JP7431721B2 - ベルセトラグを用いて胃不全麻痺の症状を治療する方法 - Google Patents
ベルセトラグを用いて胃不全麻痺の症状を治療する方法 Download PDFInfo
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- JP7431721B2 JP7431721B2 JP2020505338A JP2020505338A JP7431721B2 JP 7431721 B2 JP7431721 B2 JP 7431721B2 JP 2020505338 A JP2020505338 A JP 2020505338A JP 2020505338 A JP2020505338 A JP 2020505338A JP 7431721 B2 JP7431721 B2 JP 7431721B2
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- gastroparesis
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- GKLVYJBZJHMRIY-UHFFFAOYSA-N technetium atom Chemical compound [Tc] GKLVYJBZJHMRIY-UHFFFAOYSA-N 0.000 description 1
- 150000003512 tertiary amines Chemical class 0.000 description 1
- 150000003536 tetrazoles Chemical class 0.000 description 1
- 229960004559 theobromine Drugs 0.000 description 1
- 229940124597 therapeutic agent Drugs 0.000 description 1
- 229960000984 tocofersolan Drugs 0.000 description 1
- 230000000699 topical effect Effects 0.000 description 1
- 230000002110 toxicologic effect Effects 0.000 description 1
- 231100000027 toxicology Toxicity 0.000 description 1
- 230000037317 transdermal delivery Effects 0.000 description 1
- 230000007704 transition Effects 0.000 description 1
- CYRMSUTZVYGINF-UHFFFAOYSA-N trichlorofluoromethane Chemical compound FC(Cl)(Cl)Cl CYRMSUTZVYGINF-UHFFFAOYSA-N 0.000 description 1
- 229940029284 trichlorofluoromethane Drugs 0.000 description 1
- 125000005591 trimellitate group Chemical group 0.000 description 1
- YFTHZRPMJXBUME-UHFFFAOYSA-N tripropylamine Chemical compound CCCN(CCC)CCC YFTHZRPMJXBUME-UHFFFAOYSA-N 0.000 description 1
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 1
- 229960000281 trometamol Drugs 0.000 description 1
- 208000016752 upper digestive tract disease Diseases 0.000 description 1
- 230000009385 viral infection Effects 0.000 description 1
- 230000009278 visceral effect Effects 0.000 description 1
- 238000005303 weighing Methods 0.000 description 1
- 150000003751 zinc Chemical class 0.000 description 1
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- 235000004835 α-tocopherol Nutrition 0.000 description 1
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Description
発明の分野
