JP6788725B2 - 腎機能障害を有するファブリー患者の治療方法 - Google Patents
腎機能障害を有するファブリー患者の治療方法 Download PDFInfo
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- JP6788725B2 JP6788725B2 JP2019229050A JP2019229050A JP6788725B2 JP 6788725 B2 JP6788725 B2 JP 6788725B2 JP 2019229050 A JP2019229050 A JP 2019229050A JP 2019229050 A JP2019229050 A JP 2019229050A JP 6788725 B2 JP6788725 B2 JP 6788725B2
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- migalastat
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- renal dysfunction
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Description
本明細書で使用される用語は、本発明の文脈の中で、及び各用語が使用される具体的な文脈において、概して当該技術分野におけるその通常の意味を有する。本発明の組成物及び方法並びにそれをどのように作成及び使用すればよいかを説明するにおいて実施者に更なる手引きを与えるため、特定の用語を以下で、又は本明細書中の他の箇所で考察する。
a.(ステージ0)正常腎機能−GFRが90mL/min/1.73m2を上回り、且つタンパク尿がない;
b.(ステージ1)−GFRが90mL/min/1.73m2を上回り、腎臓損傷のエビデンスがある;
c.(ステージ2)(軽度)−GFRが60〜89mL/min/1.73m2であり、腎臓損傷のエビデンスがある;
d.(ステージ3)(中等度)−GFRが30〜59mL/min/1.73m2である;
e.(ステージ4)(重度)−GFRが15〜29mL/min/1.73m2である;
f.(ステージ5)腎不全−GFRが15mL/min/1.73m2未満である。
ファブリー病は、まれな進行性の重篤なX連鎖性リソソーム蓄積障害である。GLA遺伝子の突然変異が、スフィンゴ糖脂質代謝に必要なリソソーム酵素α−Gal Aの欠損を引き起こす。幼児期に始まるα−Gal A活性の低下が、GL−3及び血漿lyso−Gb3を含めたスフィンゴ糖脂質の蓄積を引き起こし、疼痛、胃腸症状、腎不全、心筋症、脳血管イベント、及び早期の死亡を含めたファブリー病の症状及び致死的続発症につながる。早期の療法開始及び生涯にわたる治療が、疾患の進行を遅らせ、平均余命を延ばす機会を提供する。
LSDに関連する酵素の小分子阻害薬の結合は、突然変異酵素及び対応する野生型酵素の両方の安定性を増加させることができる(米国特許第6,274,597号明細書;同第6,583,158号明細書;同第6,589,964号明細書;同第6,599,919号明細書;同第6,916,829号明細書、及び同第7,141,582号明細書を参照のこと、全て参照により本明細書に援用される)。詳細には、幾つかの標的リソソーム酵素の特異的で選択的な競合阻害薬であるグルコース及びガラクトースの小分子誘導体を投与すると、インビトロで細胞内の酵素の安定性が有効に増加し、ひいてはリソソームへの酵素のトラフィッキングが増加した。従って、リソソーム内の酵素量が増加することにより、酵素基質の加水分解が増加するものと予想される。この戦略の背後にあった当初の理論は以下のとおりであった:突然変異酵素タンパク質はERにおいて不安定であるため(Ishii et al.,Biochem.Biophys.Res.Comm.1996;220:812−815)、酵素タンパク質は正常な輸送経路(ER→ゴルジ体→エンドソーム→リソソーム)において遅れ、早まって分解される。従って、突然変異酵素に結合してその安定性を増加させる化合物が酵素の「シャペロン」として働き、ERを出てリソソームに移ることのできる量を増加させ得る。加えて、一部の野生型タンパク質のフォールディング及びトラフィッキングは不完全で、場合によっては一部の野生型タンパク質の最大70%がその最終的な細胞部位に到達する前に分解されるため、シャペロンを野生型酵素の安定化に使用して、ERを出てリソソームに輸送されることのできる酵素の量を増加させることができる。
進行性の腎機能悪化はファブリー病の主要な合併症である。例えば、古典型ファブリー表現型に関連する患者は、最終的には透析又は腎移植が必要となり得る進行性腎機能障害を呈する。
GFR=141×min(Scr/κ,1)α×max(Scr/κ,1)−1.209×0.993年齢×1.018[女性の場合]×1.159[黒人の場合]
式中:
Scrはmg/dL単位の血清クレアチニンであり、
κは女性では0.7、及び男性では0.9であり、
αは女性では−0.329、及び男性では−0.411であり、
minはScr/κの最小値又は1を示し、及び
maxはScr/κの最大値又は1を示す。
GFR(mL/min/1.73m2)=175×(Scr)−1.154×(年齢)−0.203×(女性の場合0.742)×(アフリカ系アメリカ人の場合1.212)
