Pharmaceutical composition for vascular malformation and method for treating vascular malformation

Abstract

The present invention relates to a pharmaceutical composition for treating or treating vascular malformations, which contains seeracephala (seeracephala) or a pharmaceutically acceptable salt thereof as an active ingredient, and the daily use amount of seeracephala (seeracephala) is in the range of 50 mg to 100 mg.

Description

Technical Field

[0001] The present invention relates to a pharmaceutical composition for vascular malformations containing serabelisib and a method for treating vascular malformations using serabelisib. Background Art

[0002] Vascular malformations refer to diseases in which the formation of blood vessels or lymphatic vessels is abnormal, and they do not regress naturally but develop as growth progresses, etc., and are thus widely known as diseases that require lifelong disease treatment and management. In addition, depending on the lesion site, etc., when malformations are found in veins or lymphatic vessels, they are called low-flow vascular malformations. Low-flow vascular malformations can be classified into venous malformations (VM) and lymphatic malformations (LM), etc. In addition, when malformations are found in multiple of veins, arteries, capillaries, and lymphatic vessels, they are called mixed vascular malformations. Mixed vascular malformations can be classified into Klippel-Trenaunay syndrome (KTS) and Parkes-Weber syndrome, etc. It has been reported that in patients with these diseases, in the PI3K pathway, which plays an important role in cell functions such as cell growth, proliferation, survival, motility, and metabolism, gain-of-function mutations in the functions of PI 3Kα and genes encoding its upstream and downstream kinases occur, and thus activation of the PI3K pathway is suggested to be the pathogenesis of the disease.

[0003] According to the "Diagnosis and Treatment Guidelines for Hemangiomas, Vascular Malformations, and Lymphatic Malformations 2017", as treatment methods for venous malformations, conservative therapies and invasive treatments are described, but there is no description of drug therapies. It has been reported that as treatment methods for lymphatic malformations, surgical therapies such as resection, sclerotherapy using sclerosing agents, and medical treatments are performed, and as treatment drugs, sirolimus (mTOR inhibitor), etc. have been confirmed to be effective (Non-Patent Document 1).

[0004] Currently, sirolimus has obtained drug approval for lymphangioleiomyomatosis and refractory lymphatic diseases in Japan, and alpelisib has obtained rapid approval for PIK3CA-related overgrowth spectrum (PROS) in the United States (Non-Patent Documents 2 and 3).

[0005] The PI3K pathway has been shown to be deeply involved in the pathogenesis of vascular malformations. As its in-vivo proteins, PI 3K, AKT, and mTOR are known, and inhibitors thereof have also been studied and developed as anticancer agents. These existing molecule-targeted inhibitors have been reported to frequently cause hyperglycemia, and since hyperglycemia results from the inhibitory effect of the PI3K pathway, it is considered to be a common side effect of PI3K pathway inhibitors (Non-Patent Document 4).

[0006] On the other hand, vascular malformations are diseases that require long-term drug treatment, and the adverse reactions (side effects) associated with the pharmacological effects of the drugs may significantly impair the quality of life (QOL) of patients.

[0007] In practice, the following side effects are known for the existing treatment drugs for vascular malformations. Sirolimus (mTOR inhibitor): immunosuppression, hyperglycemia (frequency unknown) (Non-Patent Document 2) Alpelisib (PI3Kα inhibitor): hyperglycemia (Non-Patent Document 3)

[0008] As described above, in the existing treatment methods and drugs for vascular malformations, there is a problem that side effects such as hyperglycemia occur simultaneously at the effective dosage, and there is a need for a drug that can separate the efficacy and side effects. However, as described above, side effects such as hyperglycemia are considered to be related to the PI3Kα inhibitory effect, so it is thought that the frequency of side effects will also increase in proportion to the efficacy. Therefore, it is completely uncertain whether there is a drug or its dosage that can separate the efficacy from side effects such as hyperglycemia.

[0009] Serabelisib is a compound having a PI 3Kα inhibitory effect. By inhibiting the signal transduction pathway of the activated PI3K pathway, it inhibits abnormal vascular formation and excessive formation of bone and soft tissues, and is expected to have a therapeutic effect on vascular malformations.

[0010] Serabelisib is a compound represented by the following formula (I) (hereinafter, sometimes referred to as "serabelisib" or "ART-001", but both represent the same compound). [Chemical Formula 1]

[0011] In Patent Document 1, it is disclosed that serabelisib has excellent PI 3Kα inhibitory activity and can be used for the treatment of PI3Kα-mediated diseases. In Patent Document 2, a pharmaceutical composition containing serabelisib as an active ingredient is disclosed. In Non-Patent Document 5, the results of the safety and compatibility of a single administration of serabelisib to humans are shown.