本発明は、ベルセトラグ又はその薬学的に許容可能な塩を、ヒト患者に約0.5mg/日~約30mg/日投与することによってそのヒト患者の特発性又は糖尿病性胃不全麻痺に関連する症状を治療するため及び/又はその症状の治療における使用のための、ベルセトラグ(1-イソプロピル-2-オキソ-1,2-ジヒドロキノリン-3-カルボン酸{(1S,3R,5R)-8-[(R)-2-ヒドロキシ-3-(メタンスルホニル-メチル-アミノ)プロピル]-8-アザビシクロ[3.2.1]オクタ-3-イル}アミド)及びそれを含む医薬組成物に関する。
上部消化管の胃十二指腸領域で発生する基本的な消化機能の変化は、多くの人々に影響を与える非常に一般的な状態である。消化管のさまざまな性質の障害は、1つ以上の消化管の機能を損なう。構造的及び神経的異常は、消化管のあらゆるレベルで腸内容物の動きを遅らせるか、閉塞するか、又は加速する可能性がある。胃腸壁が炎症性及び潰瘍性の状態になると、分泌、運動及び吸収が妨げられる。肝臓、膵臓若しくは胆嚢の炎症又は閉塞により、代謝が変化し、局所若しくは全身症状、又はその両方を引き起こす可能性がある。消化管障害の多くの臨床徴候は非特異的であり、さまざまな障害によって引き起こされる可能性がある。人口の少なくとも20%は、胃十二指腸機能の障害に起因する慢性症状を有しており、この状態は患者の通常の活動に大きく影響を与え、以下の1つ以上の症状によって特徴付けられる。その症状とは、悪心(吐き気)、鼓腸、食後膨満感、早期満腹、嘔吐、上腹部痛、心窩部灼熱感、灼熱感を伴うか又は伴わない胃逆流、及び胃腸運動障害である。症状は慢性的であり、少なくとも週に1回、かつ少なくとも6か月間にわたって生じるが、臓器的(器質的)には説明できない(Tack,J.,et al.Gastroenterology.2006; 130; 1466-1479(非特許文献1))。
めるアセチルコリンエステラーゼ阻害剤である(Kusunoki H. et al. Neurogastroenterol Motil 2012; 24: 540-545(非特許文献8))。日本における機能性ディスペプシア患者を対象とした二重盲検プラセボ対照試験では、プラセボに割り当てられた患者の35%と比較して、積極的治療に割り当てられた患者の52%において症状が改善し(MatsuedaK. et al. Gut 2012; 61: 821-828(非特許文献9))、食後膨満感、上腹部鼓腸及び早期満腹において有意な改善が認められたが、上腹部痛又は不快感には認められなかった。5-ヒドロキシトリプタミン-1A受容体に作用して胃底の弛緩をもたらすブスピロン及びタンドスピロンなどの薬物もまた機能性ディスペプシアに関して試験されており、ブスピロンは、ランダム化クロスオーバー試験に登録された17名の機能性ディスペプシア患者において胃底の弛緩や鼓腸及び食後膨満感の減少に有効であることが証明された(TackJ. et al. Clin Gastroenterol Hepatol 2012; 10: 1239-1245(非特許文献10))。
144名の患者を対象とした二重盲検プラセボ対照研究では、4週間のタンドスピロン治療後の奏効率(response rate)は、プラセボの12.7%と比較して31.5%であった(Miwa H. et al. Am J Gastroenterol 2009; 104: 2779-2787(非特許文献11))。
304(特許文献5)に対応する2016年4月5日提出の米国特許出願番号11/398,119(特許文献4)で開示された。本明細書に引用されたすべての特許、特許出願及び文書は、参照によりその全体がそれぞれ本明細書に組み込まれている。
ベルセトラグ(VEL)は式Iの化合物であり、式IIで表される結晶性の塩酸塩を形成する。
であり、個人(罹患率(morbidity)と死亡率(mortality))と社会(ヘルスケアの利用(healthcare utilization))の両方に大きな負担をかける可能性がある(Parkman, H.P., et al., Gastroenterology, 2004, 127(5), 1592-1622; Parkman, H.P., et al., Clin. Gastroenterol. Hepatol., 2011, 9(12), 1056-1064; Jung, et al., Gastroenterology, 2009, 136(4), 1225-1233)。胃不全麻痺の登録簿(registry)に登録されている患者の分析において、患者の89%が慢性症状を示し、かつ慢性症状を有する前記患者のうちの75%が経時的な症状の悪化又は断続的な悪化を示した。メトクロプラミドのような、短期的な治療の選択肢が有益である可能性が高い場合において、わずか11%の患者が事実上、症状は周期的であると評価した(Parkman, H.P., et al., Clin. Gastroenterol. Hepatol., 2011, 9(12), 1056-1064)。
