunostimulants Myelodysplastic syndromes 日本国内での開発 【メモ】Chugai Pharmaceutical and Dainippon Sumitomo Pharma are jointly developing WT 4869, a therapeutic peptide vaccine, for the treatment of myelodysplastic syndromes (MDS) and solid tumours. The companies intend to develop WT 4869 as a therapeutic vaccine targeting various tumour types. WT 4869 is based on the WT1 protein, which is a product of the Wilm's tumour gene 1 that is known to highly expressed in leukaemia and most solid tumours. It is expected that administration of WT 4869 will be efficacious in the treatment of leukaemia and other types of cancers that express WT1, by inducing WT1-specific cytotoxic T-lymphocytes that have the potential to attack tumour cells. WT 4869 is in clinical development in Japan. Chugai Pharmaceutical and Dainippon Sumitomo Pharma are jointly conducting a phase I/II clinical trial of WT 4869 in Japan in myelodysplastic syndromes 1 2. WT 4869 is also in phase I development in Japan for the treatment of solid tumours.
●解説
■骨髄異形成症候群[MDS]
●骨髄異形成症候群とは 血液の成分は、血漿と、身体のすみずみに酸素などを運ぶ赤血球や、細菌を殺す白血球や、出血を止める血小板などの血液細胞で構成されています。血液の細胞成分やそのもとになる細胞（造血幹細胞ないし血液前駆細胞）は骨髄で造られます。正常な状態では、造血支持組織の中で、幹細胞や前駆細胞が赤血球、白血球、血小板に成熟し、それぞれの働きと役割を担うことになります。
一般的に血液のがんは、血液の細胞成分やそのもとになる細胞が何らかの異常をきたし、一部の細胞だけが増えてしまったり、それにより他の細胞成分が増えることができなくなった状態です。その発症のメカニズムはまだ特定できていません。いろいろな原因が重なりあっておこると考えられています。
骨髄異形成症候群という病気も、細胞の中にある遺伝子や、それが乗っている染色体の異常であるということがわかってきています。この病気は血液の大もとの１個の幹細胞がわずかに異常をおこし、極めてゆっくりと身体の血液成分全体に異常がおきてくる状態と考えられます。その結果、骨髄が血液を造るという正常な働きをしなくなり、身体全体に正常な血液細胞を送り出せなくなるため、さまざまな身体の異常があらわれてきます。
骨髄異形成症候群は、以前から「前白血病状態」とか「くすぶり型白血病」と呼ばれたり、あるいは、治療に反応しにくい原因不明の貧血の一部として扱われてきました。この病気には、厳密には、いろいろな程度や状態があり、いくつかの病態が重なりあい、移行しつつあるものとして考えられています。
この病気は50歳以上の年齢及び高齢者に多く、我が国でも人口の高齢化とともに増加傾向にあると考えられています。しかし、この病気の数％は若年者にもおこります。抗がん剤などの薬物療法、あるいは放射線療法を受けた場合などには、二次性の骨髄異形成症候群がおこることもあります。また骨髄異形成症候群から、急性白血病になってしまう場合もあります。急性白血病については、「急性骨髄性白血病（成人）」の項を参照して下さい。
■診断
●症状 骨髄異形成症候群に特有の症状というものはありませんが、病気の種類と進行度にしたがって、疲れやすい、だるい、立ちくらみがするなどの貧血症状、皮膚に青あざが出るといった出血傾向、原因不明の発熱などの症状が出現します。これらは、身体の中の血液の不足や異常により引きおこされる病態なのですが、なかなか診断がつかないために、「白血球減少症」とか「汎血球減少症」などの暫定的な病名をつけられることもあります。
これらの症状を自覚したら、まずかかりつけの医師に相談し、必要ならば専門医師を受診すべきでしょう。
●診断 自覚症状や今までかかった病気の経歴に加えて、診断には一般的な血液検査や骨髄液検査が必要です。それら検査に基づいて以下の５つのタイプに分類されます。それによって治療法が異なります。
●検査所見に基づく診断
１）不応性貧血 貧血を主症状としますが、白血球減少、血小板減少を伴うこともあります。骨髄の中の未熟な芽球（悪性と考えられる細胞）は５％以下です。 ２）鉄芽球性貧血 不応性貧血とほぼ同じ特徴を示しますが、骨髄の中に環状の鉄分を含んだ未熟な赤芽球が認められるのが特徴です。１と２をあわせると、頻度は骨髄異形成症候群の中の30～40％を占めます。 ３）骨髄芽球の増加した不応性貧血 骨髄の中の未熟な芽球が５％以上、20％以下の状態です。典型的な血液及び骨髄の異形成像が認められます。この病態の頻度は20～30％です。 ４）骨髄芽球が悪性化し、かつ増加している不応性貧血 骨髄の中の未熟な芽球が20％以上、30％以下の状態です。末梢血にも未熟な芽球が出現しはじめます。頻度は同じく30～40％です。最近の考え方では、未熟な芽球が20％以上になると、すでに急性白血病へ移行したものとみなし、治療を開始します。 ●原因別診断
また、原因別に以下のように、一次性の骨髄異形成症候群と二次性のものに分けて考えられてもいます。
一次性の骨髄異形成症候群 発病の原因となる放射線療法も抗がん剤による化学療法も受けたことがなく原因が明らかでない場合 二次性の骨髄異形成症候群 他の疾病に対する放射線療法を受けたことが原因である場合、または抗がん剤による化学療法を受けたことが原因である場合
●病期（ステージ） 骨髄異形成症候群には、他の固形がんのような確定的な病期分類というのはありません。ただし、あえて分類するとすれば、診断の項目の１)不応性貧血と、３)骨髄芽球の増加した不応性貧血と４)骨髄芽球が悪性化し、かつ増加している不応性貧血は、段階的に進行することも多く、一応の病期分類と理解することができます。
■治療 治療方法には、症状に応じた対症的な治療と積極的な治療方法とがあります。年齢、健康状態によっても違ってきます。治療もその種類と進行度に応じて異なります。
１) 無治療、経過観察 不応性貧血の初期では、診断が確定してからも輸血をする必要もなく、無治療で経過観察のみでよい場合も少なくありません。 ２）赤血球輸血、血小板輸血 対症療法のひとつです。貧血が進行している場合、その症状改善のために赤血球輸血を行います。貧血の進行は病状の進行と無関係ではありません。通常、ヘモグロビン値が８g/dl以下になった場合、貧血による症状が出てきますので、輸血の適応と考えられます。血小板数が少なく、出血傾向のある場合には血小板輸血が必要です。血小板数が１万/μl以上であれば、出血症状のない限り血小板輸血は必要ありません。白血球減少症には無治療で経過をみますが、身体の抵抗力が弱って感染症を併発しやすくなります。 ３）化学療法及び細胞増殖因子などによる生物学的治療 これらについては有効性が証明されていないので、いくつかの臨床試験が行われています。 (1)化学療法 抗がん剤には、注射薬または内服薬があります。化学療法は、骨髄中のがん細胞を減らす目的で行われますが、白血球減少症、血小板減少症、脱毛、吐き気といった副作用もおこります。 (2)生物学的治療法、細胞増殖因子など 自分の身体の細胞をさらに刺激して、病気といっそう闘うようにしむける治療です。身体自体にすでに存在するものをさらに実験的につくりなおして改良し、薬として注射して病気に対する身体の防御力を高めたり、保ったりさせます。白血球を増やす薬物や赤血球、血小板を増やす薬剤が、骨髄異形成症候群に有効であるかどうか、現在さまざまの臨床研究が進められております。 ４）造血幹細胞移植 比較的発症年齢が若い場合には、造血幹細胞移植治療が実施されます。また最近では、60歳までの中高年者を対象に薬剤の強度を落とした同種造血幹細胞移植の試みがなされています。
