Therapeutic agent for hereditary cerebral small vessel disease

Abstract

One embodiment of the present invention is a therapeutic agent for hereditary cerebral small vessel disease that contains adrenomedullin or the like as an active ingredient.

Description

Treatment for hereditary cerebral small vessel disease

[0001] As one embodiment of the present invention, a therapeutic agent for hereditary cerebral small vessel disease containing adrenomedullin or the like as an active ingredient is disclosed, which is useful, for example, in the field of pharmaceuticals.

[0002] Autosomal dominant (overt) cerebral arteriopathy with subcortical injury and leukoencephalopathy (hereinafter also referred to as "CADASIL"), autosomal recessive (latent) leukoencephalopathy with baldness and degenerative spondylosis Hereditary cerebral small vessel diseases, exemplified by conditions such as andleukoencephalopathy (CARASIL), pseudoxanthoma elasticum, are rare diseases characterized by cognitive impairment and caused by mutations in specific causative genes. Among these, CADASIL is a representative hereditary cerebral small vessel disease, an autosomal dominant (overt) genetic disease caused by mutations in the NOTCH3 gene, with a prevalence of 2.5 per 100,000 people. It is a type of hereditary leukoencephalopathy in which cerebral white matter lesions gradually progress, leading to repeated strokes and hemorrhages, and causing depressive symptoms, dementia, and motor dysfunction. While this disease has traditionally been called "autosomal dominant cerebral arteriovenous disease" in the medical field, it has recently been proposed to call it "autosomal overt cerebral arteriovenous disease." However, conventional antiplatelet agents used to prevent stroke recurrence are ineffective, and no drugs have been shown to have anti-dementia effects. Therefore, currently, there is no established effective treatment for acute and chronic ischemic conditions based on cerebral small vessel disease. The earliest change in CADASIL is damage to the brain's white matter. The brain is broadly divided into superficial gray matter and deep white matter, and the white matter mainly functions as a communication network between nerve cells. Among the various symptoms associated with CADASIL, cognitive impairment only worsens over time, significantly impacting the patient's quality of life and also involving social issues such as the need for care, making improvement highly desirable. Early cognitive impairment in CADASIL is caused by damage to the white matter. Subsequently, if gray matter damage also occurs, cognitive impairment in CADASIL worsens further.Cognitive impairment is a common symptom in other hereditary cerebral small vessel diseases, making the establishment of a treatment method particularly desirable.

[0003] Adrenomedullin (hereinafter also referred to as "adrenomedullin") is a vasoactive peptide hormone discovered in 1993 from human pheochromocytoma tissue. Adrenomedullin has a variety of physiological activities, including vasodilation, regulation of vascular permeability, suppression of apoptosis and oxidative stress in vascular endothelium, regulation of vascular smooth muscle proliferation, and angiogenesis. Furthermore, its association with inflammation has recently attracted attention. Due to the strong anti-inflammatory, angiogenic, and oligodendrocyte progenitor cell differentiation-promoting effects of adrenomedullin, it has been expected to alleviate cerebral white matter lesions caused by chronic ischemia in CADASIL, and research has been progressing. However, to date, there is no animal model that appropriately reflects mutations in the single-pass transmembrane receptor NOTCH3 gene. In the first place, the ratio of white matter to gray matter in humans is remarkably large compared to animal species other than primates, making it difficult to evaluate white matter damage in animal models, and there are many uncertainties regarding its extrapolation to humans. Regarding sporadic cerebral small vessel disease, there is a report of a BCAS model in which microcoils are placed in both common carotid arteries of adult mice to surgically induce hypoperfusion. In this model, overexpression of adremedullin has been reported to have protective effects on ischemic tissue and improve cognitive function. However, for white matter damage and cognitive impairment in hereditary (congenital) cerebral small vessel disease, there are no suitable animal models, and the effectiveness of adremedullin has not been demonstrated. Furthermore, although adremedullin is a bioactive peptide (endogenous substance) present in the human body and is generally expected to have low antigenicity and be safe, in the chronic ischemic state observed in CADASIL, there is a risk that a decrease in blood pressure may lead to the onset of cerebral infarction, and angiogenesis may lead to the onset of cerebral hemorrhage sometimes observed in CADASIL. Therefore, the safety of adremedullin for clinical application to cognitive impairment in CADASIL has not been definitively established.

[0004] As described above, in the medical field, the development of a therapeutic agent with established clinical efficacy for various symptoms of hereditary cerebral small vessel disease, such as cognitive dysfunction in hereditary cerebral small vessel disease, has been awaited.