クレアチニンクリアランス(mL/min)=[(140−年齢)×体重(Kg)*]÷72×血清クレアチニン(mg/dL)
[* 女性の場合、0.85を乗じる]
本明細書に記載される投与レジメンのうちの1つ以上は、何らかの程度の腎機能障害を有するファブリー患者に特に好適である。幾つかの研究で、ファブリー患者における150mgのミガラスタット塩酸塩、1日おき(QOD)の使用が調査されている。一つの研究は、67人のERT未経験患者における6ヵ月間の二重盲検プラセボ対照期間を含む24ヵ月試験であった。別の研究は、12ヵ月非盲検延長(OLE)を伴う57人のERT経験患者における実薬対照18ヵ月試験であった。両方の研究とも、推算糸球体濾過率(eGFR)が≧30mL/min/1.73m2の患者が含まれた。従って、両方の研究とも正常腎機能のファブリー患者並びに軽度及び中等度腎機能障害患者が含まれたが、いずれの研究も重度腎機能障害の患者は含まなかった。
本明細書に記載される投与レジメンは、様々な程度の腎機能障害を有するファブリー患者の腎機能を安定化させることができる。1つ以上の実施形態において、腎機能障害を有するファブリー患者には、約100mg〜約150mg FBEのミガラスタット又はその塩が1日おきに1回の頻度で投与される。1つ以上の実施形態において、患者には、123mgのミガラスタット又は150mgのミガラスタット塩酸塩など、123mg FBEのミガラスタット又はその塩が1日おきに投与される。1つ以上の実施形態において、患者は軽度又は中等度腎機能障害を有する。具体的な実施形態において、患者は軽度腎機能障害を有する。他の具体的な実施形態において、患者は中等度腎機能障害を有する。患者はERT未経験者又はERT経験者であり得る。
本明細書に記載される投与レジメンは、ファブリー患者のLVMiを改善することができる。表現型に関わらず、未治療のファブリー患者におけるLVMi及び心肥大の自然歴は(Patel,O’Mahony et al.2015)、+4.07〜+8.0g/m2/年の進行性のLVMiの増加である(Kampmann,Linhart et al.2008;Wyatt,Henley et al.2012;Germain,Weidemann et al.2013)。未治療のファブリー患者は典型的には時間の経過に伴いLVMiの増加を呈するため、LVMiの低下及びその維持の両方が、ミガラスタット療法の利益の指標である。
腎機能障害を有する非ファブリー対象においてミガラスタットHClの薬物動態及び安全性を調べるため臨床試験を実施した。軽度、中等度、及び重度腎機能障害、及び正常腎機能を有する対象に単回150mgミガラスタットHCl用量を投与した。腎機能障害研究に関するFDAガイダンスに従いeGFRをコッククロフト・ゴールト式によって推算した。
Cmax 最高実測濃度
tmax 最高濃度到達時間
AUC0−t 漸増濃度については線形台形公式及び漸減濃度については対数公式を用いて計算した、時間0から最終計測可能濃度までの濃度−時間曲線下面積
AUC0−∞ 以下の式を用いて計算した、無限大まで外挿した濃度−時間曲線下面積:
AUC0−∞=AUC0−t+Ct/λZ
[式中、Ctは最終計測可能濃度であり、及びλZは見かけの終末消失速度定数である]
λz 見かけの終末消失速度定数、式中、λZは終末相における対数濃度対時間プロファイルの線形回帰の傾きの大きさである
t1/2 見かけの終末消失半減期(可能な場合)、式中
t1/2=(ln2)/λZ
CL/F 用量/AUC0−∞として計算した、経口クリアランス
Vd/F 用量/AUC0−∞・λZとして計算した、経口分布容積
C48 投与後48時間濃度
実施例1の腎機能障害試験では、正常腎機能の対象と比べてeGFR値≦35mL/minで、曲線下面積(AUC)及びQOD用量に続く投与後48時間におけるミガラスタットのトラフ濃度(C48)の2倍〜4倍の一貫した増加が観察された。
上記のコンピュータモデリングは血漿ミガラスタット曝露のシナリオを提供するが、ファブリー患者の腎機能障害は考慮しない。即ち、データは薬力学的成分(血漿lyso−GB3)を含まない。従って、2人の腎機能障害を有するファブリー患者を評価した。一方の患者(P1)は中等度腎機能障害を有したとともに、他方の患者(P2)は重度腎機能障害を有した。以下の表5は、ERT未経験ファブリー患者の試験及び実施例1の腎機能障害試験からの中等度障害の対象と比較したP1の血漿ミガラスタット濃度を示す。6ヵ月の間隔をあけてとった2組のミガラスタット濃度計測値があり、患者は過去にミガラスタットで治療されたことがあった。表6はP2についての同様の情報を示し、但し、実施例1の腎機能障害試験からの重度障害を有する患者と比較した。適用可能突然変異を有するファブリー患者においてERT未経験者試験を行い、ここではまばらな血液試料採取から母集団PKを実施した。ERT未経験者試験の結果と比較することにより、大部分が正常な、しかし一部は軽度に、及び幾人かは中等度に障害されたファブリー患者を含むファブリー母集団のPKを比較することが可能となる。重度腎機能障害を有する患者は試験から除外したため、ERT未経験者試験にこれらの患者はいなかった。
本例は、実施例1の腎機能障害対象のミガラスタット投与の追加的なコンピュータシミュレーションを提供する。