●診断、及び病期別の治療、及び生存率
１） 明らかな原因がなく発病した一次性の骨髄異形成症候群 (1)不応性貧血及び鉄芽球性貧血 無治療、経過観察ないし輸血治療が主体となります。経過をみているだけで悪化するものは60～80％と多く、５年～10年生存率が10～20％とされています。長期生存の場合には、長期間の輸血による合併症（肝炎、鉄分の沈着など）の対策が必要となります。急性白血病に移行するのは10％前後です。 (2)骨髄芽球の増加した不応性貧血 対症治療に加えて、抗がん剤による化学療法（白血病治療薬の少量持続投与や標準的な併用治療）の適応となる場合があります。1/3以上が急性白血病に移行します。 (3)骨髄芽球が悪性化し、かつ増加している不応性貧血 病状がさらに進行していて、抗がん剤による化学療法が通常必要とされます。 (2)～(3)の病型の予後は非常に悪く、２年生存率が約20％、５年生存率が約10％以下です。化学療法により40～50％が、悪性細胞が減少した寛解状態に到達しますが、その持続期間は１年程度で化学療法による治癒は期待できません。つまり現在の治療手段では、造血幹細胞移植を除いては治癒は望めません。したがって、新しい化学療法、同種骨髄移植の臨床試験、あるいは新規薬剤の臨床試験などの治療研究が積極的に進められております。 ２）二次性の骨髄異形成症候群 病型ごとの治療法は同じです。しかし、二次性の場合には化学療法に対する効果や予後も非常に悪く、治癒はほとんど望めません。したがって、症状がある場合、貧血、出血などを改善する対症治療をはじめに行い、その後は原因となった病気の治療をします。同じく化学療法の臨床試験、あるいは新規の薬剤の臨床試験が積極的に進められております。
●治療の副作用と対策 輸血は主に赤血球輸血を行います。最近の血液製剤は安全性が高くなってきていますが、輸血による急性、慢性の副作用がおこることもあります。特に不応性貧血の場合、輸血の回数がどうしても多くなりますから、赤血球輸血に含まれている鉄分が身体の主要臓器に蓄積したり、皮膚に沈着したりして、肝硬変や心不全になったり皮膚が黒色になることがあります。
抗がん剤の投与を受けている場合は、白血球減少症、血小板減少症などの副作用が出ます。抗がん剤により正常な血液細胞も障害を受けやすいためです。
●予後 骨髄異形成症候群は、初期の病型であっても血液を造るおおもとの幹細胞が、がん化したのですから、それが自然に正常なものに戻るということはありません。 つまり治る病気ではありません。また、60～80％は５年以内に死亡する病気です。 死因は主に感染症及び出血です。 高齢者に多い病気であること、また根治治療がないということから、輸血などの対症治療を続けることが多いのですが、次第に正常な血液の成分がなくなっていく場合や、途中から急性白血病になる場合もあります。 ただし、対症療法により貧血症状や出血傾向が改善したり、発熱や全身倦怠感といった症状がとれることは期待できます。つまり病気を治すことはできなくても、病気の症状や進行に気をつけていれば、しばらくは日常生活を支障なく送ることができます。
さらに最近では、新しい細胞刺激因子を使う治療方法や抗がん剤による化学療法、あるいは若年者のみならず、中高年者にも積極的に同種造血幹細胞移植療法が開発、推進されつつあります。
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[1232]●製品 lenalidomide (Revlimid [Celgene])
日本語版註）lenalidomide (Revlimid [Celgene])レナリドマイド(レブリミド)
【別名】CC-5013; CDC-501 【開発元】Celgene Corporation [DBR_ID]
【化学名】3-(4-amino-1,3-dihydro-1-oxo-2H-isoindol-2-yl)-2,6-piperidinedione ;C13H13N3O3; mw=259.3;CAS REG NR=191732-72-6
【承認】FDA申請=2005.4.7、FDA承認=Dec 27, 2005、発売=2006.; 【製剤】カプセル中5mgまたは10mg含有 【適応】(骨髄異形成症候群)for the treatment of patients with transfusion dependent anemia due to low or intermediate-1 risk myelodysplastic syndromes associated with a deletion 5 q cytogenetic abnormality with or without additional cytogenetic abnormalities. 【用法用量】１日10mgが初回推奨用量。 【作用】thalidomideアナログ。 【特徴】 【製品情報】www.revlimid.com 【添付文書】http://www.celgene.com/PDF/RevlimidPI.pdf 【EU】Revlimid [Celgene]申請=2005.8(MDS)、申請=2006.2(MM=多発性骨髄腫) 【日本】未開発 【その他】本剤の催奇形性等はRevAssist[SM] Risk Minimization Action Plan (RiskMAP)に沿って管理。本剤はこのRevAssistSM(患者・医師・看護婦・薬局を登録管理)を通じてのみ配布される。
US Pharmacopeial Commission AMA: United States Adopted Names - lenalidomide USAN LENALIDOMIDE PRONUNCIATION le na lid oh mide THERAPEUTIC CLAIMS immunomulator intended for use in the treatment of multiple myeloma, myelodysplastic syndromes, solid tumors including glioma and metastatic melanoma, Crohn's disease, and heart failure CHEMICAL NAMES 1. 2,6-piperidinedione, 3-(4-amino-1,3-dihydro-1-oxo-2H-isoindol-2-yl)- 2. 3-(4-amino-1-oxo-1,3-dihydro-2H-isoindol-2-yl)piperidine-2,6-dione MOLECULAR FORMULA C13H13N3O3 MOLECULAR WEIGHT 259.3 TRADEMARK Revlimid MANUFACTURER Celgene Corporation CODE DESIGNATIONS CC-5013; CDC-501 CAS REGISTRY NUMBER 191732-72-6 BIAM --- BIAM -ABC順|BIAM -会社順 NLM: MeSH HOme ---MeSH Online search
【日本語版コメント1232】
「骨髄異形成症候群」(MDS)という疾患が注目されている。
