MLリソース：遺伝性血管浮腫
Hereditary Angioedema(HAE)/遺伝性血管性浮腫Supported by Nobelpharma Co.Ltd.
in a part.
■個別製品日本語版註）人血漿由来C1－インアクチベーター濃縮製剤Lyophilized Human C1-inactivator Concentrate(Berinert[CSL Behring])ベリナート®P静注用500
【別名】BI3.012 【開発元】旧Behringwerke社→現CSL Behring [DBR_ID]08504
【化学名】
【承認】FDA承認=2009.10.12、米国発売=2010.1.27 ; 【製剤】Each vial of Berinert contains 500 units plasma-derived C1 Esterase Inhibitor (Human) lyophilized concentrate for reconstitution with 10 mL of diluent (sterile water) 【適応】(遺伝性血管性浮腫（HAE）の成人、青年期患者の急性腹部、顔面発作の治療薬) indicated for the treatment of acute abdominal or facial attacks of hereditary angioedema (HAE) in adult and adolescent patients 【用法用量】20単位/Kgを１分間4mLの速度で静注
【作用】C1-インアクチベーターは478個のアミノ酸残基からなる分子量105,000の糖蛋白で、活性化補体第１成分(C1)の他、血液凝固・線溶系の第m歛因子、第m杪因子、プラスミン及びカリクレインに対して阻止作用を有する。C1-インアクチベーターは、1対1のモル比で前述の活性物質と複合体を形成することによって、その活性を阻害する。 【特徴】
【製品情報】www.berinert.com 【添付文書】Berinert-PI
【提携】 【EU】 ドイツ、スイス、アメリカなど22ヶ国で承認されている。
【日本】ベリナート®P静注用500[CSLベーリング]承認1990.6.29(2009.1.8販売名変更による)、薬価収載1990.8.24(2009.3.24販売名変更による)、発売1990.9.3 【製剤～日本】1バイアル10ml中に、健常人血漿1mL中のヒトC1-インアクチベーター活性の500倍以上を含有。 【適応～日本】遺伝性血管神経性浮腫の急性発作 【用法用量～日本】本剤を添付の日局注射用水全量で徐々に溶解し、直接静注するか、点滴静注する。直接静注の場合は、緩徐に行う。 通常、成人には1,000～1,500倍を投与する。本剤投与後、数時間以内に効果の発現が認められないか、あるいは、不十分な場合には、500～1,000倍を追加投与する。また、24時間後でも症状の改善が不十分な場合には、その症状に応じて繰り返し投与する。 【添付文書～日本】添付文書 - インタビューフォーム
【開発の経緯】
本剤は、CLB Behring(旧ベーリングベルケ社)が開発した乾燥濃縮人C1-インアクチベーター製剤である。C1-インアクチベーターは、活性化補体第一成分(C1)、血液凝固・線溶系、カリクレイン系に対して広範な阻止作用を有するインヒビターである。
C1-インアクチベーター製剤は、遺伝性血管神経性浮腫（HAE：hereditaryangioedema）の治療薬として既に1977年からドイツで販売されているが、1985年にパスツリゼーション処理C1-インアクチベーター製剤への切り替えが実施されたことを契機として、本邦においてヘキストジャパン株式会社（現サノフィ・アベンティス株式会社）が1986年3月にHAE患者を対象に臨床試験を開始し、1990年6月に承認された。審査の段階において、本剤の対象となるHAE患者の本邦における患者数は、十数家系100から150例と推定され、他に本疾患に有効な薬剤がないことから本剤は稀用医薬品（稀少疾病用医薬品）に1994年12月7日付けで承認され、再審査期間が6年から10年に延長された。 2004年10月にCSLベーリング株式会社（旧ZLBべーリング株式会社）に承継された。
[1345]●ヒトＣ１エステラーゼ阻害物質Human C1 inhibitor(Cinryze[ViroPharma SPRL])日本語版註）ヒトＣ１エステラーゼ阻害物質Human C1 inhibitor(Cinryze[ViroPharma SPRL])
【別名】 【開発元】蘭Sanquin Blood Supply Foundationが創製、Lev Pharmaceuticals, Incが開発権のライセンスを受けたが、その後Lev社は2008.10.21にViropharma Incに買収され権利が移転した。 [DBR_ID]
【化学名】a sterile, stable, lyophilized preparation of C1 esterase inhibitor derived from human plasma. CINRYZE is manufactured from human plasma purified by a combination of filtration and chromatographic procedures. The specific activity of CINRYZE is 4.0 - 9.0 units/mg protein.
【承認】FDA申請=2007.7.31、FDA承認=2008.10.10、米国発売=2008.11.5 ; 【製剤】A C1 esterase inhibitor approximately 500 Units (lyophilized) in a 8 mL vial. 【適応】(遺伝性血管性浮腫（HAE）を有する思春期若年者や成人の血管浮腫発作の予防) indicated for routine prophylaxis against angioedema attacks in adolescent and adult patients with Hereditary Angioedema (HAE). 【用法用量】3-4日毎に1000単位を静注。１分1mLの速度で注入。
【作用】C1 inhibitor is a normal constituent of human blood and is one of the serine proteinase inhibitors (serpins). The primary function of C1 inhibitor is to regulate the activation of the complement and intrinsic coagulation (contact system) pathway. C1 inhibitor also regulates the fibrinolytic system. Regulation of these systems is performed through the formation of complexes between the proteinase and the inhibitor, resulting in inactivation of both and consumption of the C1 inhibitor. 【特徴】
【製品情報】www.cinryze.com 【添付文書】Cinryze-PI
【提携】 【EU】EMEA申請2008.7.1
【日本】未開発 【その他】
[1345]●エカランタイドecallantide（Kalbitor - Dyax）日本語版註）エカランタイドecallantide（Kalbitor - Dyax）
【別名】DX-88 【開発元】Dyax Corpダイアックス社 [DBR_ID]
【化学名】a 60-amino-acid protein produced in Pichia pastoris yeast cells by recombinant DNA technology.
【承認】FDA申請=2008.9.23、FDA諮問委承認勧告=2009.2.4、FDA承認=2009.11.27、米国発売=2010.2.2 ; 【製剤】Single use glass vial containing 10 mglmL of ecallantide as a solution for injection 【適応】(遺伝性血管性浮腫の急性発作に対する治療薬) indicated for treatment of acute attacks of hereditary angioedema (HAE) in patients i 6 years of age and older. 【用法用量】30mg (3 mL), administered subcutaneously in three io mg (I mL) injections. If an attack persists, an additional dose of 30 mg may be administered within a 24 hour period. (
【作用】(エカランタイドはC1抑制因子の欠損で活性化しているこの血清カリクレインを強力かつ特異的に阻害する薬剤) Hereditary angioedema (HAE) is a rare genetic disorder caused by mutations to C1-esterase-inhibitor (C1-INH) located on Chromosome 1 1q and inherited as an autosomal dominant trait. HAE is characterized by low levels of C 1 - INH activity and low levels of C4. C 1 - INH functions to regulate the activation of the complement and intrinsic coagulation (contact system pathway) and is a major endogenous inhibitor of plasma kallkrein. The kallikrein-kinin system is a complex proteolytic cascade involved in the initiation of both inflammatory and coagulation pathways. One critical aspect of this pathway is the conversion of High Molecular Weight (HMW) kininogen to bradykinin by the protease plasma kallikrein. In HAE, normal regulation of plasma kallkrein activity and the classical complement cascade is therefore not present. During attacks, unregulated activity of plasma kallikrein results in excessive bradykinin generation. Bradykinin is a vasodilator which is thought by some to be responsible for the characteristic HAE symptoms of localized swelling, inflammation, and pain.KALBITOR is a potent (Ki = 25 pM), selective, reversible inhibitor of plasma kallikrein. KALBITOR binds to plasma kallikrein and blocks its binding site, inhibiting the conversion ofHMW kininogen to bradykinin. By directly inhibiting plasma kallikrein, KALBITOR reduces the conversion ofHMW kininogen to bradykinin and thereby treats symptoms of the disease during acute episodic attacks of HAE.
【特徴】a human plasma kallkrein inhibitor for injection for subcutaneous use. Ecallantide is a 60-amino-acid protein produced in Pichia pastoris yeast cells by recombinant DNA technology.
【製品情報】www.kalbitor.com 【添付文書】KALBITOR-PI
【提携】 【EU】EU申請2010.7.6；欧州では承認審査段階にありイタリアの製薬会社シグマ・タウが販売する予定です。[2010.6.21契約]シグマ・タウは欧州、北アフリカ、中近東、ロシアの権利獲得
【日本】ecallantide(「エカランタイド」、米国での販売名Kalbitor®)[[シミック]開発準備中 【その他】
[1345,1378]●icatibant(Firazyr[Jerini AG])
日本語版註）icatibant(Firazyr[Jerini AG])
【別名】HOE 140 【開発元】Sanofi-Aventisが創製したが、独Jerini AGが2001.11.13に全世界のライセンスを獲得した。その後2008.07.03にJerini AGがShire Limitedにより買収 [DBR_ID]
【化学名】a synthetic decapeptide with five non-proteinogenic amino acids. D-Arginyl-L-arginyl-L-prolyl-L[(4R)-4-hydroxyprolyl]-glycyl-L[3-(2-thienyl)alanyl]-Lseryl-D-(1,2,3,4-tetrahydroisoquinolin-3-ylcarbonyl)-L[(3aS,7aS)-octahydroindol-2-ylcarbonyl]-Larginine, acetate salt
【承認】FDA申請=2007.10.8、FDA不許可通知=2008.4.24 、FDA再申請=2008.6.23、FDA承認勧告=23-Jun-2011、FDA承認=25-Aug-2011、米国発売=Aug-2011 ; 【製剤】prefilled syringe Injection:Each syringe delivers 3 mL solution with a concentration of 10 mg per mL 【適応】to treat acute attacks of hereditary angioedema (HAE) in adults 18 years of age and older. It is not known if FIRAZYR is safe or effective for children under 18 years of age. 【用法用量】30mgを下腹部に皮下注。 不十分なときは６時間を空けて投与するが、24時間以内には３回迄
【作用】Icatibant is a competitive antagonist selective for the bradykinin B2 receptor, with an affinity similar to bradykinin. Hereditary angioedema is caused by an absence or dysfunction of C1-esterase-inhibitor, a key regulator of the Factor XII/kallikrein proteolytic cascade that leads to bradykinin production. Bradykinin is a vasodilator which is thought to be responsible for the characteristic HAE symptoms of localized swelling, inflammation, and pain. Icatibant inhibits bradykinin from binding the B2 receptor and thereby treats the clinical symptoms of an acute, episodic attack of HAE. 【特徴】
【製品情報】www.firazyr.com 【添付文書】Firazyr-PI
【提携】[2005.11.7]Icatibantのアメリカ・カナダでの開発、販売権をKos Pharmaceuticals, Inc.にサブライセンス →2006.11.6 Kosは米Abbottにより買収 →2007.9.17 AbbottとのIcatibant契約を解消、北米の権利を再取得
【EU】Firazyr[Jerini AG] 申請受理2007.8.16 承認勧告2008.4.24 承認2008.07.15
【製剤～EU】Each pre-filled syringe of 3 ml contains icatibant acetate equivalent to 30 mg icatibant. Each ml of the solution contains 10 mg of icatibant. 【適応～EU】indicated for symptomatic treatment of acute attacks of hereditary angioedema (HAE) in adults (with C1-esterase-inhibitor deficiency). 【用法用量～EU】１回30mgを皮下注。 効果不十分なとき6時間経過後再度皮下注、24時間以内に３度目は投薬しないこと。 【添付文書～EU】Firazyr-PI
【日本】未開発 【その他】
[]●conestat alfa(Ruconest(TM)[Pharming NV])日本語版註）conestat alfa(Ruconest(TM)[Pharming NV])
【日本語版コメント1378～【短信】遺伝性血管浮腫治療薬イカチバントIcatibant(Firazyr - Shire)】
【別名】Rhucin®欧州外; rhC1INH 【開発元】Pharming NV [DBR_ID]
【化学名】Conestat alfa is the recombinant analogue of the human C1 esterase inhibitor (rhC1INH) produced by recombinant DNA technology in the milk of transgenic rabbits.
【承認】FDA申請=2011.1予定、FDA承認= ; 【製剤】 【適応】 【用法用量】
【作用】Conestat alfa, recombinant human complement component 1 (C1) esterase inhibitor (rhC1INH), is an analogue of human C1INH and is obtained from the milk of rabbits expressing the gene encoding for human C1INH. The amino acid sequence of conestat alfa is identical to that of endogenous C1INH. 【特徴】The efficacy and safety of Ruconest as a treatment of acute angioedema attacks in patients with HAE has been evaluated in two double blind randomized placebo controlled and four open label clinical studies. The doses evaluated in the clinical studies ranged from a single vial of 2100 U (corresponding to 18-40 U/kg), to 50 and 100 U/kg. Efficacy of Ruconest as a treatment for acute angioedema attacks was demonstrated by significantly shorter time to beginning of relief of symptoms and time to minimal symptoms and few therapeutic failures.