[0005] Maki T, et. al., Stroke 2011, 42, 1122 - 1128

[0006] As one of its embodiments, the present invention aims to disclose a therapeutic agent for hereditary cerebral small vessel disease containing adrenomedullin etc. as an active ingredient, particularly a drug for improving and treating various symptoms such as disorders of cerebral blood flow, white matter lesions and / or cognitive dysfunction in the cerebral white matter in hereditary cerebral small vessel disease.

[0007] In order to solve the above problems, the present inventors conducted a clinical trial (jRCT2051210117) for the first time and intensively studied. As a result, for the first time, it was demonstrated that adrenomedullin has clinically significant effects on improving and treating disorders of cerebral blood flow, white matter lesions and / or cognitive dysfunction etc. which are the basis in the treatment of human CADASIL, and at the same time, it was also confirmed that adrenomedullin shows high safety in its application to humans, thus leading to the completion of the present invention. Hereinafter, the present invention will be described by specifically citing embodiments of the present invention. However, the present invention is not limited to these embodiments.

[0008] [1] A therapeutic agent for hereditary cerebral small vessel disease, comprising as an active ingredient adrenomedullin or a derivative thereof having adrenomedullin activity, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof. [2] The therapeutic agent according to [1] above, wherein the hereditary cerebral small vessel disease is a disease selected from CADASIL, CARASIL, pseudoxanthoma elastica, cerebral small vessel disease due to heterozygous HTRA1 mutation, PADMAL, CARASAL, COL4A1 / COL4A2-associated cerebral small vessel disease, RVCL-S, Fabry disease, MELAS, and MELAS-like syndrome due to POLG1 mutation. [3] The therapeutic agent according to [1] above, wherein the hereditary cerebral small vessel disease is CADASIL. [4] The therapeutic agent according to any one of [1] to [3] above, which is an agent for improving cerebral blood flow in the cerebral white matter in hereditary cerebral small vessel disease. [5] The therapeutic agent described in [4] above, wherein the improvement in cerebral blood flow is the improvement of circulatory impairment of cerebral blood flow. [6] The therapeutic agent described in [5] above, wherein the circulatory impairment of cerebral blood flow is a decrease in cerebral blood flow. [7] The therapeutic agent described in any of [1] to [6] above, which is a therapeutic agent for cognitive impairment in hereditary cerebral small vessel disease. [8] The therapeutic agent described in [7] above, which is an agent for improving and / or inhibiting the progression of cognitive impairment. [9] The therapeutic agent described in [7] or [8] above, wherein the cognitive impairment is early cognitive impairment in hereditary cerebral small vessel disease.

[10] The therapeutic agent described in [9] above, wherein the early cognitive impairment is executive function impairment.

[11] The therapeutic agent described in any of [1] to [6] above, which is a therapeutic agent for ischemic pathology in the cerebral white matter in hereditary cerebral small vessel disease.

[12] The therapeutic agent described in

[11] above, wherein the ischemic pathology in the cerebral white matter is a cerebral white matter lesion.

[13] The therapeutic agent according to any one of [1] to

[12] above, wherein the adrenomedullin or a derivative thereof having adrenomedullin activity is a peptide selected from the group consisting of: (i) a peptide consisting of the amino acid sequence of adrenomedullin; (ii) a peptide consisting of the amino acid sequence of adrenomedullin, wherein two cysteine ​​residues in the amino acid sequence form a disulfide bond; (iii) a peptide in which the disulfide bond is substituted with an ethylene group and has adrenomedullin activity; (iv) a peptide in which one to fifteen amino acid residues are deleted, substituted or added in any of the peptides from (i) to (iii) and has adrenomedullin activity; (v) a peptide in which the C-terminus is amidated in any of the peptides from (i) to (iv); and (vi) a peptide in which a glycine residue is added to the C-terminus of any of the peptides from (i) to (iv).

[14] Adrenomedullin or a derivative thereof having adrenomedullin activity, the following: (a) a peptide consisting of the amino acid sequence of Sequence ID No. 1 below (single letter notation in parentheses).

[0009] (Sequence ID 1) TyrArgGlnSerMetAsnAsnPheGlnGly LeuArgSerPheGlyCysArgPheGlyThrCysThrValGlnLysLeuAlaHisGlnIle TyrGlnPheThrAspLysAspLysAspAsn ValAlaProArgSerLysIleSerProGln GlyTyr (YRQSMNNNFQG LRSFGCRFGT CTVQKLAHQI YQFTDKDKDN VAPRSKISPQ GY)

[0010] or a peptide consisting of the amino acid sequence of SEQ ID NO: 1, wherein the cysteine ​​residue at position 16 and the cysteine ​​residue at position 21 form a disulfide bond; (b) a peptide consisting of the amino acid sequence of SEQ ID NO: 2 (single letter notation in parentheses),