上記に記載したとおり、ファブリー患者において150mgのミガラスタット塩酸塩、1日おき(QOD)を使用して幾つかの試験が実施された。一つの試験は、67人のERT未経験患者における6ヵ月の二重盲検プラセボ対照期間を含む24ヵ月試験であった。他の試験は、12ヵ月非盲検延長(OLE)を伴う57人のERT経験患者における実薬対照18ヵ月試験であった。ERT未経験者試験及びERT経験者試験の両方とも、eGFRが≧30mL/min/1.73m2のファブリー患者を含んだ。これらの試験の試験デザインを図10A〜図10Bに示す。
Claims (31)
- それを必要とするヒト患者においてファブリー病を治療するための、有効量のミガラスタット又はその塩を含む医薬であって、
患者が、α−ガラクトシダーゼAにおいて、L3V、L3P、R4M/Y207S、A13T、A13P、A15T、A15G、F18C、A20D、W24R、W24G、W24C、D33G、N34D、N34T、G35E、G35V、L36S、L36W、A37T、M42K、M42I、H46P、E48Q、N53D、N53L、L54F、Q57L、P60T、P60S、F69L、M72I、G80D、D83N、G85S、G85N、E87D、L89F、M96I、S102L、G104V、L106F、A108T、D109G、R112G、Y123C、H125L、S126G、G128E、I133M、D136E、N139S、K140T、G144D、F145S、P146S、P146R、Y152H、D165H、D165G、L166G、L167V、C174R、C174G、D175E、L180W、L180F、Y184N、K185E、p.M187_S188dup、M187I、G195V、R196G、I198T、V199A、V199G、Y200C、E203V、E203D、Y207H、M208R、P210S、P210L、K213M、P214S、P214L、N215S/D313Y、I219L、I219T、R220Q、R220P、Q221P、N224T、H225D、N228S、F229L、I232T、I242V、I242F、I242T、W245G、N249K、Q250R、Q250H、I253S、A257G、G258R、G260E、G261S、G261C、M267T、I270M、G271S/D313Y、G271D、W277G、W277C、T282I、M284V、I289S、M290L、M290I、A291T、L294S、M296L、M296T、D299E、R301L、I303F、S304N、S304T、A307T、A309V、L311V、Q312H、D313Y、D313Y/G411D、V316I、V316G、I319F、I319T、Q321H、D322N、D322E、P323R、G325R、K326N、Q330R、G334E、F337S、P343L、W349S、A352G、A352V、R356G、R356Q、R356P、E358Q、E358D、G360C、G361E、G361A、P362T、A368T、G375E、T385A、V390M、K391T、G395E、G395A、T412N、E418G、及びM421Vからなる群から選択されるHEKアッセイ適用可能突然変異を有する医薬。 - ミガラスタット又はその塩が1日おきに1回患者に投与される、請求項1に記載の医薬。
- 約123〜約300mgのミガラスタット又はその塩が1日おきに1回患者に投与される、請求項1に記載の医薬。
- 約150mgのミガラスタット又はその塩が1日おきに1回投与される、請求項1に記載の医薬。
- 約150mgのミガラスタット塩酸塩が1日おきに1回患者に投与される、請求項1に記載の医薬。
- ミガラスタット又はその塩がα−ガラクトシダーゼ活性を増加させる、請求項1〜5のいずれか一項に記載の医薬。
- 患者が男性である、請求項1〜6のいずれか一項に記載の医薬。
- 患者が女性である、請求項1〜6のいずれか一項に記載の医薬。
- 患者が腎機能障害を有する、請求項1〜8のいずれか一項に記載の医薬。
- 患者が軽度又は中等度腎機能障害を有する、請求項9に記載の医薬。
- 突然変異が、L3V、L3P、R4M/Y207S、A13T、A13P、A15T、A15G、F18C、A20D、W24R、W24G、W24C、D33G、N34D、N34T、G35E、及びG35Vからなる群から選択される、請求項1〜10のいずれか一項に記載の医薬。
- 突然変異が、L36S、L36W、A37T、M42K、M42I、H46P、E48Q、N53D、N53L、L54F、Q57L、P60T、P60S、F69L、M72I、G80D、及びD83Nからなる群から選択される、請求項1〜10のいずれか一項に記載の医薬。
- 突然変異が、G85S、G85N、E87D、L89F、M96I、S102L、G104V、L106F、A108T、D109G、R112G、Y123C、H125L、S126G、G128E、I133M、D136E、及びN139Sからなる群から選択される、請求項1〜10のいずれか一項に記載の医薬。
- 突然変異が、K140T、G144D、F145S、P146S、P146R、Y152H、D165H、D165G、L166G、L167V、C174R、C174G、D175E、L180W、L180F、Y184N、及びK185Eからなる群から選択される、請求項1〜10のいずれか一項に記載の医薬。
