JPWO2021105331A5 - - Google Patents
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- JPWO2021105331A5 JPWO2021105331A5 JP2022531531A JP2022531531A JPWO2021105331A5 JP WO2021105331 A5 JPWO2021105331 A5 JP WO2021105331A5 JP 2022531531 A JP2022531531 A JP 2022531531A JP 2022531531 A JP2022531531 A JP 2022531531A JP WO2021105331 A5 JPWO2021105331 A5 JP WO2021105331A5
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- JP
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- Prior art keywords
- tadalafil
- selexipag
- macitentan
- pharmaceutically acceptable
- acceptable salt
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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- 229960000835 tadalafil Drugs 0.000 claims description 26
- IEHKWSGCTWLXFU-IIBYNOLFSA-N tadalafil Chemical compound C1=C2OCOC2=CC([C@@H]2C3=C([C]4C=CC=CC4=N3)C[C@H]3N2C(=O)CN(C3=O)C)=C1 IEHKWSGCTWLXFU-IIBYNOLFSA-N 0.000 claims description 26
- 206010064911 Pulmonary arterial hypertension Diseases 0.000 claims description 24
- 229940118365 Endothelin receptor antagonist Drugs 0.000 claims description 22
- 239000002308 endothelin receptor antagonist Substances 0.000 claims description 22
- 229960001039 macitentan Drugs 0.000 claims description 22
- JGCMEBMXRHSZKX-UHFFFAOYSA-N macitentan Chemical compound C=1C=C(Br)C=CC=1C=1C(NS(=O)(=O)NCCC)=NC=NC=1OCCOC1=NC=C(Br)C=N1 JGCMEBMXRHSZKX-UHFFFAOYSA-N 0.000 claims description 22
- 150000003839 salts Chemical class 0.000 claims description 22
- 229960003841 selexipag Drugs 0.000 claims description 22
- QXWZQTURMXZVHJ-UHFFFAOYSA-N selexipag Chemical group C=1C=CC=CC=1C1=NC(N(CCCCOCC(=O)NS(C)(=O)=O)C(C)C)=CN=C1C1=CC=CC=C1 QXWZQTURMXZVHJ-UHFFFAOYSA-N 0.000 claims description 22
- 239000000018 receptor agonist Substances 0.000 claims description 18
- 229940044601 receptor agonist Drugs 0.000 claims description 18
- 238000011295 triple combination therapy Methods 0.000 claims description 18
- 108091006335 Prostaglandin I receptors Proteins 0.000 claims description 17
- 239000000890 drug combination Substances 0.000 claims description 16
- 229940123333 Phosphodiesterase 5 inhibitor Drugs 0.000 claims description 15
- 239000002590 phosphodiesterase V inhibitor Substances 0.000 claims description 14
- 238000002648 combination therapy Methods 0.000 claims description 12
- 210000001147 pulmonary artery Anatomy 0.000 claims description 12