遺伝子・染色体の異常から骨髄が血液を造るという正常な働きをしなくなり、貧血、皮膚内出血等の症状を示す。 患者調査2002年度で、「D46骨髄異形成症候群」患者数は8千人(1999年度6千人)だが実際はもっと多いだろう。
- MDSは60才以上多く発症。 米国で1-3万人、EUで毎年3-4万人の新患者発生。 生存率はMDSタイプにより６か月から６年。 大半が出血と感染で死亡。 acute myelogenous leukemia (AML)(骨髄性白血病)への形質変換が患者の40%に生じる。
骨髄異形成症候群治療薬の開発はミニブーム状態で世界で２０製品が開発中。 承認第一号がazacitidine(Vidaza [Pharmion])-FDA2004.5認可。 今回2005.12承認のlenalidomide (Revlimid [Celgene])が２番手で、他に多発性骨髄腫などの適応追加で申請中。 第８回未承認薬使用問題検討会議(06.4.27)検討品目。→詳細は参考資料●MLリソース：骨髄異形成症候群[MDS]に纏めた。＜日本語版コメント要約＞
・サリドマイド類縁体のレナリドミドが、5q欠失を伴う骨髄異形成症候群（MDS）による輸血依存性貧血で、lowまたはlow-intermediate riskの患者の治療薬としてFDAに承認された。
・2臨床試験において、本剤による輸血非依存達成率は63%および67%であった。
・サリドマイドと構造が似ているため、レナリドミドは妊婦には禁忌で、限定販売プログラムを通じてのみ販売される。
●承認データ：FDA ●2004.5.1 以降 Drugs@FDA
Drug Name(s) =REVLIMID FDA Application No. =NDA # 021880 Active Ingredient(s)=LENALIDOMIDE Company =CELGENE Dosage Form/Route =CAPSULE; ORAL 5MG,10MG Strength = - Approval Date=12/27/2005[000] :Label[添付文書]|Letter[承認書]|Review ※承認条件１ 市販後リスク管理 Revlimid RiskMAP(略称RevAssist[SM]) 1)本薬剤は患者・医師・看護婦・薬局を登録管理したRevAssistを通じてのみ配布 2)Revlimidの研修資料の準備 3)安全性サーベイランスのための報告・データ収集システム 4)妊娠期間中の薬剤暴露減少化のモニター・評価・改善ならびにRevAssistプログラム下 の安全使用制限の遵守 ※承認条件２ 市販後調査
プロトコール
提出期限試験開始 最終報告
提出期限内容 2006.6 2006.9 2007.12 胚・胎児発生毒性 2005.3 2005.8 2008.12 多施設RCT:CC-5013-MDS-004
有効性・安全性2004.11 2006.3 2007.12 腎障害を持つ患者でのlenalidomideの薬物動態
(2/3が未変化で尿中排泄。 腎障害を持つ多発性骨髄腫患者で暴露(血漿AUC)が正常腎機能患者と比べ56%も高かった。)2006.6 RevAssist関連
●Electronic Orange Book Application Number: 021880 Active Ingredient : LENALIDOMIDE Proprietary Name : REVLIMID [CELGENE] CAPSULE; ORAL 5MG,10MG Approval Date : Dec 27, 2005 Exclusivity Data : NCE DEC 27,2010 ODE DEC 27,2012 Patent Data : 5635517 JUL 24,2016 Y 6045501 AUG 28,2018 U-694 6315720 OCT 23,2020 U-694 6555554 JUL 24,2016 Y 6561976 AUG 28,2018 U-694 6561977 OCT 23,2020 U-694 6755784 OCT 23,2020 U-694 6908432 AUG 28,2018 U-694
●FDA Advisory Committees 参考●ML_ADD資料：FDA諮問委員会～議題 FDA Advisory Committees FDAAdvisorycommittee.com CDER■Oncologic Drugs - http://www.fda.gov/ohrms/dockets/ac/cder06.html#OncologicDrugs Oncologic Drugs 2005 | 2004 | 2003 | 2002 | 2001 | 2000 FDAAdvisorycommittee.com: Oncologic Drugs
ML 開催日 議題 備考 1228
12322005.09.14 Celgene Revlimid For Myelodysplastic Syndromes; GSK Arranon For T-cell Lymphoblastic Leukemia, Lymphoma
【Arranon[GSK]】※本剤はT細胞急性リンパ芽球性白血病およびT細胞リンパ芽球性リンパ腫の適応承認を求めていた。※Brief Information※【審議結果】成人の臨床benefitは全員一致、小児の臨床benefitは11-1で勧告。 骨髄芽球数5%以内と末梢血球数の完全回復という完全寛解[CR]の定義に照らして、CRは小児13%、成人18%だった。 効果についてのデータが最小限であるため、GSKは６年間のP3確認試験を実施し640例を収集、Event-free survival を主要エンドポイントとする。
【Revlimid[Celgene]】※骨髄異形成症候群(myelodysplastic syndrome;MDS)の適応をPhase IIデータに基づき申請。 ※Brief Information
※【審議結果】諮問委はrisk/benefit分析について10-5だったが効果について疑義なしとの意見。しかしCelgene社のsingle-arm試験が「推奨用量に根拠がなく、安全性プロファイルの記述不十分」ということに、13-2。 患者の80%がneutropenia and thrombocytopeniaの毒性のため用量減少している。Revlimid[Celgene]
Arranon[GSK]
●EU承認 ●EMEA - Human Medcines ●List of Authorized Products (EPARs)★[A-Z 承認品目] ■[Enterprise and Industry DG] Directorate F - Consumer Goods -http://pharmacos.eudra.org/ ★The Community Register[承認製品リスト] - 医薬品は1995.10以降。 各製品データシートにリンク。 [医薬品]Community Register of medicinal products for human use - [年月別] - 取下げ・中断 - 却下 [総合索引～成分別]General index on active ingredient [総合索引～銘柄別]General index on brand name
●未承認薬使用問題検討会議
第８回 ワーキンググループ検討結果報告書で報告された。 [資料 ２－３]レナリドミド[2-3]pdf 平成18年4月27日
会議名 掲載案件名 開催日 未承認薬使用問題検討会議 第８回資料 06/04/27 第８回開催について 06/04/27 資料 ２－３ (註) 第8 回未承認薬使用問題検討会議（平成18 年4 月27 日）における検討等を踏ま え、当日の配付資料から赤字部分を修正しています。
医薬品名 レナリドミド（米国での販売名：Revlimid） 概要 抗悪性腫瘍薬（経口剤） 対象疾病 骨髄異形成症候群 外国承認状況 米国（5q 欠損の染色体異常を伴う低又は中等度リスクの骨髄異形成症候群による輸血依存性の貧血）