[0012] However, to date, in the pharmaceutical composition containing serabelisib as an active ingredient, neither the therapeutic effect on actual patients with vascular malformations nor the relationship between this therapeutic effect and the safety such as side effects has been disclosed or suggested. Prior Art Documents

[0013] Patent Documents Patent Document 1: International Publication No. 2011 / 022439 Patent Document 2: International Publication No. WO 2022 / 004859

[0014] Non-Patent Document Non-Patent Document 1: Guidelines for the Diagnosis and Treatment of Hemangiomas, Vascular Malformations, and Lymphatic Malformations 2017, Research Grants for Policies on Intractable Diseases, etc. from the Ministry of Health, Labour and Welfare in FY2014-2016, "Research Group on Intractable Hemangiomas, Vascular Malformations, Lymphangiomas, Lymphangiomatosis and Related Diseases", 2017 Non-Patent Document 2: Package Insert of Rapalimus (registered trademark), 2021 (revised), Nobel Pharma Non-Patent Document 3: HIGHLIGHTS OF PRESCRIBING INFORMATION, "VIJOICE (registered trademark) (alpelisib) tablets, for oral use", 2019, U.S. Food and Drug Administration Non-Patent Document 4: "Complications of hyperglycaemia with PI3K-AKT-mTOR inhibitors in patients with advanced solid tumours on Phase I clinical trials", British Journal of Cancer, 2015, 113: 1541-1547 Non-Patent Document 5: "SAFETY AND PHARMACOKINETICS OF NOVEL PI 3Kalpha INHIBITOR ART-001 IN ORAL PEDIATRIC FORMULATION FOR THE TREATMENT OF VASCULAR MALFORMATIONS", American Society for Clinical Pharmacology and Therapeutics Annual Meeting, 2021, 122 nd : Abs PII-041 Summary of the Invention Problems to be Solved by the Invention

[0015] To date, among the existing therapeutic drugs for vascular malformations, the occurrence of side effects such as hyperglycaemia has not been suppressed. In particular, for alpelisib (U.S. trade name) which has the same mechanism of action as sereliotin (the same PI3Kα inhibitor) )Regarding [this], precautions when used as a drug were reported, and side effects of hyperglycemia were found.

[0016] One of the problems to be solved by the present invention is to balance the suppression of side effects and the clinical effectiveness against vascular malformations in the treatment of vascular malformations using sereliux as an active ingredient. Means for Solving the Problem

[0017] The present inventors conducted in-depth research and found that in the treatment of vascular malformations using sereliux as an active ingredient, by limiting the daily dose of sereliux to the range of 50 mg to 100 mg, it is possible to balance the suppression of side effects and the clinical effectiveness against vascular malformations.

[0018] As described above, the side effect of hyperglycemia caused by alpelisib, a conventional drug for treating vascular malformations, was suggested to be related to its PI3Kα inhibitory effect. Therefore, it was considered that the frequency of side effects increased in proportion to the drug efficacy. Sereliux is also a PI3Kα inhibitor like alpelisib and is considered to exert its drug effect based on the same mechanism of action. Nevertheless, the present inventors found that there is a dose that can balance the suppression of the occurrence of hyperglycemia side effects caused by sereliux and the effectiveness against vascular malformations. This is an extremely unexpected and astonishing insight from the perspective of the problem of hyperglycemia side effects existing in conventional drugs. Furthermore, the present inventors clarified that even when administered for a long period (24 weeks) at such a dose, the effectiveness and safety can be ensured, thus completing the present invention.