- BNRNXUUZRGQAQC-UHFFFAOYSA-N sildenafil Chemical compound CCCC1=NN(C)C(C(N2)=O)=C1N=C2C(C(=CC=1)OCC)=CC=1S(=O)(=O)N1CCN(C)CC1 BNRNXUUZRGQAQC-UHFFFAOYSA-N 0.000 claims description 12
- 206010061818 Disease progression Diseases 0.000 claims description 10
- 230000005750 disease progression Effects 0.000 claims description 10
- 238000002560 therapeutic procedure Methods 0.000 claims description 9
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Natural products CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 8
- 102000011016 Type 5 Cyclic Nucleotide Phosphodiesterases Human genes 0.000 claims description 6
- 108010037581 Type 5 Cyclic Nucleotide Phosphodiesterases Proteins 0.000 claims description 6
- SECKRCOLJRRGGV-UHFFFAOYSA-N Vardenafil Chemical compound CCCC1=NC(C)=C(C(N=2)=O)N1NC=2C(C(=CC=1)OCC)=CC=1S(=O)(=O)N1CCN(CC)CC1 SECKRCOLJRRGGV-UHFFFAOYSA-N 0.000 claims description 6
- 229960003310 sildenafil Drugs 0.000 claims description 6
- 229960000438 udenafil Drugs 0.000 claims description 6
- IYFNEFQTYQPVOC-UHFFFAOYSA-N udenafil Chemical compound C1=C(C=2NC=3C(CCC)=NN(C)C=3C(=O)N=2)C(OCCC)=CC=C1S(=O)(=O)NCCC1CCCN1C IYFNEFQTYQPVOC-UHFFFAOYSA-N 0.000 claims description 6
- 229960002381 vardenafil Drugs 0.000 claims description 6
- -1 5,6-diphenylpyrazin-2-yl Chemical group 0.000 claims description 4
- OJQMKCBWYCWFPU-UHFFFAOYSA-N ACT-333679 Chemical compound C=1C=CC=CC=1C1=NC(N(CCCCOCC(O)=O)C(C)C)=CN=C1C1=CC=CC=C1 OJQMKCBWYCWFPU-UHFFFAOYSA-N 0.000 claims description 4
- 206010020772 Hypertension Diseases 0.000 claims description 4
- 102100026476 Prostacyclin receptor Human genes 0.000 claims description 4
- 229960002414 ambrisentan Drugs 0.000 claims description 4
- OUJTZYPIHDYQMC-LJQANCHMSA-N ambrisentan Chemical compound O([C@@H](C(OC)(C=1C=CC=CC=1)C=1C=CC=CC=1)C(O)=O)C1=NC(C)=CC(C)=N1 OUJTZYPIHDYQMC-LJQANCHMSA-N 0.000 claims description 4
- 229960003065 bosentan Drugs 0.000 claims description 4
- GJPICJJJRGTNOD-UHFFFAOYSA-N bosentan Chemical compound COC1=CC=CC=C1OC(C(=NC(=N1)C=2N=CC=CN=2)OCCO)=C1NS(=O)(=O)C1=CC=C(C(C)(C)C)C=C1 GJPICJJJRGTNOD-UHFFFAOYSA-N 0.000 claims description 4
- 125000004106 butoxy group Chemical group [*]OC([H])([H])C([H])([H])C(C([H])([H])[H])([H])[H] 0.000 claims description 4
- 238000003745 diagnosis Methods 0.000 claims description 4
- 230000009977 dual effect Effects 0.000 claims description 4
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 4
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 4