- 突然変異が、p.M187_S188dup、M187I、G195V、R196G、I198T、V199A、V199G、Y200C、E203V、E203D、Y207H、M208R、P210S、P210L、K213M、P214S、P214L、及びN215S/D313Yからなる群から選択される、請求項1〜10のいずれか一項に記載の医薬。
- 突然変異が、I219L、I219T、R220Q、R220P、Q221P、N224T、H225D、N228S、F229L、I232T、I242V、I242F、I242T、W245G、N249K、Q250R、及びQ250Hからなる群から選択される、請求項1〜10のいずれか一項に記載の医薬。
- 突然変異が、I253S、A257G、G258R、G260E、G261S、G261C、M267T、I270M、G271S/D313Y、G271D、W277G、W277C、T282I、M284V、I289S、M290L、及びM290Iからなる群から選択される、請求項1〜10のいずれか一項に記載の医薬。
- 突然変異が、A291T、L294S、M296L、M296T、D299E、R301L、I303F、S304N、S304T、A307T、A309V、L311V、Q312H、D313Y、D313Y/G411D、V316I、及びV316Gからなる群から選択される、請求項1〜10のいずれか一項に記載の医薬。
- 突然変異が、I319F、I319T、Q321H、D322N、D322E、P323R、G325R、K326N、Q330R、G334E、F337S、P343L、W349S、A352G、A352V、R356G、R356Q、及びR356Pからなる群から選択される、請求項1〜10のいずれか一項に記載の医薬。
- 突然変異が、E358Q、E358D、G360C、G361E、G361A、P362T、A368T、G375E、T385A、V390M、K391T、G395E、G395A、T412N、E418G、及びM421Vからなる群から選択される、請求項1〜10のいずれか一項に記載の医薬。
- それを必要とするヒト患者においてファブリー病を治療するための、有効量のミガラスタット又はその塩を含む医薬であって、
患者が、L3V、L3P、R4M/Y207S、A13T、A13P、A15T、A15G、F18C、A20D、W24R、W24G、W24C、D33G、N34D、N34T、G35E、G35V、L36S、L36W、A37T、M42K、M42I、H46P、E48Q、N53D、N53L、L54F、Q57L、P60T、P60S、F69L、M72I、G80D、D83N、G85S、G85N、E87D、L89F、M96I、S102L、G104V、L106F、A108T、D109G、R112G、Y123C、H125L、S126G、G128E、I133M、D136E、N139S、K140T、G144D、F145S、P146S、P146R、Y152H、D165H、D165G、L166G、L167V、C174R、C174G、D175E、L180W、L180F、Y184N、K185E、p.M187_S188dup、M187I、G195V、R196G、I198T、V199A、V199G、Y200C、E203V、E203D、Y207H、M208R、P210S、P210L、K213M、P214S、P214L、N215S/D313Y、I219L、I219T、R220Q、R220P、Q221P、N224T、H225D、N228S、F229L、I232T、I242V、I242F、I242T、W245G、N249K、Q250R、Q250H、I253S、A257G、G258R、G260E、G261S、G261C、M267T、I270M、G271S/D313Y、G271D、W277G、W277C、T282I、M284V、I289S、M290L、M290I、A291T、L294S、M296L、M296T、D299E、R301L、I303F、S304N、S304T、A307T、A309V、L311V、Q312H、D313Y、D313Y/G411D、V316I、V316G、I319F、I319T、Q321H、D322N、D322E、P323R、G325R、K326N、Q330R、G334E、F337S、P343L、W349S、A352G、A352V、R356G、R356Q、R356P、E358Q、E358D、G360C、G361E、G361A、P362T、A368T、G375E、T385A、V390M、K391T、G395E、G395A、T412N、E418G、又はM421Vの1以上の突然変異を含む参照表に記載の、α−ガラクトシダーゼにおけるHEKアッセイ適用可能突然変異を有する、医薬。 - 参照表が、以下の突然変異:
