JP5859438B2 - ラキニモドを用いたbdnf関連疾患の治療 - Google Patents
ラキニモドを用いたbdnf関連疾患の治療 Download PDFInfo
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- JP5859438B2 JP5859438B2 JP2012524692A JP2012524692A JP5859438B2 JP 5859438 B2 JP5859438 B2 JP 5859438B2 JP 2012524692 A JP2012524692 A JP 2012524692A JP 2012524692 A JP2012524692 A JP 2012524692A JP 5859438 B2 JP5859438 B2 JP 5859438B2
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Description
本明細書において用いられるとき、他に言及がない限り、以下の用語のそれぞれは以下に示される定義を有する。
例1:再発寛解型多発性硬化症を患うヒト対象におけるBDNF濃度に対するラキニモドの効果を示す臨床試験
1日当たり0.6mgのラキニモドを、ナトリウム塩の形態で、経口で1日1回の錠剤の処方で用い、再発寛解型多発性硬化症(RRMS)の患者における試験を開始した。調査は、多国籍、多施設、無作為化、二重盲検、並行群間比較、プラセボ対照試験でありRRMSを有する対象における2用量のラキニモド投与の有効性、耐容性および安全性を評価した。適格な対象を、以下の3つの群に無作為化した:
1.1日1回の経口(p.o.)の0.6mgのラキニモド;
2.1日1回の経口(p.o.)の0.3mgのラキニモド;および
3.1日1回の経口(p.o.)の対応するプラセボ。
1.マクドナルド基準により定義される確定されたMSの診断;
2.RRMS疾患の経過;
3.スクリーニング以前の12か月に少なくとも1回の記録された再発数n;
4.それらのMRIスキャンスクリーニングにおいて少なくとも1つのガドリニウム増強のある病変;
5.Kurtzke EDSSスコアが1.0〜5.0(変換済)であり歩行可能;
6.18〜50歳の間(両端を含む)の年齢;
7.スクリーニング時のMRIスキャン以前の少なくとも30日間に無再発、およびコルチコステロイドまたはACTH不使用;
8.スクリーニングから無作為化までの間に無再発、およびコルチコステロイド不使用;
9.受胎調節のための確かな方法が実施された出産可能な女性;
10.調査期間中においてプロトコルの要件に従うことを厭わない、または従うことができる;および
11.試験の開始前に、署名された書面でのインフォームドコンセントが可能である。
1.何れかの形態の進行性MSを患っている;
2.スクリーニング来診以前の6か月以内の免疫抑制性または細胞毒性性治療の使用(アザチオプリン、シクロホスファミドおよびメトトレキサートを含む);
3.スクリーニング以前の6か月以内の実験的薬物の使用および/または薬物臨床試験への参加;
4.スクリーニング以前の2か月以内の免疫調節剤(IFN−β 1aおよび1b、酢酸ガラティラメル、ラキニモドならびにIVIGを含む)による先の治療;
5.ベースライン来診以前の2週間以内のCYP3A4の強力阻害剤、例えば、経口のケトコナゾールおよびエリスロマイシンの使用;
6.アミオダロンの先の使用;
7.ベースライン来診以前の1か月におけるフルオキセチンの使用;
8.スクリーニング以前の2週間以内のテオフィリンおよびワルファリンなどのCYP1A2の基質の使用;
9.スクリーニング来診以前の最近2年以内のクラドリビンによる先の治療;
10.潜在的に免疫抑制が禁忌となる対象、例えば、B/C型肝炎またはHIV;
11.先の全身放射線照射または全身リンパ組織放射線照射;
12.スクリーニング以前の2カ月以内の長期のコルチコステロイド治療(30日または30日以上の継続);
13.妊娠または授乳中;
14.病歴、身体検査、ECG、アブノーマル臨床検査および胸部X線により決定されるような、安全且つ完全な試験の参加を不可能にする臨床上著しいまたは不安定な内科的または外科的状態を有する対象、