[0011] (Sequence ID 2) TyrArgGlnSerMetAsnAsnPheGlnGly LeuArgSerPheGlyCysArgPheGlyThrCysThrValGlnLysLeuAlaHisGlnIle TyrGlnPheThrAspLysAspLysAspGlyValAlaProArgSerLysIleSerProGln GlyTyr (YRQSMNNNFQG LRSFGCRFGT CTVQKLAHQI YQFTDKDKDG VAPRSKISPQ GY)

[0012] or a peptide consisting of the amino acid sequence of SEQ ID NO: 2, wherein the cysteine ​​residue at position 16 and the cysteine ​​residue at position 21 form a disulfide bond; (c) a peptide consisting of the amino acid sequence of SEQ ID NO: 3 (single letter notation in parentheses),

[0013] (SEQ ID NO: 3) TyrArgGlnSerMetAsnAsnPheGlnGly ProArgSerPheGlyCysArgPheGlyThr CysThrValGlnLysLeuAlaHisGlnIle TyrGlnPheThrAspLysAspLysAspGly ValAlaProArgSerLysIleSerProGln GlyTyr (YRQSMNNFQG PRSFGCRFGT CTVQKLAHQI YQFTDKDKDG VAPRSKISPQ GY)

[0014] or a peptide consisting of the amino acid sequence of SEQ ID NO: 3, wherein the cysteine ​​residue at position 16 and the cysteine ​​residue at position 21 form a disulfide bond; (d) a peptide consisting of the amino acid sequence of SEQ ID NO: 4 (single letter notation in parentheses),

[0015] (Sequence ID 4) TyrArgGlnSerLeuAsnAsnPheGlnGly LeuArgSerPheGlyCysArgPheGlyThrCysThrValGlnLysLeuAlaHisGlnIle TyrHisPheThrAspLysAspLysAspGlySerAlaProArgSerLysIleSerProGln GlyTyr (YRQSLNNFQG LRSFGCRFGT CTVQKLAHQI YHFTDKDKDG SAPRSKISPQ GY)

[0016] or a peptide consisting of the amino acid sequence of SEQ ID NO: 4, wherein the cysteine ​​residue at position 16 and the cysteine ​​residue at position 21 form a disulfide bond; (e) a peptide consisting of the amino acid sequence of SEQ ID NO: 5 (single letter notation in parentheses),

[0017] (Sequence ID 5) TyrArgGlnSerMetAsnGlnGlySerArg SerThrGlyCysArgPheGlyThrCysThr MetGlnLysLeuAlaHisGlnIleTyrGln PheThrAspLysAspLysAspGlyMetAla ProArgAsnLysIleSerProGlnGlyTyr (YRQSMNQGSR STGCRFGTCT MQKLAHQIYQ FTDKDKDGMA PRNKISPQGY)

[0018] or a peptide consisting of the amino acid sequence of SEQ ID NO: 5, wherein the cysteine ​​residue at position 14 and the cysteine ​​residue at position 19 form a disulfide bond; (f) a peptide consisting of the amino acid sequence of SEQ ID NO: 6 (single letter notation in parentheses),

[0019] (Sequence ID 6) TyrArgGlnSerMetAsnGlnGlySerArg SerAsnGlyCysArgPheGlyThrCysThr PheGlnLysLeuAlaHisGlnIleTyrGln LeuThrrAspLysAspLysAspGlyMetAla ProArgAsnLysIleSerProGlnGlyTyr (YRQSMNQGSR SNGCRRFGTCT FQKLAHQIYQ LTDKDKDGMA PRNKISPQGY)

[0020] A therapeutic agent according to any one of the above [1] to

[12] , which is a peptide selected from the group consisting of: a peptide having the amino acid sequence of SEQ ID NO: 6, wherein the cysteine ​​residue at position 14 and the cysteine ​​residue at position 19 form a disulfide bond; (g) a peptide in any of the peptides (a) to (f) in which the disulfide bond is substituted with an ethylene group and has adrenomedullin activity; (h) a peptide in any of the peptides (a) to (g) in which 1 to 15 amino acid residues are deleted, substituted, or added and has adrenomedullin activity; (i) a peptide in any of the peptides (a) to (h) in which the C-terminus is amidated; and (j) a peptide in any of the peptides (a) to (h) in which a glycine residue is added to the C-terminus.

[15] The therapeutic agent according to any one of [1] to

[12] above, wherein the adrenomedullin or a derivative thereof having adrenomedullin activity is a peptide having the amino acid sequence of SEQ ID NO: 1, wherein the cysteine ​​residue at position 16 and the cysteine ​​residue at position 21 form a disulfide bond, and the C-terminus is amidated.

[16] The therapeutic agent according to any one of [1] to

[15] above, which is administered to humans.

[17] The therapeutic agent according to

[16] above, which is for intravenous administration of adrenomedullin or a derivative thereof having adrenomedullin activity, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof, as adrenomedullin, at a rate of 1.0 to 20.0 ng / kg body weight / min, continuously for 4 to 12 hours per day for 7 to 21 days.