●Celgene Corporation - http://www.celgene.com/ ;7 Powder Horn Drive Warren, New Jersey 07059 USA 1986 Delawareに設立。 2000.8.31 バイオ製薬企業Signal Pharmaceuticals, Inc,San Diegoを買収。 2002.12.31 バイオ治療・さい帯血銀行Anthrogenesis Corporation, New Jersey を買収 現Celgene Cellular Therapeutics (“CCT”), ●Products REVLIMID (lenalidomide) -骨髄異形成症候群 - http://www.revlimid.com/ THALOMID[R] (thalidomide) -らい性結節性紅斑(ENL：erythema nodosum leprosum) - http://www.thalomid.com/ FOCALIN(R)/FOCALIN XR(TM)(dexmethlyphenidate HCl) - ADHD治療薬 - 両剤の全世界販売権(カナダ除く)をNovartisにライセンス。XRは2005.5.27 FDA認可。 ALKERAN(R) (melphalan) - 多発性骨髄腫 - 2003.3 GSKから販売権を取得。 ●Investor Relations ★SEC Filings Annual Filings 10-K[2006.3.15] - [pdf] - [xls] Annual Filings 10-K[2005.3.16] - [pdf] - [xls] Annual Filings 10-K[2004.3.15] - [pdf] - [xls] Annual Filings 10-K[2003.3.31] - [pdf] - [xls] Annual Filings 10-K[2002.3.29] - [pdf] - [xls] Annual Filings 10-K[2001.3.21] - [pdf] - [xls] ★Financial Reports 2004 Annual Report[2004.5.10] - [pdf] ★Press Releases Celgene Corporation Reports Record Operating Performance for 2005[2006.1.26] Celgene Corporation Reports Record Revenue and Operating Profits[2006.4.27] REVLIMID(R) Marketing Authorization Application Accepted by EMEA for Review[2006.4.7] FDA Grants Priority Review for REVLIMID(R) sNDA for Treatment of Relapsed or
Refractory Multiple Myeloma[2006.3.3] FDA Grants REVLIMID(R) NDA Approval[2005.12.27] REVLIMID(R) Clinical Results as Oral Treatment Regimen in Newly Diagnosed Multiple
Myeloma Presented at the 47th American Society of Hematology Meeting[2005.12.13] REVLIMID(R) Clinical Results as Oral Treatment Regimen in Myelofibrosis Presented
at the 47th American Society of Hematology Meeting[2005.12.13] REVLIMID(R) Clinical Results as Oral Treatment Regimen in Chronic Lymphocytic Leukemia
Presented at the 47th American Society of Hematology Meeting[2005.12.12] Revlimid(R) Improves Overall Survival and Delays Time to Disease Progression in
Previously Treated Multiple Myeloma Patients[2005.12.11] 107 Abstracts on Clinical Data Evaluating REVLIMID(R) and Thalidomide To Be
Presented at The 47th American Society of Hematology Meeting[2005.12.8] REVLIMID(R) Marketing Authorization Application Accepted by EMEA for Review[2005.10.26] REVLIMID(R) PDUFA Date Extended Three Months By FDA[2005.10.3] FDA Oncologic Drugs Advisory Committee Recommends REVLIMID(R) for Full Approval[2005.9.14] FDA and Celgene Revlimid(R) Briefing Documents for Advisory Committee Meeting Available Online[2005.9.13] [2005.] ●Research ●Patient Support ●Medical Services～医療関係者用(要登録)
●参考資料 レブリミドの新薬申請を承認 ＭＤＳ治療でＦＤＡ[共同通信,8p;2006.1.4]
[1201]●製品 5-Azacytidine ５-アザシチジン azacitidine(Vidaza [Pharmion])
日本語版註）5-Azacytidine ５-アザシチジン azacitidine(Vidaza [Pharmion])
【別名】NSC-102816;U-18496 【開発元】Pharmacia [DBR_ID]14511-422D
【化学名】4-amino-1-β-D-ribofuranosyl-s-triazin-2(1H)-one; CAS 320-67-2
【承認】FDA申請=2003.12.29、FDA承認=19-May-2004、米国発売=2004.7.1 ; 【製剤】皮下注射 1 vial中 【適応】Vidaza is indicated for treatment of patients with the following myelodysplastic syndrome(骨髄異形成症候群) subtypes: refractory anemia or refractory anemia with ringed sideroblasts (if accompanied by neutropenia or thrombocytopenia or requiring transfusions), refractory anemia with excess blasts, refractory anemia with excess blasts in transformation, and chronic myelomonocytic leukemia. 【用法用量】毎日75mg/m2を７日間皮下注射する。４週毎に行う。
【作用】メチル化阻害剤；骨髄中の異常なhematopoietic細胞への直接的な殺細胞作用およびDNAのメチル化阻害を引き起こすことにより、抗癌効果を発現すると考えられる。 【特徴】MDSの初の治療薬；a pyrimidine nucleoside analog of cytidine.