【製品情報】 【添付文書】
【提携】2010.9.13北米開発販売権をSantarus, Incにライセンス
【EU】Ruconest[Pharming Group N.V]；EU申請=2006.7.21、EU不許可=2008.3.20、EU再申請=2009.9.3、EU承認=2010.10.28
【製剤～EU】One vial contains 2100 units of conestat alfa, corresponding to 2100 units per 14 ml after reconstitution, or a concentration of 150 units/ml. 【適応～EU】Ruconest is indicated for treatment of acute angioedema attacks in adults with hereditary angioedema (HAE) due to C1 esterase inhibitor deficiency. 【用法用量～EU】[成人体重84Kg未満]50単位/kg静注 [成人体重84Kg以上]4200単位(２バイアル)静注 【製品情報～EU】Ruconest 【添付文書～EU】Ruconest-PI
【日本】未開発 【その他】
遺伝性血管性浮腫(HAE)の日本の患者数は約1000人(シミック社)、日本の治療薬はベリナートP静注用500のみだが、米国では最近３剤が承認発売された。Cinryze[ViroPharma SPRL])、FDA承認2008.10.10、米国発売2008.11.5、EU承認2011.6.15、日本未開発；エカランタイドecallantide（Kalbitor[Dyax社]FDA承認2009.11.27、米国発売2010.2.2、EU申請2010.7.6、日本開発準備中[シミック]）、icatibant(Firazyr[Shire]EU承認2008.07.15、米承認2011.8.25、米発売2011.8、日本未開発)。
これ以外にも欧州では1剤が販売されている。 conestat alfa(Ruconest(TM)、欧州外Rhucin@ﾀ[Pharming NV]EU承認2010.10.28、米2010.12.28申請、2011.2.28FDA受付拒否、日本未開発)。
【日本語版コメント1345～遺伝性血管浮腫の3つの新薬:Cinryze(Viro),Berinert(CSL Behring),ecallantide（Kalbitor - Dyax）】
遺伝性血管性浮腫(HAE;Meddra-Jでは遺伝性血管浮腫)は、補体成分C1 インヒビター(C1INH)の欠損によるもので、症状と徴候は血管性浮腫と似ているが，浮腫は補体成分が消費されてしまうまで進行し，しばしば消化管が侵され，悪心，嘔吐，疝痛，および腸閉塞の徴候を引き起こす点で異なる。 因みに補体研究会から「遺伝性血管性浮腫 (HAE) ガイドライン 2010」が公開されている。
患者数は欧米では5～15万人に1人程度とされているが(米国6000人)、日本では大規模疫学調査が行なわれていないため不明(500人程度との説あり)。 一般的には致死的な疾患ではないとされるが、2002年1月調査で『HAE』の医師認知度44.8%であったにもかかわらず、全国救命救急センターを対象に実施したアンケート調査で『HAE』を経験施設が4施設(4.5%)に及んだことに注目。 喉頭部に浮腫が発生したにも関わらず、適切に治療されない場合、その致死率は30%に及ぶことも特筆すべき。また、あらゆる年齢で発症することも特徴的。
治療薬は、日本ではベリナート®P静注用500のみだが、米国では最近３剤が承認発売された。
C1－インアクチベーター製剤は、ベリナート®P静注用500/Berinert[CSL Behring])FDA承認2009.10.12、米国発売2010.1.27、EU販売(独1977年等)、日本発売1990.9.3；Cinryze[ViroPharma SPRL])、FDA承認2008.10.10、米国発売2008.11.5、EU申請2008.7.1、日本未開発；エカランタイドecallantide（Kalbitor[Dyax社]FDA承認2009.11.27、米国発売2010.2.2、EU申請2010.7.6、日本開発準備中[シミック]）。
これ以外にも欧州では２剤が販売されている。 conestat alfa(Ruconest(TM)、欧州外Rhucin@劯Pharming NV]EU承認2010.10.28、米2011.1申請予定、日本未開発)、icatibant(Firazyr[Jerini AG]EU承認2008.07.15、米再申請2008.6.23、日本未開発)。
【市場】 【開発中の新薬】 ●「治験」ホームページ[厚生労働省] - 開発中の新薬[＜情報提供：日本製薬工業協会＞] /2010.11.20 会社別開発中新薬一覧。 検索機能なし。７９社から情報提供●New Medicines in Development[PhRMA 米製薬協] /2010.11.16
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) カルビトールecallantide(「エカランタイド」、米国での販売名Kalbitor®)[シミック] 遺伝性血管性浮腫 開発準備中 米発売201002 シミック株式会社は、Dyax Corp/ダイアックス社から日本の開発販売権獲得[2010.9.30] 【メモ】エカランタイドはC1抑制因子の欠損で活性化しているこの血清カリクレインを強力かつ特異的に阻害する薬剤としてダイアックス社が発見し開発した治療薬で、遺伝性血管性浮腫の急性発作に対する治療薬として米国では2009年12月に承認され2010年2月から販売されている新薬です。欧州では承認審査段階にありイタリアの製薬会社シグマ・タウが販売する予定です。 日本の患者数約1000人、申請予定2013下期、発売予定2014下期 【メモ】 from Wolters Kluwer Health's Adis R&D Insight 【解説資料】 ●メルクマニュアル第18版日本語版 遺伝性血管性浮腫 【データ】 ●厚生労働省：重篤副作用疾患別対応マニュアル ○血管性浮腫 ●重篤副作用総合対策検討会（第４回）[2007.12.13] （８）血管性浮腫 【臨床ガイドライン】 ●遺伝性血管性浮腫 (HAE) ガイドライン 2010[pdf,5p] by 補体研究会 【総説記事・文献】 【ニュース・トピックス】 ●『HAE』を学ぶ[医薬経済社2010.3.5] 今回取り上げるのは、CSLベーリングメディア勉強会での講演「医療現場で見逃される遺伝性血管性浮腫とは」(医療法人社団望星会、順天堂大学医学部腎臓内科客員准教授・大井洋之氏)。ドクターにも良く知られていない『HAE』の現状について聴いた。
Registered Name Company Status Indication 備考 Cinryze(TM)(Complement C1 inhibitor) Sanquin Blood Supply Foundation (Originator)/ViroPharma(Licensee) 米承認2008.10.10 Hereditary angioedema Firazyr® (Icatibant) sanofi-aventis (Originator)/Jerini AG(Licensee) 米申請2007.10.29
欧承認2008.7.15Hereditary angioedema [2001.11.13世界独占契約]
独Jerini AGは、2008.07.03に、Shire plcにより買収されたRuconest(TM)(Rhucin®欧州外)(conestat alfa,a recombinant version of the human C1 inhibitor (C1INH) protein) Pharming NV 欧承認2010.10.28
米国申請2011.1予定Hereditary angioedema 2010.9.13北米開発販売権をSantarus, Incにライセンス 米 『HAE』の患者数はどの程度いるのでしょうか。欧米では5～15万人に1人程度とされています。日本では大規模な疫学調査が行なわれていないため有病率はわかりません。『HAE』の診断にあたっては、図2にある症候に注意する必要があります。特筆すべきは喉頭浮腫です。喉頭部に浮腫が発生したにも関わらず、適切に治療されない場合、その致死率は30%に及びます。また、あらゆる年齢で発症することも特徴的です。
2002年1月、全国の救命救急センターを対象に実施したアンケート調査(99年1月時点で救命救急センターとして登録されていた142施設を対象。回答数88施設)によれば、『HAE』を知っていたのは39施設(44.3%)。そのうち『HAE』を経験したのは4施設(4.5%)に止まっていました。
これだけであれば、『HAE』自体が極めて稀な疾患であることから、認知度も低いといえるかも知れません。しかし一方で、『HAE』を知らなかったと回答した49施設のうち、14施設で「『HAE』と考えられる症例に遭遇した」と回答しています。救命救急施設でそれなりに受診されているものの、肝心の医師に疾患が認知されていないことの証左といえるのではないでしょうか。
全国2100の医療施設から9279名のドクターを対象としたアンケート調査(回答率48.4%)でも、『HAE』を知っていたのは2013名(44.8%)に止まっています。診療科別に『HAE』の認知度を見てみると、皮膚科で93.2%、血液内科で60.3%と高く、以下、小児科(50.5%)、歯科口腔外科(45.3%)、呼吸器内科(42.0%)、救命救急科(41.3%)、耳鼻咽喉科(40.1%)、消化器内科(34.6%)、麻酔科(30.0%)、消化器外科(16.1%)となっています。
【リンク・リソース】 【主要サイト】 [CSLベーリング社l]遺伝性血管性浮腫 (HAE) - 希少疾患 遺伝性血管性浮腫（HAE）の研究活動を本格化[2009.8.6] [CSLベーリング社l]ベリナート®P静注用500 ●補体研究会 遺伝性血管性浮腫 (HAE) ●血管腫・血管奇形の患者会 代表者（木村香織）、2006年5月に発足 ●血管腫・血管奇形IVR研究会 Japanese Society of Interventional Radiology for Vascular Anomalies 事務局：財団法人 脳神経疾患研究所附属 総合南東北病院 血管内治療研究所･総合血管内治療センター 〒963-8563 福島県郡山市八山田7丁目115 TEL 024-934-5322/FAX 024-934-3165 ●血管腫・血管奇形研究会
●解説
■遺伝性血管性浮腫（Hereditary angioedema: HAE）
●概要
HAE は、補体成分C1 インヒビター(C1INH)の欠損によるもので、疾患を知っていれば診断は比較的容易である。
●分類/病型
1.１型（ HAE全体の 85%）常染色体優性遺伝 C１インヒビタータンパク量低値、 C1インヒビター活性低値 2.２型（ HAE全体の 15%）常染色体優性遺伝 C１インヒビタータンパク量正常または上昇、 C1インヒビター活性低値 3.３型（稀）エストロゲン依存性、女性に発症、病態の詳細は不明であるが、一部に は凝固第 XII因子の変異を認める。 C１インヒビタータンパク量正常、C1インヒビター活性正常 家族歴のない弧発例は、HAE全体の約 25％に認められている。 その他に後天性血管性浮腫（ Acquired angioedema: AAE）、薬剤性血管性浮腫などがある。
●疫学
1 万人に1 人～15 万人に1 人（5 万人に1 人との報告が多い）
●症状
症状と徴候は血管性浮腫と似ているが，浮腫は補体成分が消費されてしまうまで進行し，しばしば消化管が侵され，悪心，嘔吐，疝痛，および腸閉塞の徴候を引き起こす点で異なる。
●原因
遺伝性血管性浮腫は，補体活性化の古典経路を調節する蛋白である，C1抑制因子の欠損（1型；85％）または機能異常（2型；15％）によって引き起こされる。遺伝は常染色体優性遺伝である。腫瘍性疾患において補体成分が消費される，または単クローン性ガンマグロブリン血症においてC1抑制因子に対する自己抗体が産生されると，C1抑制因子の欠損が起こりうる（後天性欠損）。発作は外傷またはウイルス性疾患によって突然引き起こされ，情緒的ストレスにより悪化する
●診断
診断は，C2およびC4（C1の基質）レベルの低下，正常レベルのC1q（C1の分断断片），ならびにC1抑制因子の機能低下の検出による。C1抑制因子の蛋白レベルは1型では低く，2型では上昇しているか正常である。後天性のC1抑制因子欠損ではC1qレベルが低い。
a. 遺伝性血管性浮腫を疑う症候 皮下浮腫、粘膜下浮腫（痒みを伴わない、あらゆる部位） 消化器症状（腹痛、吐き気、嘔吐、下痢） 喉頭浮腫（３歳以下では稀、喉頭浮腫を生じたにもかかわらず適切に治療をされない 場合の致死率は３０％） 発作は精神的ストレス、外傷や抜歯、過労などの肉体的ストレス、妊娠、生理、薬物 などで誘発される。 発作は通常２４時間でピークとなり７２時間でおさまるが、それ以上続くこともある。 家族歴がある。 あらゆる年齢で発症する。 b. スクリーニング C1 インヒビター活性（保険適応）で低値となる。 発作時に、C4 はHAE の９８％で低値となるため、C4 測定は有効な目安になる。 c. さらに詳しく病型を検討する場合 C1 インヒビター定量（保険適応外）を行う。 低値であれば 1 型HAE 正常値ならば 2 型HAE d. 家族歴がない場合、後天性血管性浮腫との鑑別が必要となる C1q（保険適応外）が低値であれば後天性とされているが、遺伝性の場合でも低値を 示す場合がある。確定診断のためには、遺伝子解析が必要となる。 e. ３型HAE を疑う場合は、第XII 因子の変異の可能性がある。
●検査
遺伝性血管性浮腫を軽度疑う場合 血清C4 測定を行う。 低値→C1 インヒビター活性測定を行う。 正常→遺伝性血管性浮腫はほぼ否定できる。 遺伝性血管性浮腫を強く疑う場合 C1 インヒビター活性測定を行う 低値→C1 インヒビター欠乏による血管性浮腫と診断できる。→以下のように 病型の鑑別を行う 家族歴がある→遺伝性血管性浮腫と診断できる。→C1 インヒビター定 量を行う→低値の場合は１型、正常または上昇の場合は２型と診断できる。 家族歴がない→血清C1q 測定を行い低値ならば後天性血管性浮腫の可 能性があるとされるが例外も多い。→確定診断のためには遺伝子解析が 望ましい。 正常→３型や薬剤性血管性浮腫を疑う→薬剤服用歴(とくに降圧剤、 エストロゲン製剤)の確認。なお３型は日本人での報告はないが、欧米の 報告では家族性があり女性のみに発症する。
●治療
治療は，肝臓でのC1抑制因子合成を促進するため弱化アンドロゲン（例，スタノゾロール2mg，経口投与，1日3回，またはダナゾール200mg，経口投与，1日3回）で行う。発作を予防するため歯科または医療処置の直前に新鮮凍結血漿を投与することを推奨する専門家もいるが，この手法は標準的ではなく，理論上は基質を供給することによって血管性浮腫の発作を誘発する可能性がある。急性期の治療に，精製C1抑制因子および遺伝子組み換えC1抑制因子を用いる。
４．発作時の治療 １．皮下浮腫（顔、頚部以外） 経過観察、 トラネキサム酸（１５ｍｇ/kg 4 時間毎）、 C1 インヒビター補充療法（５０ｋｇ以下 ５００単位、５０ｋｇ以上 １０００ ～１５００単位 静注） ２．皮下浮腫（顔、頚部） トラネキサム酸（１５ｍｇ/kg 4 時間毎）、 C1 インヒビター補充療法（５０ｋｇ以下 ５００単位、５０ｋｇ以上 １０００ ～１５００単位 静注） ３．腹部症状 トラネキサム酸（１５ｍｇ/kg 4 時間毎）、 C1 インヒビター補充療法（５０ｋｇ以下 ５００単位、５０ｋｇ以上 １０００ ～１５００単位 静注） ４、喉頭浮腫 C1 インヒビター補充療法（５０ｋｇ以下 ５００単位、５０ｋｇ以上 １０００ ～１５００単位 静注） ICU における気管内挿管、気管切開５．短期予防 １. 歯科治療（侵襲性が弱い場合）など小ストレス時 C1 インヒビター補充療法の準備の上ならば予防は必要なし ２．歯科治療（侵襲性が強い場合）外科手術など大ストレス時 術前１時間前のC1 インヒビター補充療法（５０ｋｇ以下 ５００単位、５０ｋｇ 以上 １０００～１５００単位 静注）更に２度目のC1 インヒビター補充療法の 準備をしておく ６．長期予防 １ヶ月に１回以上、１ヶ月に５日以上の発作期間、喉頭浮腫の既往歴の場合検討する。 1. トラネキサム酸 30-50mg/kg/日を１日２‐３回に分けて服用 副作用 筋肉痛、筋力低下、疲労感、血圧低下 2. ダナゾール 2.5mg/kg/日（最大200mg/日）を１ヶ月、もし無効ならば300mg/日を１ヶ月、更 に無効ならば400mg/日を１ヶ月 200mg/日で有効ならばその後 100mg/日を１ヶ月、50mg/日または100mg/隔日 へ減量する。 禁忌：小児、妊婦、授乳中、癌患者 副作用：男性化、肝障害、高血圧、脂質異常、多血症、出血性膀胱炎 経過観察：６ヶ月毎の血液検査が必要、また 200mg/日以上の場合 ６ヶ月毎の 腹部エコー、200mg/日以下の場合 １年毎の腹部エコーが必要（肝腫瘍出現 の可能性があるため）
��発作時の治療 皮下浮腫
顔、頚部以外皮下浮腫
顔、頚部腹部症状 喉頭浮腫 経過観察 ＋ ＋ ＋ ＋ トラネキサム酸 ＋ ＋ ＋ ＋ C1インヒビター ＋／‐ ＋ ＋ ＋ ICUでの処置 ‐ ‐ ‐ ＋
●薬物治療
●予後