L3V、L3P、R4M/Y207S、A13T、A13P、A15T、A15G、F18C、A20D、W24R、W24G、W24C、D33G、N34D、N34T、G35E、G35V、L36S、L36W、A37T、M42K、M42I、H46P、E48Q、N53D、N53L、L54F、Q57L、P60T、P60S、F69L、M72I、G80D、D83N、G85S、G85N、E87D、L89F、M96I、S102L、G104V、L106F、A108T、D109G、R112G、Y123C、H125L、S126G、G128E、I133M、D136E、N139S、K140T、G144D、F145S、P146S、P146R、Y152H、D165H、D165G、L166G、L167V、C174R、C174G、D175E、L180W、L180F、Y184N、K185E、p.M187_S188dup、M187I、G195V、R196G、I198T、V199A、V199G、Y200C、E203V、E203D、Y207H、M208R、P210S、P210L、K213M、P214S、P214L、N215S/D313Y、I219L、I219T、R220Q、R220P、Q221P、N224T、H225D、N228S、F229L、I232T、I242V、I242F、I242T、W245G、N249K、Q250R、Q250H、I253S、A257G、G258R、G260E、G261S、G261C、M267T、I270M、G271S/D313Y、G271D、W277G、W277C、T282I、M284V、I289S、M290L、M290I、A291T、L294S、M296L、M296T、D299E、R301L、I303F、S304N、S304T、A307T、A309V、L311V、Q312H、D313Y、D313Y/G411D、V316I、V316G、I319F、I319T、Q321H、D322N、D322E、P323R、G325R、K326N、Q330R、G334E、F337S、P343L、W349S、A352G、A352V、R356G、R356Q、R356P、E358Q、E358D、G360C、G361E、G361A、P362T、A368T、G375E、T385A、V390M、K391T、G395E、G395A、T412N、E418G、及びM421Vの各々を含む、請求項21に記載の医薬。 - ミガラスタット又はその塩が1日おきに1回患者に投与される、請求項21又は22に記載の医薬。
- 約123〜約300mgのミガラスタット又はその塩が1日おきに1回患者に投与される、請求項21又は22に記載の医薬。
- 約150mgのミガラスタット又はその塩が1日おきに1回投与される、請求項21又は22に記載の医薬。
- 約150mgのミガラスタット塩酸塩が1日おきに1回患者に投与される、請求項21又は22に記載の医薬。
- ミガラスタット又はその塩がα−ガラクトシダーゼ活性を増加させる、請求項21〜26のいずれか一項に記載の医薬。
- 患者が男性である、請求項21〜27のいずれか一項に記載の医薬。
- 患者が女性である、請求項21〜27のいずれか一項に記載の医薬。
- 患者が腎機能障害を有する、請求項21〜29のいずれか一項に記載の医薬。
- 患者が軽度又は中等度腎機能障害を有する、請求項30に記載の医薬。
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Families Citing this family (11)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
SI2533050T1 (sl) | 2006-05-16 | 2014-07-31 | Amicus Therapeutics, Inc. | MoĹľnosti zdravljenja Fabrijeve bolezni |
PT2252313E (pt) | 2008-02-12 | 2015-08-26 | Amicus Therapeutics Inc | Método para previsão da resposta ao tratamento farmacológico de doenças com chaperonas |
JP7098529B2 (ja) * | 2016-03-22 | 2022-07-11 | アミカス セラピューティックス インコーポレイテッド | Gla遺伝子にg9331a変異を有する患者においてファブリー病を処置する方法 |
MX2019014410A (es) | 2017-05-30 | 2020-02-10 | Amicus Therapeutics Inc | Metodos de tratamiento de pacientes con enfermedad de fabry que tienen insuficiencia renal. |
KR20200128676A (ko) | 2018-02-06 | 2020-11-16 | 아미쿠스 세라퓨틱스, 인코포레이티드 | 임신 환자의 파브리병 치료를 위한 미갈라스타트의 용도 |
KR20240017128A (ko) * | 2018-08-20 | 2024-02-06 | 아미쿠스 세라퓨틱스, 인코포레이티드 | Gla 유전자에 돌연변이를 갖는 환자에서 파브리 질병을 치료하는 방법 |
KR20220019796A (ko) * | 2019-06-11 | 2022-02-17 | 아미쿠스 세라퓨틱스, 인코포레이티드 | 신장 손상을 갖는 환자에서 파브리 질병을 치료하는 방법 |
AU2020327019A1 (en) | 2019-08-07 | 2022-03-03 | Amicus Therapeutics, Inc. | Methods of treating Fabry disease in patients having a mutation in the GLA gene |