- 230000036593 pulmonary vascular resistance Effects 0.000 claims description 4
- 230000000284 resting effect Effects 0.000 claims description 4
- 239000003112 inhibitor Substances 0.000 claims description 3
- 239000003795 chemical substances by application Substances 0.000 claims 17
- 229940000425 combination drug Drugs 0.000 claims 3
- 101000605431 Mus musculus Phospholipid phosphatase 1 Proteins 0.000 claims 2
- 238000000034 method Methods 0.000 description 17
- 229940127314 Prostacyclin Receptor Agonists Drugs 0.000 description 1
- 239000000556 agonist Substances 0.000 description 1
- 230000000977 initiatory effect Effects 0.000 description 1
Description
ＥＯＳ分析の安全性の観察結果は、ＥＯＭＯＰの所見と一致している。
本発明には、次の態様が含まれる。
［項１］
肺動脈性肺高血圧症（ＰＡＨ）を有する患者における疾患進行のリスクを低減する方法であって、それを必要とする患者に、エンドセリン受容体アンタゴニスト（ＥＲＡ）、５型ホスホジエステラーゼ（ＰＤＥ－５）阻害剤、及びプロスタサイクリン受容体アゴニスト（ＩＰ受容体アゴニスト）の初期３剤併用療法を施すことを含む、方法。
［項２］
前記疾患進行のリスクの低減が、前記ＥＲＡ及び前記ＰＤＥ－５阻害剤の初期２剤併用療法を受ける、ＰＡＨを有する患者集団に対するものである、項１に記載の方法。
［項３］
前記ＥＲＡが、マシテンタン、ボセンタン、又はアンブリセンタン、又はこれらの薬学的に許容される塩であり、前記ＰＤＥ－５阻害剤が、タダラフィル、シルデナフィル、バルデナフィル、又はウデナフィル、又はこれらの薬学的に許容される塩であり、前記ＩＰ受容体アゴニストが、セレキシパグ、４－［（５，６－ジフェニルピラジン－２－イル）（イソプロピル）アミノ］ブトキシ｝酢酸（ＭＲＥ－２６９）、又はこれらの薬学的に許容される塩である、項１又は２に記載の方法。
［項４］
前記ＥＲＡがマシテンタンであり、前記ＰＤＥ－５阻害剤がタダラフィルであり、前記ＩＰ受容体アゴニストがセレキシパグである、項３に記載の方法。
［項５］
前記患者が、ＰＡＨに対して治療ナイーブである、項１～４のいずれか一項に記載の方法。
［項６］
前記患者の初期ＰＡＨ診断が、前記初期３剤併用療法の開始から６ヶ月以内に行われる、項１～５のいずれか一項に記載の方法。
［項７］
前記患者が、前記初期３剤併用療法の開始時に約２５ｍｍＨｇ以上の安静時平均肺動脈高血圧（ｍＰＡＰ）、約１５ｍｍＨｇ以下の平均肺動脈楔入圧（ＰＡＷＰ）、及び約２４０ダイン・秒／ｃｍ
５
以上の肺血管抵抗（ＰＶＲ）を有する、項１～６のいずれか一項に記載の方法。
［項８］
前記患者が、前記初期３剤併用療法の開始時に約５０メートル以上の６分間歩行距離（６ＭＷＤ）を有する、項１～７のいずれか一項に記載の方法。
［項９］
前記マシテンタンが、１日１回、約１０ｍｇの量で投与される、項４～８のいずれか一項に記載の方法。
［項１０］
前記タダラフィルが、１日１回、約２０ｍｇ～約４０ｍｇの量で投与される、項４～９のいずれか一項に記載の方法。
［項１１］
前記タダラフィルが、１日１回、約４０ｍｇの量で投与される、項４～１０のいずれか一項に記載の方法。
［項１２］
前記セレキシパグが、１日２回、約２００μｇ～約１６００μｇの量で投与される、項４～１１のいずれか一項に記載の方法。
［項１３］
前記マシテンタン、前記タダラフィル、及び前記セレキシパグのそれぞれが、１つ以上の錠剤の形態で経口投与される、項４～１２のいずれか一項に記載の方法。
［項１４］
前記マシテンタン及び前記タダラフィルが、単一の錠剤の形態で経口投与され、前記セレキシパグが、１つ以上の別個の錠剤の形態で経口投与される、項４～１２のいずれか一項に記載の方法。
［項１５］
前記初期３剤併用療法が、前記初期２剤併用療法に対して前記疾患進行のリスクを約３０～４０％減少させる、項２～１４のいずれか一項に記載の方法。
［項１６］
前記疾患進行が、ＰＡＨの悪化による入院、ＰＡＨの臨床的悪化、又は死亡を含む、項１～１５のいずれか一項に記載の方法。
［項１７］
肺動脈性肺高血圧症（ＰＡＨ）を有する患者における疾患進行のリスクを低減するための、エンドセリン受容体アンタゴニスト（ＥＲＡ）、５型ホスホジエステラーゼ（ＰＤＥ－５）阻害剤、及びプロスタサイクリン受容体アゴニスト（ＩＰ受容体アゴニスト）の初期３剤併用療法。
［項１８］
前記疾患進行のリスクの低減が、前記ＥＲＡ及び前記ＰＤＥ－５阻害剤の初期２剤併用療法を受ける、ＰＡＨを有する患者集団に対するものである、項１７に記載の初期３剤併用療法。
［項１９］
