JP2021533142A - 膝および/または股関節痛の安全で効果的な処置用の医薬組成物 - Google Patents
膝および/または股関節痛の安全で効果的な処置用の医薬組成物 Download PDFInfo
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Abstract
Description
本発明は、パラセタモール/アセトアミノフェン、経口NSAIDS、およびオピオイド療法を含む、標準的な療法に対する不耐性、または標準的な療法での不十分な疼痛軽減の履歴を有する、中程度から重度の膝および/または股関節痛の患者を処置するための方法および組成物を含む。このサブセットの患者は、ファシヌマブのようなNGFアンタゴニストでの処置が有益と思われる、医学的な必要性を満たしていない患者集団を表し、これは、効能のあることを証明でき、他の標準的な療法より良好な安全性プロファイルをもたらし得る。
特定の態様において、本開示の方法および組成物は、股関節および/または膝関節痛の処置用に、高用量の抗NGF抗体またはその断片を投与される患者のサブセットにおいて発症する関節症を防ぐために使用される。
本出願の実施例の項で示す通り、約9mgおよび約6mgの用量は、膝および/または股関節痛を処置する3mgおよび1mgの用量の抗NGF抗体と比較して、特定の利点があり得る。例えば、高用量により、疼痛を軽減させ、および/または、低用量より高速で膝もしくは股関節での機能を高めることができる。しかし、高用量(例えばファシヌマブ約9mgまたは約6mg)を投与される患者の小さなサブセットにおいて、関節症のような治療下に発現した有害事象(TEAE)は起こり得る。
本発明は、それを必要とする対象における、1つまたはそれ以上の疼痛関連パラメーターを改善するための方法であって、NGFアンタゴニスト、例えば、本発明の抗NGF抗体またはその抗原結合断片を含む医薬組成物を対象に投与することを含む、方法を含む。
上記に詳細に開示される通り、本発明は、それを必要とする対象に、NGFアンタゴニストを含む医薬組成物を投与することを含む、方法を含む。本明細書で使用される場合、「NGFアンタゴニスト」は、NGFと結合するか、または相互作用し、NGFがインビトロまたはインビボでの細胞で発現している場合、NGFの正常な生物学的機能を阻害する、任意の薬剤である。NGFアンタゴニストの分類の非限定的な例として、小分子NGFアンタゴニスト、抗NGFアプタマー、ペプチド系NGFアンタゴニスト(例えば「ペプチボディ」分子)、およびヒトNGFに特異的に結合する抗体またはその抗原結合断片が挙げられる。
トランスジェニックなマウスにおいてヒト抗体を産生するための方法は、当該技術分野で知られている。任意のこのような公知の方法は、ヒトNGFに特異的に結合するヒト抗体を作製する本発明の文脈において使用することができる。
本発明は、NGFアンタゴニストを患者に投与することを含む方法であって、NGFアンタゴニストは、医薬組成物に含有される、方法を含む。本発明の医薬組成物は、好適な担体、添加剤、および、好適な移動、送達、耐性などをもたらす他の薬剤で製剤化される。多数の適切な処方は、全ての薬剤師に知られている処方集:Remington’s Pharmaceutical Sciences、Mack Publishing Company、Easton、PAで見出すことができる。これらの処方として、例えば、粉剤、ペースト剤、軟膏剤、ゼリー剤、ワックス、油剤、脂質、小胞を含有する脂質(カチオン性またはアニオン性)(例えばLIPOFECTIN(商標))、DNA複合体、吸収ペースト剤の無水物、水中油型および油中水型の乳剤、乳剤カーボワックス(様々な分子量のポリエチレングリコール)、半固体ゲル剤、ならびに、カーボワックスを含有する半固体混合物が挙げられる。また、Powellら「Compendium of excipients for parenteral formulations」PDA(1998)J Pharm Sci Technol 52:238〜311頁を参照のこと。
本発明の方法にしたがって対象に投与されるNGFアンタゴニスト(例えば、抗NGF抗体)の量は、一般に、治療有効量である。本明細書で使用される場合、成句「治療有効量」とは、以下の1つまたはそれ以上をもたらすNGFアンタゴニストの量を意味する:(a)1つもしくはそれ以上の疼痛関連パラメーターの改善(本明細書の他の場所で定義);および/または、(b)疼痛の1つもしくはそれ以上の症状もしくは徴候の検出可能な改善。「治療有効量」はまた、対象における疼痛の進行を阻害する、防止する、低減する、または遅延させるNGFアンタゴニストの量を含む。
