MLリソース：レストレスレッグス症候群
Restless Leg Syndromes,レストレスレッグス症候群,下肢静止不能症候群 夜間むずむず脚 Nocturnal Leg Cramps 729.82 むずむず脚症候群
■個別収録製品
[1372]●ガバペンチンエナカルビルgabapentin enacarbil(Horizant Extended Release Tablets [GSK])日本語版註）ガバペンチンエナカルビルgabapentin enacarbil(Horizant Extended Release Tablets [GSK])
【別名】Solzira™;GSK1838262/XP13512;ASP8825 【開発元】ゼノポートXenoPort Inc. [DBR_ID]
【化学名】(1-{[({(1RS)-1-[(2-Methylpropanoyl)oxy]ethoxy}carbonyl)amino]methyl} cyclohexyl) acetic acid. a molecular formula of C16H27NO6;m.w.=329.39
【承認~RLS】FDA申請16-Sep-2008、取下げ10-Nov-2008、再申請9-Jan-2009、FDA承認=6-Apr-2011、米国発売July 2011 ; 【承認~帯状疱疹後神経痛】FDA申請=9-Aug-2011、 【製剤】Each HORIZANT Extended-Release Tablet contains 600 mg of gabapentin enacarbil 【適応】(中等度～重度のレストレスレッグス症候群（むずむず脚症候群）) indicated for the treatment of moderate-to-severe primary Restless Legs Syndrome (RLS) in adults. 【用法用量】１日１回600mgを午後５時頃に食事と共に服用
【作用】Gabapentin enacarbil is a prodrug of gabapentin and, accordingly, its therapeutic effects in RLS are attributable to gabapentin.
The precise mechanism by which gabapentin is efficacious in RLS is unknown. Gabapentin is structurally related to the neurotransmitter gamma-aminobutyric acid (GABA) but has no effect on GABA binding, uptake, or degradation. Gabapentin enacarbil and gabapentin have been tested in radioligand binding assays, and neither exhibited affinity for a number of other common receptor, ion channel, or transporter proteins.
In vitro studies have shown that gabapentin binds with high affinity to the α2δ subunit of voltage-activated calcium channels; however, the relationship of this binding to the therapeutic effects of gabapentin enacarbil in RLS is unknown. 【特徴】
【製品情報】www.horizant.com 【添付文書】Horizant-PI
【提携】[8-FEB-2007] XenoportはGSKにXP13512のアジアを除く全世界の独占共同開発および販売権をライセンス 【EU】
【日本】ASP8825(XP13512)[アステラス製薬]申請2009.11.19 【その他】
●[1014,1214]ropinirol HCl(Requip[GSK])
【別名】SK&F-101468 【開発元】GSK [DBR_ID]34814=23881-1160
【化学名】4-[2-(dipropylamino)ethyl]-1,3-dihydro-2H-indol-2-one monohydrochloride
【承認】FDA申請=、FDA承認=Sep 19, 1997 ; 【承認～RLS】FDA申請=2003.7.3、FDA承認=2005.5.4 【製剤】錠剤0.25mg,0.5mg,1mg,2mg,3mg,4mg,5mg 【適応】1)for the treatment of the signs and symptoms of idiopathic Parkinson's disease. 2)for the treatment of moderate-to-severe primary Restless Legs Syndrome (RLS). 【用法用量】初回１日当たり0.25mg x３回を推奨。 【作用】脳内のドパミン受容体を直接刺激する第2世代のドパミン受容体作動薬。(非麦角アルカロイドD2受容体作動薬a non-ergoline dopamine agonist.) ドパミン作動薬はドパミン受容体を刺激して安定した抗パーキンソン作用を示します。 【特徴】(日本神経学会) 有効性と安全性の点からは有用であると判定できる．しかし，Cochrane reviewerのコメントにあるように，ブロモクリプチンと同等。 安全性については他剤との比較では差異は認められていない．悪心についてはブロモクリプチンより低率で，投与中断を来たす症例は少ないことが示されている．しかし，眠気の頻度が高く，危惧される点ではある 【製品情報】www.requip.com 【添付文書】Requip 添付文書 【EU】パーキンソン病の治療薬として世界58ヶ国で承認; RLSに関してはAdartrel (ropinirole)[GSK] - CHMP勧告(2005.9.15) 【日本】SK&F-101468(ロピニロール)錠剤[GSK] ドパミンD2受容体作動薬。パーキンソン病 レキップ錠0.25mg,1mg,2mg[グラクソ・スミスクライン株式会社]承認2006.10.20、薬価収載2006.12.1、発売2006.12.6 【製剤～日本】1錠中にロピニロール塩酸塩0.285mg,1.14mg,2.28mg（ロピニロールとして0.25mg,1mg,2mg） 【適応～日本】パーキンソン病 【用法用量～日本】通常、成人にはロピニロールとして1回0.25mg、1日3回(1日量0.75mg)から始め、1週毎に1日量として0.75mgずつ増量し、4週目に1日量を3mgとする。以後経過観察しながら、必要に応じ、1日量として1.5mgずつ1週間以上の間隔で増量し、維持量(標準1日量3～9mg)を定める。いずれの投与量の場合も1日3回に分け、経口投与する。 【インタビューフォーム～日本】レキップ-IF 【添付文書～日本】レキップ-PI 【その他】
●[1014,1257]pramipexole HCl(Mirapex [Boehringer In])
日本語版註）pramipexole HCl(Mirapex [Boehringer In])
【別名】SND-919 【開発元】Boehringer Ing[GE] [DBR_ID]29483-1160
【化学名】(S)-2-amino-4,5,6,7-tetrahydro-6-(propylamino)benzothiazole dihydrochloride monohydrate.
【承認】FDA申請=1995.12、FDA承認=Jul 1, 1997 ; 【製剤】錠剤0.125mg,0.25MG,0.5mg,1mg,1.5mg 【適応】indicated for the treatment of the signs and symptoms of idiopathic Parkinson's disease. 【用法用量】初回時、１日0.375mgを３回分割して服用。 【作用】非麦角系，ベンゾチアゾール誘導体でD2作動薬a dopamine agonist 【特徴】[日本神経学会]有効性について、早期，進行期パーキンソン病双方に有効。最近の臨床試験であるため，ほとんどがRCTである。これらの試験に於いて，プラミペキソールはパーキンソン病の早期治療薬および，進行期パーキンソン病の治療薬として，L-ドーパとの同等性が示された。 安全性については他のドパミン作動薬とほぼ同等とされ，安全である．副作用としては疲労感，めまい感，眠気，幻覚，起立性低血圧がめだつ．なお，服薬開始後の眠気などの予告なしの睡眠発作が注目されてきており，交通事故との関連が問題視されている。 【製品情報】www.mirapex.com 【添付文書】Mirapex -Full Prescribing Information
【EU】Sifrol INN: pramipexole & Mirapexin INN: pramipexole[Boehringer Ing]パーキンソン病EU中央審査方式申請1996.5、承認1997.10.14(SIFROL)/1997.10.27(Daquiran)/1998.2.23(Mirapexin)で適応症は「パーキンソン病(L-DOPA 併用のみ)」；2003.3時点で世界45ヵ国で承認。
【日本】ビ・シフロール錠0.125mg,0.5mg[日本ベーリンガーインゲルハイム]BI・Sifrol/ 承認2003.12.2、薬価収載2003.12、発売2004.1.15 【製剤～日本】1錠中 塩酸プラミペキソール水和物 0.125mg,0.5mg 【適応～日本】パーキンソン病 【用法用量～日本】通常、成人には塩酸プラミペキソール水和物として1日量0.25mgからはじめ、2週目に1日量を0.5mgとし、以後経過を観察しながら、1週間毎に1日量として0.5mgずつ増量し、維持量（標準1日量1.5～4.5mg）を定める。1日量が塩酸プラミペキソール水和物として1.5mg未満の場合は2回に分割して朝夕食後に、1.5mg以上の場合は3回に分割して毎食後経口投与する。なお、年齢、症状により適宜増減ができるが、1日量は4.5mgを超えないこと。 【添付文書～日本】ビ・シフロール錠 添付文書 - [pdf] | インタビューフォーム 【その他】●RLS適応
【承認～RLS】FDA申請=2005.7.28、FDA承認=2006.11.7 ; 【適応】Provides for the use of Mirapex (pramipexole dihydrochloride) Tablets for the treatment of moderate-to-severe primary Restless Legs Syndrome (RLS). 【用法用量】就寝2-3時間前に初回0.125mgから開始。 4-7日毎に7.5mg迄増量可。 【作用】RLSに対する本剤の正確なメカニズムは不明だが神経薬理学的エビデンスからprimary dopaminergic systemが関与。 【特徴】 【製品情報】www.mirapex.com 【添付文書】Mirapex -Full Prescribing Information
【EU～RLS】Sifrol INN: pramipexole & Mirapexin INN: pramipexole[Boehringer Ing] CHMP承認勧告2006.2.23 RLS；EU承認2006.4 【適応～EU】indicated for symptomatic treatment of moderate to severe idiopathic Restless Legs Syndrome 【用法用量～EU】in dosages up to 0.54 mg of base (0.75 mg of salt). 【製品情報～EU】www.sifrol.com 【添付文書～EU】Sifrol Product Information,Mirapexin Product Information
【日本】ビ・シフロール錠[日本ベーリンガーインゲルハイム]BI・Sifrol P3(RLS) 【その他】
【日本語版コメント1372～下肢静止不能症候群治療薬ガバペンチンエナカルビル(Horizant -GSK)】
レストレスレッグス症候群は、むずむず脚症候群とも呼ばれ、その有病率は成人の２～５％と推定され、40歳以上の中高年、特に女性に多いと考えられている。RLSにより日常生活（QOL）に支障をきたす患者は約200万人以上といわれる。一部の調査では、不眠症と診断された患者の10人に1人の割合でRLSであると報告されている。 欧米でRLSの適応を認可されているのは、プラミベキソール(ビ・シフロール[日本ベーリンガーインゲルハイム];日本は承認2010.1.20)、ロチゴチンrotigotine貼付剤(Neupro[大塚製薬];日本はP3)およびロピニロール(Requip[GSK];日本ではP3中止、パーキンソン病で申請中)の３製品のみ。 四番手としてガバペンチン・エナカルビル(Horizant[GSK])が米国承認(2011.4.8)、日本ではアステラス製薬(ASP8825(XP13512))が申請中(2009.11.19)。
【日本語版コメント1257~下肢静止不能症候群治療薬プラミペキソール（Mirapex－ Boehringer Ingelheim）】
レストレスレッグズ症候群(RLS;別名：下肢静止不能症候群、むずむず脚症候群)は、その特徴として、足を動かしたくなる抑えきれない程の衝動や、脚部におけるムズムズとした疼きや締めつけられるような、不快で苦痛な感覚があげられる。 メーカー発表では米国では成人のおよそ10人に1人、日本では成人人口の1%以上の患者数と推測。 原因やメカニズムは不明だがドパミン関与説か有力で、近年抗パーキンソン病薬の適応追加として開発されてきた。
RLS治療薬として承認されたのは、ロピニロール(レキップ錠[GSK])と塩酸プラミペキソール(ビ・シフロール[日本BI])の２製品だけで各2005,2006年の承認だが、これは欧米の話で、日本では唯一ビ・シフロール[日本BI]がP3段階で開発中。
日本でもRLSの病識のない患者が多く実態も不明だが、欧米で２剤で年間3.5億ドル売れ、かなり好調なのでメーカー側も力を入れていることから、患者の満足度も高そうだ。
【日本語版コメント1214~下肢静止不能症候群治療薬ロピニロール(Requip)】
グラクソ・スミスクラインが米国FDAより「Requip Tablets」の『下肢静止不能症候群(むずむず足症候群)』(Restless Legs Syndromes; RLS)に対する承認を世界で初めて取得した。
RLSは1940年代前半に神経科医師であるカール・エクボム博士によって発見された疾患で、その特徴として、足を動かしたくなる抑えきれない程の衝動や、脚部におけるムズムズとした疼きや締めつけられるような、不快で苦痛な感覚があげられる。RLSの症状は主に休息時(座っている時や横になって寝ている時など)に起こり、足を動かすことによって一時的に治まります。これらの症状は、患者の睡眠等を著しく障害し日中も注意が散漫になったりする。 メーカー発表では米国では成人のおよそ10人に1人、日本では成人人口の1%以上の患者数と推測。
RLS治療薬として承認されたのは、ropinirolだけだが、他の抗パーキンソン病薬も同様の効果があり、特に特に塩酸プラミペキソール(ビ・シフロール[日本BI])はP3段階で申請間近い。 しかし日本ではどこも未開発。
【市場】 Schwarz Pharma AG社によると、RLS剤世界市場規模はUS$350mn、年成長率29%。 下記３品目いずれもパーキンソン病薬として販売され、RLS適応追加は、ropiniroleが2005年,pramipexoleが2006年に 追加適応を取得。 rotigotineはまだ。★Requip (ropinirole) パーキンソン病/レストレスレッグ症候群 [2006] 高い可能性を持つ「レキップ」、 パーキンソン病治療薬/レストレスレッグ症候群(むずむず足症候群)の治療薬である「レキップ」の売上は74%増の2億6,800万ポンドでした。 GSKは昨年12月にFDAに対しRequip 14hrの申請を行いました。 Requip extended release 申請2006.10(米国：RLS) Requip Modutab/XL 24 hour (パーキンソン病 １日１回) FDA申請2007.2 /EMEA申請2005.12 ・Sales of Requip, for Parkinson’s disease and Restless Legs Syndrome (RLS), grew 74% to ￡268 million and, in December, the FDA accepted GSK’s file for approval of the new formulation Requip CR. ・In addition, in 2005 there was a rapid uptake of a number of high potential products such as Requip, for restless legs syndrome (sales up 34% to ￡156 million). ・特許失効2007a (USA) and 2008b (Europe). Parkinson's disease用途特許切れは2008 (USA) and 2011b(Europe) . Litigation challenging the validity of the Parkinson’s use patent is ongoing in the USAe ★sifrol / mirapexin / mirapex (pramipexole) パーキンソン病/RLS [2006] Parkinson’s disease and restless legs syndrome sifrolR / mirapexinR / mirapexR (pramipexole), a product from Boehringer Ingelheim research, is a dopamine agonist that was first approved in 1997 for the treatment of the signs and symptoms of idiopathic Parkinson’s disease (PD), as monotherapy or in combination with levodopa. After a decade of treatment for Parkinson’s patients, a new key milestone was achieved with the approval of sifrolR / mirapexinR / mirapexR for the symptomatic treatment of moderate to severe idiopathic restless legs syndrome (RLS) in 2006, both in the European Union and the USA. sifrolR / mirapexinR / mirapexR continued to show strong growth in 2006 in the Parkinson’s disease indication, too. At the end of October 2006, the brand ranked No. 6 among Boehringer Ingelheim’s best-selling products, with total net sales of EUR 536 million, up 23 % against the same period in 2005. It is the world’s best-selling dopamine agonist, with a market share of more than 22 %. The estimated cumulative worldwide exposure since 1997 is 2.2 million patient years. ★Neupro(R) (rotigotine transdermal patch)(Rotigotine CDS;SPM 962) 抗パーキンソン病薬 [2006] - 2005.3.29 FDA申請。 EMEA申請は2004.9.29。新dopamine agonistで1日1回皮膚パッチ。 1998年にAderis Pharmaceuticals, Inc., USAから世界の開発・販売権を取得。 - 単独療法のEU 2006.2承認後、2006.3独・英発売に続き欧州12ヵ国で発売。 2007.1に進行性パーキンソン病での Levodopa併用で承認。 米国承認は2007.半ば予定。 抗パ剤世界市場規模はUS$2.9bn、年成長率8%。 Restless Legs Syndrome (RLS)の適応拡大:P3で欧米申請は2007.半ば予定。 RLS剤世界市場規模はUS$350mn、年成長率29%。 【開発中の新薬】 ●開発中の新薬[＜情報提供：日本製薬工業協会＞] 2011.12.18