前記ＥＲＡが、マシテンタン、ボセンタン、又はアンブリセンタン、又はこれらの薬学的に許容される塩であり、前記ＰＤＥ－５阻害剤が、タダラフィル、シルデナフィル、バルデナフィル、又はウデナフィル、又はこれらの薬学的に許容される塩であり、前記ＩＰ受容体アゴニストが、セレキシパグ、４－［（５，６－ジフェニルピラジン－２－イル）（イソプロピル）アミノ］ブトキシ｝酢酸（ＭＲＥ－２６９）、又はこれらの薬学的に許容される塩である、項１７又は１８に記載の初期３剤併用療法。
［項２０］
前記ＥＲＡがマシテンタンであり、前記ＰＤＥ－５阻害剤がタダラフィルであり、前記ＩＰ受容体アゴニストがセレキシパグである、項１９に記載の初期３剤併用療法。
［項２１］
前記患者が、ＰＡＨに対して治療ナイーブである、項１７～２０のいずれか一項に記載の初期３剤併用療法。
［項２２］
前記患者の初期ＰＡＨ診断が、前記初期３剤併用療法の開始から６ヶ月以内に行われる、項１７～２１のいずれか一項に記載の初期３剤併用療法。
［項２３］
前記患者が、前記初期３剤併用療法の開始時に約２５ｍｍＨｇ以上の安静時平均肺動脈高血圧（ｍＰＡＰ）、約１５ｍｍＨｇ以下の平均肺動脈楔入圧（ＰＡＷＰ）、及び約２４０ダイン・秒／ｃｍ
５
以上の肺血管抵抗（ＰＶＲ）を有する、項１７～２２のいずれか一項に記載の初期３剤併用療法。
［項２４］
前記患者が、前記初期３剤併用療法の開始時に約５０メートル以上の６分間歩行距離（６ＭＷＤ）を有する、項１７～２３のいずれか一項に記載の初期３剤併用療法。
［項２５］
前記マシテンタンが、１日１回、約１０ｍｇの量で投与されるように製剤化される、項２０～２４のいずれか一項に記載の初期３剤併用療法。
［項２６］
前記タダラフィルが、１日１回、約２０ｍｇ～約４０ｍｇの量で投与されるように製剤化される、項２０～２５のいずれか一項に記載の初期３剤併用療法。
［項２７］
前記タダラフィルが、１日１回、約４０ｍｇの量で投与されるように製剤化される、項２０～２６のいずれか一項に記載の初期３剤併用療法
［項２８］
前記セレキシパグが、１日２回、約２００μｇ～約１６００μｇの量で投与されるように製剤化される、項２０～２７のいずれか一項に記載の初期３剤併用療法。
［項２９］
前記マシテンタン、前記タダラフィル、及び前記セレキシパグのそれぞれが、１つ以上の錠剤の形態で経口投与されるように製剤化される、項２０～２８のいずれか一項に記載の初期３剤併用療法。
［項３０］
前記マシテンタン及び前記タダラフィルが、単一の錠剤の形態で経口投与されるように製剤化され、前記セレキシパグが、１つ以上の別個の錠剤の形態で経口投与されるように製剤化される、項２０～２８のいずれか一項に記載の初期３剤併用療法。
［項３１］
前記初期３剤併用療法が、前記初期２剤併用療法に対して前記疾患進行のリスクを約３０～４０％減少させる、項１８～３０のいずれか一項に記載の初期３剤併用療法。
［項３２］
前記疾患進行が、ＰＡＨの悪化による入院、ＰＡＨの臨床的悪化、又は死亡を含む、項１７～３１のいずれか一項に記載の方法。
The safety observations of the EOS analysis are consistent with the EOMOP findings.
The present invention includes the following aspects.
[Section 1]
A method of reducing the risk of disease progression in patients with pulmonary arterial hypertension (PAH) in need of endothelin receptor antagonists (ERAs), phosphodiesterase type 5 (PDE-5) inhibitors. , and a prostacyclin receptor agonist (IP receptor agonist).
[Section 2]
2. The method of paragraph 1, wherein said reducing the risk of disease progression is for a patient population with PAH receiving initial dual combination therapy of said ERA and said PDE-5 inhibitor.
[Section 3]
The ERA is macitentan, bosentan, or ambrisentan, or a pharmaceutically acceptable salt thereof, and the PDE-5 inhibitor is tadalafil, sildenafil, vardenafil, or udenafil, or a pharmaceutically acceptable salt thereof. the IP receptor agonist is selexipag, 4-[(5,6-diphenylpyrazin-2-yl)(isopropyl)amino]butoxy}acetic acid (MRE-269), or a pharmaceutically acceptable salt thereof. 3. The method according to item 1 or 2, wherein the salt is
[Section 4]
4. The method of paragraph 3, wherein the ERA is macitentan, the PDE-5 inhibitor is tadalafil, and the IP receptor agonist is selexipag.