[18] The therapeutic agent described in

[17] above, for intravenous administration of adrenomedullin or a derivative thereof having adrenomedullin activity, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof, as adrenomedullin, at a rate of 15 ng / kg body weight / min, continuously for 8 hours per day for 14 days.

[0021]

[19] A method for treating hereditary cerebral small vessel disease, comprising administering a therapeutically effective amount of adrenomedullin or a derivative thereof having adrenomedullin activity, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof, to a subject requiring administration.

[20] Adrenomedullin or a derivative thereof having adrenomedullin activity, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof, for use in the treatment of hereditary cerebral small vessel disease.

[21] Use of adrenomedullin or a derivative thereof having adrenomedullin activity, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof, in the manufacture of a pharmaceutical product for the treatment of hereditary cerebral small vessel disease.

[0022] In one embodiment of the present invention, a therapeutic agent for hereditary cerebral small vessel disease containing adremedullin or the like as an active ingredient is disclosed, particularly an agent for improving and treating impaired cerebral blood flow in the cerebral white matter, cerebral white matter lesions and / or cognitive impairment in hereditary cerebral small vessel disease.

[0023] Figure 1 shows the time-series evaluation results of the rate of change in cerebral blood flow in the cerebral white matter induced by adremedullin, as shown in section "A. Effects on Cerebral White Matter (1) Effects on Cerebral Blood Flow" below. Figure 2 shows the time-series evaluation results of the rate of change in white matter MD induced by adremedullin, as shown in section "A. Effects on Cerebral White Matter (2) Effects on White Matter Integration Ability" below. Figure 3 shows the time-series evaluation results of the rate of change in white matter FA induced by adremedullin, as shown in section "A. Effects on Cerebral White Matter (2) Effects on White Matter Integration Ability" below. Figure 4 shows the time-series evaluation results of the change in the total MoCA score induced by adremedullin, as shown in section "B. Effects on Cognitive Impairment (1) MoCA Test" below. Figure 5 shows the time-series evaluation results of the change in completion time of TMT PART-A induced by adremedullin, as shown in the section "B. Effects on Cognitive Impairment (2) TMT Test" below. Figure 6 shows the time-series evaluation results of the change in completion time of TMT PART-B induced by adremedullin, as shown in the section "B. Effects on Cognitive Impairment (2) TMT Test" below. Figure 7 shows the time-series evaluation results of the change in WAIS-IV (Age-Adjusted Standardized Scores for Cognitive Task) scores induced by adremedullin, as shown in the section "B. Effects on Cognitive Impairment (3) Wechsler Adult Intelligence Scale" below. Figure 8 shows the time-series evaluation results of the change in WAIS-IV (age-adjusted standard score for digit span task) score induced by adremedullin, as shown in section "B. Effects on cognitive impairment (3) Wechsler Adult Intelligence Scale" below. Figure 9 shows the time-series evaluation results of the change in CDR Global Score score induced by adremedullin, as shown in section "B. Effects on cognitive impairment (4) CDR test" below. Figure 10 shows the time-series evaluation results of the change in Sum of Boxes score induced by adremedullin, as shown in section "B. Effects on cognitive impairment (4) CDR test" below.

[0024] The present invention will be described below with reference to its embodiments, but the present invention is not limited to these. Those skilled in the art can modify the following embodiments in various ways without departing from the meaning of the present invention, and such modifications are also included within the scope of the present invention.

[0025] One embodiment disclosed by the present invention is "[A] A therapeutic agent for hereditary cerebral small vessel disease, containing as an active ingredient adrenomedullin or a derivative thereof having adrenomedullin activity, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof (hereinafter also referred to as "adrenomedullin, etc.")" (Embodiment A). Hereinafter also referred to as "this therapeutic agent."

[0026] (Hereditary Cerebral Small Vessel Diseases) Hereditary cerebral small vessel diseases are hereditary vascular diseases of the brain that primarily affect the small blood vessels of the brain. Known hereditary cerebral small vessel diseases include CADASIL, CARASIL, pseudoxanthoma elastica, cerebral small vessel disease due to heterozygous HTRA1 mutation, PADMAL, CARASAL, COL4A1 / COL4A2-associated cerebral small vessel disease, RVCL-S, Fabry disease, MELAS, and MELAS-like syndrome due to POLG1 mutation. The causative genes for each of the above diseases have been identified. These are shown in Table 1 below.

[0027]

[0028] A common symptom among the various hereditary cerebral small vessel diseases mentioned above is ischemic changes in the cerebral white matter. Furthermore, impaired cerebral blood flow in the cerebral white matter, cerebral white matter lesions, and cognitive impairment are also common symptoms resulting from this change.