Gastroenterology, 2009, 136(4), 1225-1233)。
本明細書及び付随する特許請求の範囲において、特に明示しない限り、以下の用語は以下の意味で定義される。
本発明はまた、胃不全麻痺の治療に使用する医薬組成物に関する。本発明の結晶性塩酸塩は、通常、医薬組成物の形態で患者に投与される。このような医薬組成物は、許容可能な投与経路であれば、どのような経路であっても、患者に投与することができる。前記許容可能な投与経路としては、経口投与、直腸投与、膣内投与、鼻腔投与、吸入、局所投与(経皮投与を含む)及び非経口投与様式が含まれるが、投与経路はこれらに限定されない。
経口投与用のゼラチン硬カプセル(hard gelatin capsule)を次のように調製する。
経口投与用のゼラチン硬カプセル(hard gelatin capsule)を次のように調製する。
経口投与用のカプセル剤を次のように調製する。
経口投与用の錠剤を次のように調製する。
テアリン酸マグネシウム及びタルク(前もって、ふるい(No.60メッシュU.S.シーブ(No. 60 mesh U.S. sieve ))に通したもの)を顆粒に加える。混合後、混合物を錠剤機(tablet machine)で圧縮して、100mgの重量の錠剤を得る。
経口投与用の錠剤を次のように調製する。
経口投与用の一本割線入り錠剤(シングルスコア錠剤)(single-scored tablet)を次のように調製する。
経口投与用の懸濁液を次のように調製する。
吸入投与用の乾燥粉末を次のように調製する。
定量吸入器での吸入投与用の乾燥粉末を次のように調製する。
注射製剤を次のように調製する。
経口投与用のカプセル剤を次のように調製する。
経口投与用のカプセル剤を次のように調製する。
本発明はまた、ヒト患者へのベルセトラグの許容可能な投与経路にも関し、その投与経路には、経口、非経口、口腔(buccal)、舌下、直腸、腹腔内、又は気管内の投与経路が含まれるが、これらに限定されない。例えば、非経口投与は、注入(infusion)、注射(injection)、又は移植(implantation)によるものであってもよい。非経口的な投与には、皮下経路、筋肉内経路、静脈内経路、経皮を介した経路、又は移植による経皮的な投与も含まれる。ベルセトラグが非経口投与される場合、ベルセトラグは液体、固体又はゲルの形態であってもよい。 同様に、ベルセトラグが経口投与される場合、ベルセトラグ
は液体、カプセル剤、錠剤、チュアブル錠又は溶解性フィルムの形態であってもよい。
1.0 臨床試験材料
1.1 結晶性ベルセトラグ塩酸塩の調製
ベルセトラグの調製については、米国特許第7,375,114B2号に記載され、ベルセトラグ塩酸塩については、米国特許第7,728,004B2号に記載されている。
ベルセトラグ塩酸塩の水和物の調製については、米国特許第7,728,004B2号にも記載されている。1-イソプロピル-2-オキソ-1,2-ジヒドロキノリン-3-カルボン酸{(1S,3R,5R)-8-[(R)-2-ヒドロキシ-3-(メタンスルホニル-メチル-アミノ)プロピル]-8-アザビシクロ[3.2.1]オクタ-3-イル}アミド塩酸塩(139mg、0.28ミリモル)を注射用滅菌水(2mL)に溶解した。数時間かけて、溶液は濁った懸濁液になった。懸濁液を撹拌し、周囲温度で一晩静置すると、白色沈殿物が生じた。固体を濾過により収集し、周囲条件(約40~50%の相対湿度)で2分間乾燥させ、表題の化合物(130mg、収率91%)を得た。
臨床環境(clinical setting)で試験された医薬組成物は、本質的に、原薬(ベルセトラグ塩酸塩(velusetrag HCI))、ヒドロキシプロピルメチルセルロース、微結晶セルロース、乳糖一水和物及びステアリン酸マグネシウムからなる固体ブレンドであった。それぞれ5mg、15mg又は30mgのベルセトラグを含む3つの配合製剤(blended formulation)を、ノバストラボ(Novast Lab)で製造した。配合製剤の組成(成分)を以下の表1に示す。
2.1 フェーズ2a(第2a相)試験と試験結果
第2a相試験は、多施設、無作為化、二重盲検、プラセボ対照、不完備型3期固定シーケンスクロスオーバー(incomplete 3 period fixed sequence crossover)の第2相試験として実施され、糖尿病性の胃不全麻痺患者(n=18)又は特発性の胃不全麻痺患者(n=16)において、胃排出に対するベルセトラグの効果を評価した(4時間を超える[13C]-オクタン酸呼気試験([13C]-octanoate breath testing)によって評価した)。ベルセトラグの投与量が異なる3パターン(5mg[n=26]、15mg[n=25]又は30mg[n=25])において、それぞれの量のベルセトラグを1週間の治療期間に1日1回投与し、治療期間の間に1週間のウォッシュアウト(休薬)期間を設けた。無作為抽出された被験者(又は患者、対象者)に、治験登録の前に少なくとも3ヶ月の間、胃不全麻痺の症状を記録(文書化)させた。この研究において、スクリーニング時の胃排出遅延の記録(文書化)が、重要な選択(算入)基準(inclusion criterion)であった。遅延は、オクタン酸呼気試験の胃排出の半減期(gastric emptying half time)(GE t1/2)において、GE t1/2>180分と定義される。180分とは、健康な被験者の95%信頼区間の上限である。胃排出の半減期は、胃内容物の半分が空になったとみなされるときに、胃排出曲線(gastric emptying curve)から推定される時間として定義される。