15.インフォームドコンセントを与えることが不可能、もしくは試験の完了が不可能、または対象が任意の理由のために試験に不適切な候補者であると試験員にみなされた場合;
16.Gdに対する感受性の既知の病歴;または
17.MRIスキャニングを無事に受けることが不可能。
以下の表中における結果は、ラキニモド0.6mg/日群とプラセボ群の両方における平均BDNF濃度を表す。
鬱病および不安障害は、約7〜20%の生涯有病率を有する厄介な疾患である。動物モデルは、新規な抗鬱剤を確認するための探索において不可欠な手段である。様々なパラダイムが開発されており、前臨床の設定において新規な化合物の抗鬱様の可能性を検出するために役立つ(Cryan、2002;Ganbarana、2001)。
Balb/cマウスを、6つの群(5匹/群)に分けて、3日間にわたり毎日、ラキニモド(経管栄養によりラキニモドナトリウム溶液の形態で、経口で1、5、10および25mg/kg)、フルオキセチン(陽性対照、経口で10mg/kg)または媒体を投与した。3日目において投与後90分に、マウスは強制水泳試験を受けた。行動はビデオ記録され、Ethovisionソフトウエア(Noldus、オランダ)を用いて分析された。結果を図4に示す。
結果は、ラキニモドは、1mg/kgでの移動性の増大および静止の減少と、より多い用量(25mg/kgのラキニモド)での有意性への傾向とにより表わされるように有意な抗鬱活性を示したことを示す。この実験において、陽性対照のフルオキセチンは、おそらく時間および用量が不最適な条件であったことにより有意な効果を示さなかった。
Balb/cマウスを6つの群(5匹/群)に分けて、3日間にわたり毎日、ラキニモド(経管栄養によりラキニモドナトリウム溶液の形態で0.5、1、5および25mg/kg、p.o.)、フルオキセチン(陽性対照、10mg/kg、po)または媒体を投与した。3日目において投与後90分に、マウスは強制水泳試験に曝された。行動はビデオ記録され、Ethovisionソフトウエア(Noldus、オランダ)を用いて分析された。結果を図5に示す。
結果は、ラキニモドが、5および25mg/kgで移動性の増加および静止の減少により表わされるように有意な抗鬱活性を示したことを示す。陽性対照のフルオキセチンは、同じ活性の傾向を示した。これは、おそらく時間および用量が不最適な条件であることによる。
不安障害は、異常で病的な恐怖および不安のいくつかの異なる形態を包含する網羅的な用語である。現在の精神医学的な診断基準は、広く様々な不安障害を認めている。最近の調査により、18%ものアメリカ人がそれらの1または1以上の影響を受け得ることが分かっている(Kessler他)。この障害は、全般性不安、パニック障害、恐怖症、心的外傷後ストレス障害(PTSD)、強迫性障害(OCD)、分離不安および小児期不安を含むいくつかの分類に分けられる。
Balb/c雄性マウスを、6つの群(5匹/群)に分けて、3日間にわたり毎日、ラキニモド(経管栄養によりラキニモドナトリウム溶液の形態で1、5、10および25mg/kg、p.o.)、フルオキセチン(陽性対照、10mg/kg、po)または媒体を投与した。3日目において投与後90分に、マウスは20分間にわたりオープンフィールドに曝された。挙動はビデオ記録され、Ethovisionソフトウエア(Noldus、オランダ)を用いて分析された。運動性パラメータに関する結果を図6に示す。不安パラメータに関する結果を図7および8に示す。
運動性パラメータ −ラキニモドおよびフルオキセチンは、このモデルにおけるフィールド内での運動性パラメータを有意に変更しなかった。
Balb/c雄性マウスを、6つの群(5匹/群)に分けて、3日間にわたり毎日、ラキニモド(経管栄養によりラキニモドナトリウム溶液の形態で0.5、1、5および25mg/kg、p.o.)、フルオキセチン(陽性対照、10mg/kg、po)または媒体を投与した。3日目において投与後90分に、マウスは20分間にわたりオープンフィールド試験に曝された。行動はビデオ記録され、Ethovisionソフトウエア(Noldus、オランダ)を用いて分析された。運動性パラメータの結果を図9に示す。不安パラメータの結果を図10に示す。
運動性パラメータ −ラキニモド(0.5〜25mg/kg/d×3d、po)は、Balb/cマウスにおけるオープンフィールドでの運動性(0.5〜5mg/kg)のわずかな増加を誘導した。