[0019] That is, the present invention includes the following inventions. [Item 1] A pharmaceutical composition for treating or treating vascular malformations, which contains sereliux or a pharmaceutically acceptable salt thereof as an active ingredient, and the daily dose (dosage) of sereliux is in the range of 50 mg to 100 mg. [Item 2] A pharmaceutical composition for reducing the swollen lesions of a patient with vascular malformations, which contains sereliux or a pharmaceutically acceptable salt thereof as an active ingredient, and the daily dose of sereliux is in the range of 50 mg to 100 mg. [Item 3] A pharmaceutical composition for reducing the pain of a patient with vascular malformations, which contains sereliux or a pharmaceutically acceptable salt thereof as an active ingredient, and the daily dose of sereliux is in the range of 50 mg to 100 mg. [Item 4] The pharmaceutical composition according to any one of Items 1 to 3, which reduces the volume of the target lesion by more than 20% during or after treatment compared to before treatment. [Item 5] The pharmaceutical composition according to any one of Items 1 to 4, which can treat vascular malformations while suppressing the occurrence of side effects during treatment. [Item 6] The pharmaceutical composition as described in Item 5, wherein the side effect produced during the treatment is hyperglycemia. [Item 7] A pharmaceutical composition for treating or managing vascular malformations, which comprises serelaxin or a pharmaceutically acceptable salt thereof as an active ingredient, and is administered in an amount that takes into account both: (a) The volume of the target lesion is reduced by more than 20% during or after the treatment as compared with that before the treatment, and (b) The side effect of drug-induced hyperglycemia does not occur during the treatment. [Item 8] The pharmaceutical composition as described in Item 7, wherein the daily dosage of serelaxin ranges from 50 mg to 100 mg. [Item 9] The pharmaceutical composition as described in any one of Items 1 to 8, wherein the content of serelaxin ranges from 2 w / w% to 40 w / w% relative to the total amount of the composition. [Item 10] The pharmaceutical composition as described in Item 9, wherein the content of serelaxin is 20 w / w% relative to the total amount of the composition. [Item 11] The pharmaceutical composition as described in any one of Items 1 to 10, wherein the vascular malformation is a low-flow type vascular malformation or a mixed type vascular malformation. [Item 12] The pharmaceutical composition as described in any one of Items 1 to 11, wherein the vascular malformation is a venous malformation, a lymphatic malformation or Klippel-Trenaunay syndrome. [Item 13] The pharmaceutical composition as described in Item 12, wherein the vascular malformation is a venous malformation. [Item 14] The pharmaceutical composition as described in Item 12, wherein the vascular malformation is a lymphatic malformation. [Item 15] The pharmaceutical composition as described in Item 12, wherein the vascular malformation is Klippel-Trenaunay syndrome. [Item 16] The pharmaceutical composition as described in any one of Items 1 to 15, which is administered once a day during a treatment period of at least two weeks. [Item 17] The pharmaceutical composition as described in Item 16, which is administered once a day during a treatment period of at least 4 weeks, at least 12 weeks, at least 24 weeks, at least 36 weeks, at least 48 weeks, at least 52 weeks, at least 2 years or at least 3 years. [Item 18] A method for treating or managing vascular malformations, which comprises administering serelaxin or a pharmaceutically acceptable salt thereof as an active ingredient to a subject in need thereof, in a daily dosage range of 50 mg to 100 mg of serelaxin. [Item 19] A method for reducing the swollen lesion of a patient with vascular malformations, which comprises administering serelaxin or a pharmaceutically acceptable salt thereof as an active ingredient to a subject in need thereof, in a daily dosage range of 50 mg to 100 mg of serelaxin. [Item 20] A method for reducing pain in patients with vascular malformations, comprising administering to a subject in need thereof, elesclomol or a pharmaceutically acceptable salt thereof as an active ingredient, in a daily dosage range of 50 mg to 100 mg of elesclomol. [Item 21] The method according to any one of Items 18 to 20, wherein the volume of the target lesion is reduced by more than 20% during or after treatment as compared with before treatment. [Item 22] The method according to any one of Items 18 to 21, which is capable of treating low-flow vascular malformations while suppressing the occurrence of side effects generated during treatment. [Item 23] The method according to Item 22, wherein the side effect generated during treatment is hyperglycemia. [Item 24] A method for treating or treating vascular malformations, comprising administering to a subject in need thereof, elesclomol or a pharmaceutically acceptable salt thereof as an active ingredient, in a dosage that takes into account both of the following: (a) The volume of the target lesion is reduced by more than 20% during or after treatment as compared with before treatment, and (b) No side effect of drug-induced hyperglycemia occurs during treatment. [Item 25] The method according to Item 24, wherein the daily dosage of elesclomol is in the range of 50 mg to 100 mg. [Item 26] The method according to any one of Items 18 to 25, wherein the vascular malformation is a low-flow vascular malformation or a mixed vascular malformation. [Item 27] The method according to any one of Items 18 to 26, wherein the vascular malformation is a venous malformation, a lymphatic malformation or Klippel-Trenaunay syndrome. [Item 28] The method according to Item 27, wherein the vascular malformation is a venous malformation. [Item 29] The method according to Item 27, wherein the vascular malformation is a lymphatic malformation. [Item 30] The method according to Item 27, wherein the vascular malformation is Klippel-Trenaunay syndrome. [Item 31] The method according to any one of Items 18 to 30, wherein elesclomol is administered once a day during a treatment period of at least two weeks. [Item 32] The method according to Item 31, wherein elesclomol is administered once a day during a treatment period of at least 4 weeks, at least 12 weeks, at least 24 weeks, at least 36 weeks, at least 48 weeks, at least 52 weeks, at least 2 years or at least 3 years. Advantages of the Invention