製品 億円 単位 2010 2009 2008 2007 2006 2005 2004 2003 2002 2001 2000 備考 Sifrol/Mirapex[Boehringer Ing] 618 EURm 668(-16.6) 801(+6.6) 752(+17) 644(+20) 536(+23.4) 434(+52.2) 285(+71) 232 236 179 133 [pramipexole]パーキンソン病薬;2006年からRLS ビ・シフロール[日本ベーリンガーインゲルハイム] 64 億円 134(+4) 129(+21) 106.29(+65) 64(+56) 41 [pramipexole]ドバミン作動性パーキンソン病薬 Requip [GSK] 327 ￡m 233(+11) 209 266(-23) 346(+29) 268(+72) 156(+34) 116(+25) 99(+13) 89(+21) 75[+25] 58[+20] [ropinirole] 米 44(+69) 26 102(-57) 238(+35) 176(>+100) 80(+50) 欧 137(-1) 138 133(+46) 91(+12) 81(+19) 68(+21) Emerging Markets 3(+50) 他 49(+14) 31(+82) 17(+55) 11(+38) 11(+38) 8(+22) Requip XL [GSK] 327 ￡m 123 43(-) - [ropinirole]パーキンソン病 米 32 9(-) 欧 89 34(-) Emerging Markets 他 2 - Neupro [UCB[旧Schwarz Pharma AG]] EURm 82(+34) 61 16.5 9.5 - [Rotigotine CDS]パーキンソン病;発売2006 ●New Medicines in Development[PhRMA 米製薬協] /2007.6.21
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) ASP8825（XP13512）(一般名gabapentin encarbil) 経口 [アステラス製薬] レストレスレッグス症候群(下肢静止不能症候群)
(ガバペンチンのプロドラッグ)申請2009.11.19 ゼノポート 有痛性糖尿病性神経障害
(ガバペンチンのプロドラッグ)第II相中止 ゼノポート；2010Q1除外 【メモ】アステラス製薬は、2005年にXenoPort社からASP8825/XP13512の日本およびアジアにおける独占的開発、販売権を取得し、国内において第II相試験を実施していました。本試験は、474例の下肢静止不能症候群患者を対象に12週間にわたりプラセボと比較した、二重盲検比較試験です。対象患者に1日1回、夕食後に600mg、900mgまたは1200mgのASP8825/XP13512またはプラセボを投与し、症状の改善（ベースラインと最終観察時点でのRLS重症度スケール（International RLS）の評価尺度によるスコア変化で評価）を主要評価項目としています。 ASP8825/XP13512の1200mg投与群では、主要評価項目でプラセボ群との間に統計学的有意差をもって改善が認められました。また、副次評価項目のうち臨床全般印象改善尺度（Clinical Global Impression-Improvement scale）について、600mg、900mg、1200mg、それぞれの投与群においてプラセボ群との間に有意差が認められました。 ASP8825/XP13512投与により、軽微または軽症から中等度の傾眠、めまいが報告されていますが、本試験期間中に本剤に起因する重篤な有害事象は報告されませんでした。 from 疼痛治療剤ASP8825/XP13512の第II相試験結果[2009.3.3] SPM 962（NEUPRO＊）「ロチゴチン rotigotine」CDS 貼付剤[大塚製薬] パーキンソン病
(1日1回投与の経皮パッチ剤)第Ⅲ相 承認（アメリカ、欧州） 国内：自社開発;導入品独シュワルツ・ファーマ社（Schwarz Pharma AG)と2002.11.14契約 むずむず脚症候群(レストレス・レッグス症候群)
(1日1回投与の経皮パッチ剤)第Ⅲ相 承認（アメリカ、欧州） 国内：自社開発;導入品独シュワルツ・ファーマ社（Schwarz Pharma AG)と2002.11.14契約 【メモ】大塚製薬 経皮吸収型貼付剤として開発中の「ロチゴチン」に関し、レストレスレッグス症候群への治療効果を国内臨床第III相試験で確認[2011.10.20]
New data show low incidence of augmentation of Restless Legs Syndrome with 5-year Neupro® (rotigotine) treatment[2011.4.14]~米国では2008.4市場回収のまま
UCB Receives Complete Response Letter from U.S. FDA Regarding Neupro® (Rotigotine)[2010.4.23]
New data showed sustained 5-year benefit of Neupro® (rotigotine transdermal system) on symptoms of Restless Legs Syndrome[2010.4.13]
UCB brings Neupro® back to all patients in Europe[2009.6.29]~2008.6に欧州で使用制限されていたのを本日解除された。 欧州でRLS適応は2008.8に承認。
UCB receives CHMP positive opinion on bringing Neupro® back to all patients in Europe[2009.5.29]
UCB receives U.S. FDA Complete Response Letter for Neupro® in Restless Legs Syndrome and Advanced Parkinson's disease[2008.12.19]~米国ではパーキンソン病薬として2007.7に発売され、2007.12にRLSと進行性パーキンソン病のsNDA申請していたが、2008.4市場回収していた。
UCB to implement full cold-chain for Neupro®[2008.6.4]
Neupro® recommended for approval in Europe for Restless Legs Syndrome[2008.4.25]
Neupro® Filed with the FDA for the Treatment of Advanced-Stage Parkinson's Disease[2007.12.13]
Neupro® Filed with the FDA for the Treatment of Restless Legs Syndrome[2007.12.13]
Neupro® Filed in Europe for the Treatment of Restless Legs Syndrome[2007.12.5]
UCB announces The U.S. Launch of Neupro® (Rotigotine Transdermal System) for the Treatment of Early-Stage Parkinson's Disease[2007.7.16]
SKF101468（ロピニロール）錠剤（徐放性）[GSK] 【新剤型】ドーパミンD2受容体作動薬。パーキンソン病 申請中 発売中 自社品 【新剤型】ドーパミンD2受容体作動薬。レストレスレッグ症候群 第Ⅲ相(2010?中止) 発売中 自社品 【メモ】
Horizant Extended Release Tablets (gabapentin enacarbil/ガバペンチン・エナカルビル)[GSK] 中等度～重度のレストレスレッグス症候群（むずむず脚症候群) 米国承認2011.4.8 【メモ】ＦＤＡ レストレスレッグス症候群治療薬としてＧＳＫの「Horizant」承認/FDA approves Horizant to treat restless legs syndrome[2011.4.8]
～米国食品医薬品局（ＦＤＡ）は2011年4月7日、グラクソ・スミスクラインとゼノポートが開発した「Horizant」（一般名：ガバペンチン・エナカルビル）１日1回徐放製剤に関し、中等度～重度のレストレスレッグス症候群（むずむず脚症候群）を適応症として承認したと発表。ガバペンチンは癲癇発作治療に用いられる薬剤であるが、ガバペンチン・エナカルビルを含むHorizantは体内に吸収されるとガバペンチンに転換するとしており、すべての癲癇治療薬には自殺念慮を引き起こす可能性があるとの警告が付されていることから、Horizantにも同様の警告が付される予定。またHorizantは、眠気・めまいを引き起こし、運転・機械操作などの能力を損なわせる可能性がある旨、ＦＤＡ患者向け医薬品ガイドにて説明し処方するものとしている。ビ・シフロールMirapex(プラミベキソール)[日本ベーリンガーインゲルハイム] パーキンソン病
(ドパミン作用薬;D2/D3作動薬)発売2004.1.15
承認2003.10.16販売 SND919;Ba679;国際的大型化期待 「ビ・シフロール®錠 0.125mg / 0.5mg（一般名：プラミペキソール）」[日本ベーリンガーインゲルハイム] 【追加適応症】レストレスレッグス症候群 承認2010.1.20 発売（欧州）
発売（米国）①自社，②自社，⑤パーキンソン病 【メモ】「むずむず脚症候群/レストレスレッグス症候群」（以下むずむず脚症候群）の治療にプラミペキソール（製品名：ビ･シフロール(R)）を用いた場合、オーギュメンテーションの発現率がプラセボと比較し有意差が認められなかったとする無作為化二重盲検プラセボ対照試験の結果1が、米国シアトルで開催中の米国神経学会議（AAN）第61回学術集会で発表された。オーギュメンテーションはむずむず脚症候群の症状発現時間の早期化や症状の強さの増大、また、異常感覚の現れる部位の広がりなどを特徴とし、レボドパ製剤による治療を受ける患者にしばしば認められている。既存のデータから、プラミペキソールによる治療ではレボドパ製剤よりもオーギュメンテーションの発現頻度は低く、また軽度であることが示唆されていた。しかしオーギュメンテーションの発現頻度を比較する目的でデザインされたプラセボ対照比較試験は、今回発表されたものが初めて。 from [記事2009.4.28] ●その他のリスト除外 KW-6002(Istradefylline)[協和発酵] 抗パーキンソン剤(Restless Legs Syndome) 第Ⅱ相（前期）（米） 自社（Restless Legs Syndome：レストレスレッグス症候群 での臨床試験（第Ⅱ相前期）を米国で05年7月より実施中)
RLSは明確な有効性が認められなかった為、2007年1月に中止【解説資料】 ●むずむず脚症候群 - Wikipedia [薬事日報]むずむず脚症候群[2006.7.19] ◆レストレスレッグス症候群（ＲＬＳ）という神経疾患がある。むずむず脚症候群とも呼ばれ、ふくらはぎの辺りに虫が這うような不快感があり、脚を動かさずにはいられない。夜間に症状が増悪するケースが多いため、慢性的な睡眠不足に陥る ◆欧米には、１２００万人もの患者がいるとされる。ある医師がインターネットで調査した結果では、国内には１～５％程度のＲＬＳ患者がいると推定されたという。だがＲＬＳという疾病に対する認知度の低さから、もっと多くの患者が潜在しているとも考えられる ◆ＲＬＳの症状を改善させる薬としては、ＥＵが今年４月、パーキンソン病に用いられるプラミペキソールに効能追加を承認した。国内では、４２人の特発性ＲＬＳ患者を対象として実施されたフェーズII試験の成績が良好だったことから、９月から全国規模で多施設臨床試験を行う予定という [共同通信]脚の不快感で不眠に～レストレスレッグス症候群[2006.8.22] - 財団法人神経研究所付属睡眠学センター（東京都渋谷区）の井上雄一研究部長はこう話し「病気に対する知識が普及すれば、患者の苦痛がもっと救われるようになるのではないか」と期待している。 井上部長らが昨年実施したインターネット調査では、調査対象１万２９２人の中で同症候群と考えられる人は４２９人（約４・２％）。しかし、このうち治療を受けている人は約８・２％にすぎなかった [NINDS] Restless Legs Syndrome Information [NHLBI] Restless Legs Syndrome [FDA]Treating Restless Legs Syndrome[2006] 【データ】 日本の患者数は不明。 ■疫学データ Large multinational general population study shows that Restless Legs Syndrome
Registered Name Company Indication Status 備考 Aplindore(DAB-452) Neurogen
がWyethから全世界権利取得Restless legs syndrome 米I Istradefylline(KW-6002) 協和発酵 Restless legs syndrome
Parkinson's disease米IIa中止
米申請2007.4.27RLSは明確な有効性が認められなかった為、2007年1月に中止 Pramipexole Boehringer Ingelheim Restless legs syndrome 米Preregistration Ropinirole controlled release GlaxoSmithKline Restless legs syndrome 米Preregistration XP 13512 XenoPort Restless legs syndrome
(see also pain)
(gabapentin prodrug)米II/III GSKにアジア以外世界ライセンス/2007.2.8
2005.12アジアはアステラスにライセンスrotigotine CDS(SPM-962) Aderis Pharmaceuticalsが創製
Schwarz Pharmarestless legs syndrome Phase III
is common, under-diagnosed, and can negatively impact sleep and daily activities[2005.6.13] - RLS診断基準に関する初の多国籍研究。 参加患者15,391人中RLS症状を持つ2.7%は、 RLS sufferersと定義され、週２－３回の中等度～重度RLSを経験(n=416)。 うち81%(n=337)は開業医(primary care)に通院しているが、RLSの診断を受けていたのは 6.2%に過ぎない。 RLS頻度の男女比は5.4%:9.0%と女性は男性の２倍。 以下の雑誌で発表。 ■市場調査レポート レストレスレッグ症候群(RLS)：疾患別新薬開発レポート - RESTLESS LEGS SYNDROME DRUG MARKET WILL EXCEED $1 BILLION IN 2015[2006.10.30] Decision Resources社によると、RLS薬市場は2005年$200 million から2015年$1 billion 超。 市場調査報告書：パーキンソン病／下肢静止不能症候群の治療薬 【臨床ガイドライン】 次の欧州神経学会連合[EFNS]のガイドラインが唯一のもの。 ●EFNS guidelines on management of restless legs syndrome and periodic limb movement disorder in sleep - Guideline #48[2006,pdf,17p] European Journal of Neurology 2006, 13: 1049.1065 ～レベルＡで推奨される薬剤は、Cabergoline, Gabapentin, Levodopa/benserazide, pergolide ropinirole, Rotigotine CDS 【総説記事・文献】 Restless Legs Syndrome K. A. Jellinger European Journal of Neurology, Volume 12, Issue 6: 490-490. doi: 10.1111/j.1468-1331.2005.01121.x Restless Legs Syndrome Journal of Sleep Research, Volume 15, Issue s1: 62-64. doi: 10.1111/j.1365-2869.2006.00540_27.x Restless Legs Syndrome - 2 Journal of Sleep Research, Volume 15, Issue s1: 175-181. doi: 10.1111/j.1365-2869.2006.00540_46.x Restless Legs Syndrome - 1 Journal of Sleep Research, Volume 15, Issue s1: 88-93. doi: 10.1111/j.1365-2869.2006.00540_32.x Restless legs syndrome and its correlation with other sleep problems in the general adult population of Japan
Minori ENOMOTO, Lan LI, Sayaka ARITAKE, Yukihiro NAGASE, Tatsuhiko KAJI, Hirokuni TAGAYA, Masato MATSUURA, Yoshitaka KANEITA, Takashi OHIDA and Makoto UCHIYAMA
The epidemiological study presented here was conducted to examine the association between sleep problems and restless legs syndrome (RLS) among a large sample taken from the general population of Japan. The presence of RLS was established by asking...