●参考資料
●メルクマニュアル第18版日本語版 - 遺伝性血管性浮腫 ●遺伝性血管性浮腫 (HAE) ガイドライン 2010[pdf,5p] by 補体研究会
●データ
●臨床ガイドラインなど
●総説記事・文献
●ニュース・トピックス
●リンク＆リソース
●主要サイト
[1345]●製品 人血漿由来C1－インアクチベーター濃縮製剤Lyophilized Human C1-inactivator Concentrate(Berinert[CSL Behring])ベリナート®P静注用500
日本語版註）人血漿由来C1－インアクチベーター濃縮製剤Lyophilized Human C1-inactivator Concentrate(Berinert[CSL Behring])ベリナート®P静注用500
【別名】BI3.012 【開発元】旧Behringwerke社→現CSL Behring [DBR_ID]08504
【化学名】
【承認】FDA承認=2009.10.12、米国発売=2010.1.27 ; 【製剤】Each vial of Berinert contains 500 units plasma-derived C1 Esterase Inhibitor (Human) lyophilized concentrate for reconstitution with 10 mL of diluent (sterile water) 【適応】(遺伝性血管性浮腫（HAE）の成人、青年期患者の急性腹部、顔面発作の治療薬) indicated for the treatment of acute abdominal or facial attacks of hereditary angioedema (HAE) in adult and adolescent patients 【用法用量】20単位/Kgを１分間4mLの速度で静注
【作用】C1-インアクチベーターは478個のアミノ酸残基からなる分子量105,000の糖蛋白で、活性化補体第１成分(C1)の他、血液凝固・線溶系の第m歛因子、第m杪因子、プラスミン及びカリクレインに対して阻止作用を有する。C1-インアクチベーターは、1対1のモル比で前述の活性物質と複合体を形成することによって、その活性を阻害する。 【特徴】
【製品情報】www.berinert.com 【添付文書】Berinert-PI
【提携】 【EU】 ドイツ、スイス、アメリカなど22ヶ国で承認されている。
【日本】ベリナート®P静注用500[CSLベーリング]承認1990.6.29(2009.1.8販売名変更による)、薬価収載1990.8.24(2009.3.24販売名変更による)、発売1990.9.3 【製剤～日本】1バイアル10ml中に、健常人血漿1mL中のヒトC1-インアクチベーター活性の500倍以上を含有。 【適応～日本】遺伝性血管神経性浮腫の急性発作 【用法用量～日本】本剤を添付の日局注射用水全量で徐々に溶解し、直接静注するか、点滴静注する。直接静注の場合は、緩徐に行う。 通常、成人には1,000～1,500倍を投与する。本剤投与後、数時間以内に効果の発現が認められないか、あるいは、不十分な場合には、500～1,000倍を追加投与する。また、24時間後でも症状の改善が不十分な場合には、その症状に応じて繰り返し投与する。 【添付文書～日本】添付文書 - インタビューフォーム
【開発の経緯】
本剤は、CLB Behring(旧ベーリングベルケ社)が開発した乾燥濃縮人C1-インアクチベーター製剤である。C1-インアクチベーターは、活性化補体第一成分(C1)、血液凝固・線溶系、カリクレイン系に対して広範な阻止作用を有するインヒビターである。
C1-インアクチベーター製剤は、遺伝性血管神経性浮腫（HAE：hereditaryangioedema）の治療薬として既に1977年からドイツで販売されているが、1985年にパスツリゼーション処理C1-インアクチベーター製剤への切り替えが実施されたことを契機として、本邦においてヘキストジャパン株式会社（現サノフィ・アベンティス株式会社）が1986年3月にHAE患者を対象に臨床試験を開始し、1990年6月に承認された。審査の段階において、本剤の対象となるHAE患者の本邦における患者数は、十数家系100から150例と推定され、他に本疾患に有効な薬剤がないことから本剤は稀用医薬品（稀少疾病用医薬品）に1994年12月7日付けで承認され、再審査期間が6年から10年に延長された。 2004年10月にCSLベーリング株式会社（旧ZLBべーリング株式会社）に承継された。US Pharmacopeial Commission AMA: United States Adopted Names BIAM --- BIAM -ABC順|BIAM -会社順 NLM: MeSH HOme ---MeSH Online search08504-3320 C1-INACTIVATOR by HOECHST AG[WG]
BERINERT-P;BERINERT-P ﾍﾞﾘﾅｰﾄP;BI-3.012;C1-INA;C1-INACTIVATOR;C1-INHIBITOR;ﾍﾞﾘﾅｰﾄP
《JA》BERINERT-P ﾍﾞﾘﾅｰﾄP（ヘキスト・ジャパン㈱）09-90＊HANESｼｮｳｺｳｸﾞ∥《WG》BERINERT-P（BEHRINGWERKE AG）-90＊
【日本語版コメント1345～遺伝性血管浮腫の3つの新薬:Cinryze(Viro),Berinert(CSL Behring),ecallantide（Kalbitor - Dyax）】
遺伝性血管性浮腫(HAE;Meddra-Jでは遺伝性血管浮腫)は、補体成分C1 インヒビター(C1INH)の欠損によるもので、症状と徴候は血管性浮腫と似ているが，浮腫は補体成分が消費されてしまうまで進行し，しばしば消化管が侵され，悪心，嘔吐，疝痛，および腸閉塞の徴候を引き起こす点で異なる。 因みに補体研究会から「遺伝性血管性浮腫 (HAE) ガイドライン 2010」が公開されている。
患者数は欧米では5～15万人に1人程度とされているが(米国6000人)、日本では大規模疫学調査が行なわれていないため不明(500人程度との説あり)。 一般的には致死的な疾患ではないとされるが、2002年1月調査で『HAE』の医師認知度44.8%であったにもかかわらず、全国救命救急センターを対象に実施したアンケート調査で『HAE』を経験施設が4施設(4.5%)に及んだことに注目。 喉頭部に浮腫が発生したにも関わらず、適切に治療されない場合、その致死率は30%に及ぶことも特筆すべき。また、あらゆる年齢で発症することも特徴的。
治療薬は、日本ではベリナート®P静注用500のみだが、米国では最近３剤が承認発売された。
C1－インアクチベーター製剤は、ベリナート®P静注用500/Berinert[CSL Behring])FDA承認2009.10.12、米国発売2010.1.27、EU販売(独1977年等)、日本発売1990.9.3；Cinryze[ViroPharma SPRL])、FDA承認2008.10.10、米国発売2008.11.5、EU申請2008.7.1、日本未開発；エカランタイドecallantide（Kalbitor[Dyax社]FDA承認2009.11.27、米国発売2010.2.2、EU申請2010.7.6、日本開発準備中[シミック]）。
これ以外にも欧州では２剤が販売されている。 conestat alfa(Ruconest(TM)、欧州外Rhucin@劯Pharming NV]EU承認2010.10.28、米2011.1申請予定、日本未開発)、icatibant(Firazyr[Jerini AG]EU承認2008.07.15、米再申請2008.6.23、日本未開発)。→詳細は参考資料●MLリソース：遺伝性血管浮腫に纏めた。＜日本語版コメント要約＞
・米国では過去2年間に、妊婦を除く青年期および成人期の遺伝性血管浮腫（HAE）の予防または治療薬として、3つの新薬が承認された。
・C1エステラーゼ阻害薬Cinryzeは、3～4日ごとに予防的に静注投与することにより、HAE発作の頻度と重症度が減少する。
・C1エステラーゼ阻害薬Berinertとカリクレイン阻害薬エカランチドは、HAEの急性発作に対する治療効果が示されている。
・HAEの予防に長年用いられてきたダナゾールやスタノゾロールなどの作用の弱いアンドロゲンと、Cinryzeとの直接比較データはない。
●承認データ：FDA ●FDA Newsroom - FDA Press Releases FDA Approves Berinert to Treat Abdominal Attacks, Facial Swelling Associated With Hereditary Angioedema[2009.10.9] ●Index to Drug-Specific Information ●FDA[Vaccines, Blood & Biologics> Blood & Blood Products>] Approved Products - C1 Esterase Inhibitor
★Drug Name(s) =Berinert[CSL Behring GmbH] [Proper Name:] C1 Esterase Inhibitor (Human) [Tradename:] Berinert [Manufacturer:] CSL Behring GmbH, License #1765 [Indication:] Treatment of acute abdominal or facial attacks of hereditary angioedema (HAE) in adult and adolescent patients. Package Insert - Berinert (PDF - 354KB) October 9, 2009 Approval Letter - Berinert Summary Basis for Regulatory Action - Berinert, October 8, 2009 (PDF - 264KB) Approval History, Letters, Reviews and Related Documents - Berinert
●FDA Advisory Committees 参考●ML資料：FDA諮問委員会～議題 FDA Advisory Committees 該当なし
●EU承認 ●ema - Human Medcines ●List of Authorized Products (EPARs)★[A-Z 承認品目] 該当なし
●CSL Limited[オーストラリア] ■Our Products ●Product Finder ●Complete Product List ■Our Businesses ●CSL Behring ●CSL Plasma ●CSL Biotherapies - Immunohaematology ●CSL Biotherapies - Australia ●CSL Biotherapies - New Zealand ●CSL Biotherapies - United States ●Research & Development Global R&D Product Pipeline ■Investors ●Financial Reports Annual Reports 2009 - 2010 ●Briefings & Presentations ★Results Briefings Full Year Results for 2006 - 23 August 2006[pdf,95p] - Media Release[pdf,6p] ★Operational Briefing ～R&D Briefing R&D Briefing 2006[pdf,65p;2006.12.14] ★Annual General Meeting ●ASX Releases～オーストラリア証券取引所・有価証券報告書 [14/12/2006] R & D Presentation[pdf,65p] Annual Report and Notice of Annual General Meeting[2006.9.15,PDF,243P] ●Newsroom CSL announces acquisition of CytoGamｮ from MedImmune[2006.11.6] CSL Full-year Result Announcement for 2006[2006.8.23] ZLB BEHRING Restructuring and Integration On Track[2004.5.11]～ZLB Bioplasmaも統合の方向で CSL Completes Acquisition of Aventis Behring to create ZLB Behring[2004.4.1]～買収により社名変更
●CSL Behring[米] - http://www.cslbehring.com/ 2004.3 CSLはAventis Behringを買収し、ZLB Behringを設立。 ■Products ●Bleeding Disorders(血液凝固因子) ●Critical Care(集中治療)～ショック、火傷、脱水症状 ～Albuminar/Berinert/Streptase/Beriplex P/N/Haemocomplettan P/Kybernin P/Fibrogammin P *日本未導入Beriplex P/N(Human prothrombin complex) Haemocomplettan P(Human fibrinogen) Streptase(Streptokinase) *Kybernin P(Human antithrombin III concentrate)/[日本]アンスロビンＰ ●Immunoglobulins(ヒト免疫グロブリン) ●Pulmonary(Zemaira(R) Human alpha1-proteinase inhibitor)～肺気腫(pulmonary emphysema)*日本未導入 ●Wound Healing(創傷治癒)～Beriplast P/Tachocomb/Fibrogammin P ●CSL Research & Development ★Product pipeline ●News Room - News Releases CSL Behring Receives Canadian Notice of Compliance for Berinert@�[2010.6.1]
CSL Behring announces completion of national marketing authorizations of Berinert@� after MRP in 23 European countries[2010.5.27]
Surveys Reveal High Frequency of Prodromal Symptoms Prior to Acute Hereditary Angioedema Attacks[2010.3.1]
Study Shows C1-Esterase Inhibitor Concentrate Rapidly Relieves Acute, Successive Attacks of Hereditary Angioedema at All Body Sites[2010.3.1]
CSL Behring Launches Berinert@� Expert Network (B.E.N.mV), Support System for Hereditary Angioedema Healthcare Providers, Patients and Caregivers[2010.1.27]
CSL Behring Announces FDA Approval of Berinert@�, First and Only Therapy Approved for the Treatment of Acute Abdominal and Facial Attacks of Hereditary Angioedema in U.S.[2009.10.12]
Rapid Treatment of Hereditary Angioedema Attacks at the Onset of Prodromal Symptoms Decreases Morbidity and Mortality[2009.3.15]
C1-Esterase Inhibitor Concentrate Rapidly Relieves Acute Swelling Attacks Across All Body Sites in Patients with Hereditary Angioedema, According to Study[2009.3.15]
CSL Behring Submits NDS to Health Canada Requesting Approval of C1-Esterase Inhibitor for the Treatment of Hereditary Angioedema[2008.4.17]
C1-Esterase Inhibitor Concentrate Rapidly Relieves Abdominal and Facial Attacks in Patients with Hereditary Angioedema, According to Pivotal Study[2008.3.18]