本発明の方法は、特定の実施形態によると、NGFアンタゴニストと組み合わせて、対象に、1つまたはそれ以上の追加の治療剤を投与することを含む。本明細書で使用される場合、表現「と組み合わせて」とは、追加の治療剤を、NGFアンタゴニストを含む医薬組成物の前に、後に、または同時に投与することを意味する。用語「と組み合わせて」はまた、NGFアンタゴニストおよび第2の治療剤の逐次投与または併用投与を含む。
本発明は、治療効果を達成する限り、週に約4回、週に2回、週に1回、2週間ごとに1回、3週間ごとに1回、4週間ごとに1回、5週間ごとに1回、6週間ごとに1回、8週間ごとに1回、12週間ごとに1回の投与頻度、または、それより少ない頻度で、NGFアンタゴニストを含む医薬組成物を対象に投与することを含む、方法を含む。ファシヌマブのような抗NGF抗体を含む医薬組成物の投与に関与する、特定の実施形態において、約1、3、6、または9mgの量での4週間ごとに1回の投与を利用することができる。ファシヌマブのような抗NGF抗体を含む医薬組成物の投与に関与する、特定の実施形態において、約1、3、6、または9mgの量での8週間ごとに1回の投与を利用することができる。ファシヌマブのような抗NGF抗体を含む医薬組成物の投与に関与する、特定の実施形態において、約1、3、6、または9mgの量での12週間ごとに1回の投与を利用することができる。
患者。的確な患者は40〜80才であり;放射線学的な確認を伴う、OAに対する米国リウマチ学会基準に基づいて、膝および/または股関節(スクリーニング来診の時点で最も症状が出ている指標関節を指定)のOAの診断を受けており(0〜4の尺度で、2以上のKellgren−Lawrence[K−L]等級分け);通常の鎮痛医薬を投与しながらのスクリーニング、および無作為化来診の両方で、4以上の西オンタリオ大学およびマクマスター大学変形性関節炎指数(WOMAC)疼痛下位尺度スコアとして定義される、指標関節における中程度から重度の疼痛を示したが、これは、鎮痛療法の中断の7日後に起こった。患者は、アセトアミノフェンおよび1つ以上の経口NSAIDでの不十分な疼痛軽減またはそれらに対する不耐性の履歴を有し、オピオイドでの不十分な疼痛軽減、オピオイドに対する不耐性、またはオピオイド使用に対する不同意の履歴を有する必要があった。患者はまた、OA痛に対する通常の鎮痛剤の使用の履歴を有する必要があった(スクリーニングの前の4週間、平均で4日/週)。患者は、他の関節疾患、スクリーニング前の30日以内の指標関節の外傷、活発な線維筋痛もしくは別の中程度から重度の疼痛状態、または39超のボディーマスインデックスの履歴がある場合は除外した。
患者の素質。合計で1,214名の患者をスクリーニングし、421名を無作為化して、ファシヌマブ(n=338)またはプラセボ(n=83、図1)を投与した。421名の無作為化した患者のうち、419名の患者に、1以上の用量の試験医薬を投与した(プラセボおよびファシヌマブ9mgに無作為化された各々1名の患者は、試験薬投与の前に中止した)。合計で342名の患者が、36週の試験期間全てを完了した(ファシヌマブ:n=294;87%;プラセボ:n=67;81%)。
中程度から重度のOAの患者を含む、このIIb/III相試験において、ファシヌマブは、疼痛および身体機能を改善する点でプラセボより優れていた。ファシヌマブを投与した患者は、プラセボを投与したものと比較して、WOMAC疼痛下位尺度スコアにおいて、統計的に有意で、臨床的に重要な軽減を示した。WOMAC疼痛下位尺度スコアでのプラセボ調整した群の平均的な改善は、MCIDを超えた、0.78から1.40ポイントの範囲であった(Bellamy N.London、Ontario、Canada:Victoria Hospital;1995年)。WOMAC疼痛下位尺度スコアでの30%以上および50%以上の軽減の閾値に対するレスポンダー解析により、実質的に大きな割合のファシヌマブを投与した患者が、プラセボを投与したものより、疼痛で閾値の改善を達成したことを確認した。WOMAC身体機能下位尺度スコアでの改善もまた、プラセボと比較して、ファシヌマブで統計的に有意で、臨床的に重要であった。さらに、歩行時の疼痛の顕著な軽減は、NRSスコアで明らかなように、4用量全てでファシヌマブ療法の開始の7日以内に達成した(Salaffi Fら、Eur J Pain 2004年;8:283〜91頁)。