Sleep and Biological Rhythms, Volume 4, Issue 2: 153-159. doi: 10.1111/j.1479-8425.2006.00220.xPrevalence of restless legs syndrome in non-institutionalized Japanese elderly
SOICHI MIZUNO, md, TSUYOSHI MIYAOKA, md, TAKUZI INAGAKI, md AND JUN HORIGUCHI, md
Abstract The purpose of the present paper was to evaluate the prevalence of restless legs syndrome (RLS) in a non-institutionalized Japanese elderly population. The subjects consisted of 8900 elderly people >65 years of age belonging to the Seniors Associa...
Psychiatry and Clinical Neurosciences, Volume 59, Issue 4: 461-465. doi: 10.1111/j.1440-1819.2005.01399.x●特集 Restless legs syndrome BRAIN and NERVE 61巻5号（2009.05） 【ニュース・トピックス】 【リンク・リソース】 ●[MedlinePlus] Restless Legs 【主要サイト】 ●むずむず脚症候群」(RLS）友の会 RLS Foundation[米] -http://www.rls.org/ - Restless Legs Syndrome Foundation, Inc. RLS (Restless Legs Syndrome) Support Group[米] -http://www.rlshelp.org/ International Restless Legs Syndrome Study Group ■メーカー系 restlesslegs.com by GSK レストレスレッグス症候群 by 日本ベーリンガーインゲルハイム ■関連学会 日本睡眠学会～関連データなし
●解説
■
●分類
「むずむず脚症候群」はヨーロッパでは17世紀からこれに相当する病気の報告があり、1960年になり米国のエクボン博士により、同博士の名前を取って、「エクボン症候群」(Ekbom Syndrome)と初めて名前が付けられた。日本では、1997年日本睡眠学会に米国より現状調査の依頼があり、日本国内で俄かに注目されるようになった。現在では、この「むずむず脚症候群」は広く見られる神経疾患で、患者が脚を動かさずにはいられない状況から、「レストレスレッグス症候群」(「下肢静止不能症候群」；Restless Legs Syndrome＝略称「RLS」)とも 呼ばれる。この項では、以下RLSと記載する。
RLSは、睡眠障害の一つとして取り扱われている。 ●睡眠障害国際分類[ICSD] INTERNATIONAL CLASSIFICATION OF SLEEP DISORDERS(ICSD) 睡眠障害の国際分類 by ASDA in USA, 1990 １．睡眠異常 Dyssomnias A.内因性睡眠障害 Intrinsic Sleep Disorders 12.レストレス・レッグ症候群 Restless Legs Syndrome 780.52-5 - 註)睡眠時などに脚がむずむずする、俗に「むずむず脚症候群」。 ２．睡眠時異常行動 PARASOMNIAS B.睡眠覚醒移行障害 Sleep-Wake Transition Disorders 4.夜間むずむず脚 Nocturnal Leg Cramps 729.82 むずむず脚症候群 詳細→ ●MLリソース：不眠症治療薬[睡眠薬][1063_add]
●疫学
欧米では、1200万人もの患者がいるといわれている。
日本では、ある医師がインターネットで調査した結果では、国内には推定で3～4%程度のRLS患者がいると推定されている。判明している患者で、およそ130万人。症状の軽い人も含めると、実に200万人近い。更にRLSという疾病に対する認知度の低さから、もっと多くの患者が潜在しているとも考えられ、この顕在・潜在患者を含めると約500万人近く存在するとも推測される。RLS患者の70-80％に睡眠中の周期性四肢運動（PLM）を伴うことが報告されています。PLMとは無意識に起こる足の親指や膝関節の背屈運動で、睡眠障害をもたらす原因になります。RLSはPLMを伴うことからも、入眠障害や熟睡障害（中途覚醒）のような重い睡眠障害の要因として知られています。
年代別と性別では、40歳以上の中高年に多く、特に40～60歳の女性に多く見られる。 不眠症患者の10人に1人の割合で、RLSの人がいるといわれている。 要約すると、 ・欧米での患者数は、1200万人 ・日本国内の患者数は、推定で人口の3～4% ・40歳以上の中高年に目立つ ・40代で発症し、年を重ねていくほど悪くなることが多い ・女性の患者が男性の患者に比べて、1.5倍 症状が進むと、不安や抑うつなどの精神障害を合併することが有る
●症状
自覚症状としては、じっとした姿勢や、横になったりしていると、主に下肢の部分に（患者によっては、脚のみならず腰から背中やまた腕や手など全身にまで現れる）「むずむずする」・「じっとしていられない」・「痒い」だけでなく、「ピンでなぞられているような」・「針で刺すような」・「火照るような」・「蟻やミミズなどの虫が這っているような」などの異様な感覚が現われ、時には「振動」のような感覚まで感じたりする場合もある。また「激しい痛み」を感じるなどさまざま。この苦しさは、「脚の中に手を突っ込んでかき回したいぐらい苦しい」と表現する患者もいて、この症状の辛さを表している。このむずむずとした不快感や痛みなどの不快な異常感覚・身体症状が、下肢や腰・背中・腕などに出現するため、患者はこれを抑えるため、常に脚を動かしたり、身体をさすらなければならない状況に追い立てられる。
3分の1の患者では週に2回以上、中等症から重症の症状が起こる。特に夕方から夜間にかけて症状が増強するという特徴（勿論、日中でも症状が出現）があり、入眠障害・熟睡障害や中途覚醒のような睡眠障害の要因となり、また日常の座ったままや、じっとした姿勢の活動を阻害されるため、放置していると日常生活に大きな影響を及ぼす。この結果、副次的症状として昼間の疲労感を引き起こす。
●原因
正確な原因は不明だが、これまでの研究は、 ・神経伝達物質であるドパミンの機能低下 ・中枢神経における鉄分の不足による代謝の異常 ・脊髄（せきずい）や末梢神経の異常 ・遺伝的な要素 などが考えられている。脳内での鉄分の欠乏や、ドパミンの合成異常がかかわっているという仮説が有力である。
●診断
●検査
●治療
基本的にドーパミン機能の促進剤、あるいは抗てんかん薬の一種のクロナゼパムをごく少量使用
●薬物治療
RLSの異常感覚は、薬物治療で軽快する場合が多い。とりわけドーパミン神経の機能を高める薬である「L-DOPA製剤」や「ドーパミン受容体刺激薬」がRLSによい効果があることは、これまでの研究や臨床経験から知られている。また抗けいれん薬（クロナゼパム・バルプロ酸など）も効果が見られる。この疾患に、睡眠導入剤（サイレース）や抗うつ薬を処方されると、むずむず感が解消されないまま眠気だけがどんどん増し、却ってRLSの症状を悪化させる可能性がある。
欧米では中等度以上の症例には、パーキンソン病の治療にも使われるドーパミン受容体作動薬を第一に使う。 現在「プラミペキソール」のRLSへの適用追加に向けた臨床試験が国内でも進められている。
^ パーキンソン病治療薬「プラミペキソール」のRLSへの適用は、欧州(EU)では、2006年4月に中等症から重症のRLSを適応症として効能追加の承認を受け、更に米国（食品医薬品局(FDA)）では、2006年11月10日に軽症から中等症のRLSの追加適応承認を受けた。一方、日本国内ではこの薬はあまり用いられていない。しかし、パーキンソン病の一部として適用を受けている。
RLSの治療法 ビ･シフロールR、レストレスレッグ症候群（RLS）治療に奏功[2004.5.7] - ドパミン作動性パーキンソン病治療剤として発売されているビ･シフロール（一般名：プラミペキソール） (ベーリンガーインゲルハイム) グラクソ・スミスクライン、米国FDAより「RequipR Tablets」の『下肢静止不能症候群
(むずむず足症候群)』に対する承認を世界で初めて取得[2005.5.18]
●予後
●参考資料
●むずむず脚症候群 - Wikipedia
[1372]●製品 ガバペンチンエナカルビルgabapentin enacarbil(Horizant Extended Release Tablets [GSK])
日本語版註）ガバペンチンエナカルビルgabapentin enacarbil(Horizant Extended Release Tablets [GSK])
【別名】Solzira™;GSK1838262/XP13512;ASP8825 【開発元】ゼノポートXenoPort Inc. [DBR_ID]
【化学名】(1-{[({(1RS)-1-[(2-Methylpropanoyl)oxy]ethoxy}carbonyl)amino]methyl} cyclohexyl) acetic acid. a molecular formula of C16H27NO6;m.w.=329.39
【承認~RLS】FDA申請16-Sep-2008、取下げ10-Nov-2008、再申請9-Jan-2009、FDA承認=6-Apr-2011、米国発売July 2011 ; 【承認~帯状疱疹後神経痛】FDA申請=9-Aug-2011、 【製剤】Each HORIZANT Extended-Release Tablet contains 600 mg of gabapentin enacarbil 【適応】(中等度～重度のレストレスレッグス症候群（むずむず脚症候群）) indicated for the treatment of moderate-to-severe primary Restless Legs Syndrome (RLS) in adults. 【用法用量】１日１回600mgを午後５時頃に食事と共に服用
【作用】Gabapentin enacarbil is a prodrug of gabapentin and, accordingly, its therapeutic effects in RLS are attributable to gabapentin.
The precise mechanism by which gabapentin is efficacious in RLS is unknown. Gabapentin is structurally related to the neurotransmitter gamma-aminobutyric acid (GABA) but has no effect on GABA binding, uptake, or degradation. Gabapentin enacarbil and gabapentin have been tested in radioligand binding assays, and neither exhibited affinity for a number of other common receptor, ion channel, or transporter proteins.
In vitro studies have shown that gabapentin binds with high affinity to the α2δ subunit of voltage-activated calcium channels; however, the relationship of this binding to the therapeutic effects of gabapentin enacarbil in RLS is unknown. 【特徴】
【製品情報】www.horizant.com 【添付文書】Horizant-PI
【提携】[8-FEB-2007] XenoportはGSKにXP13512のアジアを除く全世界の独占共同開発および販売権をライセンス 【EU】
【日本】ASP8825(XP13512)[アステラス製薬]申請2009.11.19 【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
【日本語版コメント1372～下肢静止不能症候群治療薬ガバペンチンエナカルビル(Horizant -GSK)】
レストレスレッグス症候群は、むずむず脚症候群とも呼ばれ、その有病率は成人の２～５％と推定され、40歳以上の中高年、特に女性に多いと考えられている。RLSにより日常生活（QOL）に支障をきたす患者は約200万人以上といわれる。一部の調査では、不眠症と診断された患者の10人に1人の割合でRLSであると報告されている。 欧米でRLSの適応を認可されているのは、プラミベキソール(ビ・シフロール[日本ベーリンガーインゲルハイム];日本は承認2010.1.20)、ロチゴチンrotigotine貼付剤(Neupro[大塚製薬];日本はP3)およびロピニロール(Requip[GSK];日本ではP3中止、パーキンソン病で申請中)の３製品のみ。 四番手としてガバペンチン・エナカルビル(Horizant[GSK])が米国承認(2011.4.8)、日本ではアステラス製薬(ASP8825(XP13512))が申請中(2009.11.19)。→詳細は参考資料●MLリソース：レストレス・レッグ症候群に纏めた。＜日本語版コメント要約＞
・ガバペンチンの新規長期放出型製剤ガバペンチンエナカルビルが、中等症～重症の下肢静止不能症候群（RLS）の治療薬として承認された。
・臨床試験において、本剤はプラセボに比べてInternational Restless Legs Scale（IRLS）スコアおよびClinical Global Impression-Improvement（CGI-I）スケールでの評価を有意に改善した。
・主な副作用は傾眠／鎮静と浮動性めまいで、運転能力の障害も認められた。
●承認データ：FDA ●FDA Newsroom - FDA Press Releases FDA approves Horizant to treat restless legs syndrome[2011.4.7] ●Index to Drug-Specific Information ●2004.5.1 以降 Drugs@FDA
★Drug Name(s) =HORIZANT (GABAPENTIN ENACARBIL) FDA Application No. =(NDA) 022399 Active Ingredient(s)=gabapentin enacarbil Company =GLAXO GRP LTD Dosage Form/Route =TABLET, EXTENDED RELEASE; ORAL Strength =600MG - Approval Date=04/06/2011[000][Approval]:Label[添付文書]|Letter[承認書]|Review|Summary Review TO Glaxo Group Limited 申請January 8, 2009 適応for the use of Horizant (gabapentin enacarbil) for the treatment of moderate-to-severe primary Restless Legs Syndrome (RLS) in adults. Original Approval or Tentative Approval Date=April 6, 2011 Chemical Type= 1 New molecular entity (NME) Review Classification= S Standard review drug
●Electronic Orange Book Application Number: N022399 Active Ingredient : gabapentin enacarbil Proprietary Name : HORIZANT [GLAXO GRP LTD] TABLET, EXTENDED RELEASE; ORAL 600MG Approval Date : Apr 6, 2011 Exclusivity Data : NCE Apr 6, 2016 Patent Data : 6818787 Nov 6, 2022 Y Y 8026279 Nov 10, 2016 Y Y 8048917 Nov 6, 2022 Y Y
●EU承認 ●ema - Human Medcines ●List of Authorized Products (EPARs)★[A-Z 承認品目] 該当なし
●XenoPort, Inc ●Horizant ●research & development~パイプライン ■Investor ●Annual Reports 2009 Annual Report ●SEC Filings ★10-K Annual report[2011.3.1] - [pdf,220p] ●Press Releases - http://www.xenoport.com/default.asp 設立 2001年 ●会社決算
($ 000) 2010 2009 2008 2007 2006 2005 (Joint活動収入) 1,364 24,758 28,981 104,898 - (提携収入) 1,515 9,515 13,015 8,924 10,606 総収入 2,879 34,273 41,996 113,822 10,606 研究開発費 52,546 70,747 83,172 74,397 65,434 販売・一般管理費 28,323 31,807 26,391 18,755 14,921 リストラ費用 5,275 - - - - 営業経費 合計 86,144 102,554 109,563 93,152 80,355 営業利益 (83,265) (68,281) (67,567) 20,670 (69,749) 経常利益 (82,469) (67,056) (62,946) 28,815 (64,313) 当期純利益 (82,469) (66,334) (62,540) 28,193 (64,313) 従業員数[連結] 108
●Gabapentin Enacarbil (Known as Horizant in the United States) kﾀ A Transported Prodrug of Gabapentin 【2010】
Our most advanced product candidate is being developed in Japan for the potential treatment of restless legs syndrome and in the United States for thepotential treatment of RLS and PHN. We hold composition-of-matter patents and methods-of-synthesis patents on Horizant in the United States andcomposition-of-matter patents on gabapentin enacarbil in Japan. We also hold patents or pending patent applications in the United States and outside theUnited States that are directed to the formulations and methods of synthesis and use of gabapentin enacarbil.Parent Drug Background
Gabapentin enacarbil is metabolized by the body to release gabapentin, a drug that has been sold by Pfizer Inc as Neurontin since 1993 and is currentlysold as a generic drug by a number of companies. Gabapentin is approved for marketing in the United States as adjunctive therapy in the treatment of partialseizures in patients with epilepsy and for the management of PHN. In addition, based on a variety of published medical studies, gabapentin is prescribed byphysicians to treat a wide range of psychiatric, neurological and pain conditions. Gabapentin has a side effect profile that is considered favorable, withdizziness and somnolence, or drowsiness, as the most commonly reported side effects.