[2008.3.6]
CSL Behring Reaches Primary Endpoint in Clinical Study of C1-INH for Treatment of Hereditary Angioedema[2007.11.26]
CSL Behring Completes Enrollment of Phase III Clinical Study of C1 Inhibitor in Treating Hereditary Angioedema[2007.10.12]
■CSL Behring United States ●US Products ●Newsroom
●ＣＳＬベーリング株式会社 - http://www.cslbehring.co.jp/ 2001年4月1日よりアベンティス ベーリング ジャパン株式会社は、アベンティスベーリン グの日本法人としてプロモーション活動を開始。 2004年5月6日よりZLBベーリング株式会社に社名変更。 2007年4月1日ＺＬＢベーリング株式会社よりＣＳＬベーリング株式会社へ社名変更
2004年4月1日、オーストラリアを拠点とするバイオ医薬品企業CSL社グループ傘下のZLBバイオプラズマ社（本社：スイス）と、血漿蛋白製剤市場で世界第2位のシェアを有するアベンティス ベーリング社（本社：アメリカ）が統合され、ZLBベーリング社（本社：アメリカ）が設立されました。（こちら をご参照下さい）
これに伴い、日本法人であるアベンティス ベーリング ジャパン株式会社は、2004年5月6日をもちまして、ZLBベーリング株式会社と社名を改めることとなりましたのでご報告致します。尚、今後のベーリング製品の取扱いにつきましては、日本における事業移管が完了（2004年10月1日を予定）するまでは、従来どおり「製品の輸入及び国内販売」に関してはアベンティス ファーマ株式会社(本社：東京都港区、代表取締役会長兼社長：ジェームズ･ミッチャム)が継続し、「製品情報提供活動」はアベンティス ベーリング ジャパン株式会社（5月6日以降の社名：ZLBベーリング株式会社）(本社：東京都中央区、代表取締役社長：ヘルマン・ストレンガー)が継続して行ってまいります。
〈CSL社について〉
1916年、オーストラリアにワクチン及び細菌学的製剤を供給する連邦血清研究所として設立。生物由来製剤の開発、製造、販売に特化した企業グループを傘下に置き、血漿分画製剤、医薬品および診断薬、細胞培養試薬領域に事業を展開している。特に、静注用免疫グロブリン製剤の分野における専門技術で世界的に高い評価を受けている。〈ZLBバイオプラズマ社について〉
1949年、スイス赤十字の血漿分画製剤部門ZLB（Zentrallaboratorium in Bern）として設立。2000年にCSL社によって買収された血漿分画製剤に特化した会社。2004年4月1日、アベンティス ベーリング社と統合され、ZLBベーリングが設立される。〈アベンティス ベ－リング社について〉
アベンティス ベーリング社は、蛋白治療製剤業界の世界的リーダーであり、血液凝固疾患、免疫不全疾患、α1アンチプロテアーゼ欠損症、プラズマエキスパンダー、創傷治癒といった領域で30以上の製剤を提供。2004年4月1日、ZLBバイオプラズマ社と統合され、ZLBベーリングが設立される。●ニュースルーム ●血漿分画製剤について ●医療関係者向け情報 ●e-血液.com
[1345]●製品 ヒトＣ１エステラーゼ阻害物質Human C1 inhibitor(Cinryze[ViroPharma SPRL])
日本語版註）ヒトＣ１エステラーゼ阻害物質Human C1 inhibitor(Cinryze[ViroPharma SPRL])
【別名】 【開発元】蘭Sanquin Blood Supply Foundationが創製、Lev Pharmaceuticals, Incが開発権のライセンスを受けたが、その後Lev社は2008.10.21にViropharma Incに買収され権利が移転した。 [DBR_ID]
【化学名】a sterile, stable, lyophilized preparation of C1 esterase inhibitor derived from human plasma. CINRYZE is manufactured from human plasma purified by a combination of filtration and chromatographic procedures. The specific activity of CINRYZE is 4.0 - 9.0 units/mg protein.
【承認】FDA申請=2007.7.31、FDA承認=2008.10.10、米国発売=2008.11.5 ; 【製剤】A C1 esterase inhibitor approximately 500 Units (lyophilized) in a 8 mL vial. 【適応】(遺伝性血管性浮腫（HAE）を有する思春期若年者や成人の血管浮腫発作の予防) indicated for routine prophylaxis against angioedema attacks in adolescent and adult patients with Hereditary Angioedema (HAE). 【用法用量】3-4日毎に1000単位を静注。１分1mLの速度で注入。
【作用】C1 inhibitor is a normal constituent of human blood and is one of the serine proteinase inhibitors (serpins). The primary function of C1 inhibitor is to regulate the activation of the complement and intrinsic coagulation (contact system) pathway. C1 inhibitor also regulates the fibrinolytic system. Regulation of these systems is performed through the formation of complexes between the proteinase and the inhibitor, resulting in inactivation of both and consumption of the C1 inhibitor. 【特徴】
【製品情報】www.cinryze.com 【添付文書】Cinryze-PI
【提携】 【EU】EMEA申請2008.7.1
【日本】未開発 【その他】
US Pharmacopeial Commission AMA: United States Adopted Names BIAM --- BIAM -ABC順|BIAM -会社順 NLM: MeSH HOme ---MeSH Online search
●承認データ：FDA ●FDA Newsroom - FDA Press Releases ●Index to Drug-Specific Information ●FDA[Vaccines, Blood & Biologics> Blood & Blood Products>] Approved Products - C1 Esterase Inhibitor
★Drug Name(s) =CINRYZE(Lev Pharmaceuticals, Inc) [Proper Name:] C1 Esterase Inhibitor (Human) [Tradename:] CINRYZE [Manufacturer:] Lev Pharmaceuticals, Inc., License #1780 [Indication:] For routine prophylaxis against angioedema attacks in adolescent and adult patients with Hereditary Angioedema (HAE). -Supporting Documents Package Insert - CINRYZE (PDF - 409KB) October 10, 2008 Approval Letter - CINRYZE FDA Licenses for Marketing New Therapy for Rare Genetic Disease Summary Basis for Regulatory Action - CINRYZE Approval History, Letters, Reviews and Related Documents - CINRYZE
●FDA Advisory Committees 参考●ML資料：FDA諮問委員会～議題 FDA Advisory Committees CBER■Blood Products - http://www.fda.gov/AdvisoryCommittees/CommitteesMeetingMaterials/BloodVaccinesandOtherBiologics/BloodProductsAdvisoryCommittee/default.htm 2010 | 2009 | 2008 | 2006 | 2005 | 2004 | 2003
ML 開催日 議題 備考 1345 2008.05.02 Lev Pharmaceutical's plasma-derived C1 esterase inhibitor (CINRYZE)
※資料Briefing Information | Slides | 議事要旨Minutes | 議事録Transcript - [2] - [3] | 【審議結果】[]Y=,N=,保留=CINRYZE
●EU承認 ●ema - Human Medcines ●List of Authorized Products (EPARs)★[A-Z 承認品目] ★該当なし Committee for Orphan Medicinal Products (COMP)Monthly report 7-8 April 2010
�� 主成分 名称 申請者 適応症 Human C1 inhibitor Cinryze ViroPharma SPRL EU/3/09/668 Treatment of angioedema caused by C1 inhibitor deficiency
●Viropharma Inc (Nasdaq: VPHM). ViroPharma Incorporated to Acquire U.S. Vancocin Brand from Lilly[2004.10.18] 2008.10.21 バイオ製薬企業Lev Pharmaceuticals, Inc.を買収。Cinryzeを獲得。 ●Products ★Vancocin(R) (Vancomycin Hydrochloride Capsules, USP) to treat antibiotic-associated pseudomembranous colitis caused by Clostridium difficile infection (CDI), or C. difficile, and enterocolitis caused by Staphylococcus aureus, including methicillin-resistant strains. ★Cinryze(TM) C1 Inhibitor (human) - angioedema attacksの予防 patients with Hereditary Angioedema (HAE;遺伝性血管浮腫) ●Pipeline ●Media ●News 11/15/10 Cinryze(R) (C1 esterase inhibitor [human]) Data Presented at 2010 Annual Meeting of the American College of Allergy, Asthma & Immunology (ACAAI)
11/09/10 ViroPharma Announces Six Upcoming Presentations of Cinryze(TM) (C1 Esterase Inhibitor (Human)) Data at 2010 Annual Meeting of the American College of Allergy, Asthma & Immunology (ACAAI)
10/25/10 ViroPharma Announces Completion of Enrollment in Phase 2 Study Evaluating Subcutaneous Delivery of Cinryze(TM) (C1 Esterase Inhibitor [Human])
10/22/10 ViroPharma Receives Complete Response Letter for Cinryze(TM) (C1 Esterase Inhibitor [Human]) Industrial Scale Supplement
08/05/10 ViroPharma Announces Publication of Cinryze(TM) (C1 Esterase Inhibitor [Human]) Phase 3 Trial Results in Hereditary Angioedema (HAE) in the New England Journal of Medicine
06/21/10 ViroPharma Files Prior Approval Supplement (PAS) for Cinryze(TM) (C1 Esterase Inhibitor [Human]) Industrial Scale Manufacturing
05/17/10 ViroPharma Announces Availability of Cinryze(TM) (C1 Esterase Inhibitor [Human]) Final Open-Label Data
05/17/10 ViroPharma Introduces New Reconstitution System for Cinryze(TM) (C1 Esterase Inhibitor [Human])
04/27/10 ViroPharma Announces Initiation of Phase 2 Evaluation of Subcutaneous Delivery of Cinryze(TM) (C1 Esterase Inhibitor [Human])
03/31/10 ViroPharma Announces Initiation of Phase 2 Study of Cinryze(TM) (C1 Esterase Inhibitor [Human]) in Pediatric Patients
03/24/10 ViroPharma Announces Acceptance of Cinryze(TM) (C1 Esterase Inhibitor [Human]) Marketing Authorization Application (MAA) by European Medicines Agency (EMA)
03/19/10 ViroPharma Launches 'Ryze Above(TM)', A Personalized Patient Resources Program For Patients With Hereditary Angioedema (HAE)
03/19/10 Scientific Data Relating to Cinryze(TM) (C1 Esterase Inhibitor [Human]) Presented at First International Congress of the Southern European Allergy Society
02/24/10 ViroPharma Incorporated Reports Fourth Quarter and Full Year 2009 Financial Results
01/11/10 ViroPharma Provides 2010 Cinryze(TM) (C1 Esterase Inhibitor [Human]) Outlook
01/11/10 ViroPharma Expands Global Licensing, Commercialization and Development Rights for Cinryze(TM) (C1 esterase inhibitor [human])
06/04/09 ViroPharma Receives Complete Response Letter for Cinryze(TM) Supplemental Biologics License Application for Acute Treatment of Hereditary Angioedema
05/26/09 Scientific Data Relating to Cinryze(TM) Presented at 6th Annual C1 Inhibitor Deficiency Workshop