DIGEST Iは、網羅的な第2b相(フェーズ2b)(Phase 2b)、12週間、多施設、無作為化、二重盲検、プラセボ対照、平行4群試験(parallel 4-group study)であり、この試験により、プラセボと比較して、ベルセトラグの3つの投与レベル(投与量)(5mg、15mg、30mg)について評価した。この試験では、糖尿病性又は特発性の胃不全麻痺(GP)の被験者(患者)に対し、約12週間、各投与量のベルセトラグを1日1回投与した。試験を完了した各被験者(患者)は、試験に約19週間携わった。その内訳は、スクリーニング期間(1週間のベースライン期間を含む最長5週間)、治療期間(12週間)及びフォローアップ期間(2週間)である。
軽度:兆候や症状を認識しているが、容易に耐えうる
中等度:通常の活動を妨げるほどの不快感がある
重度:無能力となり、仕事や通常の活動を行うことができない
表2に示すように、合計233人の患者を、無作為に3パターンの投与量のベルセトラグ(5mg、15mg、又は30mg)のいずれか又はプラセボを服用する者に割り付け、12週間、食物とともに又は食物なしで1日1回(QD)、朝に投与した。
総スコアを使用してGCSI PROを評価した。GCSI PROの平均3は症状ドメインスコアを意味する。LS平均GCSI-24H総スコアとベースラインからの変化を表5にまとめる。
表6及び7は、特発性サブグループと糖尿病性サブグループにおける、4、8、14週GCSI-24H総スコアでのベースラインとプラセボからの最小二乗(LS)平均の変化を示す。
GCSI-24Hの分析で、評価可能な232人の被験者のうち、2人の被験者のデータが欠落しており、分析から除外された。したがって、合計230人の被験者が分析に含まれた。
一次エンドポイントの評価時点は4週目で、8週目と12週目に感度分析を実施した。治療効果の持続性及び/又はタキフィラキシーを評価するために、12週目を二次エンドポイントとした。
合計で、232人の被験者でGRSの心理測定評価がなされた。初期の心理測定レビューが実施された後、GRSのスコアリングから4項目が削除され、別の項目を1つのドメインから別のドメインに移動した。解釈(観察)の問題により、便秘のドメインは削除された。その後の心理測定分析により、残りの6つのGRSドメインに対する一次元の適切な適合性が確立された。
個々の症状ドメインで症状を見ると、ベルセトラグ5mgを用いた場合、GRSのすべての症状ドメインで改善がみられた(図26~28参照)。
サマリスコア1について、糖尿病性胃不全麻痺に羅患した患者グループで評価した。結果を表14に示す。
サマリスコア2は、糖尿病性胃不全麻痺に罹患した患者のグループで評価された。結果を表15に示す。
特発性胃不全麻痺に罹患した患者のグループで要約スコア1について評価した。結果を表16に示す。
特発性胃不全麻痺に罹患した患者のグループでサマリスコア2について評価した。結果を表17示す。
毎週のレスポンダーを、症状がベースラインから臨床的に関連して変化した被験者として規定(定義)した。ベースラインからの変化に対する反応閾値(response thresholds)又はMCIOを表18にまとめる。
ベルセトラグ5mgを投与された被験者の半数以上(54%)が、サマリスコア1のレスポンダー規定(定義)を満たした。ベルゼトラグ5mg(LS比率(LS proportion):0.53)とプラセボ(LS比率:0.37)の間のレスポンダーの割合の差は16%で、被験者はITT分析セット(ITT analysis set)の症状において、1.9倍の割合で持続的な臨床反応を示している可能性が高い(表19)。週ごとのレスポンダーにとって、ベルゼトラグ5mgでは、1週目から14週目まで、プラセボよりも高い奏功率(反応率)(response rate)を示した。ベルセトラグ5mgとプラセボとの違いは、1週目か
ら4週目及び9週目で統計的に有意であった。
サマリスコア1と同様に、ベルセトラグ5mgを投与された被験者の半数以上(54%)が、サマリスコア2のレスポンダー規定(定義)を満たした。ベルゼトラグ5mg(LS比率:0.53)とプラセボ(LS比率:0.33)の間のレスポンダーの割合の差は20%で、被験者はITT分析セット(ITT analysis set)の症状において、2.2倍の割合で持続的な臨床反応を示している可能性が高い(表20)。週ごとのレスポンダーにとって、1週目から14週目まで、ベルゼトラグ5mgでは、プラセボよりも高い奏功率(反応率)(response rate)を示した。5mgのベルセトラググループとプラセボグループとの結果の違いは、2、3、7、10、及び12週で統計的に有意であった。