[0029] (CADASIL) Among the various diseases listed above, we will explain CADASIL, which is the most common and representative hereditary cerebral small vessel disease. Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarct and Leukoencephalopathy (CADASIL), accompanied by subcortical infarction and leukoencephalopathy, is an autosomal dominant genetic disease caused by the NOTCH3 mutation, and is a rare and intractable disease with a prevalence of 2.5 per 100,000 people. Migraines accompanied by aura begin in early adulthood, followed by gradual progression of cerebral white matter lesions identified by computed tomography (CT) and magnetic resonance imaging (MRI). From middle age onward, even without stroke risk factors, lacunar infarcts recur in the subcortical white matter, leading to depressive symptoms and vascular dementia based on cerebral small vessel disease. Pathologically, it is characterized by degeneration of smooth muscle in cerebral small vessels and accumulation of granules that stain intensely with osmium on electron microscopy (granular osmiophilic material, GOM), and is definitively diagnosed by genetic or pathological examination. While reduced cerebral blood flow due to degeneration of cerebral small vessels is considered a major cause of lacunar infarction, cerebral white matter lesions, and dementia, recent findings suggest that abnormal differentiation of oligodendrocytes itself may also be a contributing factor.

[0030] In this therapeutic agent, "treatment" means obtaining the desired pharmacological and / or physiological effect. This effect may be "preventive" in the sense of completely or partially preventing the progression of the disease or its symptoms, or it may be "therapeutic" in the sense of partially or completely curing the disease and / or side effects caused by the disease. In this therapeutic agent, such "preventive" aspects are also included in the concept of "treatment."

[0031] (Specific effects on hereditary cerebral small vessel disease) As described above, adrenomedullin and the like are effective in treating hereditary cerebral small vessel disease. Their specific effects include, for example, (1) improvement of cerebral blood flow in the cerebral white matter in hereditary cerebral small vessel disease, (2) treatment of cognitive impairment in hereditary cerebral small vessel disease, and (3) treatment of ischemic conditions in the cerebral white matter in hereditary cerebral small vessel disease. However, these are not the only effects. Adrenomedullin and the like exert their therapeutic effects on hereditary cerebral small vessel disease by comprehensively utilizing the various effects described above. The following describes each of these therapeutic effects.

[0032] (1) Effect on improving cerebral blood flow (i) As described in the section on examples below, adrenomedullin has been shown to have the effect of improving cerebral blood flow in the cerebral white matter in patients with CADASIL, a representative hereditary small vessel disease of the brain. Generally, cerebral blood flow impairment is more severe in the cerebral white matter than in the cerebral gray matter (Sci Rep. 2016; 6: 32179), and considering that the essence of the pathophysiology of CADASIL is leukoencephalopathy, it was not something that even those skilled in the art could have predicted that adrenomedullin would have the effect of improving cerebral blood flow not only in the cerebral gray matter but also in the cerebral white matter in patients with CADASIL. For this reason, no clinical trials have been conducted with changes in cerebral blood flow in the cerebral white matter as the primary endpoint. (ii) In hereditary cerebral small vessel disease, damage to the cerebral white matter leads to degeneration of cerebral small vessels, impairing cerebral blood flow in the cerebral white matter and causing circulatory disorders. Therefore, the "improvement of cerebral blood flow" by this therapeutic agent includes, as one aspect, "improvement of circulatory disorders of cerebral blood flow." Furthermore, the above-mentioned circulatory disorders include "decreased cerebral blood flow," and the "improvement of cerebral blood flow" includes, as one aspect, "improvement of decreased cerebral blood flow." This "decreased cerebral blood flow" is considered to be a major cause of the onset of cerebral white matter lesions and cognitive impairment. Therefore, the "improvement of cerebral blood flow in the cerebral white matter" achieved by this therapeutic agent is a fundamental therapeutic effect that leads to the treatment of various symptoms in hereditary cerebral small vessel disease. Here, "improvement" includes both aspects: suppressing the worsening of cerebral blood flow disorders and restoring and enhancing cerebral blood flow disorders.