【製品情報】http://www.vidaza.com/ 【添付文書】Vidaza -Full Prescribing Information[pdf]
【提携】Pharmion社はPharmacia(Pfizer子会社)から2001年全世界権利をライセンス導入
【EU】★Vidaza (azacitidine) Myelodysplastic Syndromes [Celgene Europe Ltd.]2004.9 申請 - 承認17-Dec-2008
【日本】[] 【製剤～日本】 【適応～日本】 【用法用量～日本】 【製品情報～日本】 【添付文書～日本】 - インタビューフォーム 【その他】
[ナカライテスク株式会社 オンラインカタログ]５-アザシチジン●14511-422D azacitidine by Pharmacia 5-AC;5-AZACYTIDINE;AZA-C;AZACITIDINE[USAN];LADAKAMYCIN;NSC-102816;U-18496;ｱｻﾞｼﾁｼﾞﾝ
【日本語版コメント1201】
骨髄異形成症候群(MDS)は、造血幹細胞のクローン性異常による骨髄の機能異常を伴った骨髄異形成と血球減少によって特徴づけられる症候群。 原因はde novoで生ずる場合と化学療法あるいは放射線療法によって生ずる場合とがある。 多様な病態の集合体ともいうべき症候群で、輸血などの補助療法が中心となることも多く、標準的な治療法は確立していない。
- MDSは60才以上多く発症。 米国では1-3万人、EUで毎年3-4万人の新患者発生。 日本の患者数は8千人(患者装置2002)。 生存率はMDSタイプにより６か月から６年。 大半が出血と感染で死亡。 骨髄性白血病[AML]への形質変換が患者の40%に生じる。
今回取上げたのは、骨髄異形成症候群の適応を世界で初めてFDA承認された5-Azacytidine。 昨2004年7月米国発売以来、医療機関に広く受け入れられ、売上高も2004年度(半年)$47.1millin、2005年度$229-245millionを予定。→詳細は参考資料●MLリソース：骨髄異形成症候群[MDS]に纏めた。＜日本語版コメント用要約＞
・シチジンのピリミジンヌクレオシド類似体、アザシチジンが、初の骨髄異形成症候群（MDS）の治療薬としてFDAに承認された。
・本剤はMDS患者の症状を改善し、輸血の必要性をなくし、白血病の発現を遅延させた。
・生存期間もおそらく延長させると思われる。
●承認データ：FDA ●2004.5.1 以降 Drugs@FDA
Drug Name(s) =Vidaza FDA Application No. =NDA # 050794 Active Ingredient(s)=AZACITIDINE Company =PHARMION Corp Dosage Form/Route =INJECTABLE; SUBCUTANEOUS:100MG/VIAL Strength = - Approval Date=05/19/2004 :Label[添付文書]|Letter[承認書]|Review
●Electronic Orange Book Application Number: 050794 Active Ingredient : AZACITIDINE Proprietary Name : VIDAZA [PHARMION] INJECTABLE; SUBCUTANEOUS 100MG/VIAL Approval Date : May 19, 2004 Exclusivity Data : ODE MAY 19,2011 Patent Data : -
●FDA Advisory Committees 参考●ML_ADD資料：FDA諮問委員会～議題 FDA Advisory Committees FDAAdvisorycommittee.com
●[PMDA]新薬の承認審査に関する情報
販売名 承認取得者名 一般名 審査報告書 申請資料概要 承認年月又は報告年月 部会審議／報告の別
●EU承認 ●ema - Human Medcines ●List of Authorized Products (EPARs)★[A-Z 承認品目] ★Vidaza (azacitidine) Myelodysplastic Syndromes - 17/12/2008 Authorised 1. Summary for the public 2. All Authorised Presentations 3. Vidaza : EPAR - Public assessment report 4. Procedural steps taken and scientific information after authorisation Product Information, please see below Annex I - Summary of product Characteristics Annex IIA - Manufacturing Authorisation Holder responsible for Batch Release Annex IIB - Conditions of the Marketing Authorisation Annex IIIA - Labelling Annex IIIB - Package Leaflet [Name] Vidaza [EMEA Product number] EMEA/H/C/000978 [Active substance] azacitidine [INN or common name] azacitidine [Therapeutic area] Myelodysplastic Syndromes [ATC Code] L01BC07 [Treatment of rare diseases] This medicine has an "orphan designation" which means that it is used to treat life-threatening or chronically debilitating conditions that affect no more than f ive in 10,000 people in the European Union, or are medicines which, for economic reasons, would be unlikely to be developed without incentives. [Marketing Authorisation Holder] Celgene Europe Ltd. [Revision] 5 [Date of issue of Market Authorisation valid throughout the European Union] 17/12/2008 [Pharmaco-therapeutic Group] Antineoplastic agents [Therapeutic Indication]
Vidaza is indicated for the treatment of adult patients who are not eligible for haematopoietic stem cell transplantation with:
・ intermediate-2 and high-risk myelodysplastic syndromes (MDS) according to the International Prognostic Scoring System (IPSS),
・ chronic myelomonocytic leukaemia (CMML) with 10-29 % marrow blasts without myeloproliferative disorder,
・ acute myeloid leukaemia (AML) with 20-30 % blasts and multi-lineage dysplasia, according to World Health Organisation (WHO) classification.