糖尿病性胃不全麻痺サブグループでは、レスポンダーのLS比率は、プラセボグループの37%と比較して、サマリスコア1の5mgベルセトラググループで51%であった(OR:1.8[p=0.2871])。
特発性胃不全麻痺サブグループでは、レスポンダーのLS比率は、プラセボグループの被験者の38%と比較して、サマリスコア1の5mgベルセトラググループで54%であった(OR:2.0[p=0.2224])。
全体として、28日目の平均GES保持率(貯留率)(retention)の結果は、3つのベルセトラグ治療グループのすべてと比較して、プラセボグループ(26.0%~81.2%の範囲)で高かった。
二次エンドポイントとして、スクリーニングの間にGESを行い、28日目のGESを完了した一部の被験者(各治療グループ内の約半分の被験者)の胃排出の変化を評価した。結果を表28にまとめる。
特発性又は糖尿病性胃不全麻痺の合計232人の被験者に、ベルセトラグを少なくとも1回投与した。DIGEST I試験では、重大な有害事象は報告されなかった。
Claims (12)
- 糖尿病性又は特発性胃不全麻痺のヒト患者における食後膨満感、早期満腹、鼓腸、上腹部痛、心窩部灼熱感、悪心及び嘔吐のいずれか1つ以上の胃不全麻痺の主要な症状を予防、軽減、改善、緩和、治療するための医薬組成物であって、
1-イソプロピル-2-オキソ-1,2-ジヒドロキノリン-3-カルボン酸{(1S,3R,5R)-8-[(R)-2-ヒドロキシ-3-(メタンスルホニル-メチル-アミノ)プロピル]-8-アザビシクロ[3.2.1]オクタ-3-イル}アミド(ベルセトラグ)又はその薬学的に許容可能な塩を含み、かつ
前記医薬組成物の投与量が、ベルセトラグ換算で5mg/日である医薬組成物。 - 薬学的に許容可能な塩が塩酸塩である請求項1記載の医薬組成物。
- ベルセトラグが、結晶形及び/又は水和物である請求項1記載の医薬組成物。
- 特発性胃不全麻痺の患者において、ベルセトラグの1日投与量が5mgで、4週目での、毎日、7日間の平均複合GCSI-24Hスコア(daily and 7-day mean composite GCSI-24H score)のベースラインからの変化が、プラセボと比較して0.6ポイントを超える、又は、特発性胃不全麻痺の患者において、ベルセトラグの1日投与量が5mgで、8週目での、毎日、7日間の平均複合GCSI-24Hスコアのベースラインからの変化が、プラセボと比較して0.6ポイントを超える、若しくは、特発性胃不全麻痺の患者において、ベルセトラグの1日投与量が5mgで、毎日、7日間の平均複合GCSI-24Hスコアのベースラインからの変化が、プラセボと比較して、治療時間にわたって持続する請求項1記載の医薬組成物。
- 糖尿病性胃不全麻痺の患者において、ベルセトラグの1日投与量が5mgで、4週目での、毎日、7日間の平均複合GCSI-24Hスコアのベースラインからの変化が、プラセボと比較して0.2ポイントを超える、又は、糖尿病性胃不全麻痺の患者において、ベルセトラグの1日投与量が5mgで、8週目での、毎日、7日間の平均複合GCSI-24Hスコアのベースラインからの変化が、プラセボと比較して0.1ポイントを超える、又は、糖尿病性胃不全麻痺の患者において、ベルセトラグの1日投与量が5mgで、毎日、7日間の平均複合GCSI-24Hスコアのベースラインからの変化が、プラセボと比較して、治療時間にわたって持続する、若しくは、糖尿病性胃不全麻痺の患者において、ベルセトラグの1日投与量が30mgで、14週目での、毎日、7日間の平均複合GCSI-24Hスコアのベースラインからの変化が、プラセボと比較して0.1ポイントを超える請求項1記載の医薬組成物。
- ヒト患者において、医薬組成物を用いた治療が、高血糖症又は血液中のグルコースの著しい増加を引き起こさない請求項1~5のいずれか一項に記載の医薬組成物。
- 経口、非経口、口腔(buccal)、舌下、直腸、腹腔内、又は気管内投与される請求項1~6のいずれか一項に記載の医薬組成物。
- 非経口投与が、注入(infusion)、注射(injection)、移植(implantation)又は経皮的である請求項7記載の医薬組成物。
- 経皮的投与が、皮下投与、筋肉内投与、静脈内投与、経皮を介した投与又は移植によるものである請求項8記載の医薬組成物。
- 液体、カプセル剤、錠剤、チュアブル錠又は溶解性フィルムの形態で経口投与される請求項7記載の医薬組成物。
- 液体、固体又はゲルの形態で非経口投与される請求項7記載の医薬組成物。
- 食物とともに又は食物なしで経口摂取する請求項1~10のいずれか一項に記載の医薬組成物。
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