JPWO2020234782A5

JPWO2020234782A5 -

Info

Publication number: JPWO2020234782A5
Application number: JP2021568760A
Authority: JP
Publication date: 2023-05-26

Description

上記の臨床試験及び前臨床エビデンスからのデータは１０ｍｇ～２００ｍｇの１日用量の化合物（Ｉ）が、好塩基球及びマスト駆動皮膚疾患の治療に安全で且つ薬理学的に有効であることを示している。

以下の態様を包含し得る。
［１］慢性自発性蕁麻疹（ＣＳＵ）の治療を、そのような治療を必要する対象に行うために使用する、式（Ｉ）の化合物

又はその薬学的に許容される塩であって、式（Ｉ）の化合物の１日用量は約１０ｍｇ～約２００ｍｇである、式（Ｉ）の化合物又はその薬学的に許容される塩。
［２］前記１日用量は約１０ｍｇ～約１００ｍｇである、上記［１］に記載の使用のための式（Ｉ）の化合物又はその薬学的に許容される塩。
［３］前記１日用量は約１００ｍｇである、上記［１］に記載の使用のための式（Ｉ）の化合物又はその薬学的に許容される塩。
［４］前記１日用量は約５０ｍｇである、上記［１］に記載の使用のための式（Ｉ）の化合物又はその薬学的に許容される塩。
［５］前記１日用量は約３５ｍｇである、上記［１］に記載の使用のための式（Ｉ）の化合物又はその薬学的に許容される塩。
［６］前記１日用量は約２５ｍｇである、上記［１］に記載の使用のための式（Ｉ）の化合物又はその薬学的に許容される塩。
［７］前記１日用量は約２０ｍｇである、上記［１］に記載の使用のための式（Ｉ）の化合物又はその薬学的に許容される塩。
［８］前記式（Ｉ）の化合物は、約１０ｍｇ、約３５ｍｇ、約５０ｍｇ又は約１００ｍｇの用量で１日１回投与される、上記［１］に記載の使用のための式（Ｉ）の化合物又はその薬学的に許容される塩。
［９］前記式（Ｉ）の化合物又はその薬学的に許容される塩は、約１０ｍｇ、約２５ｍｇ、約５０ｍｇ又は約１００ｍｇの用量で１日２回投与される、上記［１］に記載の使用のための式（Ｉ）の化合物又はその薬学的に許容される塩。
［１０］前記式（Ｉ）の化合物での治療の前に、前記対象はＣＳＵ用全身性薬剤で既に治療されたことがある、上記［１］～［９］のいずれか一項に記載の使用のための式（Ｉ）の化合物又はその薬学的に許容される塩。
［１１］前記全身性薬剤は、Ｈ１－抗ヒスタミン薬（Ｈ１－ＡＨ）、Ｈ２－抗ヒスタミン薬（Ｈ２－ＡＨ）、及びロイコトリエン受容体拮抗薬（ＬＴＲＡ）、並びにこれらの組み合わせからなる群から選択される、上記［１０］に記載の使用のための式（Ｉ）の化合物又はその薬学的に許容される塩。
［１２］前記式（Ｉ）の化合物での治療の前に、前記対象はＣＳＵ用全身性薬剤で治療されたことがない、上記［１］～［９］のいずれか一項に記載の使用のための式（Ｉ）の化合物又はその薬学的に許容される塩。
［１３］前記対象は中等度から重度のＣＳＵを有する、上記［１］～［１２］のいずれか一項に記載の使用のための式（Ｉ）の化合物又はその薬学的に許容される塩。
［１４］前記対象は以下の基準：
ａ）式（Ｉ）の化合物又はその薬学的に許容される塩での治療の前に、前記対象は、１６以上のＵＡＳ７スコアを有する；
ｂ）前記式（Ｉ）の化合物又はその薬学的に許容される塩での治療の前に、前記対象は、８以上のＨＳＳ７スコアを有する
の少なくとも１つに従って選択される、上記［１］～［１２］のいずれか一項に記載の使用のための式（Ｉ）の化合物又はその薬学的に許容される塩。
［１５］前記対象は成人である、上記［１］～［１４］のいずれか一項に記載の使用のための式（Ｉ）の化合物又はその薬学的に許容される塩。
［１６］前記対象は治療の４週目又は１２週目までに、以下のうちの：
ａ）ＵＡＳ≦６で判断される蕁麻疹及び掻痒の減少、若しくは蕁麻疹及び掻痒の完全な消失（ＵＡＳ７＝０）；又は
ｂ）皮膚科関連ＱＯＬ評価指標（ＤＬＱＩ）＝０～１；
ｃ）血管性浮腫活動性スコア（ＡＡＳ７）がゼロで判断される血管浮腫がないこと
少なくとも１つを達成する、上記［１］～［１５］のいずれか一項に記載の使用のための式（Ｉ）の化合物又はその薬学的に許容される塩。
［１７］前記対象は、完全な蕁麻疹及び掻痒の応答（［ＵＡＳ７］＝０）及び／又は皮膚科関連ＱＯＬ評価指標（ＤＬＱＩ）＝０～１及び／又は前記治療の完了後４週目に血管性浮腫の消失の継続（ＡＡＳ７＝０）によって判断される持続的応答を達成する、上記［１］～［１６］のいずれか一項に記載の使用のための式（Ｉ）の化合物又はその薬学的に許容される塩。
［１８］前記式（Ｉ）の化合物又はその薬学的に許容される塩は医薬製剤に配合され、前記医薬製剤は薬学的に許容される担体をさらに含む、上記［１］～［１７］のいずれか一項に記載の使用のための式（Ｉ）の化合物又はその薬学的に許容される塩。
［１９］前記式（Ｉ）の化合物又はその薬学的に許容される塩は、約０．５～３時間のＴ _ｍａｘを有する、上記［１］～［１７］のいずれか一項に記載の使用のための式（Ｉ）の化合物又はその薬学的に許容される塩。 Data from the above clinical trials and preclinical evidence indicate that daily doses of 10 mg to 200 mg of compound (I) are safe and pharmacologically effective in the treatment of basophil and mast-driven skin disorders. ing.