●CHMP Press Releases ●CHMP: Committee meeting reports諮問委員会審議品目一覧 - Summaries of Opinion ---Substance/INN Trade Name Pharmaceuticalform Strength OpinionAdoption Date ●[EU Referrals] human medicinal products[医薬品のReferralリスト]Refferal=紹介の意だが、国別審査方式による製品リスト
●Pharmion Corporation ●Products http://www.vidaza.com/ Vidaza -Full Prescribing Information[pdf]
●Media Center ★News Releases EMEA Accepts Pharmion's Marketing Authorization Application for Vidaza(TM)
商品名 適応 段階 導入先 対象国 競合品 VIDAZA[TM] Myelodysplastic Syndromes Marketed Pharmacia (now part of Pfizer) US Thalomid(R) and Revlimid(TM), each from Celgene, and Decitabine, from Supergen Inc Thalidomide Pharmion Multiple myeloma ENL Marketed Celgene Australia,New Zealand, Turkey, and Israel VelcadeTM, from Millenium Pharmaceuticals Inc., and RevlimidTM, from Celgene Corporation
(azacitidine for injectable suspension) for Review[2004.9.21] - MDSは60才以上多く発症。 EUで毎年3-4万人の新患者発生。 生存率はMDSタイプによ り６か月から６年。 大半が出血と感染で死亡。 acute myelogenous leukemia (AML) (骨髄性白血病)への形質変換が患者の40%に生じる。 Pharmion Launches Vidaza(TM) (Azacitidine for Injectable Suspension)[2004.7.6] FDA Approves Pharmion's Vidaza(TM) (azacitidine for injectable suspension) for
the Treatment of Myelodysplastic Syndromes (MDS)[2004.5.19]
●他の資料 ●Vidaza May Lift Pharmion Past Street Estimates[Forbes: 2004.10.4] - Vidazaの年間ピーク売上高は$300 million超と見込まれる。 July 2004発売以降１２か月売上高は、Pharmion社によると$244 million。 同社MDS専門医での調査では、91%が併用療法で使用し、41%がOff-label使用するという。 News - FDA Approves Vidaza (Azacitidine) for Treatment of Myelodysplastic Syndromes -the American Cancer Society and the Aplastic Anemia and MDS International Foundation によると、米国でMDS新規患者は毎年１～３万人発生。
●ニュース ●MDS Foundation -http://www.mds-foundation.org/ - 医師・研究者により設立。 第８回国際シンポ(2005.5)は長崎で開催。 小児急性骨髄性白血病[米国がん研究所の PDQ] ●Lenalidomide (Revlimid) by Celgene -thalidomide誘導体 Efficacy of Lenalidomide in Myelodysplastic Syndromes[pdf] N Engl J Med 2005;352:549-57.
[1247]●製品 デシタビンdecitabine (Dacogen [MGI Pharma])
日本語版註）デシタビンdecitabine (Dacogen [MGI Pharma])ダコジェン
【別名】5-aza-2'-deoxycytydine 【開発元】SuperGen, Incが創製し、2004.9 MGI Pharma,Incに全世界の独占開発・製造販売権を供与。 [DBR_ID]
【化学名】4-amino-1-(2-deoxy-β-D-erythro-pentofuranosyl)-1,3,5-triazin-2(1H)-one
【承認】FDA申請=14-Nov-2005、FDA承認=May 2, 2006、米国発売=2006.5.26 ; 【製剤】Each 20 mL, single dose, glass vial contains 50 mg decitabine 【適応】(骨髄異形成症候群)myelodysplastic syndrome (MDS). 【用法用量】[初回サイクル]15mg/m2を３時間の静注、これを３日間８時間毎に繰り返す。 [以降サイクル]前記サイクルを６週毎に最低４サイクルを繰り返す 【作用】DNAメチル基転移酵素の阻害により腫瘍細胞成長阻害もしくはcytotoxicity 【特徴】 【製品情報】www.dacogen.com 【添付文書】Dacogen-PI 【EU】2005.11申請取下げ、再申請予定; MGIは北米以外の開発・販売権をCilag GmbH(J&J系)に再許諾。 【日本】未開発 【その他】前臨床試験でメラノーマ、大腸癌、卵巣癌に有効。AMLがP3、CMLはP2
【日本語版コメント1247】
骨髄異形成症候群[MDS]は、最近、青島幸男元東京都知事の死因として注目された後天的な造血幹細胞異常による疾患。 国際的には2004年からazacitidine(Vidaza[Pharmion])、lenalidomide(REVLIMID[Celgene])、今回３番手のDecitabine(Dacogen[MGI])が発売された。 従来療法は補助的なものであったから、初の専用新薬azacitidineは2005年度売上高125.6百万ドルと商業的には成功を収めた。 それでも奏功率は低くて、最高レベルでも30%台であることから改良が望まれるが、３剤共日本での開発予定はない。 依然根治手段としては骨髄移植しかない。日本では、「骨髄異形成症候群」を適応症として認可されているのは、注射用エンドキサン50mg,100mg[塩野義製薬;シクロホスファミド]、スタラシドカプセル50,100[日本化薬;シタラビン オクホスファート]、グラン[麒麟麦酒株;フィルグラスチム]、ノイトロジン注50,100,250μg[中外製薬;レノグラスチム]のみ。
→詳細は参考資料●MLリソース：骨髄異形成症候群[MDS]に纏めた。＜日本語版コメント要約＞
・2番目のヌクレオシドアナログ、デシタビンが骨髄異形成症候群（MDS）の治療薬としてFDAに承認された。
・臨床試験における奏効率は、デシタビン＋支持療法で17%、支持療法のみで0%であった。
・本剤が、先に承認されているアザシチジンを上回る利点を持つかどうかは不明。
●承認データ：FDA ●2004.5.1 以降 Drugs@FDA
Drug Name(s) =DACOGEN FDA Application No. =NDA # 021790 Active Ingredient(s)=DECITABINE Company =MGI PHARMA INC Dosage Form/Route =INJECTABLE; INTRAVENOUS 50MG/VIAL Strength = - Approval Date=05/02/2006[000] :Label[添付文書]|Letter[承認書]|Review
●Electronic Orange Book Application Number: 021790 Active Ingredient : DECITABINE Proprietary Name : DACOGEN [MGI PHARMA INC] INJECTABLE; INTRAVENOUS 50MG/VIAL Approval Date : May 2, 2006 Exclusivity Data : NCE MAY 02,2011 Patent Data : -
●MGI Pharma,Inc ●PRODUCTS Aloxi(R) (palonosetron hydrochloride) injection ... 制吐剤 Dacogen(TM)(decitabine) for Injection ... 骨髄異形成症候群 GLIADEL(R) Wafer (polifeprosan 20 with carmustine implant) ...脳腫瘍薬 Hexalen(R) (altretamine) Capsules ...膀胱癌 Salagen(R) (pilocarpine hydrochloride) Tablets ...シェーグレン症候群 ●PIPELINE ●INVESTORS ★Annual Reports ★SEC Filings 10-K Annual Filings[2006.3.16] - [PDF] 10-K Annual Filings[2005.3.11] - [pdf] ●News & MEDIA Dacogen(TM) (Decitabine) for Injection Data Presented at the American Society of Hematology (ASH) 48th Annual Meeting and Exposition[2006.12.11] MGI PHARMA Announces Specific J Code Assignment for Dacogen(TM)[2006.10.31] MGI PHARMA Reports Third Quarter 2006 Financial Results[2006.10.18] - Dacogen 2006Q3売上高$11.9 million; 2006Q2=$5.2 million Dacogen(TM) (Decitabine) for Injection Receives U.S. Orphan Drug Designation for Patients with AML[2006.8.10] Dacogen(TM) (Decitabine) For Injection Receives European Orphan Drug Designation for Patients With AML[2006.8.1] MGI PHARMA Announces License Agreement with Cilag GmbH, a Johnson & Johnson Company, for Dacogen(TM) (decitabine) for Injection; Ex-North America Development & Commercialization Agreement[2006.7.6] MGI PHARMA Announces Commercial Availability of Dacogen(TM) (Decitabine) for Injection[2006.5.26] U.S. FDA Approves Dacogen(TM) (Decitabine) for Injection; Dacogen(TM) Approved for