[0033] (2) Treatment of cognitive impairment (i) As described in the section on examples below, adrenomedullin has been shown to maintain cognitive function and even improve impaired cognitive function in patients with CADASIL, a representative hereditary cerebral small vessel disease. As mentioned earlier, cognitive function in patients with CADASIL only deteriorates over time, so it was not something that even those skilled in the art could have predicted that adrenomedullin would not only maintain cognitive function but also improve impaired cognitive function. (ii) Here, "cognitive impairment" refers to a state of cognitive decline associated with hereditary cerebral small vessel disease. "Cognitive impairment" is generally classified into "mild cognitive impairment (MCI)" and "dementia" depending on the level of decline, but the "cognitive impairment" of this treatment agent encompasses both. Mild cognitive impairment (MCI) refers to a condition in which memory and attention are impaired, but daily life is not significantly affected, and is distinguished from dementia. According to one statistic, if mild cognitive impairment (MCI) is left untreated, it is said that approximately 40% of those affected will progress to dementia within five years. In contrast, dementia refers to a condition in which brain functions (cognitive functions) such as memory and judgment are significantly impaired due to various causes such as some kind of illness or disorder, causing difficulties in daily life and work. There are various types of diseases (causes) that cause dementia, and it is classified into several types depending on the underlying disease. The four main types are Alzheimer's disease, Lewy body dementia, vascular dementia, and frontotemporal dementia. Dementia associated with hereditary cerebral small vessel disease (for example, CADASIL) falls under vascular dementia. Dementia is further classified according to its severity into mild dementia (CDR1), moderate dementia (CDR2), and severe dementia (CDR3). (iii) Early cognitive impairment in hereditary cerebral small vessel diseases such as CADASIL is caused by damage to the white matter. If cortical damage also occurs later, cognitive impairment worsens further. As mentioned above, adrenomedullin improves cerebral blood flow in the degenerated cerebral white matter, so adrenomedullin and similar drugs are particularly useful in treating early cognitive impairment in hereditary cerebral small vessel diseases.This is strongly suggested by the fact that, as described in the section on examples below, adrenomedullin was effective in treating "executive function impairment" that is impaired from the early stages of CADASIL, a representative hereditary cerebral small vessel disease. Thus, even those skilled in the art could never have predicted that adrenomedullin would be effective in treating cognitive impairment that develops early in hereditary cerebral small vessel disease.

[0034] (3) Treatment of ischemic conditions (i) As described in the section on examples below, adrenomedullin has been shown to have the effect of alleviating and treating cerebral white matter lesions, which are a chronic ischemic condition, in patients with CADASIL, a representative hereditary cerebral small vessel disease. (ii) As described above, in hereditary cerebral small vessel disease, damage to the cerebral white matter leads to impaired circulation of cerebral blood flow in the cerebral white matter, and ischemic changes and damage occur in the cerebral white matter tissue due to insufficient blood flow. Here, ischemic damage in the tissue in question is called an "ischemic condition." A typical example of such an "ischemic condition" in the cerebral white matter is a "cerebral white matter lesion," which is visualized in MRI images. However, the etiology of cerebral white matter lesions in CADASIL is not limited to the above, and degeneration of oligodendrocyte precursor cells and dilation of the perivascular space are also among the etiologies. Ultimately, all causes of cerebral white matter lesions result in a decrease in cerebral blood flow, leading to cognitive impairment. Furthermore, when cerebral white matter lesions occur, the demand for blood flow in the white matter decreases, ultimately resulting in a decrease in cerebral blood flow. Thus, the decrease in cerebral blood flow in the cerebral white matter and cerebral white matter lesions occur and progress bidirectionally.

[0035] (Adrenomedullin) The active ingredient in this therapeutic agent, adrenomedullin, may be a human-derived peptide isolated and identified from human pheochromocytosis tissue (SEQ ID NO: 1), or a peptide (ortholog) derived from other non-human mammals (e.g., warm-blooded animals) such as pigs (SEQ ID NO: 2), dogs (SEQ ID NO: 3), cattle (SEQ ID NO: 4), rats (SEQ ID NO: 5), or mice (SEQ ID NO: 6). In vivo, these peptides have two cysteine ​​residues in their amino acid sequence that form a disulfide bond, and their C-terminus is amidated. In this specification, the peptide having a disulfide bond and a C-terminal amide group may be referred to as "natural adrenomedullin" or simply "adrenomedullin." In each embodiment of the present invention, any of the above peptides can be applied as an active ingredient.

[0036] In this specification, "C-terminal amidation" refers to a form of post-translational modification of peptides in vivo, specifically, a reaction in which the main chain carboxyl group of the C-terminal amino acid residue of a peptide is converted to an amide group. Furthermore, in this specification, "formation of a disulfide bond of a cysteine ​​residue" or "disulfidation of a cysteine ​​residue" also refers to a form of post-translational modification of peptides in vivo, specifically, a reaction in which two cysteine ​​residues in the amino acid sequence of a peptide form a disulfide bond (-S-S-). Many physiologically active peptides produced in vivo are initially biosynthesized as larger molecular weight precursor proteins, which then undergo post-translational modification reactions such as C-terminal amidation and / or disulfidation of cysteine ​​residues during intracellular translocation to become mature physiologically active peptides. C-terminal amidation usually proceeds through the action of a C-terminal amidase on the precursor protein. In the case of physiologically active peptides having a C-terminal amide group, a glycy residue is bound to the C-terminal carboxyl group to be amidated in the precursor protein, and this glycy residue is converted to the C-terminal amide group by a C-terminal amidase. Furthermore, the C-terminal propeptide of the precursor protein contains repeating sequences of basic amino acid residue combinations such as Lys-Arg or Arg-Arg (Mizuno, Biochemistry Vol. 61, No. 12, pp. 1435-1461 (1989)). Disulfideation of cysteine ​​residues can proceed under oxidative conditions. In vivo, disulfideation of cysteine ​​residues usually proceeds by the action of protein disulfide isomerases on the precursor protein.