The following aspects may be included.
[1] A compound of formula (I) for use in treating chronic spontaneous urticaria (CSU) in a subject in need of such treatment

or a pharmaceutically acceptable salt thereof, wherein the daily dose of the compound of formula (I) is from about 10 mg to about 200 mg.
[2] A compound of formula (I) or a pharmaceutically acceptable salt thereof for use according to [1] above, wherein said daily dose is about 10 mg to about 100 mg.
[3] A compound of formula (I) or a pharmaceutically acceptable salt thereof for use according to [1] above, wherein said daily dose is about 100 mg.
[4] A compound of formula (I) or a pharmaceutically acceptable salt thereof for use according to [1] above, wherein said daily dose is about 50 mg.
[5] A compound of formula (I) or a pharmaceutically acceptable salt thereof for use according to [1] above, wherein said daily dose is about 35 mg.
[6] A compound of formula (I) or a pharmaceutically acceptable salt thereof for use according to [1] above, wherein said daily dose is about 25 mg.
[7] A compound of formula (I) or a pharmaceutically acceptable salt thereof for use according to [1] above, wherein said daily dose is about 20 mg.
[8] The compound of formula (I) for use according to [1] above, wherein the compound of formula (I) is administered once daily at a dose of about 10 mg, about 35 mg, about 50 mg or about 100 mg. A compound or a pharmaceutically acceptable salt thereof.
[9] The above-described [1], wherein the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered twice daily at a dose of about 10 mg, about 25 mg, about 50 mg, or about 100 mg. A compound of formula (I) or a pharmaceutically acceptable salt thereof for use.
[10] The subject according to any one of [1] to [9] above, wherein prior to treatment with the compound of formula (I), the subject has previously been treated with a systemic agent for CSU. A compound of formula (I) or a pharmaceutically acceptable salt thereof for use.
[11] the systemic agent is selected from the group consisting of H1-antihistamines (H1-AH), H2-antihistamines (H2-AH), and leukotriene receptor antagonists (LTRA), and combinations thereof; A compound of formula (I) or a pharmaceutically acceptable salt thereof for use according to [10] above.
[12] The use of any one of [1] to [9] above, wherein the subject has not been treated with a systemic agent for CSU prior to treatment with the compound of formula (I). A compound of formula (I) or a pharmaceutically acceptable salt thereof for
[13] The compound of formula (I) or a pharmaceutically acceptable salt thereof for use according to any one of [1] to [12] above, wherein the subject has moderate to severe CSU .
[14] The subject has the following criteria:
a) said subject has a UAS7 score of 16 or greater prior to treatment with a compound of formula (I) or a pharmaceutically acceptable salt thereof;
b) said subject has an HSS7 score of 8 or greater prior to treatment with said compound of formula (I) or a pharmaceutically acceptable salt thereof;
A compound of formula (I) or a pharmaceutically acceptable salt thereof for use according to any one of [1] to [12] above, selected according to at least one of
[15] A compound of formula (I) or a pharmaceutically acceptable salt thereof for use according to any one of [1] to [14] above, wherein the subject is an adult.
[16] The subject has, by Week 4 or Week 12 of treatment, any of the following:
a) reduction in urticaria and pruritus as judged by UAS≦6, or complete disappearance of urticaria and pruritus (UAS7=0); or
b) Dermatology-related QOL index (DLQI) = 0-1;
c) No angioedema with an angioedema activity score (AAS7) of zero
A compound of formula (I), or a pharmaceutically acceptable salt thereof, for use according to any one of [1] to [15] above, which achieves at least one.
[17] The subject has a complete urticaria and pruritus response ([UAS7] = 0) and/or a dermatology-related QOL index (DLQI) = 0-1 and/or at 4 weeks after completion of the treatment A compound of formula (I) for use according to any one of [1] to [16] above, which achieves a sustained response as judged by continued resolution of angioedema (AAS7=0); a pharmaceutically acceptable salt thereof.
[18] The above [1] to [17], wherein the compound of formula (I) or a pharmaceutically acceptable salt thereof is incorporated into a pharmaceutical preparation, and the pharmaceutical preparation further comprises a pharmaceutically acceptable carrier. A compound of formula (I) or a pharmaceutically acceptable salt thereof for use according to any one of the claims.
[19] The compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of [1] to [17] above, wherein the T _max is about 0.5 to 3 hours. A compound of formula (I) or a pharmaceutically acceptable salt thereof for use.