Patients with all FAB Classifications of MDS; Commercial Launch Planned For Late May[2006.5.3] MGI PHARMA Reports Fourth Quarter and Full Year 2005 Financial Resul[2006.2.8] MGI PHARMA Reports Fiscal 2003 Results and Provides 2004[2004.2.11] MGI PHARMA Announces Expiration of Tender Offer for Guilford Pharmaceuticals Notes Due 2008[2005.11.29] MGI PHARMA Completes Acquisition of Guilford Pharmaceuticals[2005.10.3] ●10-K Annual Filings[2006.3.16] - [PDF] ,6-8pDacogen Injection Overview
In September 2004, we obtained exclusive worldwide rights to the development, commercialization, manufacturing and distribution of Dacogen (decitabine) injection (“Dacogen”) for all indications from SuperGen, Inc. Dacogen is an investigational anti-cancer therapeutic which is currently in development for the treatment of patients with MDS and AML. A Dacogen regulatory application for the treatment of MDS is being reviewed for marketing approval by the FDA in the United States.
A pivotal phase 3 trial and two supporting phase 2 trials for the MDS indication forms the clinical basis of this application. The FDA has established May 15, 2006 as the PDUFA action goal date for the NDA.
An application before the European Medicines Agency (“EMEA”) in Europe was withdrawn in November 2005. We are working with European regulatory authorities and intend a resubmission of the European application with confirmatory data from an ongoing EORTC phase 3 trial.
The anticancer activity of Dacogen is due to both inhibition of cell growth, or cytotoxicity, which is observed at higher doses and decreasing methylation of deoxyribonucleic acid, or DNA, which is predominately observed at lower doses. Decreasing DNA methylation, or hypomethylation, is a relatively new approach to cancer treatment. Excess DNA methylation has been implicated as a fundamental factor in the development of cancers. Researchers have determined that an increase in specific methylation of DNA can result in blocking the expression of genes, such as tumor suppressor genes. In clinical trials, researchers have demonstrated that Dacogen can reverse the methylation of DNA, potentially leading to re-expression of tumor suppressor genes. In clinical trials, Dacogen has demonstrated activity in MDS, AML, and chronic myeloid leukemia (“CML”). Preclinical data suggest that Dacogen may be effective in the treatment of solid tumor cancers where DNA methylation status is believed to be important, such as melanoma, colon and ovarian cancer.
★Myelodysplastic Syndrome
MDS is a bone marrow disorder characterized by bone marrow production of abnormally functioning, immature blood cells. According to the American Cancer Society and the Aplastic Anemia & MDS International Foundation, approximately 15,000 to 25,000 new cases of MDS are diagnosed each year in the United States, although it is difficult to accurately determine the incidence because MDS is not recorded by the national tumor registry in the United States. In the majority of afflicted patients, MDS results in death from bleeding and infection. In approximately 30 percent of patients, MDS will convert to AML, a disease with a high mortality rate.
The phase 3 trial was designed to support regulatory approval of Dacogen for the treatment of patients with MDS. Dacogen received orphan drug designation for MDS in the United States and Europe, which may provide us with seven years of marketing exclusivity in the United States and ten years of marketing exclusivity in Europe if Dacogen is approved for treatment of MDS by the respective regulatory authorities. In September 2005, we received an Approvable Letter for Dacogen. While an Approvable Letter is a significant step in the drug approval process, approval from the FDA is still required to market the product. In November 2005, we submitted an Approvable Letter response to the FDA. In December 2005, we received a letter from the FDA stating that our response to the Approvable Letter was complete and a PDUFA date of May 15, 2006 had been established. The PDUFA date is the date by which the FDA aims to render a decision on a new drug application. Also in November 2005, we withdrew our Marketing Authorization Application (“MAA”) with the EMEA. We will continue to work with the European regulatory authorities and intend a resubmission of the MAA with confirmatory data from an ongoing EORTC Phase 3 trial.
In May 2004, Vidaza (azacitidine), marketed by Pharmion Corporation, was approved by the FDA as the first drug to be approved for the treatment of MDS. In December 2005, the FDA approved lenalidomide for treatment of patients categorized as low- or intermediate-1 risk MDS patients. Initial shipments of lenalidomide commenced in early 2006. If Dacogen is also approved for treatment of MDS, it will compete directly with azacitidine and lenalidomide.
