JP2019511506A - オファツムマブを用いた多発性硬化症の治療レジメンおよび治療方法 - Google Patents
オファツムマブを用いた多発性硬化症の治療レジメンおよび治療方法 Download PDFInfo
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Abstract
Description
a)負荷用量レジメンであって、最初の維持用量を投与する前の0日目、7日目、および14日目に、3〜60mg、または約3mg、もしくは約10mg、もしくは約20mg、もしくは約30mg、もしくは約60mgのオファツムマブを患者に投与することを含む負荷用量レジメン中、オファツムマブまたはその抗原結合断片を、それを必要とする患者に投与すること(好ましくは、該負荷用量は20mgのオファツムマブである);および
b)その後、維持レジメンであって、4週目およびその後4週間毎に、約3mg、もしくは約10mg、もしくは約20mg、もしくは約30mg、もしくは約60mgのオファツムマブまたはその抗原結合断片を患者に投与することを含む維持レジメン中、オファツムマブまたはその抗原結合断片を、前記患者に投与すること(好ましくは、該維持用量は20mgのオファツムマブである)を含む。
(i)他の時点における新規Gd増強病変の累積数;
(ii)12週目および24週目のa)新規Gd増強病変、b)新規/新たに拡大したT2病変、およびc)T1低強度病変の総体積;
(iii)再発のない患者の割合;
(iv)総合障害度スケール(EDSS)のスコア;
(v)多発性硬化症機能評価(MSFC)およびその構成要素のスコア;
(vi)改変疲労影響スケール(MFIS);ならびに
(vii)オファツムマブの初回調整用量の使用についての評価
が含まれた。
該試験は、再発性MS患者における、経口テリフルノミド(Aubagio(登録商標))と比較したs.c.オファツムマブの有効性、安全性、および忍容性データを得るため、並行して実施される同一デザインの第2試験と共に設計される。
これは、再発性MS患者に対する、可変の治療期間における、無作為化、二重盲検、ダブルダミー、実薬対照、並行群間、多施設試験である。適格患者を、オファツムマブ20mgのq4wでのs.c.注射投与(最初の14日間における週3回の20mg用量による最初の負荷レジメン後)またはテリフルノミド14mgの1日1回での経口投与のいずれかに無作為に割り付ける。異なる製剤に対して盲検とするため、ダブルダミーデザインが用いられてもよい:活性なオファツムマブ治療群の患者は、さらにプラセボカプセルを1日1回で経口投与される;活性なテリフルノミド治療群の患者は、さらにプラセボ含有s.c.注射を4週間毎で投与される(最初の14日間における週3回の注射による最初のレジメン後)。
本試験のためのオファツムマブの用量レジメンは、1日目、7日目、および14日目に20mgの負荷用量レジメン、続く、4週目に開始される4週間毎に投与される20mgの月1回の維持用量レジメンである。該用量選択は、リンパ組織におけるB細胞の枯渇が、有効性(MRIおよび再発によって測定される)にとって重要であり、また脳実質および髄膜のB細胞の枯渇が、作用機序の追加要因であると考えられる(血中B細胞数は、組織状態の不完全な随伴現象の評価基準である)といった臨床仮説のもと行われる。該仮説によって、望ましい有効性を得るためには、2つの条件を満たすべきであることが示唆される:
− リンパ球枯渇に対する十分に高い初期のPKを示す負荷用量レジメン
− B細胞枯渇レベルを望ましい閾値未満に保つ継続的な維持用量
滞りなく、MRI上の最大の有効性および8細胞/μL未満のB細胞の枯渇を得ることは望ましい(図1)。OMS112831/MIRROR試験の第II相のデータに基づいた探索的モデリングによって、オファツムマブ20mgのs.c.単回投与は、B細胞レベルを8細胞/μL以下に低下させるために不十分であることが示唆された(図2を参照)。図3および4でもみられるとおり、モデリング試験によって、複数回の負荷用量によるオファツムマブ20mgの投与を介して、目標の枯渇が高度に達成され得ること、また続く維持用量(同じく20mg)が、初期の枯渇を維持または増強することが予測される。より具体的には、本発明者らは、モデリングに基づき、3回の個別の20mg用量(0、1、および2週目)による負荷用量レジメンは、95%を上回る患者において目標の枯渇(8細胞/μL以下)を達成するために必要とされ、また単回60mgの負荷用量よりも有効であることが推定されると断定した。したがって、この負荷用量レジメンが選択された。