[0020] According to the present invention, in the treatment of vascular malformations using elesclomol as an active ingredient, it is possible to take into account both the suppression of the occurrence of side effects and the clinical effectiveness against vascular malformations. Detailed Embodiments

[0021] Hereinafter, the present invention will be described in detail according to specific embodiments. However, the present invention is not limited to the following embodiments, and can be implemented in any embodiment without departing from the gist of the present invention. In addition, in the various embodiments described below, the combination of any two or more embodiments is included in the scope of the present invention, unless it is clearly contradictory from its definition or context.

[0022] In this specification, for the case where a numerical range such as "A to B" or "A~B" is described, unless otherwise specified, it means "A or more and B or less", that is, a numerical value including its end values.

[0023] In this specification, when only "selpercatinib" is described, unless it is clearly different from the context or otherwise specified, it means "selpercatinib or a pharmaceutically acceptable salt thereof". However, when a pharmaceutically acceptable salt of selpercatinib is used as an active ingredient, in the description of "the daily dosage of selpercatinib", selpercatinib refers to the free selpercatinib.

[0024] In this specification, "treating" "vascular malformation" means: reducing the volume of the target lesion during or after treatment compared to before treatment. Preferably, it means that the volume of the target lesion is reduced by 20% or more.

[0025] The first aspect of the present invention relates to a pharmaceutical composition for various uses in vascular malformations, which contains selpercatinib or a pharmaceutically acceptable salt thereof as an active ingredient.

[0026] A pharmaceutical composition of one embodiment is a pharmaceutical composition for treating or treating vascular malformations, characterized in that it contains selpercatinib or a pharmaceutically acceptable salt thereof as an active ingredient, and the daily dosage of selpercatinib is in the range of 50 mg to 100 mg.

[0027] Another embodiment of the pharmaceutical composition is a pharmaceutical composition for reducing the swollen lesions of a patient with vascular malformations, characterized in that it contains selpercatinib or a pharmaceutically acceptable salt thereof as an active ingredient, and the daily dosage of selpercatinib is in the range of 50 mg to 100 mg.

[0028] Another embodiment of the pharmaceutical composition is a pharmaceutical composition for reducing the pain of a patient with vascular malformations, characterized in that it contains selpercatinib or a pharmaceutically acceptable salt thereof as an active ingredient, and the daily dosage of selpercatinib is in the range of 50 mg to 100 mg.

[0029] According to one embodiment, preferably, each of the above pharmaceutical compositions reduces the volume of the target lesion by 20% or more during or after treatment compared to before treatment.

[0030] According to one embodiment, each of the above pharmaceutical compositions preferably treats vascular malformations while suppressing the occurrence of side effects generated during the treatment. According to one embodiment, the vascular malformations treated while suppressing the occurrence (expression) of side effects are preferably low-flow vascular malformations. According to one embodiment, the side effect generated during the treatment is preferably hyperglycemia.

[0031] The pharmaceutical composition according to another embodiment is a pharmaceutical composition for treating or treating vascular malformations, characterized by comprising serelaxin or a pharmaceutically acceptable salt thereof as an active ingredient, and administered in an amount that takes into account both of the following: (a) The volume of the target lesion is reduced by more than 20% during or after the treatment compared to before the treatment, and (b) No side effect of drug-induced hyperglycemia occurs during the treatment.

[0032] According to one embodiment, the daily dose of serelaxin in the above pharmaceutical composition is preferably in the range of 50 mg to 100 mg.

[0033] The content of serelaxin in each of the above pharmaceutical compositions is not particularly limited. However, according to one embodiment, the content of serelaxin in each of the above pharmaceutical compositions is, for example, 2 w / w% to 40 w / w%, or 5 w / w% to 35 w / w%, or 10 w / w% to 30 w / w%, or 15 w / w% to 25 w / w%, or 15 w / w% to 20 w / w% relative to the total amount of the composition. According to one embodiment, the content of serelaxin in each of the above pharmaceutical compositions is 15 w / w%, 20 w / w%, or 25 w / w% relative to the total amount of the composition. According to one embodiment, the content of serelaxin in each of the above pharmaceutical compositions is 20 w / w% relative to the total amount of the composition.