以下に記載される例4.1および4.2において用いられるEPMモデルは、オープンな高い場所を避ける齧歯動物の生まれつきの恐怖を利用する。装置は、床より上に高くした、2つの囲壁アームと2つの対向するオープンアームとを有する十字迷路からなる。未処置の動物は、オープンアーム上で試験時間の約30%のみを過ごすだけであるが、ベンゾジアゼピンによる処理は、オープンアームの探索を著しく増加する(Pellowら)。これは、不安様行動の影響を調査するために最も広く用いられるモデルの1つである。
Balb/c雄性マウスを、6つの群(5匹/群)に分けて、3日間にわたり毎日、ラキニモド(経管栄養によりラキニモドナトリウム溶液の形態で0.5、1、5および25mg/kg、p.o.)、フルオキセチン(陽性対照、10mg/kg、po)または媒体を投与した。3日目において投与後90分に、マウスは5分間にわたりEPMに曝された。マウスは、オープンアームに面する中央四角(10×10cm)内に配置され、5分の探索の間、ビデオテープ記録された。通路の進入および所要時間は、4本すべての足がアームに進入したときにスコア化された。行動は、ビデオ記録されて、Ethovisionソフトウエア(Noldus、オランダ)を用いて分析された。結果を図11に示す。
ラキニモドにより処理されたマウスは、用量依存的に抗不安効果を示す。最大の効果は、25mg/kg、poの用量で得られた。
Balb/c雄性マウスを、6つの群(5匹/群)に分けて、3日間にわたり毎日、ラキニモド(経管栄養によりラキニモドナトリウム溶液の形態で0.5、1、5および25mg/kg、p.o.)、フルオキセチン(陽性対照、10mg/kg、po)または媒体を投与した。3日目において投与後90分に、マウスは5分間にわたりEPMに曝された。行動はビデオ記録され、オープンアームパラメータが、Ethovisionソフトウエア(Noldus、オランダ)を用いて分析された。結果を図12に示す。
ラキニモドにより処理されたマウスは、用量依存的に抗不安効果を示す。最大の効果は、5〜25mg/kg、poで得られた。
[付記]
[1] ヒト対象における脳由来神経栄養因子(BDNF)の血清濃度を増加する方法であって、ヒト対象におけるBDNF血清濃度を増加するために有効な量のラキニモドまたはその薬学的に許容される塩を対象に対して定期的に投与することを含む方法。
[2] 前記量のラキニモドまたはその薬学的に許容される塩が、1日に1回、ヒト対象に対して投与される前記[1]に記載の方法。
[3] 定期的な投与が、少なくとも3日間にわたり継続する前記[1]または[2]に記載の方法。
[4] 投与されるラキニモドの量が、0.1mg/日〜40.0mg/日である前記[1]〜[3]のいずれか一項に記載の方法。
[5] 投与されるラキニモドの量が、0.6mg/日である前記[4]に記載の方法。
[6] 前記量のラキニモドが経口投与される前記[1]〜[5]のいずれか一項に記載の方法。
[7] 対象が、BDNF関連疾患を患っている前記[1]〜[6]のいずれか一項に記載の方法。
[8] BDNF関連疾患が、パーキンソン病、ハンチントン病、筋萎縮性側索硬化症、抑鬱障害、不安障害、色素性網膜炎、勃起不全、記憶障害、レット症候群、アルツハイマー病、双極性障害または急性躁病である前記[7]に記載の方法。
[9] 抑鬱障害が、鬱病、癌患者における鬱病、パーキンソン病患者における鬱病、心筋梗塞後の鬱病、ヒト免疫不全症ウイルス(HIV)をもつ患者における鬱病、亜症候群性の症候性鬱病、不妊症の女性における鬱病、小児鬱病、大鬱病、単一エピソード鬱病、再発性鬱病、児童虐待に誘発される鬱病、産後鬱病、DSM−IVの大鬱病、治療抵抗性の大鬱病、重篤な鬱病、精神病性鬱病、脳卒中後の鬱病、神経障害性疼痛、混合エピソードを伴う躁鬱病および鬱病性のエピソードを伴う躁鬱病を含む躁鬱病、季節性情動障害、双極性鬱病BP I、双極性鬱病BP II、または気分変調を伴う大鬱病である前記[8]に記載の方法。
[10] 不安障害が、全般性不安、パニック障害、恐怖症、心的外傷後ストレス障害、強迫性障害、分離不安または小児期不安である前記[8]に記載の方法。
[11] ある量の第2のBDNF増加剤を対象に対して定期的に投与することをさらに含む前記[1]〜[10]のいずれか一項に記載の方法。