Claims (18)
- 多発性硬化症(MS)を治療する方法であって、
a)負荷用量レジメン中、それを必要とする患者にオファツムマブを投与すること、および
b)その後、維持用量レジメン中、前記患者にオファツムマブを投与すること
を含む方法。 - オファツムマブが、負荷用量レジメンおよび維持用量レジメン中、皮下(s.c.)注射で投与される、請求項1に記載の方法。
- 負荷用量レジメン中に投与されるオファツムマブの用量が、オファツムマブ約15mg〜約25mgの間である、請求項1に記載の方法。
- その後、維持レジメン中に投与されるオファツムマブの用量が、オファツムマブ約15mg〜約25mgの間である、請求項1に記載の方法。
- 負荷用量レジメン中に投与されるオファツムマブの用量が、オファツムマブ約18mg〜約22mgの間である、請求項1に記載の方法。
- その後、維持レジメン中に投与されるオファツムマブの用量が、オファツムマブ約18mg〜約22mgの間である、請求項1に記載の方法。
- 負荷用量レジメン中に投与されるオファツムマブの用量が、オファツムマブ約20mgである、請求項1に記載の方法。
- その後、維持レジメン中に投与されるオファツムマブの用量が、オファツムマブ約20mgである、請求項1に記載の方法。
- a)負荷用量レジメン中に投与されるオファツムマブの用量が、オファツムマブ約15mg〜約25mgの間であり、
b)その後、維持レジメン中に投与されるオファツムマブの用量が、オファツムマブ約15mg〜約25mgの間である、請求項1に記載の方法。 - a)負荷用量レジメン中に投与されるオファツムマブの用量が、オファツムマブ約18mg〜約22mgの間であり、
b)その後、維持レジメン中に投与されるオファツムマブの用量が、オファツムマブ約18mg〜約22mgの間である、請求項1に記載の方法。 - a)負荷用量レジメン中に投与されるオファツムマブの用量が、オファツムマブ約20mgであり、
b)その後、維持レジメン中に投与されるオファツムマブの用量が、オファツムマブ約20mgである、請求項1に記載の方法。 - a)投与レジメンの0日目、7日目、および14日目にオファツムマブ20mgを投与することを含む負荷用量レジメン中、それを必要とする患者に、オファツムマブを投与し、
b)投与レジメンの4週目から開始して、その後治療プロトコールの期間中に継続して4週間毎にオファツムマブ20mgを投与することを含む維持用量レジメン中、それを必要とする患者に、オファツムマブを投与する、請求項1に記載の方法。 - a)投与レジメンの0日目、7日目、および14日目にオファツムマブ20mgをs.c.注射することを含む負荷用量レジメン中、それを必要とする患者に、オファツムマブを投与し、
b)投与レジメンの4週目から開始して、その後治療プロトコールの期間中に継続して4週間毎にオファツムマブ20mgをs.c.注射することを含む維持用量レジメン中、それを必要とする患者に、オファツムマブを投与する、請求項1に記載の方法。 - 投与レジメンおよび維持レジメン中、50mg/mLの濃度でオファツムマブを含有する製剤を充填した自己注射器を用いて、オファツムマブ20mgを投与する、請求項13に記載の方法。
- 投与レジメンおよび維持レジメン中、50mg/mLの濃度でオファツムマブを含有する製剤を満たした充填済みシリンジを用いて、オファツムマブ20mgを投与する、請求項13に記載の方法。
- 多発性硬化症が、再発寛解型多発性硬化症(RRMS)である、請求項1に記載の方法。
- 多発性硬化症が、一次性進行型多発性硬化症(PPMS)である、請求項1に記載の方法。
- 多発性硬化症が、二次性進行型多発性硬化症(SPMS)である、請求項1に記載の方法。
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