[0034] The dosage form of each of the above pharmaceutical compositions is not particularly limited. However, according to one embodiment, each of the above pharmaceutical compositions is in a dosage form suitable for oral administration. According to one embodiment, each of the above pharmaceutical compositions may be tablets, capsules, granules, powders, syrups, dry syrups, enteric-coated agents, or sustained-release agents. Among them, dry syrup is preferred.

[0035] In addition to serelaxin or a pharmaceutically acceptable salt thereof as an active ingredient, each of the above drug compositions may contain any other ingredients. Specific examples of the other ingredients are not limited, and examples thereof include excipients such as mannitol, erythritol, powdered reduced maltose syrup, crystalline cellulose, and corn starch; disintegrants such as crospovidone, croscarmellose sodium, sodium starch glycolate, partially pregelatinized starch, carboxymethylcellulose calcium, and low-substituted hydroxypropyl cellulose; sweeteners such as sucrose, aspartame, acesulfame potassium, sodium saccharin, ammonium glycyrrhizinate, and thaumatin; and other additives such as fluidizing agents, coloring agents, and fragrances. These ingredients can be appropriately selected and used according to the dosage form of the drug composition and the like. These ingredients can be used alone, or two or more of them can be used in any combination and ratio.

[0036] There are no particular limitations on the ingredients and their formulation recipes that can be used in each of the above drug compositions, but for the detailed content, reference can be appropriately made to, for example, the records of "Remington: The Science and Practice of Pharmacy, 20th Edition", Lippincott Williams & Wilkins, 2000 by the University of the Sciences in Philadelphia and the records of Patent Document 2.

[0037] The second aspect of the present invention relates to various methods for vascular malformations, including administering serelaxin or a pharmaceutically acceptable salt thereof as an active ingredient to a subject.

[0038] A method according to one embodiment is a method for treating or treating a vascular malformation, characterized by including administering, to a subject in need thereof, serelaxin or a pharmaceutically acceptable salt thereof as an active ingredient in a daily dosage range of 50 mg to 100 mg of serelaxin.

[0039] Another embodiment of the method is a method for reducing the swollen lesions of a patient with a vascular malformation, characterized by including administering, to a subject in need thereof, serelaxin or a pharmaceutically acceptable salt thereof as an active ingredient in a daily dosage range of 50 mg to 100 mg of serelaxin.

[0040] Another embodiment of the method is a method for reducing the pain of a patient with a vascular malformation, characterized by including administering, to a subject in need thereof, serelaxin or a pharmaceutically acceptable salt thereof as an active ingredient in a daily dosage range of 50 mg to 100 mg of serelaxin.

[0041] According to one embodiment, compared with before treatment, each of the above methods preferably reduces the volume of the target lesion by more than 20% during or after treatment.

[0042] According to one embodiment, each of the above methods preferably treats low-flow vascular malformations while suppressing the occurrence of side effects generated during the treatment. According to one embodiment, the side effect generated during the treatment is preferably hyperglycemia.

[0043] Another embodiment of the method is a method for treating or treating vascular malformations, characterized by comprising administering to a subject in need thereof, using selisistat or a pharmaceutically acceptable salt thereof as an active ingredient, in an amount that takes into account both of the following: (a) The volume of the target lesion is reduced by more than 20% during or after the treatment compared to before the treatment, and (b) No drug-induced hyperglycemia side effect occurs during the treatment.

[0044] According to one embodiment, the daily dosage of selisistat in the above method is preferably in the range of 50 mg to 100 mg.

[0045] The third aspect of the present invention relates to the pharmaceutical composition of the first aspect and the various methods of the second aspect.

[0046] According to one embodiment, the vascular malformation is a low-flow vascular malformation or a mixed vascular malformation. According to one embodiment, the vascular malformation is one or more diseases selected from venous malformation, lymphatic malformation, or Klippel-Trenaunay syndrome.

[0047] According to one embodiment, the side effects are hyperglycemia and hypercreatininemia. According to one embodiment, the side effect is hyperglycemia. In this specification, "hyperglycemia" refers to a disease diagnosed by a doctor based on test values such as blood glucose levels as an adverse reaction (side effect) accompanying the pharmacological action of the drug.

[0048] According to one embodiment, there is no particular limitation on the subject to whom selisistat is administered in each of the above pharmaceutical compositions and methods. According to one embodiment, the subject to whom selisistat is administered is a human. According to one embodiment, the subject to whom selisistat is administered is an adult. When the subject to whom selisistat is administered is an adult, the daily dosage of selisistat is in the range of 50 mg to 100 mg. According to one embodiment, the subject to whom selisistat is administered is a child. When the subject to whom selisistat is administered is a child, the daily dosage of selisistat can be the pediatric dosage equivalent to the dosage range of 50 mg to 100 mg for adults. Such a pediatric dosage can be calculated based on the body surface area according to the Crawford equation from the dosage range of 50 mg to 100 mg for adults.