[12] 単独で服用したときの前記量の第2のBDNF増加剤が、対象におけるBDNF血清濃度を増加するために有効ではない前記[11]に記載の方法。
[13] ラキニモドの投与が、第2のBDNF増加剤の投与に実質的に先行する前記[11]または[12]に記載の方法。
[14] 第2のBDNF増加剤の投与が、ラキニモドの投与に実質的に先行する、前記[11]または[12]に記載の方法。
[15] 対象における効果が、第2のBDNF増加剤単独で治療された対象における効果よりも大きい前記[11]〜[14]のいずれか一項に記載の方法。
[16] 対象におけるBDNF血清濃度の増加が、第2のBDNF増加剤単独で治療された対象におけるBDNF血清濃度の増加よりも大きい前記[15]に記載の方法。
[17] ラキニモドの薬学的に許容される塩がラキニモドナトリウムである前記[1]〜[16]のいずれか一項に記載の方法。
[18] パーキンソン病、ハンチントン病、筋萎縮性側索硬化症、抑鬱障害、不安障害、色素性網膜炎、勃起不全、記憶障害、レット症候群、アルツハイマー病、双極性障害および急性躁病からなる群から選択されるBDNF関連疾患を患うヒト対象を治療する方法であって、ヒト対象を治療するために有効な量のラキニモドまたはその薬学的に許容される塩を定期的に投与することを含む方法。
[19] ヒト対象におけるBDNF血清濃度を増加するための薬物の製造におけるラキニモドの使用。
[20] ヒト対象におけるBDNF血清濃度を増加するための使用のために有効な量のラキニモドを含む医薬組成物。
[21] ヒト対象におけるBDNF血清濃度を増加するための使用のために有効な量のラキニモドおよび第2のBDNF増加剤を含む医薬製剤。
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18. Borsini F, et al. (2002) “Do animal models of anxiety predict anxiolytic-like effects of antidepressants?” Psychopharmacology. 163:121-41.
6. Caffe Romeo, A, et al. (2001) “A combination of CNTF and BDNF rescues rd photoreceptors but changes rod differentiation in the presence of RPE in retinal explants”. Investigative Ophthalmology & Visual Science, 42:275-82.
7. Chesselet, MF(2003) “Dopamine and Parkinson's disease: is the killer in the house?” Molecular Psychiatry, 8:369-370.
8. Ciammola, A, et al. (2007) “Low brain-derived neurotrophic factor (BDNF) levels in serum of Huntington’s disease patients”. Am J Med Gent Part B, 144b:574-577.
9. Cryan JF, et al. (2002) “Assessing antidepressant activity in rodents: recent developments and future needs”. Trend in Pharmacological Science. 23:238-45.
10. Gambarana, C., et al. (2001) “Animal models for the study of antidepressant activity”. Brain Res. Protocol. 7:11-20.
11. Howells, DW, et al. (2000) “Reduced BDNF mRNA expression in the Parkinson's disease substantia nigra”. Experimental Neurology, 166(1):127-135.