02/03/09 FDA Grants Priority Review of a Supplemental Biologics License Application for Cinryze(TM) C1 Inhibitor (Human) as Treatment for Acute Attacks of Hereditary Angioedema (HAE)
12/01/08 ViroPharma Submits Supplemental Biologics License Application for Cinryze(TM) to Treat Acute Attacks of Hereditary Angioedema
11/12/08 ViroPharma Announces Presentation of Cinryze(TM) Data in Acute Treatment of Hereditary Angioedema
10/30/08 ViroPharma to Discuss Commercialization and Launch of Cinryze(TM) on November 5, 2008
10/21/08 ViroPharma Incorporated Completes Acquisition of Lev Pharmaceuticals
- On May 2, 2008, the Blood Products Advisory Committee (BPAC) to the U.S. Food and Drug Administration (FDA) voted unanimously that there is sufficient evidence of the safety and efficacy for the approval of Cinryze for the prophylactic treatment of HAE. The data from Lev's acute treatment trial was not presented before the BPAC and is currently under active review at FDA. On May 6, 2008, Lev announced that FDA accepted for review Lev's complete response submission for Cinryze targeting an action date of October 14, 2008.
10/10/08 Cinryze(TM) Receives FDA Approval for Prophylaxis Against Hereditary Angioedema Attacks
●Lev Pharmaceuticals, Inc - Press REleases
Lev Pharmaceuticals to Submit Cinryze(TM) Application to the EMEA[2008.7.1]
Lev Pharmaceuticals Signs Agreements with CuraScript, CVS Caremark, and FFF Enterprises to Support Cinryze(TM) Commercialization[2008.6.4]
Lev Pharmaceuticals Announces Cinryze(TM) Complete Response Submission Accepted for Review by FDA [2008.5.6]
Lev Announces FDA Advisory Committee Unanimously Recommends Approval of Cinryze(TM) for Hereditary Angioedema [2008.5.2]
Lev Pharmaceuticals Announces Submission of Complete Response to FDA for Cinryze(TM) for Hereditary Angioedema [2008.4.15]
Lev Presents Results of Phase III Study Supporting Safety and Efficacy of Cinryze(TM) (C1 inhibitor) as Prophylactic Therapy for HAE [2008.3.18]
Lev Announces FDA's Blood Products Advisory Committee to Review Cinryze (TM) (C1 inhibitor) [2008.3.13]
Lev Pharmaceuticals Receives Complete Response Letter for Cinryze(TM)[2008.1.30]
Lev Presents Significant Data from Pivotal Phase III Trial of CinryzemV in Acute Treatment of Hereditary Angioedema at ACAAI Meeting [2007.11.11]
Lev Pharmaceuticals Amends CinryzemV BLA to Include Prophylactic Data [2007.10.30]
Lev’s CinryzemV BLA Accepted for Filing by FDA [2007.10.1]
Lev Pharmaceuticals Meets Primary Endpoint in Pivotal Phase III Prophylactic Trial for Hereditary Angioedema [2007.9.10]
Lev Pharmaceuticals Submits Biologics License Application for CinryzemV [2007.7.31]
Lev Pharmaceuticals Completes Phase III Prophylaxis Trial of C1-Esterase Inhibitor for Hereditary Angioedema [2007.5.31]
Lev Pharmaceuticals Reports Positive Results in Pivotal Phase III Trial for Hereditary Angioedema [2007.3.14]
Lev Pharmaceuticals' Drug Candidate for Hereditary Angioedema Focus of Broadcast News Story [2006.6.26]
ViroPharma Incorporated to Acquire U.S. Vancocin Brand from Lilly[2004.10.18] ■Investors ●Annual Reports ●SEC Filings 10-K Annual Report[2010.2.25] - [pdf] - [doc] - [xls] 10-K Annual Report[2009.3.2] - [pdf] - [doc] - [xls] ●主要製品
($ 000) 2009 2008 2007 2006 2005 2004 2003 2002 2001 製品売上高 310,449 232,307 203,770 166,617 125,853 8,348 - - - 総収入 310,449 232,307 203,770 167,181 132,417 22,389 1,612 5,537 3,385 営業利益 32,130 78,655 115,796 98,806 88,145 (12,009) (33,966) (48,912) (79,183) 当期純利益 (11,077) 67,617 95,353 66,666 113,705 (19,534) (36,942) (26,623) (78,481) 研究開発費 52,083 66,280 35,869 19,162 10,610 16,388 23,043 39,823 43,013 従業員数[連結] 188 201 115 67 48 Vancocin 213,138 232,284(+14.0) 203,750(+22.3) 166,600(+32.4) 125,900 - - - - [vancomycin]2004.10 Lillyから承継 Cinryze 97,311 23 []
[1345]●製品 エカランタイドecallantide（Kalbitor - Dyax）
日本語版註）エカランタイドecallantide（Kalbitor - Dyax）
【別名】DX-88 【開発元】Dyax Corpダイアックス社 [DBR_ID]
【化学名】a 60-amino-acid protein produced in Pichia pastoris yeast cells by recombinant DNA technology.
【承認】FDA申請=2008.9.23、FDA諮問委承認勧告=2009.2.4、FDA承認=2009.11.27、米国発売=2010.2.2 ; 【製剤】Single use glass vial containing 10 mglmL of ecallantide as a solution for injection 【適応】(遺伝性血管性浮腫の急性発作に対する治療薬) indicated for treatment of acute attacks of hereditary angioedema (HAE) in patients i 6 years of age and older. 【用法用量】30mg (3 mL), administered subcutaneously in three io mg (I mL) injections. If an attack persists, an additional dose of 30 mg may be administered within a 24 hour period. (
【作用】(エカランタイドはC1抑制因子の欠損で活性化しているこの血清カリクレインを強力かつ特異的に阻害する薬剤) Hereditary angioedema (HAE) is a rare genetic disorder caused by mutations to C1-esterase-inhibitor (C1-INH) located on Chromosome 1 1q and inherited as an autosomal dominant trait. HAE is characterized by low levels of C 1 - INH activity and low levels of C4. C 1 - INH functions to regulate the activation of the complement and intrinsic coagulation (contact system pathway) and is a major endogenous inhibitor of plasma kallkrein. The kallikrein-kinin system is a complex proteolytic cascade involved in the initiation of both inflammatory and coagulation pathways. One critical aspect of this pathway is the conversion of High Molecular Weight (HMW) kininogen to bradykinin by the protease plasma kallikrein. In HAE, normal regulation of plasma kallkrein activity and the classical complement cascade is therefore not present. During attacks, unregulated activity of plasma kallikrein results in excessive bradykinin generation. Bradykinin is a vasodilator which is thought by some to be responsible for the characteristic HAE symptoms of localized swelling, inflammation, and pain.KALBITOR is a potent (Ki = 25 pM), selective, reversible inhibitor of plasma kallikrein. KALBITOR binds to plasma kallikrein and blocks its binding site, inhibiting the conversion ofHMW kininogen to bradykinin. By directly inhibiting plasma kallikrein, KALBITOR reduces the conversion ofHMW kininogen to bradykinin and thereby treats symptoms of the disease during acute episodic attacks of HAE.
【特徴】a human plasma kallkrein inhibitor for injection for subcutaneous use. Ecallantide is a 60-amino-acid protein produced in Pichia pastoris yeast cells by recombinant DNA technology.
【製品情報】www.kalbitor.com 【添付文書】KALBITOR-PI
【提携】 【EU】EU申請2010.7.6；欧州では承認審査段階にありイタリアの製薬会社シグマ・タウが販売する予定です。[2010.6.21契約]シグマ・タウは欧州、北アフリカ、中近東、ロシアの権利獲得
【日本】ecallantide(「エカランタイド」、米国での販売名Kalbitor®)[[シミック]開発準備中 【その他】
US Pharmacopeial Commission AMA: United States Adopted Names BIAM --- BIAM -ABC順|BIAM -会社順 NLM: MeSH HOme ---MeSH Online search
●承認データ：FDA ●FDA Newsroom - FDA Press Releases FDA Approves Kalbitor for Treating Potentially Life-Threatening Attacks of Hereditary Angioedema[2009.12.2] ●Index to Drug-Specific Information ●2004.5.1 以降 Drugs@FDA
★Drug Name(s) =KALBITOR (ECALLANTIDE) FDA Application No. =(BLA) 125277 Active Ingredient(s)=ECALLANTIDE Company =DYAX CORP. Dosage Form/Route =INJECTABLE; INJECTION Strength =10MG/ML - Approval Date=11/27/2009[000][Approval]:Label[添付文書]|Letter[承認書]|Review|Summary Review 申請September 23, 2008 適応indicated for the treatment of acute attacks of hereditary angioedema in patients 16 years of age and older. Original Approval or Tentative Approval Date November 27, 2009
●FDA Advisory Committees 参考●ML資料：FDA諮問委員会～議題 FDA Advisory Committees CDER■Pulmonary-Allergy Drugs - http://www.fda.gov/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/Pulmonary-AllergyDrugsAdvisoryCommittee/default.htm Pulmonary-Allergy Drugs 2010 | 2009 | 2008 | 2007 | 2006 | 2005 | 2004 | 2003 | 2002
開催日 議題 備考 1345 2009.02.04 (BLA) # 125277, KALBITOR, ecallantide injection by Dyax Corp., for the proposed indication of treatment of acute attacks of hereditary angioedema.