Despite its substantial commercial success, we believe that gabapentin therapy can be significantly improved. Gabapentin absorption is highly variableamong patients, and there is a limit on the gabapentin exposure that can be achieved by direct oral administration of the parent drug. Published results fromclinical trials of gabapentin in epilepsy patients indicated that, for the same dose level, some patients absorbed as little as 10% of the dose of gabapentin administered while others absorbed more than 70%. We have also conducted a clinical trial of gabapentin in neuropathic painpatients in which the high variability of gabapentin absorption was confirmed. In addition, the short duration of gabapentin in blood after oral dosing requiresthat it be administered three times a day, which may lead to poor compliance with the dosing regimen and, therefore, reduced efficacy in some patients.
We believe that these suboptimal characteristics of gabapentin result from the mechanism responsible for the absorption of gabapentin. Gabapentin isactively transported across the GI tract after administration. However, the specific transporter mechanism responsible for gabapentin absorption appears tohave limited capacity, which seems to vary among individuals, and which is predominantly expressed in the upper GI tract. Due to gabapentin's poorabsorption in the lower GI tract, the use of traditional sustained-release formulations to correct the frequent dosing requirement has not been possible.
Our Transported Prodrug
Gabapentin enacarbil is designed to address the limitations of gabapentin by targeting high-capacity nutrient transporter mechanisms expressedthroughout the length of the intestinal tract. We believe that this approach can address the variable and suboptimal exposure to gabapentin experienced bypatients. By targeting transporters expressed throughout the length of the intestinal tract, we have been able to develop a sustained-release formulation ofgabapentin enacarbil that we believe provides more consistent absorption of gabapentin and has overcome the need for frequent dosing of gabapentin.
Gabapentin enacarbil is designed to rapidly convert to gabapentin once absorbed from the GI tract, resulting in limited systemic exposure to the intactTransported Prodrug. In addition to producing gabapentin, gabapentin enacarbil is metabolized to release other components with well-studied, favorablesafety characteristics. We believe that gabapentin enacarbil has demonstrated a favorable safety profile in clinical trials conducted in humans to date, whichprofile is comparable to that of gabapentin.
Phase 1 Clinical Trials
We have completed multiple safety, tolerability and pharmacokinetic Phase 1 clinical trials of gabapentin enacarbil. The results of these Phase 1 clinicaltrials indicated that all doses of gabapentin enacarbil were rapidly absorbed and converted to gabapentin, that doses up to 6000 mg produced dose-proportional gabapentin levels in the blood and that there was no evidence of saturation of drug absorption. Reported adverse events were consistent withthose reported previously for gabapentin; somnolence and dizziness were the most frequently reported adverse events. Exposure to the intact TransportedProdrug was low and transient compared to the level of gabapentin produced at all dose levels.
Initial Target Indications
Restless Legs Syndrome
Background on Restless Legs Syndrome. Restless legs syndrome is a neurological condition that causes an irresistible urge to move the legs. This urgeis usually accompanied by unpleasant sensations of burning, creeping, tugging or tingling inside the patients' legs, ranging in severity from uncomfortable topainful. These restless legs syndrome-related symptoms typically begin or worsen during periods of rest or inactivity, particularly when lying down or sitting,and may be temporarily relieved by movement such as walking or massaging the legs. Symptoms often worsen at night, and disturbed sleep is a commonresult of restless legs syndrome. Left untreated, restless legs syndrome may cause exhaustion, daytime fatigue, inability to concentrate and impaired memory.
Potential Markets. In the United States, GSK is seeking FDA approval for Horizant as a potential treatment of RLS. Although the exact prevalence rate of RLS is uncertain, a study published in Movement Disorders in 2010 indicated that approximately 2% of people in the United States are afflicted with RLS.
According to Datamonitor's 2008 Stakeholder Opinions: Restless Legs Syndrome report, there are approximately 8 million sufferers of RLS in the UnitedStates. We estimate that in 2010 there were approximately 4.6 million prescriptions written for drugs that are approved for the treatment of RLS in the UnitedStates.
In Japan, Astellas is seeking PMDA approval of gabapentin enacarbil as a potential treatment for restless legs syndrome. Although the exact prevalenceis uncertain, Astellas estimates that there are approximately 3.9 million patients with restless legs syndrome in Japan.
Current Treatments. In the United States, the currently approved and most widely prescribed treatments for RLS belong to a class of drugs calleddopamine agonists and include ropinirole (marketed as Requip by GSK), pramipexole (marketed as Mirapex by Boehringer Ingelheim GmbH) and genericcomparables of these drugs. Physicians also prescribe opioids, benzodiazepines and anticonvulsants, such as gabapentin, to treat patients with restless legssyndrome. In Japan, pramipexole was approved in 2010 for the treatment of restless legs syndrome.
GSK's U.S. Regulatory Filing. We evaluated Horizant in a Phase 3 clinical program for the treatment of RLS, and in January 2009, GSK filed anNDA with the FDA for Horizant as a treatment for RLS. In February 2010, GSK received a Complete Response letter from the FDA regarding the NDA forHorizant for RLS. In the Complete Response letter, the FDA concluded that the NDA provides substantial evidence of effectiveness for Horizant as atreatment for patients with RLS and that the FDA had not identified a clinical safety concern that would prevent approval of the 600 mg dose of Horizant.However, a preclinical signal of pancreatic acinar cell tumors in rats was determined to be of sufficient concern to preclude approval of the Horizant NDA forRLS at that time. In the Complete Response letter, the FDA acknowledged that similar preclinical findings were known for gabapentin, the parent drug of Horizant, at the time of the FDA's approval of gabapentin for refractory epilepsy, but concluded that the seriousness and severity of refractory epilepsy andthe benefit to patients provided by gabapentin justified the potential risk. In the Complete Response letter, the FDA also acknowledged that findings inlaboratory animals are not necessarily translatable to risk in humans, and the FDA noted that gabapentin products have been available for over 15 years andthey do not appear to be associated with a clinical signal for pancreatic cancer based on an analysis of spontaneous reports in the FDA's Adverse EventReporting System. However, the FDA concluded that the absence of a finding in analyses of post-marketing reports cannot be reliably interpreted as evidenceof the absence of risk.
In October 2010, GSK submitted its response to questions raised by the FDA in the Complete Response letter. GSK's response to the FDA includednew data from non-clinical studies of Horizant and two epidemiology studies, conducted by GSK, exploring gabapentin use and cancer based on the UKGeneral Practice Research Database. The resubmission also included a final safety update that provided updated or new safety information on patients inclinical studies who have been treated with Horizant. In order for the FDA to be able to consider published gabapentin non-clinical data in their assessment ofHorizant, GSK amended the NDA for Horizant from a Section 505(b)(1) to a Section 505(b)(2) application.
In November 2010, the FDA accepted for review GSK's response to the Complete Response letter for Horizant as a treatment of RLS. The FDAdesignated the resubmission as a Class 2 response and set a new PDUFA date of April 6, 2011.
XenoPort's Clinical Program. The Phase 3 clinical program encompassed multiple U.S. trials, including one 12-week, randomized, double-blind,placebo-controlled trial, known as the PIVOT (Patient Improvement in Vital Outcomes following Treatment) RLS I clinical trial (previously known asXP052), designed to evaluate the safety and efficacy of 1200 mg of Horizant versus placebo administered once a day at approximately 5:00 p.m., and asecond 12-week, randomized, double-blind, placebo-controlled trial, known as the PIVOT RLS II clinical trial (previously known as XP053), designed toevaluate the safety and efficacy of 600 mg or 1200 mg of Horizant versus placebo administered once a day at approximately 5:00 p.m. The co-primaryoutcome measures for these trials were defined to be the change from baseline in the International Restless Legs Syndrome, or IRLS, rating scale score andthe Investigator Clinical Global Impression of Improvement, or CGI-I, scale at the end of treatment. Secondary endpoints for both trials included onset ofefficacy and subjective sleep, pain, mood and quality of life assessments.
The PIVOT RLS I trial, which commenced in March 2006, enrolled 222 patients at 23 sites who were diagnosed with RLS. In April 2007, we reportedtop-line results demonstrating that treatment with 1200 mg of Horizant was associated with a statistically significant improvement in the co-primary endpointscompared to placebo. Improvements in the IRLS rating scale score were significantly greater for Horizant than for placebo (-13.2 vs. -8.8; p=0.0002). At theend of treatment, significantly more patients treated with Horizant were reported as "much improved" or "very much improved" on the Investigator CGI-Iscale compared to those treated with placebo (76% vs. 39%; p < 0.0001). During treatment over the 12-week period, the most commonly reported adverseevents for Horizant versus placebo were somnolence (27% Horizant; 7% placebo) and dizziness (20% Horizant; 5% placebo). There were no reported seriousadverse events in Horizant-treated patients.
The PIVOT RLS II trial, which commenced in August 2006, enrolled 325 patients who were diagnosed with RLS. In February 2008, we reported top-line results demonstrating that treatment with 1200 mg of Horizant was associated with a statistically significant improvement in the co-primary endpointscompared to placebo. Improvements in the IRLS rating scale score were significantly greater for 1200 mg of Horizant than for placebo (-13.0 vs. -9.8;p=0.0015). At the end of treatment, significantly more patients treated with 1200 mg of Horizant were reported as "much improved" or "very much improved"on the Investigator CGI-I scale compared to those treated with placebo (78% vs. 45% for placebo; p<0.0001).
This trial also demonstrated that treatment with 600 mg of Horizant was associated with a statistically significant improvement in the co-primaryendpoints compared to placebo. Improvements in the IRLS rating scale score were significantly greater for 600 mg of Horizant than for placebo (-13.8 vs.-9.8. p<0.0001). At the end of treatment, significantly more patients treated with 600 mg of Horizant were reported as "much improved" or "very muchimproved" on the Investigator CGI-I scale compared to those treated with placebo (73% vs. 45%, p<0.0001).
During the 12-week treatment period, the most commonly reported adverse events for Horizant were dizziness (24% 1200 mg Horizant; 10% 600 mgHorizant; 5% placebo) and somnolence (18% 1200 mg Horizant; 22% 600 mg Horizant; 2% placebo). These adverse events were generally mild or moderatein intensity. Withdrawals due to adverse events were 7% in the 1200 mg Horizant group, 6% in the 600 mg Horizant group and 6% in the placebo group.There were three reported serious adverse events in the study (one in the placebo group, two in the 600 mg Horizant group), none of which were considered treatment-related.
In addition to these two 12-week trials, the Phase 3 program also included a clinical trial, known as the PIVOT RLS Maintenance clinical trial(previously known as XP060), to assess the long-term efficacy of Horizant. The trial, which commenced in May 2006, was designed to evaluate the potentialof Horizant to maintain efficacy over the course of nine months in patients with RLS. The multi-center, double-blind, randomized, placebo-controlled,parallel-group clinical trial enrolled 327 patients diagnosed with RLS. All patients were administered 1200 mg of Horizant, taken at approximately 5:00 p.m.,for 24 weeks. Patients were assessed to determine treatment response at the end of this single-blind phase, and responders then entered the 12-week,randomized, double-blind phase of the clinical trial. Patients randomized to the placebo group received 600 mg of Horizant for two weeks and then receivedplacebo for an additional ten weeks. Patients randomized to the Horizant treatment group continued to receive 1200 mg of Horizant for the entire 12-week,double-blind period. In January 2008, we reported top-line results that showed that Horizant was generally well-tolerated during the treatment period and thatthere was a statistically significant difference between the percentage of patients treated with Horizant and placebo who met a pre-specified relapse criteriaduring the randomized phase of the study. Two hundred twenty one patients completed the 24-week, single-blind portion of the clinical trial, of which 194(88%) met the responder criteria and were randomized to double-blind treatment. Analysis of the primary endpoint indicated that treatment with Horizantresulted in a statistically significant lower proportion of relapses compared to placebo during the double-blind treatment period (23% placebo compared to 9%Horizant; p= 0.0158).
The most commonly reported adverse events during the single-blind phase of this clinical trial were somnolence (30%) and dizziness (22%), whichwere generally mild or moderate in intensity and transient in nature. The incidence of somnolence and dizziness in Horizant-treated patients during thedouble-blind portion of the trial were 3% and 2%, respectively. During the trial, there was one death that was determined to be unrelated to Horizanttreatment. There were five other serious adverse events, only one of which was judged as possibly related to Horizant treatment.
We have also conducted clinical trials and collected information that is typically required for submission of an NDA to the FDA, including anexamination of the exposure/response relationship, pharmacokinetics in a special population, drug/drug interactions, cognition, driving performance andcardiovascular safety. In addition, we have completed an open-label safety extension study that included patients from the two 12-week clinical trials toenable assessment of the safety of Horizant treatment extending up to 12 months. Data from this trial was also included in the NDA filing. The results of thePhase 3 clinical trials, combined with the results from other Horizant clinical trials in RLS patients, are intended to meet the International Committee forHarmonization, or ICH, guidelines for safety assessment.
In addition, GSK conducted a polysomnography, or sleep laboratory measurement, study of Horizant in RLS patients to explore further the potentialsleep benefits of Horizant. Results from this trial showed statistically significant benefits of Horizant versus placebo in several objective measurements ofsleep.
Astellas' Clinical Program and Regulatory Filing. In March 2009, Astellas reported results from a Phase 2 clinical trial of gabapentin enacarbil forthe treatment of symptoms in restless legs syndrome patients in Japan. The trial was a 12-week, double-blind, placebo-controlled study that enrolled 474patients who were diagnosed with restless legs syndrome. Patients were treated with 600, 900 or 1200 mg of gabapentin enacarbil or placebo, given once perday after the evening meal. The primary endpoint for the clinical trial was the change from baseline for the IRLS rating scale score at end of treatment.
Treatment with 1200 mg of gabapentin enacarbil was associated with a statistically significant improvement in the primary endpoint compared toplacebo. Statistically significant improvements over placebo were also observed on some secondary endpoints, including the investigator-rated CGI-I scale,which achieved statistical significance for each of the 600 mg, 900 mg and 1200 mg dosing cohorts.
The most commonly reported adverse events for gabapentin enacarbil were somnolence and dizziness, which were generally transient and mild tomoderate in severity. There were no treatment-emergent serious adverse events during the study period in gabapentin enacarbil-treated subjects.
In November 2009, Astellas filed an NDA with the PMDA for approval of gabapentin enacarbil as a potential treatment for restless legs syndrome in Japan. The evidence of efficacy for the NDA filing was based on data from Astellas' successful Phase 2 trial in restless legs syndrome patients conducted in Japan and our clinical program conducted in the United States.