[0049] According to one embodiment, the administration of selisistat in each of the above pharmaceutical compositions and methods can be carried out at any time before, during, or after a meal. According to one embodiment, it is preferred to administer selisistat after a meal. According to one embodiment, it is preferred to administer selisistat at least after breakfast.

[0050] There is no particular limitation on the frequency of administration of selepressin in each of the above drug compositions and each of the methods. It can be administered once a day or in multiple doses per day. According to one embodiment, selepressin in each of the above drug compositions and each of the methods is administered once a day. According to another embodiment, selepressin in each of the above drug compositions and each of the methods is administered in multiple doses per day. According to one embodiment, the administration of selepressin in each of the above drug compositions and each of the methods is preferably administered once a day after breakfast.

[0051] There is no particular limitation on the dosing interval of selepressin in each of the above drug compositions and each of the methods. However, according to one embodiment, the dosing interval of selepressin in each of the above drug compositions and each of the methods is, for example, 6 to 48 hours, 8 to 36 hours, 12 to 36 hours, 20 to 28 hours, or 22 to 26 hours.

[0052] There is no particular limitation on the treatment period using selepressin in each of the above drug compositions and each of the methods. However, according to one embodiment, the treatment period using selepressin in each of the above drug compositions and each of the methods is, for example, at least 2 weeks, at least 4 weeks, at least 12 weeks, at least 24 weeks, at least 36 weeks, at least 48 weeks, at least 52 weeks, at least 2 years, or at least 3 years. According to one embodiment, the treatment period of selepressin in each of the above drug compositions and each of the methods is, for example, at most 4 weeks, at most 12 weeks, at most 24 weeks, at most 36 weeks, at most 48 weeks, at most 52 weeks, at most 2 years, or at most 3 years. According to one embodiment, each of the above drug compositions and each of the methods is characterized in that the effectiveness and safety are ensured even with long-term administration.

[0053] The fourth aspect of the present invention relates to the use of selepressin or a pharmaceutically acceptable salt thereof in the preparation of each of the above drug compositions. The details of each drug composition are as described above.

[0054] The fifth aspect of the present invention relates to selepressin or a pharmaceutically acceptable salt thereof for use in each of the above methods. The details of each method are as described above. Examples

[0055] Hereinafter, the present invention will be described in more detail based on examples. However, the following examples are merely examples shown for convenience of explanation, and the present invention is in no way limited to the following examples.

[0056] [Trial Example] The validation trial of the efficacy and safety of ceralasertib (ART-001) in subjects with vascular malformations Verification trial Through a randomized double-blind trial with patients with vascular malformations as subjects, the efficacy of orally administering a dry syrup containing serelaxin (200 mg of serelaxin per 1 g) once a day after breakfast for 24 weeks was verified in such a way that the adult dose of serelaxin was 50 mg or the adult dose of serelaxin was 100 mg. In addition, for pediatric patients, the dose calculated by converting according to the body surface area based on the Crawford equation relative to their respective adult doses was used as the administered dose. The main evaluation item was the response rate based on the volume change (MRI) of the target lesions at the end of 24 weeks of administration.

[0057] In this trial, "baseline" refers to each measured value of the degree of symptoms serving as a benchmark before administration. The baseline was measured within a specified period before administration. The number of days of administration of the drug composition of serelaxin is the number of days with the baseline as the first day, and the expressions such as "administration period" and "number of weeks of administration" are also based on this benchmark. That is, the measurement day of the baseline is the day when the drug composition of serelaxin starts to be administered.

[0058] <Analysis of Efficacy> (1) Primary analysis of efficacy For the analysis of the main evaluation item for efficacy evaluation, the disappearance of the target lesion was defined as complete response, and a reduction in the volume of the target lesion by more than 20% compared to the screening examination was defined as partial response. The 95% confidence interval of the response rate (the proportion of the sum of complete response and partial response relative to the whole) based on the volume change (MRI) of the target lesion before administration and at the end of 24 weeks of administration was calculated by the Clopper-Pearson method, and it was verified whether the lower limit exceeded 12.5%. In addition, as a secondary evaluation item, the response rate based on the volume change (MRI) of the target lesion at the end of 12 weeks of administration was evaluated.

[0059] (2) Secondary analysis of efficacy · Evaluation of pain: Evaluate the degree of pain (VAS) at baseline, the 4th week of administration, the 12th week of administration, and the 24th week of administration.