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Claims (15)
- パーキンソン病、ハンチントン病、抑鬱障害、不安障害、色素性網膜炎、勃起不全、記憶障害、レット症候群、双極性障害または急性躁病であるBDNF関連疾患を患うヒト対象における脳由来神経栄養因子(BDNF)の濃度を増加するための薬物の製造におけるラキニモドまたはその薬学的に許容される塩の使用であって、ラキニモドまたはその薬学的に許容される塩が対象に対して定期的に投与するために製剤化されていることを含む使用。
- 定期的な投与が、1日に1回投与を具備する請求項1に記載の使用。
- 定期的な投与が、少なくとも3日間にわたり継続する請求項1または2に記載の使用。
- ラキニモドまたはその薬学的に許容される塩が、0.1mg/日〜40.0mg/日の用量での投与のために製剤化されている請求項1〜3のいずれか一項に記載の使用。
- ラキニモドまたはその薬学的に許容される塩の用量が、0.6mg/日である請求項4に記載の使用。
- ラキニモドまたはその薬学的に許容される塩が経口投与のために製剤化されている請求項1〜5のいずれか一項に記載の使用。
- BDNF関連疾患が、鬱病、癌患者における鬱病、パーキンソン病患者における鬱病、心筋梗塞後の鬱病、ヒト免疫不全症ウイルス(HIV)をもつ患者における鬱病、亜症候群性の症候性鬱病、不妊症の女性における鬱病、小児鬱病、大鬱病、単一エピソード鬱病、再発性鬱病、児童虐待に誘発される鬱病、産後鬱病、DSM−IVの大鬱病、治療抵抗性の大鬱病、重篤な鬱病、精神病性鬱病、脳卒中後の鬱病、神経障害性疼痛、混合エピソードを伴う躁鬱病および鬱病性のエピソードを伴う躁鬱病を含む躁鬱病、季節性情動障害、双極性鬱病BP I、双極性鬱病BP II、および気分変調を伴う大鬱病からなる群
より選択される抑鬱障害である請求項1〜6のいずれか1項に記載の使用。 - BDNF関連疾患が、全般性不安、パニック障害、恐怖症、心的外傷後ストレス障害、強迫性障害、分離不安および小児期不安からなる群より選択される不安障害である請求項1〜6のいずれか1項に記載の使用。
- 第2のBDNF増加剤を対象に対して定期的に投与することをさらに含む請求項1〜8のいずれか一項に記載の使用。
- ラキニモドの薬学的に許容される塩がラキニモドナトリウムである請求項1〜9のいずれか一項に記載の使用。
- パーキンソン病、ハンチントン病、抑鬱障害、不安障害、色素性網膜炎、勃起不全、記憶障害、レット症候群、双極性障害または急性躁病であるBDNF関連疾患を患うヒト対象を治療するための薬物の製造におけるラキニモドまたはその薬学的に許容される塩の使用。
- BDNF関連疾患がハンチントン病である請求項1〜11のいずれか1項に記載の使用。
- BDNF関連疾患を患うヒト対象を治療するために有効な量のラキニモドまたはその薬学的に許容される塩およびリルゾールまたはフルオキセチンである第2のBDNF増加剤を含む医薬製剤。
- BDNF関連疾患がパーキンソン病、ハンチントン病、抑鬱障害、不安障害、色素性網膜炎、勃起不全、記憶障害、レット症候群、双極性障害または急性躁病である請求項13に記載の医薬製剤。
- BDNF関連疾患がハンチントン病である請求項14に記載の医薬製剤。
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Application Number | Priority Date | Filing Date | Title |
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US27392009P | 2009-08-10 | 2009-08-10 | |
US61/273,920 | 2009-08-10 | ||
PCT/US2010/002194 WO2011019375A1 (en) | 2009-08-10 | 2010-08-09 | Treatment of bdnf-related disorders using laquinimod |
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CA (1) | CA2771203C (ja) |
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PL (2) | PL3064206T3 (ja) |
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SI (1) | SI2467372T1 (ja) |
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KR20110048571A (ko) * | 2008-09-03 | 2011-05-11 | 테바 파마슈티컬 인더스트리즈 리미티드 | 면역 기능을 지닌 2―옥소―1,2―다이하이드로―퀴놀린 조절제 |
US8598203B2 (en) * | 2009-07-30 | 2013-12-03 | Teva Pharmaceutical Industries, Ltd. | Treatment of Crohn's disease with laquinimod |
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PE20181523A1 (es) * | 2010-03-03 | 2018-09-24 | Teva Pharma | Tratamiento de lupus nefritis usando laquinimod |
US20110217295A1 (en) * | 2010-03-03 | 2011-09-08 | Asi Haviv | Treatment of lupus arthritis using laquinimod |