Neuropathic Pain
Background on Neuropathic Pain. Neuropathic pain is pain that results from damage to nerves. The damage may result from a variety of causes,including injury or illnesses such as diabetes, HIV and shingles. In addition, the toxic effects of therapy used to treat patients with cancer or HIV may alsocause nerve damage leading to neuropathic pain.
One form of chronic neuropathic pain is PHN. PHN is a complication of shingles, a painful outbreak of rash or blisters on the skin caused by areactivation of the same virus that causes chicken pox. PHN is often characterized as constant stabbing, burning or electric shock-like sensations in the areaaffected by shingles after the rash has cleared. Approximately 10% to 15% of all patients with shingles develop PHN, which can persist for many years. DPNis another form of neuropathic pain that is associated with a family of nerve disorders caused by diabetes. Over time, people with diabetes can experiencedamage to nerves leading to numbness and sometimes pain and weakness in the hands, feet and legs.
Potential Market. We estimate that the prevalence of PHN is less than 200,000 patients in the United States. In May 2006, Merck & Co. receivedFDA approval for Zostavax, a live attenuated vaccine, to help prevent shingles. In October 2006, the U.S. Centers for Disease Control and Prevention'sAdvisory Committee on Immunization Practices voted unanimously to recommend that adults 60 years of age and older be vaccinated with Zostavax for theprevention of shingles. While Zostavax is not a treatment for shingles or PHN, the availability of this vaccine could impact the future market for therapies forPHN.
Diabetes is the leading cause of neuropathy in the Western world, and neuropathy is the most common complication and greatest source of morbidityand mortality in diabetes patients. In 2007, the National Institute of Diabetes and Digestive and Kidney Diseases estimated that 17.9 million people in the United States had been diagnosed with diabetes. Epidemiologystudies indicate that about 20% of community-dwelling diabetes patients suffer from DPN, indicating that approximately 3.5 million people in the UnitedStates are afflicted with DPN.
Current Treatments. Current classes of drugs used to treat patients with neuropathic pain include anticonvulsants, antidepressants and tricyclic drugs,with anticonvulsants representing the largest share of the neuropathic pain market. Of the anticonvulsants, gabapentin is the market leader, and pregabalin(marketed as Lyrica by Pfizer) is also widely prescribed for the treatment of neuropathic pain. Duloxetine (marketed as Cymbalta by Eli Lilly and Company)is an antidepressant that is also prescribed for the treatment of DPN. Also, the FDA recently approved a once-daily formulation of gabapentin (known asGralise from Depomed Inc. and its partner for pain indications, Abbott Laboratories) for PHN. Other treatments used in selected patients include a capsaicinpatch (marketed as Qutenza by NeurogesX, Inc.) and local application of lidocaine.
Phase 2 Clinical Trial Results. We have completed a randomized, double-blind, parallel, placebo-controlled Phase 2a clinical trial of Horizant for themanagement of PHN. The trial included 101 patients at 18 clinical sites in the United States. The objective of this trial was to assess the safety, tolerability,pharmacokinetics and efficacy of 1200 mg of Horizant administered twice a day for 14 days and to compare the response to Horizant against the response to placebo. The trial included a Neurontin treatment phase to enable the evaluation of blood levels of Neurontin.
The trial met the primary endpoint of the study, demonstrating that treatment with Horizant was associated with a statistically significant reduction inpain as measured by an 11-point numerical pain scale compared to placebo (p=0.032). Additional analyses were conducted on data from those patients whoreceived both Neurontin and Horizant. When administered Horizant, patients experienced on average a 17% increase in the steady-state average bloodconcentration of gabapentin compared to a dose of Neurontin that contained roughly 50% more gabapentin (p=0.005), indicating higher bioavailability ofHorizant. Thirty-six percent of evaluated patients had an increased steady-state average blood concentration of greater than 30%. For all patients who receivedHorizant, the change in average pain score between the last seven days of the Horizant treatment from the final seven days of Neurontin treatment wasdetermined. A statistically significant reduction in pain score at the end of Horizant treatment was observed (p=0.045). Horizant was well-tolerated. The mostcommon adverse event in the Horizant treatment group was dizziness, which was mild to moderate in severity.
GSK has evaluated Horizant in two Phase 2 clinical trials for the potential treatment of PHN. In September 2009, GSK announced top-line results froma 14-week, double-blind, placebo-controlled Phase 2b clinical trial that enrolled 376 subjects with PHN who had been experiencing pain for at least threemonths following healing of the herpes zoster skin rash. Subjects were randomized to receive placebo, 1200, 2400 or 3600 mg/day of Horizant divided intotwice-daily doses. The primary endpoint of the trial was the change from baseline to the end of maintenance treatment in the 24-hour average pain intensityscore. All doses of Horizant demonstrated statistically significant improvements over placebo on the primary endpoint, with the adjusted mean change frombaseline in the 24-hour average pain intensity score of -1.66 for placebo, -2.47 for 1200 mg/day Horizant, -2.36 for 2400 mg/day Horizant and -2.72 for 3600mg/day Horizant. The pre-specified statistical analysis included adjustment for comparisons of multiple Horizant doses to placebo. The adjusted p-values forcomparison of 1200, 2400 and 3600 mg/day to placebo were 0.013, 0.029 and 0.002, respectively. Horizant was generally well tolerated at all doses in thistrial. The most common adverse events were dizziness (17% 1200 mg Horizant, 26% 2400 mg Horizant, 30% 3600 mg Horizant and 15% placebo) andsomnolence (10% 1200 mg Horizant, 11% 2400 mg Horizant, 14% 3600 mg Horizant and 8% placebo), and most of these adverse events were mild ormoderate in intensity. Withdrawals due to adverse events were 6% in the 1200 mg Horizant group, 15% in the 2400 mg Horizant group, 18% in the 3600 mgHorizant group and 13% in the placebo group. There was one serious adverse event (gastritis) in the 3600 mg/day dose group that was judged by theinvestigator to be related to treatment.
In October 2009, GSK announced top-line results from a double-blind, two-period, cross-over Phase 2 clinical trial that enrolled 138 subjects diagnosedwith PHN who had been experiencing pain for at least three months following healing of the herpes zoster skin rash. Subjects with a history of inadequateresponse to gabapentin entered a baseline period during which they received a dose of 1800 mg/day of gabapentin for two weeks. Subjects (N=96) who had a24-hour average pain intensity score of at least four on the 11-point pain intensity rating scale were then randomized to receive either 1200 mg/day of Horizant for the first 28-day treatment period followed by 3600 mg/day for thesecond 28-day treatment period, or 3600 mg/day followed by 1200 mg/day. Subjects received 2400 mg/day of Horizant for four days in between the twotreatment periods. The primary endpoint in this trial was the change from baseline to the end of the treatment period in the 24-hour average pain intensityscore. A greater reduction in the 24-hour average pain score was observed for the 3600 mg/day dose than for the 1200 mg/day dose, which reduction wasstatistically significant. Horizant was well tolerated at both doses in this study. The only treatment-emergent adverse event occurring in greater than or equalto 5% of subjects taking Horizant was nasopharyngitis.
GSK has also evaluated Horizant for the potential treatment of DPN. In April 2009, GSK completed a 14-week, double-blind, placebo-controlled,Phase 2 clinical trial of Horizant as a potential treatment for DPN patients. In the trial, 421 patients who were diagnosed with either Type 1 or Type 2 diabetesmellitus with signs and symptoms of DPN were randomized to receive either 1200 mg/day, 2400 mg/day or 3600 mg/day of Horizant administered in divideddoses taken twice daily, 300 mg/day of pregabalin as an active control, administered in divided doses three times daily, or placebo. Neither Horizant norpregabalin, the active control, demonstrated a statistically significant improvement on the primary endpoint when compared to placebo, based on the changefrom baseline to end of treatment on the 24-hour average pain intensity score, which may have been a consequence of the unexpectedly high placebo responserate observed in the study. The highest dose of 3600 mg/day of Horizant showed consistent trends towards efficacy across multiple pain endpoints. Horizantwas generally well tolerated; the two most frequently reported adverse events were dizziness and somnolence.
Clinical Development of Horizant in Neuropathic Pain. The development of Horizant as a potential treatment for PHN has been delayed based on theFebruary 2010 Complete Response letter for RLS. GSK intends to have discussions with the FDA regarding the filing of an NDA, including the possibility of pursuing a Section 505(b)(2) NDA regulatory pathway, for Horizant as a potential treatment of PHN. Although we do not have active development programsunderway, we continue to evaluate our resources and potential for pursuing development of Horizant in the United States for the potential treatment of DPN,the potential treatment of PHN, to the extent that a product label would reflect a superiority claim over a currently approved drug, and for any additionalpotential indications.
Horizant/Gabapentin Enacarbil Development, Commercialization and Partnering Strategy
Due to the large market potential for Horizant, the requirement of a primary care physician sales force to address these markets in the United States andour desire to focus our commercialization efforts in the United States, we have entered into agreements with pharmaceutical partners to maximize thepotential commercial value of Horizant. In December 2005, we entered into a license agreement with Astellas for exclusive rights to develop andcommercialize gabapentin enacarbil in Japan and five Asian countries. Astellas made an up-front payment to us of $25.0 million, has paid additional milestones of $23.0 million and may make additional milestone payments to us of up to $37.0 million. We will receive royalties on any net sales of gabapentin enacarbil in the Astellas territory. Under the terms of the agreement, Astellas is responsible for all futuredevelopment costs and Astellas is solely responsible for the manufacturing of gabapentin enacarbil to support its development and commercialization withinthe Astellas territory. Astellas may terminate the collaboration at its discretion. In such event, all gabapentin enacarbil product rights would revert to us andwe would be entitled to specified transition assistance from Astellas.
Additionally, in February 2007, we announced an exclusive collaboration with GSK to develop and commercialize Horizant/gabapentin enacarbilworldwide, excluding the Astellas territory. In November 2010, we amended and restated our collaboration agreement with GSK, pursuant to which wereacquired all rights to gabapentin enacarbil outside of the United States previously granted to GSK (which excludes the Astellas territory) and obtained theright to pursue development of Horizant for: (i) the potential treatment of DPN; (ii) the potential treatment of PHN, to the extent that a product label wouldreflect a superiority claim over a currently approved drug; and (iii) any additional indications in the United States. GSK remains responsible for seekingapproval of the NDA for RLS in the United States, further development and regulatory matters with respect to Horizant for the potential treatment of PHN,possibly seeking NDA approval through a 505(b)(2) approval process, and commercialization of Horizant in the United States for all indications.
Under the terms of the amended and restated collaboration agreement, the aggregate clinical and regulatory milestone payments that we are eligible toreceive, have been increased by $37.5 million from a total of $275.0 million to $312.5 million, of which $85.0 million has been received to date. We remaineligible to receive up to an additional $290.0 million upon the achievement of specified sales levels; however, the associated sales levels that give rise to thesepayments were lowered from the terms of our original agreement.
We plan to enter into additional agreements with pharmaceutical companies for the development and commercialization of gabapentin enacarbil outsidethe United States and the Astellas territory to the extent that we are able to find partners and negotiate agreement terms that are suitable to us.
Marketing and Sales
Under the terms of our agreement with GSK, we have co-promotion rights for Horizant in the United States. Pending FDA approval of Horizant, GSKis responsible for: establishing pricing and reimbursement; creating promotional and advertising materials; managed care contracting; receiving, accepting andfilling orders; distributing; controlling invoicing, order processing and collecting accounts receivable; and recording sales of Horizant in the United States.Under the agreement, we can delay the deployment of our sales force for up to three years following the potential approval of Horizant in the United States.We may terminate our co-promotion right at any time upon notice to GSK with no penalty to us, resulting in a compensation structure based on a royalty ofGSK's sales of Horizant.
If gabapentin enacarbil is approved within the Astellas territory, Astellas will be responsible for all commercial activities related to the marketing andsale of gabapentin enacarbil.
We plan to establish additional development and commercialization partnerships with pharmaceutical and biotechnology companies to accelerate thecompletion of regulatory approval and product introduction and to maximize the breadth of the commercial opportunity of our other product candidates.
We also plan to license to third parties for development, marketing and sales other potential drug candidates that are discovered by us but do not fallwithin the CNS therapeutic area, our primary area of interest.
Competition
Horizant/Gabapentin Enacarbil. We anticipate that, if approved in the United States for RLS, Horizant will compete with currently approvedtreatments for RLS that all belong to a class of drugs called dopamine agonists, including the following: ropinirole (marketed as Requip by GSK); genericropinirole (marketed by, among others, CorePharma, LLC, Mylan Pharmaceuticals Inc. and Wockhardt USA LLC); pramipexole (marketed as Mirapex byBoehringer Ingelheim); and generic pramipexole (marketed by, among others, Teva, Norvartis AG and Watson Pharmaceuticals, Inc.). In addition, we couldalso experience competition from the rotigotine transdermal system (a dopamine agonist patch marketed as Neupro by UCB). UCB filed its NDA for thetreatment of RLS with the FDA in 2007. In April 2010, the FDA provided UCB a Complete Response letter that recommended reformulation of rotigotinebefore making it available in the U.S. market for the treatment of restless legs syndrome.
We anticipate that, if gabapentin enacarbil is approved in Japan forthe treatment of restless legs syndrome, it will compete with pramipexole, which was approved in 2010 for the treatment of restless legs syndrome.We anticipate that, if approved for neuropathic pain in the United States, Horizant would compete with generic gabapentin (marketed by Alpharma,IVAX Corp., Pfizer and Teva, among others). Other drugs targeting neuropathic pain will represent substantial competition. These include pregabalin(marketed as Lyrica by Pfizer), duloxetine (marketed as Cymbalta by Eli Lilly) and a capsaicin patch (marketed as Qutenza by NeurogesX, Inc.). Transdermalpatches containing the anesthetic known as lidocaine are sometimes used for the management of PHN. In addition, in January 2011, the FDA approved aonce-daily formulation of gabapentin (known as Gralise from Depomed and its partner for pain indications, Abbott) for the treatment of PHN.