[0060] <Investigation Items of Efficacy> Investigate the following items and record the results.

[0061] (1) Measurement of the volume of target lesions using MRI · Measurement method: As target lesions, for vascular malformation lesions of vascular malformation components, cystic components of lymphatic malformations, lymphedema, lymph fluid, and lymphatic leakage (including intraosseous, extraosseous, and subcutaneous), select the target lesions detected by fat-suppressed T2-weighted imaging to measure the volume.

[0062] (2) Determination of the degree of pain by visual analogue scale (VAS) · Determination method: Draw a 10-cm straight line on the recording paper, define the left end as 0 and the right end as 100. Set "0" as the state of "no pain at all" and "100" as the state of "unimaginable stronger pain or the worst pain". Listen to and record at which position on the straight line the current pain level is. Note that when recorded by the agent, record their intention. In addition, as the age at the time of obtaining consent, it is divided into under 15 years old and 15 years old and above, and use the recording paper corresponding to each age group.

[0063] <Subject Patients and Main Inclusion Criteria> Patients with vascular malformations who meet the following diagnostic criteria and conditions. (1) Men and women aged 2 years or older. (2) Patients diagnosed with venous malformation, lymphatic malformation, or Klippel-Trenaunay syndrome. (3) Symptomatic patients. (4) Patients judged to be refractory.

[0064] <Main Exclusion Criteria> (1) Patients with diseases that cause diabetes or abnormal glucose metabolism. (2) Patients with renal dysfunction. (3) Patients with liver dysfunction. (4) Patients with inadequately controlled ischemic heart disease, arrhythmia, or heart failure. (5) Patients taking drugs with CYP3A4 inhibitory or inducing effects.

[0065] <Main discontinuation criteria> (1) When a test value of 140 mg / dL or higher is found in the blood glucose level (fasting) of the clinical examination conducted on each hospital visit day, discontinue the trial. (2) When all of the following criteria specified by age group are met in the clinical examination conducted on each hospital visit day, discontinue the trial. 《18 years old and above》 · Judging from the test values obtained on the start day of the clinical trial drug administration, the serum creatinine has increased by 1.5 times or more. · From the test values obtained on the day of administration of the investigational drug in the clinical trial, the serum creatinine increased by more than 0.3 mg / dL. · From the test values obtained on the day of administration of the investigational drug in the clinical trial, the serum cystatin C increased by more than 1.5-fold. · The serum cystatin C exceeded 0.95 mg / L. 《Under 18 years old》 · From the test values obtained on the day of administration of the investigational drug in the clinical trial, the serum creatinine increased by more than 1.5-fold. · From the test values obtained on the day of administration of the investigational drug in the clinical trial, the serum cystatin C increased by more than 1.5-fold. · The serum cystatin C exceeded 0.95 mg / L.

[0066] <Subjects in the clinical trial> The investigational drug was allocated to 35 patients with vascular malformations as follows, and data analysis was performed using these patient groups as subjects. The group of dry syrup of serelaxin with a dosage of 50 mg was called the "50 mg dosage group", and the group of dry syrup of serelaxin with a dosage of 100 mg was called the "100 mg dosage group". 17 people were allocated to the 50 mg dosage group and 18 people were allocated to the 100 mg dosage group. It should be noted that the demographic characteristics of the two groups were the same.

[0067] <Results of the primary and secondary evaluation items of efficacy> As the primary evaluation item, the response rate, the number of subjects, and the 95% confidence interval based on the Clopper-Pearson method for the volume change of the target lesions at week 24 of administration are shown in the following table. In addition, as the secondary evaluation item, the response rate and the number of subjects at week 12 of administration are also shown in the following table.

[0068] [Table 1]

[0069] Regarding the proportion of subjects showing efficacy, the 50 mg dosage group was 29.4% (5 / 17), and the 100 mg dosage group was 33.3% (6 / 18). Regarding the 95% confidence interval of the Clopper-Pearson method, the 50 mg dosage group was 10.3% - 56.0%, and the 100 mg dosage group was 13.3% - 59.0%. In the 100 mg dosage group, the lower limit of the 95% confidence interval exceeded 12.5%.

[0070] < Results of secondary evaluation items regarding pain> The following table shows the changes in VAS at baseline, week 4 of administration, week 12 of administration, and week 24 of administration.

[0071] [Table 2]

[0072] In the 50 mg administration group and the 100 mg administration group, the mean and median values of VAS decreased after administration.