[0037] (Adrenomedullin Derivatives) In this therapeutic agent, not only native adrenomedullin itself, but also its derivatives having adrenomedullin activity can be used as active ingredients. "Adrenomedullin derivative" or "adrenomedullin derivative" means a compound having a peptide chain corresponding to adrenomedullin as a substructure. Examples of adrenomedullin derivatives having adrenomedullin activity include, but are not limited to, compounds disclosed in the specifications of International Publication No. 2015 / 141819, International Publication No. 2017 / 047788, and International Publication No. 2018 / 181638. A person skilled in the art can prepare such compounds by purchasing adrenomedullin derivatives having adrenomedullin activity based on the above-mentioned literature, applying an appropriate conversion reaction to a purchased compound, or by preparing them themselves. The adrenomedullin derivatives disclosed in the aforementioned document can sustainably exert the pharmacological effects of adrenomedullin without substantially causing undesirable side effects.

[0038] The "adrenomedullin activity" mentioned above refers to various physiological effects, such as those exemplified below: (1) Cardiovascular system: vasodilatory effect, blood pressure lowering effect, blood pressure elevation suppression effect, increased cardiac output / improvement of heart failure effect, improvement of pulmonary hypertension effect, angiogenesis effect, lymphangiogenesis effect, improvement of vascular endothelial function effect, anti-atherosclerotic effect, myocardial protective effect (e.g., myocardial protective effect in ischemia-reperfusion injury or inflammation), suppression of remodeling after myocardial infarction, suppression of cardiac hypertrophy effect, and inhibition of angiotensin-converting enzyme effect. (2) Renal / water and electrolyte system: diuretic effect, natriuretic effect, antidiuretic hormone suppression effect, aldosterone lowering effect, renal protective effect (e.g., myocardial protective effect in hypertension or ischemia-reperfusion injury), suppression of drinking behavior effect, and suppression of salt demand effect. (3) Brain and nervous system: Neuroprotective and brain damage suppression effects, anti-inflammatory effects (e.g., control of inflammation in cerebral infarction), vasodilatory effects (e.g., alleviation of tissue damage due to acute ischemia), angiogenic effects (e.g., induction of vascular regeneration), apoptosis suppression effects (e.g., suppression of apoptosis in ischemia-reperfusion injury or inflammation), autoregulation maintenance effects, oxidative stress suppression effects, dementia improvement effects, and sympathetic nerve suppression effects. (4) Urogenital system: Erection improvement effects, blood flow improvement effects, and implantation promotion effects. (5) Digestive system: Anti-ulcer effects, tissue repair effects, mucosal regeneration effects, blood flow improvement effects, anti-inflammatory effects, and liver function improvement effects. (6) Orthopedic system: Osteoblast stimulating effects, and arthritis improvement effects. (7) Endocrine and metabolic system: Adipocyte differentiation effects, lipolysis control effects, insulin sensitivity improvement effects, insulin secretion control effects, antidiuretic hormone secretion suppression effects, and aldosterone secretion suppression effects. (8) Other effects: Circulatory improvement, anti-inflammatory effect, cytokine regulation effect, organ protection effect, oxidative stress suppression effect, tissue repair effect (e.g., anti-pressure ulcer effect), improvement of septic shock, suppression of multiple organ failure, suppression of autoimmune diseases, antibacterial effect, hair growth effect, and hair nourishment effect.

[0039] (Adrenomedullin or its derivatives having adremedullin activity) The following details "adrenomedullin or its derivatives having adremedullin activity" in this therapeutic agent. (A) Preferably, the peptide (peptide (A)) is selected from the group consisting of (i) a peptide consisting of the amino acid sequence of adrenomedullin, (ii) a peptide consisting of the amino acid sequence of adrenomedullin, wherein two cysteine ​​residues in the amino acid sequence form a disulfide bond, (iii) a peptide in which the disulfide bond is substituted with an ethylene group and which has adrenomedullin activity, (iv) a peptide in which one to fifteen amino acids are deleted, substituted or added in any of the peptides (i) to (iii) and which has adrenomedullin activity, (v) a peptide in which the C-terminus is amidated in any of the peptides (i) to (iv), and (vi) a peptide in which a glycine residue is added to the C-terminus.