[Section 5]
5. The method of any one of paragraphs 1-4, wherein the patient is treatment naive to PAH.
[Section 6]
6. The method of any one of paragraphs 1-5, wherein the initial diagnosis of PAH in the patient is made within 6 months of the initiation of the initial triple therapy.
[Section 7]
The patient has a resting mean pulmonary artery hypertension (mPAP) of about 25 mmHg or more, a mean pulmonary artery wedge pressure (PAWP) of about 15 mmHg or less, and a mean pulmonary artery wedge pressure (PAWP) of about 240 dynes/cm 5 or more at the beginning of the initial triple therapy. 7. The method of any one of paragraphs 1-6, having pulmonary vascular resistance (PVR).
[Section 8]
8. The method of any one of paragraphs 1-7, wherein the patient has a 6-minute walking distance (6MWD) of about 50 meters or more at the beginning of the initial triple therapy.
[Section 9]
9. The method of any one of paragraphs 4-8, wherein the macitentan is administered in an amount of about 10 mg once a day.
[Section 10]
10. The method of any one of paragraphs 4-9, wherein said tadalafil is administered in an amount of about 20 mg to about 40 mg once a day.
[Section 11]
11. The method of any one of paragraphs 4-10, wherein said tadalafil is administered in an amount of about 40 mg once a day.
[Section 12]
12. The method of any one of paragraphs 4-11, wherein the selexipag is administered in an amount of about 200 μg to about 1600 μg twice a day.
[Section 13]
13. The method of any one of paragraphs 4-12, wherein each of said macitentan, said tadalafil, and said selexipag is administered orally in the form of one or more tablets.
[Section 14]
13. The method of any one of paragraphs 4-12, wherein the macitentan and the tadalafil are orally administered in the form of a single tablet and the selexipag is orally administered in the form of one or more separate tablets. .
[Section 15]
15. The method of any one of paragraphs 2-14, wherein the initial three-drug combination therapy reduces the risk of disease progression by about 30-40% relative to the initial two-drug combination therapy.
[Section 16]
16. The method of any one of paragraphs 1-15, wherein the disease progression includes hospitalization due to worsening of PAH, clinical worsening of PAH, or death.
[Section 17]
Endothelin receptor antagonists (ERA), phosphodiesterase type 5 (PDE-5) inhibitors, and prostacyclin receptor agonists (IP receptors) to reduce the risk of disease progression in patients with pulmonary arterial hypertension (PAH). Initial three-drug combination therapy of body agonists).
[Section 18]
18. The initial triple combination therapy of clause 17, wherein said reduced risk of disease progression is for a population of patients with PAH receiving initial dual combination therapy of said ERA and said PDE-5 inhibitor.
[Section 19]
The ERA is macitentan, bosentan, or ambrisentan, or a pharmaceutically acceptable salt thereof, and the PDE-5 inhibitor is tadalafil, sildenafil, vardenafil, or udenafil, or a pharmaceutically acceptable salt thereof. the IP receptor agonist is selexipag, 4-[(5,6-diphenylpyrazin-2-yl)(isopropyl)amino]butoxy}acetic acid (MRE-269), or a pharmaceutically acceptable salt thereof. Item 19. The initial three-drug combination therapy according to item 17 or 18, which is a salt of
[Section 20]
20. The initial triple combination therapy of item 19, wherein the ERA is macitentan, the PDE-5 inhibitor is tadalafil, and the IP receptor agonist is selexipag.
[Section 21]
21. The initial triple combination therapy according to any one of paragraphs 17 to 20, wherein the patient is treatment naive to PAH.
[Section 22]
22. The initial triple combination therapy according to any one of paragraphs 17 to 21, wherein the patient's initial PAH diagnosis is made within 6 months from the start of the initial triple combination therapy.