[0073] [Side effects of hyperglycemia] In this trial, no subjects were diagnosed by a doctor with symptoms of hyperglycemia based on test values such as blood glucose levels.

[0074] The above results indicate that the pharmaceutical composition containing selepressin of the present invention exerts a therapeutic effect in the treatment of vascular malformations without causing the side effect of hyperglycemia, which has been a problem in the treatment with conventional drugs such as alpelisib. Industrial applicability

[0075] According to the present invention, the pharmaceutical composition containing selepressin exerts a therapeutic effect in the treatment of vascular malformations without causing the side effect of hyperglycemia, which may frequently occur in conventional drug treatments, and thus can be used more safely.

Claims

1. A pharmaceutical composition for treating or treating vascular malformations, which comprises serelaxin or a pharmaceutically acceptable salt thereof as an active ingredient, and the daily dosage of serelaxin ranges from 50 mg to 100 mg.

2. A pharmaceutical composition for reducing the swollen lesions of patients with vascular malformations, which comprises serelaxin or a pharmaceutically acceptable salt thereof as an active ingredient, and the daily dosage of serelaxin ranges from 50 mg to 100 mg.

3. A pharmaceutical composition for reducing the pain of patients with vascular malformations, which comprises serelaxin or a pharmaceutically acceptable salt thereof as an active ingredient, and the daily dosage of serelaxin ranges from 50 mg to 100 mg.

4. The pharmaceutical composition according to any one of claims 1 to 3, which reduces the volume of the target lesion by more than 20% during or after treatment compared with before treatment.

5. The pharmaceutical composition according to any one of claims 1 to 4, which can treat vascular malformations while inhibiting the occurrence of side effects during treatment.

6. The pharmaceutical composition according to claim 5, wherein the side effect generated during treatment is hyperglycemia.

7. A pharmaceutical composition for treating or treating vascular malformations, which comprises serelaxin or a pharmaceutically acceptable salt thereof as an active ingredient, and is administered in a dosage that takes into account both: (a) The volume of the target lesion is reduced by more than 20% during or after treatment compared with before treatment, and (b) No drug-induced hyperglycemia side effect occurs during treatment.

8. The pharmaceutical composition according to claim 7, wherein, The daily dosage of serelaxin ranges from 50 mg to 100 mg.

9. The pharmaceutical composition according to any one of claims 1 to 8, wherein, The content of serelaxin ranges from 2 w / w% to 40 w / w% relative to the total amount of the composition.

10. The pharmaceutical composition according to claim 9, wherein, The content of serelaxin is 20 w / w% relative to the total amount of the composition.

11. The pharmaceutical composition according to any one of claims 1 to 10, wherein, The vascular malformation is a low-flow vascular malformation or a mixed vascular malformation.

12. The pharmaceutical composition according to any one of claims 1 to 11, wherein, The vascular malformation is a venous malformation, a lymphatic malformation or Klippel-Trenaunay syndrome.

13. The pharmaceutical composition according to claim 12, wherein, The vascular malformation is a venous malformation.

14. The pharmaceutical composition according to claim 12, wherein, The vascular malformation is a lymphatic malformation.

15. The pharmaceutical composition according to claim 12, wherein, The vascular malformation is Klippel-Trenaunay syndrome.

16. The pharmaceutical composition according to any one of claims 1 to 15, which is administered once a day during a treatment period of at least two weeks.

17. The pharmaceutical composition according to claim 16, which is administered once a day during a treatment period of at least 4 weeks, at least 12 weeks, at least 24 weeks, at least 36 weeks, at least 48 weeks, at least 52 weeks, at least 2 years or at least 3 years.

18. A method for treating or treating vascular malformations, which comprises administering serelaxin or a pharmaceutically acceptable salt thereof as an active ingredient and in a daily dosage range of 50 mg to 100 mg to a subject in need thereof.

19. A method for reducing the swollen lesions of patients with vascular malformations, which comprises administering serelaxin or a pharmaceutically acceptable salt thereof as an active ingredient and in a daily dosage range of 50 mg to 100 mg to a subject in need thereof.

20. A method for reducing pain in patients with vascular malformations, comprising administering to a subject in need thereof, using selisistat or a pharmaceutically acceptable salt thereof as an active ingredient, in a daily dosage range of 50 mg to 100 mg of selisistat.

21. A method for treating or managing vascular malformations, comprising administering to a subject in need thereof, using selisistat or a pharmaceutically acceptable salt thereof as an active ingredient, in a dosage that takes into account both: (a) a reduction in the volume of the target lesion by more than 20% during or after treatment compared to before treatment, and (b) no side effect of drug-induced hyperglycemia during treatment.

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