●Glaxo SmithKleine ●GlaxoSmithKline - Media Press Releases
●医療関係者 ●プレスリリース
●グラクソ・スミスクライン
[1014,1214]●製品ropinirol HCl(Requip[GSK])
日本語版註）ropinirol HCl(Requip[GSK])
【別名】SK&F-101468 【開発元】GSK [DBR_ID]34814=23881-1160
【化学名】4-[2-(dipropylamino)ethyl]-1,3-dihydro-2H-indol-2-one monohydrochloride
【承認】FDA申請=、FDA承認=Sep 19, 1997 ; 【承認～RLS】FDA申請=2003.7.3、FDA承認=2005.5.4 【製剤】錠剤0.25mg,0.5mg,1mg,2mg,3mg,4mg,5mg 【適応】1)for the treatment of the signs and symptoms of idiopathic Parkinson's disease. 2)for the treatment of moderate-to-severe primary Restless Legs Syndrome (RLS). 【用法用量】初回１日当たり0.25mg x３回を推奨。 【作用】脳内のドパミン受容体を直接刺激する第2世代のドパミン受容体作動薬。(非麦角アルカロイドD2受容体作動薬a non-ergoline dopamine agonist.) ドパミン作動薬はドパミン受容体を刺激して安定した抗パーキンソン作用を示します。 【特徴】(日本神経学会) 有効性と安全性の点からは有用であると判定できる．しかし，Cochrane reviewerのコメントにあるように，ブロモクリプチンと同等。 安全性については他剤との比較では差異は認められていない．悪心についてはブロモクリプチンより低率で，投与中断を来たす症例は少ないことが示されている．しかし，眠気の頻度が高く，危惧される点ではある 【製品情報】www.requip.com 【添付文書】Requip 添付文書 【提携】 【EU】パーキンソン病の治療薬として世界58ヶ国で承認; RLSに関してはAdartrel (ropinirole)[GSK] - CHMP勧告(2005.9.15) 【日本】SK&F-101468(ロピニロール)錠剤[GSK] ドパミンD2受容体作動薬。パーキンソン病 レキップ錠0.25mg,1mg,2mg[グラクソ・スミスクライン株式会社]承認2006.10.20、薬価収載2006.12.1、発売2006.12.6 【製剤～日本】1錠中にロピニロール塩酸塩0.285mg,1.14mg,2.28mg（ロピニロールとして0.25mg,1mg,2mg） 【適応～日本】パーキンソン病 【用法用量～日本】通常、成人にはロピニロールとして1回0.25mg、1日3回(1日量0.75mg)から始め、1週毎に1日量として0.75mgずつ増量し、4週目に1日量を3mgとする。以後経過観察しながら、必要に応じ、1日量として1.5mgずつ1週間以上の間隔で増量し、維持量(標準1日量3～9mg)を定める。いずれの投与量の場合も1日3回に分け、経口投与する。 【インタビューフォーム～日本】レキップ-IF 【添付文書～日本】レキップ-PI 【その他】
●34814-1160
ROPINIROLE;ﾛﾋﾞﾆﾛｰﾙ;ﾛﾋﾟﾆﾛｰﾙ
●23881-1160
ROPINIROLE;ﾛﾋﾞﾆﾛｰﾙ;ﾛﾋﾟﾆﾛｰﾙREQUIP;ROPINIROLE;SK&F101468A;SKF 101468;ロピニロール
《JA》SK&F101468A（ｽﾐｽｸﾗｲﾝ･ﾋﾞｰﾁｬﾑ製薬㈱）IN IU＊93/4∥《UK》REQUIP（SMITHKLINE BEECHAM）09-96＊
●承認データ：FDA ●2004.5.1 以降 Drugs@FDA
Drug Name(s) =Requip FDA Application No. =NDA # 020658 Active Ingredient(s)=ROPINIROLE HYDROCHLORIDE Company =GLAXOSMITHKLINE Dosage Form/Route =TABLET; ORAL:EQ 0.25MG,0.5MG,1MG,2MG,3MG,4MG,5MG BASE Strength = - Approval Date=09/19/1997[000] - Approval Date=06/19/2003[012] :Letter[承認書]|Review [Labeling Revision] - Approval Date=05/04/2005[013] :Label[添付文書]|Letter[承認書] - New or Modified Indication
情報ソース●CDER New and Generic Drug Approvals: 1998-2004 Requip (ropinirole hydrochloride) Tablets, GlaxoSmithKline Application #=NDA 20-658 / S012 Approval Date=6/19/03 Letter Posted=7/8/03 承認書 Label Posted = 添付文書 Review Posted=
●Electronic Orange Book Application Number: 020658 Active Ingredient : ROPINIROLE HYDROCHLORIDE Proprietary Name : REQUIP [GLAXOSMITHKLINE] TABLET; ORAL EQ 0.25MG,05.mg,1mg,2mg,3mg,4mg,5mg BASE Approval Date : Sep 19, 1997 [0.25mg,0.5mg,1mg,2mg,5mg]; Jan 27, 1999 [3mg,4mg] Exclusivity Data : - Patent Data : 4824860 MAY 19,2008 U-212 4452808 DEC 07,2007
●EU承認 ●EMEA - Human Medcines ●List of Authorized Products (EPARs)★[A-Z 承認品目] Adartrel (ropinirole)[GSK] - CHMP勧告 EMEA CHMP PRESS RELEASE[2005.9.15] Finalised referral procedures; 同日RLS承認勧告
The CHMP finalised a referral procedure for Adartrel (ropinirole), from Laboratoires GlaxoSmithKline, with the recommendation to approve the medicinal product for the treatment of moderate to severe idiopathic restless legs syndrome. The referral was initiated because of concerns regarding efficacy and long-term safety by Spain and The Netherlands under Article 29(2) of Directive 2001/83/EC as amended. After reviewing all available evidence the Committee concluded that the benefit-risk balance for Adartel is positive and that a marketing authorisation should be granted.CHMP Monthly Report - September 2005[pdf,19p] EMEA CHMP PRESS RELEASE[2004.12.16] - The CHMP began a Community referral under Article 29(2) of Directive 2001/83/ EC as amended, for the medicinal product Adartrel (ropinirole) from Laboratoires GlaxoSmithKline, following a notification from Spain and The Netherlands. The r eferral was initiated because of concerns regarding the efficacy and long-term s afety of the medicinal product for the symptomatic treatment of moderate to severe idiopatic restless legs syndrome. CHMP Monthly report - December'04[pdf,13p] ●Human Medicines - Referrals 1/04/06 Adartrel INN: Ropinirole CHMP/416317/05 Background - Annex I, II, III, IV
●Glaxo SmithKleine ●製品サイト ★米国 Requip 添付文書 www.requip.com www.restlesslegs.com ★英国 Adartrel 添付文書[UK]SPC-Adartrel 0.25, 0.5, and 2.0 mg film-coated Tablets [Ropinirole] Adartrel 添付文書[UK]患者用PIL - Adartrel film-coated tablets [Ropinirole] 承認日=10 /05/2006 [適応症]indicated for the symptomatic treatment of moderate to severe idiopathic Restless Legs Syndrome Requip 添付文書[UK] 承認日=24th January 2002 [適応症]Treatment of idiopathic Parkinson's Disease: ●GlaxoSmithKline - Media Press Releases April 03, 2007★Once daily, extended-release ropinirole improves Parkinson's symptoms in patients not optimally controlled with levodopa★パーキンソン病治療薬Requip(R)/下肢静止不能症候群Adartrel (ropinirole HCI); 持続性製剤Requip XLはSkyepharma PLCが開発2007.4.13 FDA申請、仏承認2007.4.23
September 04, 2006★New study reveals investigational 24-hour formulation of Requip(R) (ropinirole HCI) tablets reduced "off" time for patients with Parkinson's disease★パーキンソン病治療薬Requip(R)/下肢静止不能症候群Adartrel (ropinirole HCI)
April 07, 2006★GlaxoSmithKline’s Adartrel becomes the first RLS treatment to receive a positive decision from the European Commission ★パーキンソン病治療薬Requip(R)/下肢静止不能症候群Adartrel (ropinirole HCI)
January 04, 2006★Requip(R) (ropinirole HCl) tablets significantly improve symptoms of Restless Legs Syndrome (RLS) in patients with RLS★パーキンソン病治療薬Requip(R)/下肢静止不能症候群Adartrel (ropinirole HCI)
Committee for Medicinal Products for Human Use gives positive opinion on
GlaxoSmithKline's Adartrel R (ropinirole) for RLS (Restless Legs Syndrome) [2005.9.16] Large multinational general population study shows that Restless Legs Syndrome
is common, under-diagnosed, and can negatively impact sleep and daily activities[2005.6.13] - RLS診断基準に関する初の多国籍研究。 参加患者15,391人中RLS症状を持つ2.7%は、 RLS sufferersと定義され、週２－３回の中等度～重度RLSを経験(n=416)。 うち81%(n=337)は開業医(primary care)に通院しているが、RLSの診断を受けていたのは 6.2%に過ぎない。 RLS頻度の男女比は5.4%:9.0%と女性は男性の２倍。 以下の雑誌で発表。 Restless Legs Syndrome Prevalence and Impact: REST General Population Study - Richard P. Allen et al. Arch Intern Med. 165(11)1286-1292(June 13,2005). Impact, diagnosis and treatment of restless legs syndrome (RLS) in a primary care
population: the REST (RLS epidemiology, symptoms, and treatment) primary care study - Wayne Hening et al. Sleep Medicine 5(3)237-246(May 2004) New study highlights long term effectiveness of ropinirole In Parkinson’s disease[2005.6.9] Requip(R) (ropinirole HCI) tablets first and only medication approved by the FDA
for the treatment of moderate-to-severe primary Restless Leg Syndrome (RLS) in adults[2005.5.5] ★Requip (ropinirole) パーキンソン病/レストレスレッグ症候群 [2006] 高い可能性を持つ「レキップ」、 パーキンソン病治療薬/レストレスレッグ症候群(むずむず足症候群)の治療薬である「レキップ」の売上は74%増の2億6,800万ポンドでした。 GSKは昨年12月にFDAに対しRequip 14hrの申請を行いました。 Requip extended release 申請2006.10(米国：RLS) Requip Modutab/XL 24 hour (パーキンソン病 １日１回) FDA申請2007.2 /EMEA申請2005.12 ・Sales of Requip, for Parkinson’s disease and Restless Legs Syndrome (RLS), grew 74% to ￡268 million and, in December, the FDA accepted GSK’s file for approval of the new formulation Requip CR. ・In addition, in 2005 there was a rapid uptake of a number of high potential products such as Requip, for restless legs syndrome (sales up 34% to ￡156 million). ・特許失効2007a (USA) and 2008b (Europe). Parkinson's disease用途特許切れは2008 (USA) and 2011b(Europe) . Litigation challenging the validity of the Parkinson’s use patent is ongoing in the USAe
●グラクソ・スミスクライン ●医療関係者 「レキップ錠」 添付文書/a> - インタビューフォーム ●プレスリリース 2007-05-10★1日1回服用のパーキンソン病治療薬「レキップ LP」がフランスで承認～非麦角系のドパミン受容体作動薬で初めての1日1回投与
2007-02-15★グラクソ・スミスクライン、2006年度業績発表
2006-12-06★パーキンソン病治療に新たな選択肢パーキンソン病治療薬「レキップ錠」本日発売
2006-10-20★グラクソ・スミスクライン～パーキンソン病治療薬「レキップ錠」の承認取得
グラクソ・スミスクライン、米国FDAより「Requip(R) Tablets」の『下肢静止不能症候群
(むずむず足症候群)』に対する承認を世界で初めて取得[2005.5.18]
[1014,1257]●製品pramipexole HCl(Mirapex [Boehringer In])
日本語版註）pramipexole HCl(Mirapex [Boehringer In])
【別名】SND-919 【開発元】Boehringer Ing[GE] [DBR_ID]29483-1160
【化学名】(S)-2-amino-4,5,6,7-tetrahydro-6-(propylamino)benzothiazole dihydrochloride monohydrate.