Claims

A pharmaceutical composition for use in treating chronic spontaneous urticaria (CSU) in a subject in need of such treatment, said pharmaceutical composition comprising a compound of formula (I)

or a pharmaceutically acceptable salt thereof , wherein the daily dose of the compound of formula (I) is from about 10 mg to about 200 mg.

2. The pharmaceutical composition of Claim 1, wherein said daily dose is from about 10 mg to about 100 mg.

2. The pharmaceutical composition of Claim 1, wherein said daily dose is about 100 mg.

2. The pharmaceutical composition of Claim 1, wherein said daily dose is about 50 mg.

2. The pharmaceutical composition of Claim 1, wherein said daily dose is about 35 mg.

2. The pharmaceutical composition of Claim 1, wherein said daily dose is about 25 mg.

2. The pharmaceutical composition of Claim 1, wherein said daily dose is about 20 mg.

2. The pharmaceutical composition of claim 1, wherein said compound of formula (I) is administered once daily at a dose of about 10 mg, about 35 mg, about 50 mg or about 100 mg.

2. The pharmaceutical composition of claim 1, wherein the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered twice daily at a dose of about 10 mg, about 25 mg, about 50 mg or about 100 mg.

The pharmaceutical composition of any one of claims 1-9, wherein prior to treatment with the compound of formula (I), the subject has already been treated with a systemic agent for CSU.

said systemic agent is selected from the group consisting of H1-antihistamines (H1-AH), H2-antihistamines (H2-AH), and leukotriene receptor antagonists (LTRA), and combinations thereof; A pharmaceutical composition according to claim 10 .

10. The pharmaceutical composition of any one of claims 1-9, wherein prior to treatment with the compound of formula (I), the subject has not been treated with a systemic agent for CSU.

The pharmaceutical composition of any one of claims 1-12, wherein the subject has moderate to severe CSU.

Said subjects are subject to the following criteria:
a) said subject has a UAS7 score of 16 or greater prior to treatment with a compound of formula (I) or a pharmaceutically acceptable salt thereof;
b) prior to treatment with said compound of formula (I) or a pharmaceutically acceptable salt thereof, said subject is selected according to at least one of claims 1-12 having an HSS7 score of 8 or greater; The pharmaceutical composition according to any one of

The pharmaceutical composition according to any one of claims 1-14, wherein said subject is an adult.

By Week 4 or Week 12 of treatment, the subject has any of the following:
a) reduction in urticaria and pruritus, or complete disappearance of urticaria and pruritus as judged by UAS ≤ 6 (UAS7 = 0); or b) dermatology-related QOL index (DLQI) = 0-1;
The pharmaceutical composition according to any one of claims 1 to 15, which achieves at least one of c) the absence of angioedema judged by an angioedema activity score (AAS7) of zero.

The subject has a complete urticaria and pruritus response ([UAS7]=0) and/or dermatology-related QOL index (DLQI)=0-1 and/or angioedema at 4 weeks after completion of the treatment 17. The pharmaceutical composition according to any one of claims 1 to 16, which achieves a sustained response as judged by the continued disappearance of (AAS7=0).

A pharmaceutical composition according to any one of claims 1-17, further comprising a pharmaceutically acceptable carrier.

18. The pharmaceutical composition according to any one of claims 1-17, wherein the compound of formula (I) or a pharmaceutically acceptable salt thereof has a T _max of about 0.5-3 hours.