※資料Briefing Information | Slides | 議事要旨Minutes | 議事録Transcripts | 【審議結果】[有効性のベネフィット；18歳以上で]Y=18,N=4,保留=1 [有効性のベネフィット；10-17歳で]Y=3,N=10,保留=0 [安全性；18歳以上で]Y=5,N=8,保留=0 [安全性；10-17歳以上で]Y=2,N=11,保留=0 [有効性と安全性の観点から承認するか]Y=6,N=5,保留=2KALBITOR(ecallantide) 2008.02.10 中止※(NDA) 22-150, icatibant solution for injection (proposed tradename FIRAZYR), by Jerini, for the proposed indication of treatment of attacks of hereditary angioedema. icatibant
●EU承認 ●ema - Human Medcines ●List of Authorized Products (EPARs)★[A-Z 承認品目] 該当なし ★ 1. Summary for the public 2. All Authorised Presentations 3. Scientific Discussion 4. Procedural steps taken before authorisation 5. 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 ●CHMP Press Releases ●CHMP: Committee meeting reports諮問委員会審議品目一覧 - Pending EC decisions(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
●Dyax Corp ■Products/Pipeline ●KALBITOR®(ecallantide) ●Internal Pipeline ●Licensee Pipeline ■Investors ●Financial & SEC Reports 10-K Annual report[2010.3.12] - [pdf] - [doc] - [xls] ●Press releases KALBITOR(R) (ecallantide) Data Presented at the American College of Allergy, Asthma and Immunology Annual Meeting[2010.11.14]
Dyax and CMIC Co., Ltd. Announce Partnership to Develop and Commercialize Subcutaneous DX-88 (ecallantide) for Hereditary Angioedema and Other Indications in Japan[2010.9.30]
Data from First Phase 3 Trial (EDEMA3@�) for KALBITOR®(ecallantide) Published in The New England Journal of Medicine[2010.8.5]
Dyax Features Comprehensive Financial Assistance Program On Enhanced Product Website for KALBITOR®(ecallantide)[2010.7.19]
Dyax Announces Marketing Authorization Application for DX-88 (ecallantide) Validated by European Medicines Agency[2010.7.6]
Dyax and Sigma-Tau Announce Partnership to Develop and Commercialize Subcutaneous DX-88 (ecallantide) for Hereditary Angioedema and Other Indications in Europe, North Africa, Middle East and Russia[2010.6.21]
Dyax Announces Publication of KALBITOR®(ecallantide) EDEMA4®Trial Results in the Annals of Allergy, Asthma, and Immunology[2010.6.7]
First-Ever Published Study Underscores Significant Economic Burden of Hereditary Angioedema on Patients, Families and the Healthcare System[2010.4.5]
KALBITOR®(ecallantide) Data Presented at American Academy of Allergy, Asthma and Immunology Annual Meeting[2010.3.2]
KALBITOR®(ecallantide) Now Commercially Available[2010.2.2]★米国発売2010.2.2
Dyax Launches HAE Hope, A New Online Resource for Patients with Hereditary Angioedema[2010.1.14]
Dyax Announces FDA Approval of KALBITOR®(ecallantide) for the Treatment of Acute Attacks of Hereditary Angioedema in Patients 16 Years of Age and Older[2009.12.1]
Dyax Presents Integrated Analysis of Phase 3 Data for DX-88 for Hereditary Angioedema[2009.6.8]
Dyax Announces FDA Accepts for Review the Complete Response Submission for DX-88 in Hereditary Angioedema[2009.6.8]
FDA Advisory Committee Favors Approval of DX-88 for Acute Attacks of Hereditary Angioedema[2009.2.4]
Dyax Announces FDA Advisory Committee to Review DX-88 for Hereditary Angioedema[2009.1.13]
FDA Accepts Filing and Grants Priority Review for DX-88 for Hereditary Angioedema[2008.11.21]
First-Ever Study Conducted Demonstrating Economic, Individual, and Societal Burden of Hereditary Angioedema[2008.11.10]
Dyax Announces Completion of Biologics License Application for DX-88 for Hereditary Angioedema[2008.9.24]
Dyax Enters into an Exclusive Negotiation Period with Dompe for European License to DX-88 in Angioedema Indications[2008.7.15]
Dyax Corp. and Cubist Pharmaceuticals, Inc. Sign Development and Commercialization Agreement for DX-88 Surgical Indications[2008.4.24]
- http://www.dyax.com/index.html 1995年創立 2000.08 NASDAQ上場 ●会社決算
($ 000) 2009 2008 2007 2006 2005 開発ライセンス収入 21,643 43,429 26,096 12,776 19,859 研究開発費 46,587 68,077 57,010 37,537 26,688 営業費用 75,716 95,723 76,581 62,547 51,424 営業利益 (54,073) (52,294) (50,485) (49,771) (31,565) 当期純利益 (62,419) (66,468) (56,309) (50,323) (30,944) 従業員数[連結]
●KALBITOR AND THE DX.88 FRANCHISE 【2009】DX.88 is a compound that we developed using our phage display technology, which we have shown in vitro to be a high affinity, high specificity inhibitor of human plasma kallikrein. Plasma kallikrein, an enzyme found in blood, is believed to be a key component responsible for the regulation of the inflammation and coagulation pathways. Excess plasma kallikrein activity is thought to play a role in a number of inflammatory and autoimmune diseases, including HAE. HAE is a rare, genetic disorder characterized by severe, debilitating and often painful swelling, which can occur in the abdomen, face, hands, feet and airway. HAE is caused by low or dysfunctional levels of C1 esterase inhibitor (C1.INH), a naturally occurring molecule that inhibits plasma kallikrein, a key mediator of inflammation, and other serine proteases in the blood. It is estimated that HAE affects between 1 in 10,000 to 1 in 50,000 people around the world. Despite the fact that 85% of patients experience symptoms before age 20, 68% of patients are not diagnosed until after age 20, which makes it difficult to accurately determine the size of the HAE patient population. HAE patient association registries estimate there is an immediately addressable target population of approximately 6,500 patients in the United States.
KALBITOR
In December 2009, DX.88 was approved by the FDA under the brand name KALBITOR (ecallantide) for treatment of HAE in patients 16 years of age and older regardless of anatomic location. KALBITOR, a potent, selective and reversible plasma kallikrein inhibitor discovered and developed by Dyax, is the first subcutaneous HAE treatment approved in the United States.
As part of product approval, we have established a Risk Evaluation and Mitigation Strategy (REMS) program to communicate the risk of anaphylaxis and the importance of distinguishing between hypersensitivity reaction and HAE attack symptoms. To communicate these risks, the REMS requires a Medication Guide be dispensed with each dose of KALBITOR and a "Dear Healthcare Professional" letter be provided to doctors identified as likely to prescribe KALBITOR and treat HAE patients. KALBITOR should only be administered by a healthcare professional with appropriate medical support to manage anaphylaxis and HAE.
We have also initiated a Phase 4 observational study to evaluate immunogenicity and hypersensitivity with exposure to KALBITOR for treatment of acute attacks of HAE. The study is designed to identify predictive risk factors and develop effective screening tools to mitigate the risk of hypersensitivity and anaphylaxis. This 4.year study was initiated in February 2010.
KALBITOR Access(SM)
In furtherance of our efforts to facilitate access to KALBITOR in the United States, we have created the KALBITOR Access program, designed as a one.stop point of contact for information about KALBITOR, which offers treatment support service for patients with HAE and their healthcare providers. KALBITOR case managers provide comprehensive product and disease information, treatment site coordination, financial assistance for qualified patients and reimbursement facilitation services.
Manufacturing
In connection with the commercial launch of KALBITOR in the United States, we have established a commercial supply chain, consisting of single.source third party suppliers to manufacture, test and distribute this product. All third party manufacturers involved in the KALBITOR manufacturing process are required to comply with current good manufacturing practices, or cGMPs.
To date, the DX.88 drug substance used in the production of KALBITOR has been manufactured in the United Kingdom by Avecia Biologics Limited, which was recently acquired by Merck & Co., Inc. (Avecia). As a result of previously completed manufacturing activities conducted at Avecia, we have significant inventories of DX.88 drug substance, which we believe are sufficient to supply all ongoing studies relating to DX.88 and KALBITOR, and to meet the anticipated market demand for KALBITOR well into 2011. Under existing arrangements with Avecia, they have agreed to conduct additional manufacturing runs in 2011 and 2012, as necessary to supplement existing inventory. Additionally, we are in the process of evaluating alternative arrangements for long.term commercial supply of DX.88 drug substance.
DX.88 drug substance is filled, labeled and packaged into the final form of KALBITOR drug product by Hollister.Steir at its facilities in Spokane, Washington under a commercial supply agreement. This process, known in the industry as the "fill and finish" process, is not unique to KALBITOR and alternative manufacturers are readily available in the event that we elect, or are required, to relocate the "fill and finish" process.
KALBITOR Outside of the United States
In markets outside of the United States, we intend to seek approval and commercialize KALBITOR for HAE and other angioedema indications in conjunction with one or more partners. For the European Union, our current plan is to submit a marketing authorization application with the European Medicines Agency (EMA) during the first half of 2010, seeking approval for the commercialization of KALBITOR for HAE.
DX.88 FRANCHISE
DX.88 for Treatment of Other Angioedemas
In addition to its approved commercial use, we are also developing DX.88 in other angioedema indications. One such angioedema is induced by the use of so.called ACE inhibitors. With an estimated 51 million prescriptions written annually worldwide, ACE inhibitors are widely prescribed to reduce Angiotensin Converting Enzyme (ACE) and generally reduce high blood pressure and vascular constriction. It is estimated that up to 2% of patients treated with ACE inhibitors suffer from angioedema attacks and these attacks represent approximately 30% of all angioedemas treated in emergency rooms. Research suggests the use of ACE inhibitors increases the relative activity of bradykinin, a protein that causes blood vessels to enlarge, or dilate, which can also cause the swelling known as angioedema. As a specific inhibitor of plasma kallikrein, an enzyme needed to produce bradykinin, DX.88 has the potential to be effective for treating this condition. We are working with investigators affiliated with the University of Cincinnati as they initiate an investigator sponsored study for drug.induced angioedema.
Another angioedema indication in which DX.88 has the potential to be effective is known as acquired angioedema, a condition associated with B.cell lymphoma and autoimmune disorders. We are currently working with Dr. Marco Cicardi, of the University of Milan, as he initiates a compassionate use program for DX.88 in this indication.
DX.88 for On.Pump Cardiac Surgery
Industry publications report that there are an estimated one million procedures performed worldwide each year involving on.pump cardiac surgery. On.pump cardiac procedures, which are performed for patients who have narrowings or blockages of the coronary arteries, often involve use of a heart.lung machine commonly referred to as the "pump". In these procedures, the heart is stopped with medications, and the pump does the work of the heart and lungs during surgery. This allows the surgeon to position the heart as needed, to accurately identify the arteries and to perform the bypass while the heart is stationary.
The use of the pump during cardiac procedures elicits an adverse systemic inflammatory response. Many patients undergoing on.pump cardiac procedures experience significant intraoperative blood loss that requires transfusion. Plasma kallikrein has been implicated in the body's response to on.pump heart surgery as a major contributor to the significant blood loss seen in on.pump cardiac patients and to the pathologic inflammation that plays a role in the complications of on.pump cardiac procedures.
In 2008, we entered into an exclusive license and collaboration agreement with Cubist for the development and commercialization in North America and Europe of the intravenous formulation of DX.88 for the reduction of blood loss during surgery. Under this agreement, Cubist assumed responsibility for all further development and costs associated with DX.88 in the licensed indications in the Cubist territory. Under the terms of the license agreement, we received a $15 million upfront payment and an additional $2.5 million milestone payment in 2008. In addition, we are eligible to receive (i) up to $214 million in clinical, regulatory and sales.based milestone payments, and (ii) tiered royalties, ranging from the low teens to low twenties, based on sales of DX.88 by Cubist.
Cubist has assumed responsibility for two studies of DX.88 (also known internally at Cubist as CB.500,929) within its licensed surgical indications. The first, known as CONSERV(TM)1, was a dose ranging study evaluating 5, 25 and 75 milligram doses of DX.88 versus placebo in patients undergoing primary coronary artery bypass graft (CABG) surgery who are at a low risk of bleeding complications. The second trial, known as CONSERV(TM)2, compared a single 75 milligram dose of DX.88 to tranexamic acid in patients at a higher risk of bleeding. In December 2009, enrollment in both CONSERV.1 and CONSERV.2 was closed after a statistically significant difference in mortality was observed by the Data Safety Monitoring Board between the DX.88 and control arms in CONSERV.2. No difference was observed in serious adverse events between the active and control arm in CONSERV.1 at the interim look. Cubist plans to conduct a full dataset review of safety and efficacy in the patients enrolled in both CONSERV.1 and CONSERV.2 and expects to be in a position to determine next steps for this program late in the second quarter of 2010.