【承認】FDA申請=1995.12、FDA承認=Jul 1, 1997 ; 【製剤】錠剤0.125mg,0.25MG,0.5mg,1mg,1.5mg 【適応】indicated for the treatment of the signs and symptoms of idiopathic Parkinson's disease. 【用法用量】初回時、１日0.375mgを３回分割して服用。 【作用】非麦角系，ベンゾチアゾール誘導体でD2作動薬a dopamine agonist 【特徴】[日本神経学会]有効性について、早期，進行期パーキンソン病双方に有効。最近の臨床試験であるため，ほとんどがRCTである。これらの試験に於いて，プラミペキソールはパーキンソン病の早期治療薬および，進行期パーキンソン病の治療薬として，L-ドーパとの同等性が示された。 安全性については他のドパミン作動薬とほぼ同等とされ，安全である．副作用としては疲労感，めまい感，眠気，幻覚，起立性低血圧がめだつ．なお，服薬開始後の眠気などの予告なしの睡眠発作が注目されてきており，交通事故との関連が問題視されている。 【製品情報】www.mirapex.com 【添付文書】Mirapex -Full Prescribing Information
【EU】Sifrol INN: pramipexole & Mirapexin INN: pramipexole[Boehringer Ing]パーキンソン病EU中央審査方式申請1996.5、承認1997.10.14(SIFROL)/1997.10.27(Daquiran)/1998.2.23(Mirapexin)で適応症は「パーキンソン病(L-DOPA 併用のみ)」；2003.3時点で世界45ヵ国で承認。
【日本】ビ・シフロール錠0.125mg,0.5mg[日本ベーリンガーインゲルハイム]BI・Sifrol/ 承認2003.12.2、薬価収載2003.12、発売2004.1.15 【製剤～日本】1錠中 塩酸プラミペキソール水和物 0.125mg,0.5mg 【適応～日本】パーキンソン病 【用法用量～日本】通常、成人には塩酸プラミペキソール水和物として1日量0.25mgからはじめ、2週目に1日量を0.5mgとし、以後経過を観察しながら、1週間毎に1日量として0.5mgずつ増量し、維持量（標準1日量1.5～4.5mg）を定める。1日量が塩酸プラミペキソール水和物として1.5mg未満の場合は2回に分割して朝夕食後に、1.5mg以上の場合は3回に分割して毎食後経口投与する。なお、年齢、症状により適宜増減ができるが、1日量は4.5mgを超えないこと。 【添付文書～日本】ビ・シフロール錠 添付文書 - [pdf] | インタビューフォーム 【その他】●RLS適応
【承認～RLS】FDA申請=2005.7.28、FDA承認=2006.11.7 ; 【適応】Provides for the use of Mirapex (pramipexole dihydrochloride) Tablets for the treatment of moderate-to-severe primary Restless Legs Syndrome (RLS). 【用法用量】就寝2-3時間前に初回0.125mgから開始。 4-7日毎に7.5mg迄増量可。 【作用】RLSに対する本剤の正確なメカニズムは不明だが神経薬理学的エビデンスからprimary dopaminergic systemが関与。 【特徴】 【製品情報】www.mirapex.com 【添付文書】Mirapex -Full Prescribing Information
【EU～RLS】Sifrol INN: pramipexole & Mirapexin INN: pramipexole[Boehringer Ing] CHMP承認勧告2006.2.23 RLS；EU承認2006.4 【適応～EU】indicated for symptomatic treatment of moderate to severe idiopathic Restless Legs Syndrome 【用法用量～EU】in dosages up to 0.54 mg of base (0.75 mg of salt). 【製品情報～EU】www.sifrol.com 【添付文書～EU】Sifrol Product Information,Mirapexin Product Information
【日本】ビ・シフロール錠[日本ベーリンガーインゲルハイム]BI・Sifrol P3(RLS) 【その他】
●29483-1160
MIRAPEX;PRAMIPEXOLE HCL[INNM];SND 191Y?;SND 919;SND 919Y;SUD 919CL2Y;U 98528E[;UPJOHN];塩酸プラミペキソール;プラミペキソール
《JA》SND 919Y（ﾍﾞｰﾘﾝｶﾞｰｲﾝｹﾞﾙﾊｲﾑ㈱）IN IU＊∥《US》MIRAPEX（Pharmacia and Upjohn）12-96＊FDA=961223
【日本語版コメント1257】
レストレスレッグズ症候群(RLS;別名：下肢静止不能症候群、むずむず脚症候群)は、その特徴として、足を動かしたくなる抑えきれない程の衝動や、脚部におけるムズムズとした疼きや締めつけられるような、不快で苦痛な感覚があげられる。 メーカー発表では米国では成人のおよそ10人に1人、日本では成人人口の1%以上の患者数と推測。 原因やメカニズムは不明だがドパミン関与説か有力で、近年抗パーキンソン病薬の適応追加として開発されてきた。
RLS治療薬として承認されたのは、ロピニロール(レキップ錠[GSK])と塩酸プラミペキソール(ビ・シフロール[日本BI])の２製品だけで各2005,2006年の承認だが、これは欧米の話で、日本では唯一ビ・シフロール[日本BI]がP3段階で開発中。
日本でもRLSの病識のない患者が多く実態も不明だが、欧米で２剤で年間3.5億ドル売れ、かなり好調なのでメーカー側も力を入れていることから、患者の満足度も高そうだ。→詳細は参考資料●MLリソース：レストレス・レッグ症候群＜日本語版コメント要約＞
・下肢静止不能症候群（RLS）に対する2番目のドパミンアゴニスト、プラミペキソールが承認された。
・レボドパに比べると頻度は低いものの、ドパミンアゴニストは症状が悪化するaugmentationや深夜や早朝に症状が再発するリバウンドを引き起こす可能性がある。
・先に承認されているロピニロールとの比較データはない。
●承認データ：FDA ●2004.5.1 以降 Drugs@FDA
Drug Name(s) =MIRAPEX (PRAMIPEXOLE DIHYDROCHLORIDE) FDA Application No. =(NDA) 020667 Active Ingredient(s)=PRAMIPEXOLE DIHYDROCHLORIDE Company =BOEHRINGER INGELHEIM Dosage Form/Route = Tablets, 0.125 mg, 0.25 mg, 1 mg, 1.25 mg, 1.5 mg & 0.5mg Strength = - Approval Date=07/01/1997[000] :|Letter[承認書]|Review [Approval] - Approval Date=11/07/2006[011&013] :Label[添付文書]|Letter[承認書]|[New or Modified Indication] Original Approval Date July 1, 1997 Chemical Type 1 New molecular entity (NME) Review Classification S Standard review drug
情報ソース●CDER New and Generic Drug Approvals: 1998-2004 Mirapex (pramipexolem dihydrochloride) Tablets, 0.125 mg, 0.25 mg, 1 mg, 1.25 mg, & 1.5 mg. Pharmacia & Upjohn, Inc Application #=NDA 20-667/S8 Approval Date=5/6/03 Letter Posted=7/9/03 承認書 Label Posted = 添付文書 Review Posted= Mirapex (pramipexolem dihydrochloride) Tablets, 0.125 mg, 0.25 mg, 1 mg, 1.25 mg, & 1.5 mg. Pharmacia & Upjohn, Inc Application #=NDA 20-667 Approval Date=7/1/98 Letter Posted= 承認書 Label Posted = 添付文書 Review Posted=
●Electronic Orange Book Application Number: 020667 Active Ingredient : PRAMIPEXOLE DIHYDROCHLORIDE Proprietary Name : MIRAPEX [BOEHRINGER INGELHEIM] TABLET; ORAL 0.125mg,0.25MG,0.5mg,1mg,1.5mg Approval Date : Jul 1, 1997[0.125mg,0.25MG,1mg,1.5mg] ; Feb 12, 1998 [0.5mg] Exclusivity Data : - Patent Data : 4886812 MAR 25,2011 4843086 NOV 23,2007 U-231
●EU承認 ●EMEA - Human Medcines ●List of Authorized Products (EPARs)★[A-Z 承認品目] ★Sifrol INN: pramipexole (Rev. 9) - Published 12/09/06 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 [Product] Sifrol [Marketing Authorisation Holder] Boehringer Ingelheim International GmbH ,D-55216 Ingelheim am Rhein ,Germany [Active Substance] Pramipexole dihydrochloride monohydrate [International Nonproprietary Name or Common Name] Pramipexole [Pharmaco-therapeutic Group] Anti-Parkinson drug, dopaminergic agent, dopamine agonist [ATC Code] N04B C [Therapeutic Indication] SIFROL tablets are indicated for treatment of the signs and symptoms of advanced idiopathic Parkinson's disease, alone (without levodopa) or in combination with levodopa, i.e. over the course of the diseas e, when the effect of levodopa wears off or becomes inconsistent and fluctuations of the therapeutic ef fect occur (end of dose or "on off" fluctuations). SIFROL tablets are also indicated for symptomatic treatment of moderate to severe idiopathic Restless Legs Syndrome in dosages up to 0.54 mg of base (0.75 mg of salt). [Date of issue of Marketing Authorisation valid throughout the European Union] 14 October 1997 [Orphan medicinal product designation date] Not applicable ★Mirapexin INN: pramipexole (Rev. 10) - Published 13/09/06 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 [Name of the Medicinal Product] Mirapexin [Marketing Authorisation Holder] Boehringer Ingelheim International GmbH,D-55216 Ingelheim am Rhein,Germany [Active Substance] Pramipexole dihydrochloride monohydrate [International Nonproprietary Name or Common Name] Pramipexole [Pharmaco-therapeutic Group] Anti-Parkinson drug, dopaminergic agent, dopamine agonist [ATC Code] N04B C [Therapeutic Indication] MIRAPEXIN tablets are indicated for treatment of the signs and symptoms of idiopathic Parkinson's disea se, alone (without levodopa) or in combination with levodopa, i.e. over the course of the disease, thro ugh to late stages when the effect of levodopa wears off or becomes inconsistent and fluctuations of th e therapeutic effect occur (end of dose or "on off" fluctuations). MIRAPEXIN tablets are also indicated for symptomatic treatment of moderate to severe idiopathic Restles s Legs Syndrome in dosages up to 0.54 mg of base (0.75 mg of salt). [Date of issue of Marketing Authorisation valid throughout the European Union] 23 February 1998 [Orphan medicinal product designation date] Not applicable ●CHMP Press Releases CPMP 21-22 Otober 1997[1997.10.24;pdf,9p] - Sifrol 市販許可1997.10.14 パーキンソン病 CPMP Position Statement : Dopaminergic substance and sudden sleep onset[2002.2.28] - ドパミン刺激性薬剤共通の副作用である突発的睡眠について2000.2から調査開始。この結果に基づき添付文書 を改訂する。 Public Statement on Sifrol, Daquiran, Mirapexin (Pramipexole) - sudden onset of sleep[1999.7.19] PUBLIC STATEMENT ON SIFROL, DAQUIRAN, MIRAPEXIN (Pramipexole): Recommendation to reinforce the warning on sudden onset of sleep[1999.8.3] ●Summaries of Opinion - List of Products - CHMP Opinions諮問委員会審議品目一覧 ---Substance/INN Trade Name Pharmaceuticalform Strength OpinionAdoption Date CHMP Summary of Opinion for Sifrol, INN:pramipexole[2006.2.23 ] - CHMP承認勧告2006.2.23 RLS Summary of Opinion for Mirapexin, INN:pramipexole - CHMP承認勧告2006.2.23 RLS ■[Enterprise and Industry DG] Pharmaceuticals -http://ec.europa.eu/enterprise/pharmaceuticals/index_en.htm ★Latest news on Pharmaceuticals ★Review of Pharmaceutical legislation[薬事行政Review] ★EudraLex Collection[医薬品法規～全文] ★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 [オーファン]Register of designated Orphan Medicinal Products (alphabetical)[333件、15/3/2006現在] -[年月別] - 取下げ・中断 - 却下 [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 -[List of Referred products ] [総合索引～成分別]General index on active ingredient [総合索引～銘柄別]General index on brand name ■EudraPharm.eu - EU-EMEAが2006.12設立the European medicines database - 添付文書等の詳細資料はないが、概要DB
●Boehringer Ingelheim ●Products Parkinson Disease ●News Release ■米国 Boehringer Ingelheim Corporation Mirapex -Full Prescribing Information 08 Jun 2007★Efficacy of Boehringer Ingelheim's pramipexole (Mirapexin(R)/Sifrol(R)) also demonstrated in patients with daytime RLS symptoms ★RLS/パーキンソン病薬塩酸プラミペキソール(ビ・シフロール)
10 Nov 2006★FDA approves Boehringer Ingelheim's pramipexole for the treatment of moderate-to-severe primary Restless Legs Syndrome (RLS) ★RLS/パーキンソン病薬塩酸プラミペキソール(ビ・シフロール)
31 Oct 2006★Latest data demonstrate Boehringer Ingelheim's pramipexole (Mirapexin®/Sifrol®) improves broad spectrum of symptoms of Restless Legs Syndrome (RLS)★RLS/パーキンソン病薬塩酸プラミペキソール(ビ・シフロール)
31 Oct 2006★Boehringer Ingelheim's pramipexole (Mirapexin(R)/Sifrol(R)) shown to improve depressive and motivational symptoms in Parkinson's disease★RLS/パーキンソン病薬塩酸プラミペキソール(ビ・シフロール)
04 Sep 2006★Boehringer Ingelheim's pramipexole (Sifrol(R)/Mirapexin(R)) can provide benefit of improved mood disturbance for people with Restless Legs Syndrome★RLS/パーキンソン病薬塩酸プラミペキソール(ビ・シフロール)
19 Jun 2006★Multiple new studies reinforce efficacy of Sifrol(R) / Mirapexin(R) (pramipexole) in treatment of Restless Legs Syndrome★RLS/パーキンソン病薬塩酸プラミペキソール(ビ・シフロール)
07 Apr 2006★Boehringer Ingelheim's Sifrol(R)/ Mirapexin(R) (pramipexole) is first treatment for Restless Legs Syndrome (RLS) to become approved throughout the European Union (EU) ★RLS/パーキンソン病薬塩酸プラミペキソール(ビ・シフロール)
05 Apr 2006★New data suggest pramipexole can significantly improve quality of life (QoL) for people with Restless Legs Syndrome (RLS)★RLS/パーキンソン病薬塩酸プラミペキソール(ビ・シフロール)
24 Feb 2006★Boehringer Ingelheim receives recommendation from EU scientific committee for Sifrol(R)/ Mirapexin(R)(pramipexole) for the treatment of Restless Legs Syndrome (RLS) ★RLS/パーキンソン病薬塩酸プラミペキソール(ビ・シフロール)
17 Oct 2005★New data confirm Pramipexole delivers sustained efficacy for patients with Restless Legs Syndrome★RLS/パーキンソン病薬塩酸プラミペキソール(ビ・シフロール)
19 Sep 2005★New hope for Restless Legs Syndrome (RLS) - Pramipexole relieves symptoms and improves patients・quality of life ★RLS/パーキンソン病薬塩酸プラミペキソール(ビ・シフロール)
19 Sep 2005★Restless Legs Syndrome (RLS) - New data confirm pramipexole relieves symptoms and significantly improves patients・quality of life★RLS/パーキンソン病薬塩酸プラミペキソール(ビ・シフロール)
23 June 2005★New research data on pramipexole show 95 percent effectiveness and long-term relief from the symptoms of Restless Legs Syndrome
08 March 2005★Large clinical study results show pramipexole rapidly relieves Restless Legs Syndrome symptoms and improves sleep and depressed mood
30 April 2004★Study Demonstrates Mirapex(R)/ Sifrol(R) (pramipexole) Induces Rapid Relief from Restless Legs Syndrome★パーキンソン病薬塩酸プラミペキソール(ビ・シフロール)
13 June 2003★Pramipexole potentially exerts a protective effect on neurons★パーキンソン病薬塩酸プラミペキソール(ビ・シフロール)
27 November 2002★Pramipexole now in Clinical Development for Restless Legs Syndrome indication★パーキンソン病薬塩酸プラミペキソール(ビ・シフロール)
28 October 2002★Pramipexole: First-line Treatment of Parkinson`s Disease★パーキンソン病薬塩酸プラミペキソール(ビ・シフロール)
3 April 2002★New JAMA Study Reveals Promising Results in Treatment of Early Parkinson's Disease★パーキンソン病薬塩酸プラミペキソール(ビ・シフロール)
★sifrol / mirapexin / mirapex (pramipexole) パーキンソン病/RLS [2006] Parkinson’s disease and restless legs syndrome sifrolR / mirapexinR / mirapexR (pramipexole), a product from Boehringer Ingelheim research, is a dopamine agonist that was first approved in 1997 for the treatment of the signs and symptoms of idiopathic Parkinson’s disease (PD), as monotherapy or in combination with levodopa. After a decade of treatment for Parkinson’s patients, a new key milestone was achieved with the approval of sifrolR / mirapexinR / mirapexR for the symptomatic treatment of moderate to severe idiopathic restless legs syndrome (RLS) in 2006, both in the European Union and the USA. sifrolR / mirapexinR / mirapexR continued to show strong growth in 2006 in the Parkinson’s disease indication, too. At the end of October 2006, the brand ranked No. 6 among Boehringer Ingelheim’s best-selling products, with total net sales of EUR 536 million, up 23 % against the same period in 2005. It is the world’s best-selling dopamine agonist, with a market share of more than 22 %. The estimated cumulative worldwide exposure since 1997 is 2.2 million patient years.