Claims (19)
- 膝関節または股関節に疼痛を有し、鎮痛処置に無応答であるか、または鎮痛処置の副作用を被っている対象の処置での使用のための医薬組成物であって、
治療有効量の、神経成長因子(NGF)に特異的に結合する抗NGF抗体またはその抗原結合断片
を含み、
該対象の膝関節または股関節の疼痛を軽減する、前記医薬組成物。 - 鎮痛処置は、アセトアミノフェン、オピオイド、非ステロイド性抗炎症薬(NSAID)、およびその組合せからなる群から選択され;
医薬組成物の初期用量、および1つまたはそれ以上の第2の用量は、各々、抗NGF抗体約1.0mg〜約9.0mgを含む、請求項1に記載の医薬組成物。 - 医薬組成物の初期用量、および1つまたはそれ以上の第2の用量は、各々、抗NGF抗体またはその抗原結合断片約1.0mgまたは約3mgを含み;
対象は、アセトアミノフェンでの不十分な疼痛軽減の履歴を有し;
対象は、オピオイドでの不十分な疼痛軽減、またはオピオイド使用に対する不同意の履歴を有する、請求項1または2に記載の医薬組成物。 - 神経成長因子(NGF)に特異的に結合する抗NGF抗体またはその抗原結合断片での処置に関連する関節症を回避するための医薬組成物であって、9mg未満の用量の該抗NGF抗体またはその抗原結合断片を含む、前記医薬組成物。
- 該医薬組成物の初期用量、および1つまたはそれ以上の第2の用量は、各々、1mg、2mg、3mg、4mg、または5mgからなる群から選択される量の抗NGF抗体またはその抗原結合断片を含む、請求項4に記載の医薬組成物。
- 関節症は、所定の閾値を超えて狭い関節腔を含む、請求項4または5に記載の医薬組成物。
- 関節症は、単純撮影写真で明らかな骨構造の変化を含む、請求項4または5に記載の医薬組成物。
- 皮下投与用に製剤化される、請求項4または5に記載の医薬組成物。
- 16週間にわたって;4週間ごとに1回の投与用である、請求項1から8のいずれか1項に記載の医薬組成物。
- 抗NGF抗体またはその抗原結合断片は、配列番号2のアミノ酸配列を有するHCVR、および配列番号10のアミノ酸配列を有するLCVRを含む、請求項1から9のいずれか1項に記載の医薬組成物。
- 対象は、4以上の西オンタリオ大学およびマクマスター大学変形性関節炎指数(WOMAC)疼痛下位尺度スコアとして定義される、膝および/または股関節での指標関節における中程度から重度の疼痛を有すると診断されている、請求項1から10のいずれか1項に記載の医薬組成物。
- 対象は、処置を開始する前に、0〜4の尺度で、2以上のKellgren−Lawrence[K−L]等級分けを有する、請求項1から10のいずれか1項に記載の医薬組成物。
- 抗NGF抗体またはその抗原結合断片は、それぞれ配列番号4、6、および8を含む3つの重鎖相補性決定領域(HCDR)配列(HCDR1、HCDR2、HCDR3)、ならびに、それぞれ配列番号12、14、および16を含む3つの軽鎖相補性決定領域(LCDR)配列(LCDR1、LCDR2、LCDR3)を含む、請求項1から12のいずれか1項に記載の医薬組成物。
- 抗体は、ファシヌマブである、請求項1から13のいずれか1項に記載の方法。
- 膝関節または股関節に疼痛を有する対象の処置での使用のための医薬組成物であって、該対象は、オピオイド剤を添加した履歴を有し、
治療有効量の、神経成長因子(NGF)に特異的に結合する抗NGF抗体またはその抗原結合断片
を含み、
該対象の膝関節または股関節の疼痛を軽減する、
前記医薬組成物。 - 非ステロイド性抗炎症薬(NSAID)をさらに含む、請求項15に記載の医薬組成物。
- 該医薬組成物の初期用量、および1つまたはそれ以上の第2の用量は、各々、抗NGF抗体約1.0mg〜約9.0mgを含む、請求項15または16に記載の医薬組成物。
- 該医薬組成物の初期用量、および1つまたはそれ以上の第2の用量は、各々、抗NGF抗体またはその抗原結合断片約1.0mgまたは約3mgを含み;
16週間にわたって、4週間ごとに1回の投与用である、請求項15から17のいずれか1項に記載の医薬組成物。 - 抗NGF抗体またはその抗原結合断片は、配列番号2のアミノ酸配列を有するHCVR、および配列番号10のアミノ酸配列を有するLCVRを含む、請求項15から18のいずれか1項に記載の医薬組成物。
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