DX.88 for Ophthalmic Indications
We have entered into a license agreement with Fovea Pharmaceuticals SA, which was acquired by sanofi.aventis in 2009, for the development and commercialization of DX.88 for treatment of retinal diseases in the European Union. Under this agreement, Fovea will fully fund development for the first indication, retinal vein occlusion.induced macular edema, for which a Phase 1 trial was initiated in the third quarter of 2009. We retain all rights to commercialize DX.88 in this indication outside of the European Union. Under the license agreement, we do not receive milestone payments, but are entitled to receive tiered royalties, ranging from the high teens to mid twenties, based on sales of DX.88 by Fovea in the European Union. Conversely, if we elect to commercialize DX.88 in this indication outside of the European Union, Fovea will be entitled to receive royalties from us, ranging from the low to mid teens, based on our sales of DX.88 outside the European Union. The term of the agreement continues until the expiration of the licensed patents or, if later, the eleventh anniversary of the first commercial sale of DX.88 in an ophthalmic indication. The agreement may be terminated by Fovea on prior notice to us and by either party for cause.
Goals for DX.88 Development Programs
Our goal for the ongoing development of DX.88 is to ensure that we and our various collaborators develop DX.88 in multiple indications and obtain marketing approval from the FDA and international regulatory agencies in such indications. Cash inflows from these programs, other than upfront and milestone payments, will not commence until after marketing approvals are obtained, and then only if the product candidate finds acceptance in the marketplace as a treatment for its disease indication. Because of the many risks and uncertainties related to the completion of clinical trials, receipt of marketing approvals and acceptance in the marketplace, we cannot predict when cash inflows from these programs will commence, if ever.
COMPETITION
For KALBITOR as a treatment for HAE, our principal competitors include:
kﾎViroPharma Inc.kﾀIn October 2008, ViroPharma received FDA approval for its plasma.derived C1.esterase inhibitor, known as CinryzemV, which is administered intravenously. Cinryze was approved for routine prophylaxis against angioedema attacks in adolescent and adult patients with HAE, and has orphan drug designation from the FDA. Cinryze was launched in December 2008.
ViroPharma also submitted a supplemental Biologics License Application to the FDA for the use of Cinryze as a treatment for acute attacks of HAE, and on June 3, 2009, the FDA issued a complete response letter requesting that ViroPharma conduct an additional clinical study. In June 2009, FDA approved patient labeling for Cinryze to include self.administration for routine prophylaxis, once patients are properly trained by their healthcare provider.kﾎCSL BehringkﾀIn October 2009, CSL Behring received FDA approval for its plasma.derived C1.esterase inhibitor, known as Berinert@�, which is administered intravenously. Berinert was approved for treatment of acute abdominal or facial attacks of HAE in adult and adolescent patients, and has orphan drug designation from the FDA. Berinert was launched in the US in January 2010. CSL Behring also completed Mutual Recognition Procedure in December 2008, allowing the sale of Berinert®P in more than 20 European countries. Berinert®P has been sold in a subset of European countries since 1985.
kﾎJerini AG/Shire plckﾀJerini AG received European Union market approval in July 2008 for its bradykinin receptor antagonist, known as Firazyr@�, which is delivered by subcutaneous injection. In April 2008, the FDA issued a Not Approvable letter for Firazyr. Firazyr has orphan drug designations from the FDA and in Europe. Jerini/Shire initiated a new Phase 3 United States trial in June 2009.
kﾎPharming Group NVkﾀPharming filed for market approval from the European Medicines Agency (EMA) for its recombinant C1.esterase inhibitor, known as Rhucin@�, which is delivered intravenously. In December 2007 and March 2008, Pharming received negative opinions from the EMA. In September 2009, Pharming filed a new Marketing Authorization Application (MAA) with the EMA. In January 2010, the company reported that it has received the Day 120 List of Questions from the Committee for Medicinal Products for Human Use and that at this stage, no major concerns have been raised. Pharming has also reported that a pre.BLA meeting with the FDA occurred in December 2009. Rhucin has Fast Track status from the FDA and orphan drug designations from the FDA and in Europe.
Other competitors for the treatment of HAE include companies that market or are developing corticosteroid drugs or other anti.inflammatory compounds.
The principal competitors for DX.88 as a treatment for reducing blood loss in cardiac surgery procedures are manufacturers of aminocaproic acid. A of other organizations, including Novo Nordisk A/S, Vanderbilt University and The Medicines Company, are developing other products for this indication.
[1345,1378]●製品 icatibant(Firazyr[Jerini AG])
日本語版註）icatibant(Firazyr[Jerini AG])
【別名】HOE 140 【開発元】Sanofi-Aventisが創製したが、独Jerini AGが2001.11.13に全世界のライセンスを獲得した。その後2008.07.03にJerini AGがShire Limitedにより買収 [DBR_ID]
【化学名】a synthetic decapeptide with five non-proteinogenic amino acids. D-Arginyl-L-arginyl-L-prolyl-L[(4R)-4-hydroxyprolyl]-glycyl-L[3-(2-thienyl)alanyl]-Lseryl-D-(1,2,3,4-tetrahydroisoquinolin-3-ylcarbonyl)-L[(3aS,7aS)-octahydroindol-2-ylcarbonyl]-Larginine, acetate salt
【承認】FDA申請=2007.10.8、FDA不許可通知=2008.4.24 、FDA再申請=2008.6.23、FDA承認勧告=23-Jun-2011、FDA承認=25-Aug-2011、米国発売=Aug-2011 ; 【製剤】prefilled syringe Injection:Each syringe delivers 3 mL solution with a concentration of 10 mg per mL 【適応】to treat acute attacks of hereditary angioedema (HAE) in adults 18 years of age and older. It is not known if FIRAZYR is safe or effective for children under 18 years of age. 【用法用量】30mgを下腹部に皮下注。 不十分なときは６時間を空けて投与するが、24時間以内には３回迄
【作用】Icatibant is a competitive antagonist selective for the bradykinin B2 receptor, with an affinity similar to bradykinin. Hereditary angioedema is caused by an absence or dysfunction of C1-esterase-inhibitor, a key regulator of the Factor XII/kallikrein proteolytic cascade that leads to bradykinin production. Bradykinin is a vasodilator which is thought to be responsible for the characteristic HAE symptoms of localized swelling, inflammation, and pain. Icatibant inhibits bradykinin from binding the B2 receptor and thereby treats the clinical symptoms of an acute, episodic attack of HAE. 【特徴】
【製品情報】www.firazyr.com 【添付文書】Firazyr-PI
【提携】[2005.11.7]Icatibantのアメリカ・カナダでの開発、販売権をKos Pharmaceuticals, Inc.にサブライセンス →2006.11.6 Kosは米Abbottにより買収 →2007.9.17 AbbottとのIcatibant契約を解消、北米の権利を再取得
【EU】Firazyr[Jerini AG] 申請受理2007.8.16 承認勧告2008.4.24 承認2008.07.15
【製剤～EU】Each pre-filled syringe of 3 ml contains icatibant acetate equivalent to 30 mg icatibant. Each ml of the solution contains 10 mg of icatibant. 【適応～EU】indicated for symptomatic treatment of acute attacks of hereditary angioedema (HAE) in adults (with C1-esterase-inhibitor deficiency). 【用法用量～EU】１回30mgを皮下注。 効果不十分なとき6時間経過後再度皮下注、24時間以内に３度目は投薬しないこと。 【添付文書～EU】Firazyr-PI
【日本】未開発 【その他】
【日本語版コメント1378～【短信】遺伝性血管浮腫治療薬イカチバントIcatibant(Firazyr - Shire)】
遺伝性血管性浮腫(HAE)の日本の患者数は約1000人(シミック社)、日本の治療薬はベリナートP静注用500のみだが、米国では最近３剤が承認発売された。Cinryze[ViroPharma SPRL])、FDA承認2008.10.10、米国発売2008.11.5、EU承認2011.6.15、日本未開発；エカランタイドecallantide（Kalbitor[Dyax社]FDA承認2009.11.27、米国発売2010.2.2、EU申請2010.7.6、日本開発準備中[シミック]）、icatibant(Firazyr[Shire]EU承認2008.07.15、米承認2011.8.25、米発売2011.8、日本未開発)。
これ以外にも欧州では1剤が販売されている。 conestat alfa(Ruconest(TM)、欧州外Rhucin@ﾀ[Pharming NV]EU承認2010.10.28、米2010.12.28申請、2011.2.28FDA受付拒否、日本未開発)。→詳細は参考資料●MLリソース：遺伝性血管浮腫に纏めた。
●承認データ：FDA ●FDA Newsroom - FDA Press Releases FDA approves Firazyr to treat acute attacks of hereditary angioedema[2011.8.25] ●Index to Drug-Specific Information ●2004.5.1 以降 Drugs@FDA
★Drug Name(s) =FIRAZYR (ICATIBANT ACETATE) FDA Application No. =(NDA) 022150 Active Ingredient(s)=ICATIBANT ACETATE Company =SHIRE ORPHAN THERAP Dosage Form/Route =INJECTABLE; SUBCUTANEOUS Strength =EQ 30MG BASE/3ML (EQ 10MG BASE/ML) - Approval Date=08/25/2011[000][Approval]:Label[添付文書]|Letter[承認書]|Review| 申請October 22, 2007 適応for the treatment of acute attacks of hereditary angioedema in adults 18 years of age and older. Original Approval or Tentative Approval Date August 25, 2011 Chemical Type 1 New molecular entity (NME) Review Classification P Priority review drug /O Orphan drug
●Electronic Orange Book Application Number: N022150 Active Ingredient : ICATIBANT ACETATE Proprietary Name : FIRAZYR [SHIRE ORPHAN THERAP] INJECTABLE; SUBCUTANEOUS EQ 30MG BASE/3ML (EQ 10MG BASE/ML) Approval Date : Aug 25, 2011 Exclusivity Data : ODE Aug 25, 2018 NCE Aug 25, 2016 Patent Data : 5648333 Jul 15, 2014 Y Y U - 1187
●FDA Advisory Committees 参考●ML資料：FDA諮問委員会～議題 FDA Advisory Committees CDER■Pulmonary-Allergy Drugs - http://www.fda.gov/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/Pulmonary-AllergyDrugsAdvisoryCommittee/default.htm Pulmonary-Allergy Drugs 2011 | 2010 | 2009 | 2008 | 2007 | 2006 | 2005 | 2004 | 2003 | 2002 | 2001 | 2000(会なし) | 1999 | 1998 | 1997
開催日 議題 備考 1378 2011.06.23 (NDA) 22150, icatibant solution for injection (proposed tradename Firazyr), Shire Human Genetic Therapies, for the proposed indication of treatment of acute attacks of hereditary angioedema
※資料Briefing Information | Slides | 議事要旨Minutes | 議事録Transcripts | 【審議結果】[臨床ベネフィット]Y=12,N=1,保留=0 [安全性]Y=11,N=1,保留=1 [有効性と安全性データ]Y=12,N=1,保留=0 [自己治療]Y=11,N=1,保留=1icatibant 1345 2009.02.04 (BLA) # 125277, KALBITOR, ecallantide injection by Dyax Corp., for the proposed indication of treatment of acute attacks of hereditary angioedema.