●日本ベーリンガーインゲルハイム ●製品基本情報 ビ・シフロール錠 添付文書 - [pdf] | インタビューフォーム (塩酸プラミペキソール水和物) ●製品(同社WEB非公開) ビ・シフロール錠0.125mg,0.5mg－BI・Sifrol Tablets 薬効分類名 ドパミン作動性パーキンソン病治療剤 成分・含量 1錠中 塩酸プラミペキソール水和物 0.125mg,0.5mg 効能又は効果 パーキンソン病 [用法及び用量] 通常、成人には塩酸プラミペキソール水和物として1日量0.25mgからはじめ、2週目に1日 量を0.5mgとし、以後経過を観察しながら、1週間毎に1日量として0.5mgずつ増量し、維持 量（標準1日量1.5～4.5mg）を定める。1日量が塩酸プラミペキソール水和物として1.5mg 未満の場合は2回に分割して朝夕食後に、1.5mg以上の場合は3回に分割して毎食後経口投 与する。なお、年齢、症状により適宜増減ができるが、1日量は4.5mgを超えないこと。 ●プレスリリース 2007年4月5日★ベーリンガーインゲルハイムグループ2006年グローバルの業績
2007年6月13日★プラミペキソール、「むずむず脚症候群」患者の日中の症状改善にも有益★非麦角系選択的D2受容体作動薬プラミペキソールは、これまで報告されてきた夜間の症状改善のみならず、日中に症状が現れる「むずむず脚症候群(RLS)」患者にとっても、有効性と忍容性に優れた治療選択肢であることが示されました。これは、このほどイスタンブールで開催された第11回国際運動障害学会(International Congress of Parkinson’s Disease and Movement Disorders: MDS)で発表された新たなデータにより裏付けられたものです。プラミペキソールは1日1回の服用で、午後から夕方の早い時間に発現するRLS症状を緩和するとともに1、日中の眠気症状を改善し2、中等度から重症までの患者に幅広く有効なことが改めて確認されました1,2。なおプラミペキソールは、欧米ではパーキンソン病に加えて、RLSを適応症として承認されています。日本ではパーキンソン病を適応症として承認されており、RLSについては適応追加に向けた第Ⅲ相試験が開始されています。
★RLS/パーキンソン病薬塩酸プラミペキソール(ビ・シフロール)
2007年2月13日★多彩な顔ぶれの専門家委員会が、ベーリンガーインゲルハイムの長年のパーキンソン病研究を評価★RLS/パーキンソン病薬塩酸プラミペキソール(ビ・シフロール)
2006年11月24日★ベーリンガーインゲルハイムのプラミペキソール、米国でレストレスレッグス症候群（むずむず脚症候群）の追加適応承認を取得★FDAより、同社のドパミン作動薬プラミペキソールが、中等症から重症のレストレスレッグス症候群（むずむず脚症候群）の追加適応承認を受けたと発表しました1。★RLS/パーキンソン病薬塩酸プラミペキソール(ビ・シフロール)
2006年11月1日★プラミペキソール、レストレスレッグス症候群（むずむず脚症候群）の幅広い症状を改善 また合併症を持つなど幅広い患者の治療に有用との新たなデータも発表★RLS/パーキンソン病薬塩酸プラミペキソール(ビ・シフロール)
2006年10月31日★ビ･シフロール®がパーキンソン病に伴う気分障害（抑うつ症状や意欲低下）を改善するとのメタアナリシス結果、また、同薬による早期治療開始の有用性を観る試験の概要を発表★RLS/パーキンソン病薬塩酸プラミペキソール(ビ・シフロール)
2006年10月26日★日本ベーリンガーインゲルハイム、プラミペキソールのレストレスレッグス症候群（むずむず脚症候群）への適応追加に向け第Ⅲ相試験を開始★RLS/パーキンソン病薬塩酸プラミペキソール(ビ・シフロール)
2006年9月5日★非麦角系選択的D2受容体作動薬プラミペキソール、レストレスレッグス症候群（むずむず脚症候群）患者におこる気分障害の改善にも有益★RLS/パーキンソン病薬塩酸プラミペキソール(ビ・シフロール)
2006年6月27日★レストレスレッグス症候群（むずむず脚症候群）への非麦角系選択的D2受容体作動薬プラミペキソールの有用性を裏付ける複数の試験成績が新たに発表★RLS/パーキンソン病薬塩酸プラミペキソール(ビ・シフロール)
2006年6月27日★ドパミンD2受容体作動薬プラミペキソール、日本でもレストレスレッグス症候群（むずむず脚症候群）に対する有効性が明らかに★RLS/パーキンソン病薬塩酸プラミペキソール(ビ・シフロール)
2006年6月16日★パーキンソン病患者の8割以上が「抑うつ症状」を経験しながら、その約半数は医師に相談していない実態が明らかに★RLS/パーキンソン病薬塩酸プラミペキソール(ビ・シフロール)
2006年4月11日★非麦角系選択的ドパミンD2受容体作動薬プラミペキソール、欧州（EU）全域でレストレスレッグス症候群（むずむず脚症候群）の追加適応承認を取得★EUより、同社のドパミン作動薬プラミペキソールが、中等症から重症のレストレスレッグス症候群（むずむず脚症候群）の追加適応承認を受けたと発表しました。プラミペキソールはレストレスレッグス症候群にともなう様々な症状を臨床的に有意に改善することが、これまでの臨床試験で確認されています。欧州（EU）全域でレストレスレッグス症候群の認可を受けたのはプラミペキソールが初めてです。★RLS/パーキンソン病薬塩酸プラミペキソール(ビ・シフロール)
2006年4月6日★非麦角系選択的ドパミンD2受容体作動薬プラミペキソール、レストレスレッグス症候群(むずむず脚症候群)患者の生活の質(QOL)を著しく改善★RLS/パーキンソン病薬塩酸プラミペキソール(ビ・シフロール)
2006年2月28日★非麦角系選択的ドパミンD2受容体作動薬プラミペキソール、欧州でレストレスレッグ症候群（RLS：むずむず脚症候群）への適応追加が承認の見通し★医薬品委員会(CHMP)の承認勧告を受けました。★RLS/パーキンソン病薬塩酸プラミペキソール(ビ・シフロール)
2004年5月7日★ビ･シフロール®、レストレスレッグ症候群（RLS）治療に奏功★パーキンソン病薬塩酸プラミペキソール(ビ・シフロール)
2004年1月14日★日本ベーリンガーインゲルハイム、1月15日にビ･シフロール®を新発売★パーキンソン病薬塩酸プラミペキソール(ビ・シフロール)
2003年12月12日★日本ベーリンガーインゲルハイム、ビ･シフロール®を来年1月に新発売★パーキンソン病薬塩酸プラミペキソール(ビ・シフロール)
2003年10月16日★初期からのパーキンソン病治療に適したシフロール®（一般名：プラミペキソール）の日本での製造（輸入）承認を取得★パーキンソン病薬塩酸プラミペキソール(ビ・シフロール)
2003年6月17日★ドパミン作動性パーキンソン病治療剤 シフロール®（一般名：プラミペキソール）、神経細胞保護的に作用する可能性を示す★パーキンソン病薬塩酸プラミペキソール(ビ・シフロール)
2002年11月29日★ベーリンガーインゲルハイム、シフロール®（プラミペキソール）についてRLS（レストレスレッグ症候群）への適応拡大に向けた臨床開発を本格的に開始★パーキンソン病薬塩酸プラミペキソール(ビ・シフロール)
2002年10月29日★パーキンソン病治療の第一選択薬として評価されるプラミペキソール★パーキンソン病薬塩酸プラミペキソール(ビ・シフロール)
2002年4月23日★RLS（レストレスレッグ症候群）の治療法として注目の集まるドーパミン受容体刺激剤★パーキンソン病薬塩酸プラミペキソール(ビ・シフロール)
2002年4月10日★早期パーキンソン病治療について、有望な成績が示される★パーキンソン病薬塩酸プラミペキソール(ビ・シフロール)
[]rotigotine CDS (Neupro [Schwartz Bioscience])ロチゴチン
●製品 rotigotine CDS (Neupro [Schwartz Bioscience])ロチゴチン
日本語版註）rotigotine CDS (Neupro [Schwartz Bioscience])ロチゴチン
【別名】SPM-962 【開発元】創製Aderis Pharmaceuticals→Schwarz Pharma AGが1998年全世界開発販売権取得 [DBR_ID]
【化学名】(6S)-6-{propyl[2-(2-thienyl)ethyl]amino}-5,6,7,8-tetrahydro-1-naphthalenol
【承認】FDA申請=January 19, 2005、FDA承認=May 9, 2007 ; 【製剤】Each transdermal system has a release surface area of 10, 20, and 30 cm2 and contains 4.5, 9, or 13.5 mg rotigotine, designed to continuously deliver rotigotine over a 24-hour period. 【適応】Neupro is indicated for the treatment of the signs and symptoms of early-stage idiopathic Parkinson's disease 【用法用量】初回2mg/24 hours投与、最低有効用量は4mg/24 hours 【作用】D3／D2／Dlドパミン作動薬（非エルゴリン系） 【特徴】a non-ergolinic dopamine agonist 【製品情報】www.neupro.com 【添付文書】NEUPRO -PI 【EU】Neupro INN: rotigotine[SCHWARZ PHARMA]EMEA承認2006.2.15 【日本】「ロチゴチン」CDS(大塚製薬)臨床開発中；独シュワルツ・ファーマ社（Schwarz Pharma AG)と2002.11.14契約[日本における独占的開発・販売権] 【その他】現在の経口治療薬に比べ利点があるものの、GSK社の1日1錠投与型Requip Modutabとの競合
●承認データ：FDA ●2004.5.1 以降 Drugs@FDA
Drug Name(s) =NEUPRO (ROTIGOTINE) FDA Application No. =(NDA) 021829 Active Ingredient(s)=ROTIGOTINE Company =SCHWARZ BIOSCIENCES Dosage Form/Route =FILM, EXTENDED RELEASE; TRANSDERMAL 2MG/24HR, 4MG/24HR, 6MG/24HR Strength = - Approval Date=May 9, 2007[000] :Label[添付文書]|Letter[承認書]| [Approval] Original Approval Date May 9, 2007 Chemical Type 1 New molecular entity (NME) Review Classification S Standard review drug
●Electronic Orange Book Application Number: 021829 Active Ingredient : ROTIGOTINE Proprietary Name : NEUPRO [SCHWARZ BIOSCIENCES] FILM, EXTENDED RELEASE; TRANSDERMAL 2MG/24HR, 4MG/24HR, 6MG/24HR Approval Date : May 9, 2007 Exclusivity Data : NCE MAY 09,2012 Patent Data : -
●EU承認 ●EMEA - Human Medcines ●List of Authorized Products (EPARs)★[A-Z 承認品目] ★Neupro INN: rotigotine (Rev. 3) - Published 07/05/07 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 [Marketing Authorisation Holder] SCHWARZ PHARMA Ltd Shannon, Industrial Estate, Co. Clare,Ireland [Active Substance] Rotigotine [International Nonproprietary Name or Common Name] Rotigotine [Pharmaco-therapeutic Group] Dopamine agonists ATC Code N04BC09 [Therapeutic Indication] Neupro is indicated for the treatment of the signs and symptoms of early-stage idiopathic Parkinson's disease as monotherapy (i.e. without levodopa) or in combination with levodopa, i.e. over the course of the disease, through to late stages when the effect of levodopa wears off or becomes inconsistent and fluctu ations of the therapeutic effect occur (end of dose or 'on-off' fluctuations) [Date of issue of Marketing Authorisation valid throughout the European Union] 15 February 2006 [Orphan medicinal product designation date] Not applicable ●CHMP Press Releases CHMP press release December 2005 CHMP 13-16 November 2006 [適応拡大] .. Neupro (rotigotine), from Schwarz BioSciences GmbH, to include the treatment of the signs and symptoms of advanced-stage idiopathic Parkinson’s disease in c ombination with levodopa. Neupro was first granted a marketing authorisation in the European Union on 15 February 2006 and is currently indicated to treat signs and symptoms of early stage idiopathic Parkinson’s disease. ●Summaries of Opinion - List of Products - CHMP Opinions諮問委員会審議品目一覧 ---Substance/INN Trade Name Pharmaceuticalform Strength OpinionAdoption Date rotigotine Neupro 16/11/06
●Schwarz Pharma AG ★決算2006 ・Neupro(R) (rotigotine transdermal patch)(Rotigotine CDS;SPM 962) 抗パーキンソン病薬 - 2005.3.29 FDA申請。 EMEA申請は2004.9.29。新dopamine agonistで1日1回皮膚パッチ。 1998年にAderis Pharmaceuticals, Inc., USAから世界の開発・販売権を取得。 - 単独療法のEU 2006.2承認後、2006.3独・英発売に続き欧州12ヵ国で発売。 2007.1に進行性パーキンソン病での Levodopa併用で承認。 米国承認は2007.半ば予定。 抗パ剤世界市場規模はUS$2.9bn、年成長率8%。 Restless Legs Syndrome (RLS)の適応拡大:P3で欧米申請は2007.半ば予定。 RLS剤世界市場規模はUS$350mn、年成長率29%。 ●製品売上
●Products ●Investor Relations ★News [Preliminary Report 2003] SCHWARZ PHARMA’s Results Exceed Expectations, Pipeline Advanced[2004.2.18;pdf,4p] ★Business Report -Annual Reports Annual Report 2006 - [pdf,196p] - 個別製品売上 187p(Leading SCHWARZ PHARMA Products) - 開発製品 20-22p(Products in Clinical Development) Annual Report 2005 - [pdf,150p] Annual Report 2004[pdf,122p] - 個別製品売上 109p(Leading SCHWARZ PHARMA Products) - 開発製品 6-11p(Development projects to reach market) Annual Report 2003[pdf,109p] - 個別製品売上 91p(Leading SCHWARZ PHARMA Products) - 開発製品 8-11p(Major Advances in Development Projects) ●Press Room -Press Releases SCHWARZ PHARMA Acquires Remaining Rights to Rotigotine from Aderis[2005.7] - 1998年にAderis Pharmaceuticals, Inc., USAから世界の開発・販売権を取得。 抗パーキンソン病薬RotigotineはFDA/EUに申請済み。 SCHWARZ PHARMA’s NDA for Rotigotine Transdermal System is filed by FDA[2005.3] - 2005.3.29 FDA申請。 EMEA申請は2004.9.29。 SCHWARZ PHARMA discontinues clinical trial in benign prostate hyperplasia[2004.11] - unclear preclinical findingsにより、pamirosin(SPM969)の開発中止 SCHWARZ PHARMA to Add Promising Novel Treatment Option for Pain to Its Pipeline[2004.2] - AmorePacific Corp[韓国]からVR1 (vanilloid) receptor antagonistsのPAC20030 と関連物質のライセンス契約。 韓国とインドを除く全世界の権利。 慢性疼痛を 適応として現在前臨床。2005年末に臨床試験開始予定。 ●Research & Development ★Our Development Pipeline
(Euro milllion) 2006 2005 2004 2003 2002 備考 Neupro 9.5 - [Rotigotine]パーキンソン病
●SCHWARZ PHARMA Inc.[US] - http://www.schwarzusa.com/ ●Products ●Press Room - Press Releases
●Aderis Pharmaceuticals -http://www.aderis.com/index.asp 1994.4 Ethyl Corp子会社Whitby Research Incの研究プログラム買収により設立。 1998.8 Schwarz Pharmaとパーキンソン病用パッチ剤開発で提携 2001.11 rotigotine CDS P3へ 2002.1 Discovery TherapeuticsをAderis Pharmaceuticalsに社名変更 ●Products ★Parkinson's Disease ★Restless Legs Syndrome ★Cardiac Imaging ★Atrial Fibrillation ★Wound Healing in Diabetic Foot Ulcers ●product candidates Rotigotine(SPM-962)～パーキンソン病NDA/RLS(P2) /Schwarz社提携 Binodenoson(MRE-0470)～心臓機能診断薬 P3 /King社提携 Selodenoson(DTI-0009)～抗不整脈剤 P2 / MRE-0094～糖尿病性足部潰瘍治療薬 P1 /King社提携 ●Press Releases
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- 作成：2007.6.8 最終更新:2011.12.26 小菅博之
The Medical Letter日本語版
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On Drugs and Therapeutics
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