★Other Potential Indications
Beyond the activity of Dacogen for MDS, we believe phase 1 and 2 trials demonstrate that Dacogen may be active in a variety of other hematological malignancies such as AML and CML. We began a phase 3 trial of Dacogen in AML patients in 2005 and we are currently conducting a multi-center phase 2 trial with Dacogen for the treatment of refractory CML in patients who have failed previous front-line therapy. Phase 1 results also suggest that Dacogen may be useful for treatment of non-malignant diseases such as sickle cell anemia, for which we are supplying Dacogen to investigators for their phase 2 clinical trials in this area of study. Dacogen received orphan drug designation from the FDA for sickle cell anemia in September 2002, which may provide seven years of marketing exclusivity in the United States if Dacogen is approved by the FDA for the treatment of sickle cell anemia. Further, the Dacogen clinical and scientific program is the subject of a Clinical Research and Development Agreement (“CRADA”) with the National Cancer Institute (“NCI”). Pursuant to the CRADA, we will supply Dacogen for pre-clinical and clinical trials that will be managed by the NCI and that will focus primarily on the treatment of solid tumors.
●未承認薬使用問題検討会議 平成１８年４月～６月に欧米４カ国のいずれかの国で 新たに承認された医薬品（類型Ⅰ）[pdf,4p;p3] 未承認薬使用問題検討会議 第９回資料 資料 ３ １．成分名： デシタビン（decitabine） 販売名： Dacogen 承認国： 米国（2006年5月2日承認） 会社名： MGI Pharma, Inc. 剤形・規格：注射剤・50mg１瓶 効能・効果：骨髄異形成症候群 用法・用量：15mg/m2を3時間かけて点滴静注（8時間おきに3日間繰り返す） 作用機序等：DNAメチル基転移酵素の阻害 ○適応疾病の重篤性について： 重篤な疾病である。 ○医療上の有用性について： 第Ⅲ相試験における奏効率は17％（15/89）（比較対照のsupportive care群は0％（0/81）） ○学会・患者団体からの要望： なし ○国内状況： 開発なし
[]●製品 ezatiostat hydrochloride liposomes for injection (Telintra, TLK199),
日本語版註）
【別名】 【開発元】 [DBR_ID]
【化学名】
【承認】FDA申請=、FDA承認= ; 【製剤】 【適応】 【用法用量】
【作用】 【特徴】
【製品情報】 【添付文書】
【提携】 【EU】
【日本】[] 【製剤～日本】 【適応～日本】 【用法用量～日本】 【製品情報～日本】 【添付文書～日本】 - インタビューフォーム 【その他】
● CONCLUSION: Phase 2 studies of ezatiostat hydrochloride liposomes for injection in MDS are supported by the tolerability and HI responses observed. BACKGROUND: Ezatiostat hydrochloride liposomes for injection, a glutathione S-transferase P1-1 inhibitor, was evaluated in myelodysplastic syndrome (MDS). The objectives were to determine the safety, pharmacokinetics, and hematologic improvement (HI) rate. Phase 1-2a testing of ezatiostat for the treatment of MDS was conducted in a multidose-escalation, multicenter study. Phase 1 patients received ezatiostat at 5 dose levels (50, 100, 200, 400 and 600 mg/m2) intravenously (IV) on days 1 to 5 of a 14-day cycle until MDS progression or unacceptable toxicity. In phase 2, ezatiostat was administered on 2 dose schedules: 600 mg/m2 IV on days 1 to 5 or days 1 to 3 of a 21-day treatment cycle. RESULTS: 54 patients with histologically confirmed MDS were enrolled. The most common adverse events were grade 1 or 2, respectively, chills (11%, 9%), back pain (15%, 2%), flushing (19%, 0%), nausea (15%, 0%), bone pain (6%, 6%), fatigue (0%, 13%), extremity pain (7%, 4%), dyspnea (9%, 4%), and diarrhea (7%, 4%) related to acute infusional hypersensitivity reactions. The concentration of the primary active metabolites increased proportionate to ezatiostat dosage. Trilineage responses were observed in 4 of 16 patients (25%) with trilineage cytopenia. Hematologic Improvement-Erythroid (HI-E) was observed in 9 of 38 patients (24%), HI-Neutrophil in 11 of 26 patients (42%) and HI-Platelet in 12 of 24 patients (50%). These responses were accompanied by improvement in clinical symptoms and reductions in transfusion requirements. Improvement in bone marrow maturation and cellularity was also observed.
● HDAC inhibitor が開発の主体 Entinostat (SNDX-275/MS-275) Agents for which there are at least preliminary data in MDS and AML include entinostat; belinostat (PXD101); romidepsin (FK228/FR901229/depsipepide); panobinostat; MGCD0103; valproic acid; and sodium phenylbutyrate. Table . Patient Reported Outcomes -Clinical Benefit Assessments
Additional Clinical Benefits N (%) Increased Energy 13 (34) Improved Well Being 9 (24) Increased Mobility 2 (5) Improved Daily Activities 5 (13) Decreased Antibiotics Requirements 2 (5) Decreased Bleeding Events 2 (5) Decreased Hospitalizations for Fever/Sepsis 1 (3) Other 3 (8)
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株式会社メドレット Medlet Japan KK
〒103-0024 東京都中央区日本橋小舟町１２－１０共同ビル（掘留）５Ｆ 久永&Co気付
tel.03-3664-2020 fax.03-3666-3188 URL:www.medmk.com/mm/ E-Mail: support@medmk.com
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- 関連●--------------------------------
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- ■2006 -------------------------------
★
★1232★22/08★06.04.10★031★骨髄異形成症候群の貧血治療薬レナリドミド（Revlimid - Celgene）/2p●MLリソース：骨髄異形成症候群[MDS]●MLリソース：貧血治療薬
- ■2005 -------------------------------
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- 作成：2005.3.23 最終更新:2006.12.28 小菅博之
The Medical Letter日本語版
●追加メモ to 1201,1232,1247
On Drugs and Therapeutics
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