[Section 23]
The patient has a resting mean pulmonary artery hypertension (mPAP) of about 25 mmHg or more, a mean pulmonary artery wedge pressure (PAWP) of about 15 mmHg or less, and a mean pulmonary artery wedge pressure (PAWP) of about 240 dynes/cm 5 or more at the beginning of the initial triple therapy. The initial triple combination therapy according to any one of paragraphs 17 to 22, with pulmonary vascular resistance (PVR).
[Section 24]
24. The initial triple combination therapy of any one of paragraphs 17-23, wherein the patient has a 6-minute walking distance (6MWD) of about 50 meters or more at the beginning of the initial triple therapy.
[Section 25]
25. The initial triple combination therapy of any one of paragraphs 20-24, wherein the macitentan is formulated to be administered in an amount of about 10 mg once a day.
[Section 26]
26. The initial triple combination therapy of any one of paragraphs 20-25, wherein said tadalafil is formulated to be administered in an amount of about 20 mg to about 40 mg once a day.
[Section 27]
Initial triple combination therapy according to any one of paragraphs 20 to 26, wherein the tadalafil is formulated to be administered in an amount of about 40 mg once a day.
[Section 28]
28. The initial triple combination therapy of any one of paragraphs 20-27, wherein the selexipag is formulated to be administered twice daily in an amount of about 200 μg to about 1600 μg.
[Section 29]
29. The initial triple combination therapy of any one of paragraphs 20-28, wherein each of the macitentan, the tadalafil, and the selexipag are formulated for oral administration in the form of one or more tablets.
[Section 30]
wherein said macitentan and said tadalafil are formulated for oral administration in the form of a single tablet, and said selexipag is formulated for oral administration in the form of one or more separate tablets. 29. The initial three-drug combination therapy according to any one of 20 to 28.
[Section 31]
31. The initial triple combination therapy of any one of paragraphs 18-30, wherein the initial triple combination therapy reduces the risk of disease progression by about 30-40% relative to the initial two-drug combination therapy.
[Section 32]
32. The method of any one of paragraphs 17-31, wherein the disease progression comprises hospitalization due to worsening of PAH, clinical worsening of PAH, or death.
Claims (32)
Applications Claiming Priority (7)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US201962941910P | 2019-11-29 | 2019-11-29 | |
| US62/941,910 | 2019-11-29 | ||
| US202063023452P | 2020-05-12 | 2020-05-12 | |
| US63/023,452 | 2020-05-12 | ||
| US202063076149P | 2020-09-09 | 2020-09-09 | |
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| PCT/EP2020/083593 WO2021105331A1 (en) | 2019-11-29 | 2020-11-27 | Methods of treating pulmonary arterial hypertension |
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| US20050101608A1 (en) * | 2003-09-24 | 2005-05-12 | Santel Donald J. | Iloprost in combination therapies for the treatment of pulmonary arterial hypertension |
| MY151003A (en) | 2005-09-12 | 2014-03-31 | Actelion Pharmaceuticals Ltd | Stable pharmaceutical composition comprising a pyrimidine-sulfamide |
| PT2447254T (en) | 2009-06-26 | 2018-01-04 | Nippon Shinyaku Co Ltd | Crystals |
| WO2011024874A1 (en) | 2009-08-26 | 2011-03-03 | 日本新薬株式会社 | Base addition salts |
| MX346730B (en) * | 2010-10-15 | 2017-03-30 | Gilead Sciences Inc | Compositions and methods of treating pulmonary hypertension. |
| EP3136101B1 (en) * | 2014-04-22 | 2019-12-25 | Tohoku University | Method of testing for pulmonary hypertension |
| BR112017014914B1 (en) * | 2015-01-13 | 2023-11-14 | Vivus, Inc | USE OF A COMBINATION OF TACROLIMUS AND A SECOND ACTIVE AGENT EFFECTIVE IN THE TREATMENT OR PREVENTION OF PULMONARY HYPERTENSION |
| CA3041679A1 (en) * | 2016-10-27 | 2018-05-03 | Lawrence S. ZISMAN | Combination therapy for treating pulmonary hypertension |
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