※資料Briefing Information | Slides | 議事要旨Minutes | 議事録Transcripts | 【審議結果】[有効性のベネフィット；18歳以上で]Y=18,N=4,保留=1 [有効性のベネフィット；10-17歳で]Y=3,N=10,保留=0 [安全性；18歳以上で]Y=5,N=8,保留=0 [安全性；10-17歳以上で]Y=2,N=11,保留=0 [有効性と安全性の観点から承認するか]Y=6,N=5,保留=2KALBITOR(ecallantide) 2008.02.10 中止※(NDA) 22-150, icatibant solution for injection (proposed tradename FIRAZYR), by Jerini, for the proposed indication of treatment of attacks of hereditary angioedema. icatibant
●EU承認 ●ema - Human Medcines ●List of Authorized Products (EPARs)★[A-Z 承認品目] ★Firazyr(icatibant) Angioedemas, Hereditary / 11/07/2008 /Authorised 1. Summary for the public 2. All Authorised Presentations 3. 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] Firazyr [EMEA Product number] EMEA/H/C/000899 [Active substance] icatibant [INN or common name] icatibant [Therapeutic area] Angioedemas, Hereditary [ATC Code] C01EB19 [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 five 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] Jerini AG [Revision] 2 [Date of issue of Market Authorisation valid throughout the European Union] 11/07/2008 [Pharmaco-therapeutic Group] Cardiac therapy[Therapeutic Indication]
Firazyr is indicated for symptomatic treatment of acute attacks of hereditary angioedema (HAE) in adults (with C1-esterase-inhibitor deficiency).●CHMP Press Releases ●CHMP: Committee meeting reports諮問委員会審議品目一覧 - Pending EC decisions(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
●Jerini AG - http://www.jerini.com/index_en.php ; Berlin, Germany ;従業員数108人； Proprietary Peptides-to-Drugs (P2D)技術を基盤。 ペプチド関連医薬開発中心。 子会社JPT Peptide Technologies GmbH (JPT) 1994 設立 2008.07.03 Shire Limitedにより買収 ●主要開発品目(Pipeline)/2005.10現在 市販品はなく、臨床開発が軌道に乗っているものは２品目。 Icatibant P3(欧米など) hereditary angioedema (HAE;遺伝性血管浮腫)の皮下注 - 2001年Sanofi-Aventisからのin-license品。Bradykinin B2受容体遮断薬 2006年申請予定; 他に火傷、喘息、RAILがP2 RAID=Refractory Ascites in Liver cirrhosis(肝硬変の治療抵抗性腹水) JSM6427(α5s1 Integrin) (適応AMD－加齢性黄斑変性) 2007.10 P1開始 ●Drug Pipeline ■Investor Relatopns ●Financial Reports Annual Report 2008[2009.3.30] ●Press Releases Jerini AG’s Management and Supervisory Boards Recommend that Jerini Shareholders Accept Shire Limited’s Takeover Offer[2008.8.25]
Jerini Receives European Commission Approval for Firazyr@� (Icatibant) in the Treatment of HAE[2008.7.15]
Jerini to Submit Complete Response to the FDA for Icatibant in the Treatment of HAE[2008.6.23]
Jerini Receives Positive CHMP Opinion Recommending European Approval for Icatibant in the Treatment of HAE; FDA Issues Not Approvable Letter[2008.4.24]
FDA Cancels Advisory Committee Meeting for Icatibant in the Treatment of HAE - Priority Review of Jerini’s NDA Continues[2008.1.8]
Jerini Receives NDA Filing Acceptance and Priority Review from the FDA for Icatibant in the Treatment of HAE[2007.12.21]
Jerini Submits New Drug Application for Icatibant in the Treatment of HAE to the FDA and Requests Priority Review[2007.10.29]
Jerini Initiates FDA Submission Process of New Drug Application for Icatibant in the Treatment of HAE[2007.10.8]
Jerini Regains Commercialization Rights to Icatibant for the Treatment of Hereditary Angioedema in North America[2007.9.4]
Jerini Receives EMEA Filing Acceptance of its Marketing Application for Icatibant in the Treatment of Hereditary Angioedema[2007.8.16]
Jerini Announces Positive Results from Two Phase III Trials of Icatibant for the Treatment of Hereditary Angioedema[2006.9.21]
Jerini Completes Randomization of Last Patient in Phase III European Clinical Trial (FAST-2) of Icatibant for the Treatment of Hereditary Angioedema[2006.6.7]
Jerini AG Completes Randomization of Last Patient in Phase III Clinical Trial (FAST 1) of Icatibant for the Treatment of Hereditary Angioedema[2006.4.24]
Kos and Jerini Sign Exclusive Collaboration and License Agreement[2005.11.7] - Icatibantのアメリカ・カナダでの開発、販売権をKos Pharmaceuticals, Inc.にサブライセンス →2006.11.6 Kosは米Abbottにより買収 →2007.9.17 AbbottとのIcatibant契約を解消、北米の権利を再取得
Jerini Receives FDA Fast Track Designation for Icatibant in Hereditary Angioedema.[2004.7.22]
Jerini AG and Bachem AG Announce Collaboration For Icatibant[2004.3.18] - Bachem AGに製造を委託
Jerini Granted Orphan Drug Designation by U.S. FDA for Icatibant[2003.11.18]
Aventis and Jerini sign Icatibant deal[2001.11.13] - Icatibant (HOE 140)の世界独占契約
[]●製品 conestat alfa(Ruconest(TM)[Pharming NV])
日本語版註）conestat alfa(Ruconest(TM)[Pharming NV])
【別名】Rhucin®欧州外; rhC1INH 【開発元】Pharming NV [DBR_ID]
【化学名】Conestat alfa is the recombinant analogue of the human C1 esterase inhibitor (rhC1INH) produced by recombinant DNA technology in the milk of transgenic rabbits.
【承認】FDA申請=2010.12.28、FDA受付拒否=2011.02.28[米Santarus, Inc及び>Pharming NV]、FDA承認=x ; 【製剤】 【適応】 【用法用量】
【作用】Conestat alfa, recombinant human complement component 1 (C1) esterase inhibitor (rhC1INH), is an analogue of human C1INH and is obtained from the milk of rabbits expressing the gene encoding for human C1INH. The amino acid sequence of conestat alfa is identical to that of endogenous C1INH. 【特徴】The efficacy and safety of Ruconest as a treatment of acute angioedema attacks in patients with HAE has been evaluated in two double blind randomized placebo controlled and four open label clinical studies. The doses evaluated in the clinical studies ranged from a single vial of 2100 U (corresponding to 18-40 U/kg), to 50 and 100 U/kg. Efficacy of Ruconest as a treatment for acute angioedema attacks was demonstrated by significantly shorter time to beginning of relief of symptoms and time to minimal symptoms and few therapeutic failures.
【製品情報】 【添付文書】
【提携】2010.9.13北米開発販売権をSantarus, Incにライセンス
【EU】Ruconest[Pharming Group N.V]；EU申請=2006.7.21、EU不許可=2008.3.20、EU再申請=2009.9.3、EU承認=2010.10.28
【製剤～EU】One vial contains 2100 units of conestat alfa, corresponding to 2100 units per 14 ml after reconstitution, or a concentration of 150 units/ml. 【適応～EU】Ruconest is indicated for treatment of acute angioedema attacks in adults with hereditary angioedema (HAE) due to C1 esterase inhibitor deficiency. 【用法用量～EU】[成人体重84Kg未満]50単位/kg静注 [成人体重84Kg以上]4200単位(２バイアル)静注 【製品情報～EU】Ruconest 【添付文書～EU】Ruconest-PI
【日本】未開発 【その他】
US Pharmacopeial Commission AMA: United States Adopted Names BIAM --- BIAM -ABC順|BIAM -会社順 NLM: MeSH HOme ---MeSH Online search
●EU承認 ●ema - Human Medcines ●List of Authorized Products (EPARs)★[A-Z 承認品目] ★Ruconest(conestat alfa) Angioedemas, Hereditary - 28/10/2010 -Authorised 1. Summary for the public 2. All Authorised Presentations 3. EPAR - Public assessment report 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] Ruconest [EMEA Product number] EMEA/H/C/001223 [Active substance] conestat alfa [INN or common name] conestat alfa [Therapeutic area] Angioedemas, Hereditary [ATC Code] B05 [Publication details] [Marketing Authorisation Holder] Pharming Group N.V. [Revision] 0 [Date of issue of Market Authorisation valid throughout the European Union] 28/10/2010 [Pharmaco-therapeutic Group] blood substitutes and perfusion solutions [Therapeutic Indication] Ruconest is indicated for treatment of acute angioedema attacks in adults with hereditary angioedema (HAE) due to C1 esterase inhibitor deficiency. ●CHMP Press Releases ●CHMP: Committee meeting reports諮問委員会審議品目一覧 - Pending EC decisions(Summaries of Opinion) ---Substance/INN Trade Name Pharmaceuticalform Strength OpinionAdoption Date [Pending EC decisions]Ruconest [Pharming Group N.V] - 2010.6.24 CHMPが承認勧告。for the treatment of hereditary angioedema [Pending EC decisions] ●[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
●Pharming NV[蘭] 1995年創立のbiotech企業 as a spin-off from GenPharm Intl. ●Products ■Investor Relations ●Press Releases Pharming Announces 2009 Results[2010.2.18] ●Presentation kﾎPresentation Pharming full year 2009 results - conference call press [2010.2.18] kﾎPresentation Pharming full year 2009 results - conference call analysts[2010.2.18] ●Public Report Summary[2010.5.27] ■Press Releases Pharming’s RuconestmV For HAE Granted European Marketing Authorization[2010.10.28]
Pharming And Swedish Orphan Announce Publication Of Randomized Clinical Trial Results With Pharming’s Recombinant Human C1 Inhibitor[2010.10.5]
Pharming Signs Commercialization Agreement With Santarus For Rhucin@� In North America[2010.9.13]
Pharming Plans Submission Rhucin BLA To Us FDA End 2010[2010.8.25]
Pharming And Sanofi Chimie Sign Manufacturing Agreement For The Drug Substance Of RuconestmV[2010.7.6]
Pharming Receives Positive Opinion From European Medicines Agency On Rhucin[2010.6.24]
Pharming Submits D180 Response For Rhucin MAA To EMA Without Clock Stop[2010.5.25]
Pharming Receives D180 List Of Outstanding Issues On Rhucin MAA[2010.5.21]
Swedish Orphan Biovitrum And Pharming Sign Rhucin@� Distribution Agreement[2010.4.15]
Pharming’s C1 Inhibitor Effective In Preventing AMR In Animal Model Of Transplant Rejection[2010.4.1]
Pharming Submits Response To Questions MAA Rhucin[2010.3.18]
Pharming’s C1 Inhibitor Product Potentially Effective In Reducing Complications Following Transplantation[2010.2.17]
Pharming Gives Update On Rhucin EU Marketing Authorization Application[2010.1.22]
Pharming Confirms Interaction With US FDA For Rhucin[2009.12.9]
Pharming Recombinant Human C1 Inhibitor: Results In Pre-clinical Ischaemic Reperfusion Model Confirm Potential For New Indications[2009.10.22]
Pharming’s Marketing Authorisation Application For Rhucin Validated By The European Medicines Agency (EMEA)[2009.9.23]
Pharming Submits Marketing Authorisation Application For Rhucin@� To The EMEA[2009.9.3]
Pharming Confirms Positive Results From Final Analysis Of Rhucin@� Studies[2009.7.1]
●conestat alfa(Ruconest(TM)[Pharming NV] ) 【2009】harming's lead product candidate, Rhucin@�, is the therapeutic protein recombinant human C1 inhibitor (rhC1INH) for treatment of acute attacks of HAE, a genetic disorder. The Company also develops applications of rhC1INH in the area of organ transplantation. In addition, the Company pursues the development, internally or externally, of other products in its pipeline, including recombinant human fibrinogen (rhFIB), human lactoferrin (hLF) and recombinant human collagen (rhCOL), mainly through strategic alliances and partnerships with interested parties. As a result of the progress through the regulatory evaluation process of Rhucin/rhC1INH, Pharming is seeking to lower its financial risk profile by focusing on the commercialisation of Rhucin/rhC1INH for HAE and its subsequent development in follow-on indications, such as antibody-mediated rejection (AMR) and delayed graft function (DGF).
The Company's lead product candidate, Rhucin, is the therapeutic protein rhC1INH for treatment of acute attacks of HAE, a genetic disorder. These attacks are characterised by acute painful and in some cases fatal swellings of soft tissues (edema), including regions of the skin, abdomen and the mouth and throat. Untreated HAE-attacks may last up to five days. Pharming filed a MAA for Rhucin with the EMA in 2006. In March 2008, Pharming received a negative opinion regarding its MAA. Based on the feedback of the EMA, Pharming has expanded the dossier on Rhucin substantially. By June 2009, over 400 administrations of Rhucin were analysed, with more than half of them repeat treatments (up to as much as twenty five repeat treatments per patient). There was no sign of any relevant safety issues in these repeat treatments, nor of induction of allergies and the efficacy was confirmed to be very good. Pharming has submitted a new MAA for Rhucin to the EMA on 3 September 2009 and expects to receive the final opinion from the EMA by the end of June 2010.
Pharming has entered into three commercial agreements for the development, marketing and sales of Rhucin for treatment of acute attacks of HAE in Europe. The most recent contract was concluded with Swedish Orphan in April 2010.
Pharming is also preparing for submission of its market authorisation file (BLA) of Rhucin in the United States and is currently in pre-BLA discussions with the FDA. The Company initiated the pre-BLA process with the FDA early December 2009. Pharming expects to provide further updates on the upcoming BLA filing timelines in the United States during the first half of 2010.
Pharming is also developing rhC1INH for the treatment of AMR and DGF in kidney transplantation. Despite all the technical advances that have been made during the last decades, rejection of transplanted organs remains a critical issue. Given the shortage of available organs and the high costs associated with transplantation, there is a need for additional new and safe products that reduce the chances of organ rejection. There is significant scientific evidence that rhC1INH can be used to prevent complications after organ transplantation. The Company is preparing the start of Phase II studies of rhC1INH in both AMR and DGF in kidney transplantation in the course of 2010
株式会社メドレット Medlet Japan KK
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★1378★27/24★11.11.28★096★【短信】遺伝性血管浮腫治療薬イカチバントIcatibant(Firazyr - Shire)/1p●MLリソース：遺伝性血管浮腫
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- 作成：2010.11.12 最終更新:2012.03.07 小菅博之
The Medical Letter日本語版
●追加メモ to 1345,1378
On Drugs and Therapeutics
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