CN105796556A (zh) * | 2010-03-03 | 2016-07-27 | 泰华制药工业有限公司 | 用拉喹莫德和甲氨蝶呤的组合治疗类风湿性关节炎 |
US8580819B2 (en) | 2010-07-09 | 2013-11-12 | Teva Pharmaceutical Industries Ltd. | Deuterated N-ethyl-N-phenyl-1,2-dihydro-4-hydroxy-5-chloro-1-methyl-2-oxoquinoline-3-carboxamide, salts and uses thereof |
JP2014521658A (ja) * | 2011-07-28 | 2014-08-28 | テバ ファーマシューティカル インダストリーズ リミティド | ラキニモドおよび酢酸グラチラマーを組み合わせた多発性硬化症の治療 |
BR112014008731A2 (pt) | 2011-10-12 | 2017-04-25 | Teva Pharma | tratamento de esclerose múltipla com combinação de laquinimode e fingolimode |
MX2014009373A (es) | 2012-02-03 | 2014-08-27 | Teva Pharma | Uso de laquinimod para tratar pacientes con enfermedad de crohn que fallaron en la terapia de anti-tnfa de primera linea. |
CA2863409A1 (en) | 2012-02-16 | 2013-08-22 | Teva Pharmaceutical Industries Ltd. | N-ethyl-n-phenyl-1,2-dihydro-4,5-di-hydroxy-1-methyl-2-oxo-3-quinolinecarboxamide, preparation and uses thereof |
TW201350467A (zh) | 2012-05-08 | 2013-12-16 | Teva Pharma | N-乙基-4-羥基-1-甲基-5-(甲基(2,3,4,5,6-五羥基己基)胺基)-2-側氧-n-苯基-1,2-二氫喹啉-3-甲醯胺 |
TW201400117A (zh) | 2012-06-05 | 2014-01-01 | Teva Pharma | 使用拉喹莫德治療眼發炎疾病 |
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EA201590655A8 (ru) * | 2012-09-27 | 2016-07-29 | Тева Фармасьютикал Индастриз Лтд. | Комбинация лахинимода и придопидина для лечения нейродегенеративных нарушений |
MX2015004564A (es) * | 2012-10-12 | 2015-07-21 | Teva Pharma | Laquinimod para producir el daño talamico en la esclerosis multiple. |
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IL217901A0 (en) | 2012-03-29 |
PL2467372T3 (pl) | 2017-04-28 |
RS55071B1 (sr) | 2016-12-30 |
AU2010282948B2 (en) | 2016-09-29 |
IL217901B (en) | 2018-12-31 |
CY1117916T1 (el) | 2017-05-17 |
HUE029983T2 (en) | 2017-04-28 |
EP3064206B1 (en) | 2019-03-20 |
WO2011019375A1 (en) | 2011-02-17 |
SI2467372T1 (sl) | 2016-09-30 |
AU2016277618A1 (en) | 2017-01-19 |
CA2771203A1 (en) | 2011-02-17 |
ME02495B (me) | 2017-02-20 |
SMT201600281B (it) | 2016-11-10 |
EP2467372B1 (en) | 2016-05-18 |
JP2013501784A (ja) | 2013-01-17 |
US9585878B2 (en) | 2017-03-07 |
ES2586843T3 (es) | 2016-10-19 |
US20110034508A1 (en) | 2011-02-10 |
HRP20160997T1 (hr) | 2016-10-07 |
HK1225970A1 (zh) | 2017-09-22 |
US20170239234A1 (en) | 2017-08-24 |
EP2467372A1 (en) | 2012-06-27 |
EP2467372A4 (en) | 2013-01-09 |
US20160243103A1 (en) | 2016-08-25 |
ES2731052T3 (es) | 2019-11-13 |
AU2010282948C1 (en) | 2017-03-02 |
AU2010282948A1 (en) | 2012-04-05 |
EP3064206A1 (en) | 2016-09-07 |
CA2771203C (en) | 2019-04-09 |
PL3064206T3 (pl) | 2020-02-28 |
DK2467372T3 (en) | 2016-08-22 |
PT2467372T (pt) | 2016-08-23 |
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