US11623916B2 (en) | 2020-12-16 | 2023-04-11 | Amicus Therapeutics, Inc. | Highly purified batches of pharmaceutical grade migalastat and methods of producing the same |
USD961304S1 (en) * | 2021-05-25 | 2022-08-23 | Paolo Castelli | Furniture for bathrooms |
USD960619S1 (en) * | 2021-05-26 | 2022-08-16 | Paolo Castelli | Furniture for bathrooms |
Family Cites Families (30)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US6274597B1 (en) | 1998-06-01 | 2001-08-14 | Mount Sinai School Of Medicine Of New York University | Method of enhancing lysosomal α-Galactosidase A |
ES2537089T3 (es) | 2005-06-08 | 2015-06-02 | Amicus Therapeutics, Inc. | Purificación de imino- y amino-azúcares |
SI2533050T1 (sl) | 2006-05-16 | 2014-07-31 | Amicus Therapeutics, Inc. | MoĹľnosti zdravljenja Fabrijeve bolezni |
EP2142197A4 (en) | 2007-03-30 | 2010-11-10 | Amicus Therapeutics Inc | PROCESS FOR THE TREATMENT OF FABRY DISEASE USING PHARMACOLOGICAL CHAPERONS |
US9999618B2 (en) | 2007-04-26 | 2018-06-19 | Amicus Therapeutics, Inc. | Dosing regimens for the treatment of lysosomal storage diseases using pharmacological chaperones |
US9056101B2 (en) | 2007-04-26 | 2015-06-16 | Amicus Therapeutics, Inc. | Dosing regimens for the treatment of lysosomal storage diseases using pharmacological chaperones |
PT2252313E (pt) | 2008-02-12 | 2015-08-26 | Amicus Therapeutics Inc | Método para previsão da resposta ao tratamento farmacológico de doenças com chaperonas |
US8321148B2 (en) | 2008-10-24 | 2012-11-27 | Amicus Therapeutics, Inc. | Multiple compartment dosing model |
AU2010254092B2 (en) | 2009-05-26 | 2015-11-12 | Amicus Therapeutics, Inc. | Utilization of pharmacological chaperones to improve manufacturing and purification of biologics |
US9206457B2 (en) | 2009-05-26 | 2015-12-08 | Amicus Therapeutics, Inc. | Utilization of pharmacological chaperones to improve manufacturing and purification of biologics |
CN102472952A (zh) * | 2009-07-17 | 2012-05-23 | Nec显示器解决方案株式会社 | 光圈控制电路、投影装置、光圈控制程序及光圈控制方法 |
US9066939B2 (en) | 2009-11-17 | 2015-06-30 | Baylor Research Institute | Urinary triaosylceramide (GB3) as a marker of cardiac disease |
CN103974619B (zh) | 2011-03-11 | 2017-02-15 | 阿米库斯治疗学公司 | 治疗法布里病的给药方案 |
US20120283290A1 (en) * | 2011-05-06 | 2012-11-08 | Amicus Therapeutics Inc. | Quantitation of gl3 in urine |
US20150258081A1 (en) | 2011-12-22 | 2015-09-17 | Centogene Ip Gmbh | Combination of a compound having the ability to rearrange a lysosomal enzyme and ambroxol and/or a derivative of ambroxol |
US10155027B2 (en) | 2012-07-17 | 2018-12-18 | Amicus Therapeutics, Inc. | Alpha-galactosidase A and 1-deoxygalactonojirimycin co-formulation for the treatment of fabry disease |
US9694056B2 (en) | 2012-07-17 | 2017-07-04 | Amicus Therapeutics, Inc. | α-galactosidase A and 1-deoxygalactonojirimycin co-formulation |
US20170051267A1 (en) | 2015-08-20 | 2017-02-23 | Research Foundation Of The City University Of New York | Novel alpha-galactosidase a derivatives |
JP7098529B2 (ja) | 2016-03-22 | 2022-07-11 | アミカス セラピューティックス インコーポレイテッド | Gla遺伝子にg9331a変異を有する患者においてファブリー病を処置する方法 |
US20190183869A1 (en) | 2016-07-19 | 2019-06-20 | Amicus Therapeutics, Inc. | Treatment of fabry disease in ert-naïve and ert-experienced patients |
JP2020503900A (ja) | 2017-01-10 | 2020-02-06 | アミカス セラピューティックス インコーポレイテッド | ファブリー病の処置のための組換えアルファ−ガラクトシダーゼa |
MX2019014410A (es) | 2017-05-30 | 2020-02-10 | Amicus Therapeutics Inc | Metodos de tratamiento de pacientes con enfermedad de fabry que tienen insuficiencia renal. |
WO2019017938A1 (en) | 2017-07-19 | 2019-01-24 | Amicus Therapeutics, Inc. | TREATMENT OF FABRY'S DISEASE IN PATIENTS WITHOUT SUBSTITUTED ENZYMATIC THERAPY (TES) AND PATIENTS SUBJECT TO TES |
PL3675853T3 (pl) | 2017-08-28 | 2022-12-27 | Amicus Therapeutics, Inc. | Sposoby poprawy i/lub stabilizacji czynności serca u pacjentów z chorobą fabry'ego |
HRP20240025T1 (hr) | 2018-02-06 | 2024-03-29 | Amicus Therapeutics, Inc. | Liječenje bolesnika s klasičnom fabrijevom bolešću migalastatom |
KR20200128676A (ko) | 2018-02-06 | 2020-11-16 | 아미쿠스 세라퓨틱스, 인코포레이티드 | 임신 환자의 파브리병 치료를 위한 미갈라스타트의 용도 |
KR20240017128A (ko) | 2018-08-20 | 2024-02-06 | 아미쿠스 세라퓨틱스, 인코포레이티드 | Gla 유전자에 돌연변이를 갖는 환자에서 파브리 질병을 치료하는 방법 |
KR20220019796A (ko) | 2019-06-11 | 2022-02-17 | 아미쿠스 세라퓨틱스, 인코포레이티드 | 신장 손상을 갖는 환자에서 파브리 질병을 치료하는 방법 |
AU2020327019A1 (en) | 2019-08-07 | 2022-03-03 | Amicus Therapeutics, Inc. | Methods of treating Fabry disease in patients having a mutation in the GLA gene |
CA3167476A1 (en) | 2020-02-10 | 2021-08-19 | Nina SKUBAN | Methods of treating fabry disease |
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