[0040] The peptide (A) described above is more preferably selected from the group consisting of: (i) a peptide consisting of the amino acid sequence of adrenomedullin; (ii) a peptide consisting of the amino acid sequence of adrenomedullin, wherein two cysteine ​​residues in the amino acid sequence form a disulfide bond; (v) a peptide of (i) or (ii) in which the C-terminus is amidated; and (vi) a peptide of (i) or (ii) in which a glycine residue is added to the C-terminus.

[0041] Of the peptides described in (i) to (vi), the peptide included in (v), which consists of the amino acid sequence of adrenomedullin, has amidation at its C-terminus, and in which two cysteine ​​residues in the amino acid sequence form a disulfide bond, corresponds to mature, native adrenomedullin. The peptide consisting of the amino acid sequence of adrenomedullin described in (i) corresponds to native adrenomedullin in its immature form before post-translational modifications such as C-terminal amidation and disulfideation of cysteine ​​residues. Of the peptides described in (i) to (vi), the peptides other than those described above correspond to modified forms of adrenomedullin.

[0042] The peptide (ii) can be formed by air oxidation of the thiol groups of the two cysteine ​​residues of the peptide (i) or by oxidation using a suitable oxidizing agent to convert them to disulfide bonds. By using the peptide (ii), the three-dimensional structure of the peptide can be made similar to that of native adrenomedullin. This makes it possible to make the adrenomedullin activity of the peptide (ii) substantially equivalent to that of native adrenomedullin.

[0043] The peptide (iii) can be formed by converting the disulfide bond of the peptide (ii) to an ethylene group. The substitution of a disulfide bond to an ethylene group can be carried out by methods well known in the art (O. Keller et al., Helv. Chim. Acta, 1974, Vol. 57, p. 1253). By using the peptide (iii), the three-dimensional structure of the peptide can be stabilized. As a result, the peptide (iii) can continuously express adrenomedullin activity in vivo.

[0044] In the peptide of (iv) above, the amino acid residues that are deleted, substituted or added are preferably in the range of 1 to 15, more preferably in the range of 1 to 10, still more preferably in the range of 1 to 8, particularly preferably in the range of 1 to 5, and most preferably in the range of 1 to 3. A preferred peptide of (iv) is a peptide in which the amino acid residues at positions 1 to 15, 1 to 12, 1 to 10, 1 to 8, 1 to 5 or 1 to 3 from the N-terminal side are deleted in any of the peptides of (i) to (iii) and has adrenomedullin activity. A more preferred peptide of (iv) is a peptide in which the amino acid residues at positions 1 to 15, 1 to 10 or 1 to 5 from the N-terminal side are deleted in any of the peptides of (i) to (iii) and has adrenomedullin activity. In the above-mentioned preferred peptide, one or more (for example, 1 to 5, 1 to 3, or 1 or 2) amino acid residues may be further deleted, substituted or added. By using the peptide of (iv) above, the adrenomedullin activity of the peptide can be made substantially equivalent to that of natural adrenomedullin. Also, by using the peptide of (iv) above, the peptide can continuously express adrenomedullin activity in vivo.

[0045] The peptide of (vi) above can be converted into the peptide of (v) by converting the glycine residue at the C-terminal into a C-terminal amide group by the action of a C-terminal amidating enzyme. Therefore, by administering the peptide of (vi) to a subject, a C-terminal amidated peptide can be formed in the subject's body after a certain period of time. Thereby, the peptide of (vi) can continuously express adrenomedullin activity in vivo.

[0046] (A-1) Examples of adrenomedullin or derivatives thereof having adrenomedullin activity include: (a) a peptide consisting of the amino acid sequence of SEQ ID NO: 1, or a peptide consisting of the amino acid sequence of SEQ ID NO: 1, wherein the cysteine ​​residue at position 16 and the cysteine ​​residue at position 21 form a disulfide bond; (b) a peptide consisting of the amino acid sequence of SEQ ID NO: 2, or a peptide consisting of the amino acid sequence of SEQ ID NO: 2, wherein the cysteine ​​residue at position 16 and the cysteine ​​residue at position 21 form a disulfide bond; (c) a peptide consisting of the amino acid sequence of SEQ ID NO: 3, or a peptide consisting of the amino acid sequence of SEQ ID NO: 3, wherein the cysteine ​​residue at position 16 and the cysteine ​​residue at position 21 form a disulfide bond; (d) a peptide consisting of the amino acid sequence of SEQ ID NO: 4, or a peptide consisting of the amino acid sequence of SEQ ID NO: 4, wherein the cysteine ​​residue at position 16 and the cysteine ​​residue at position 21 form a disulfide bond; (e) A peptide consisting of the amino acid sequence of SEQ ID NO: 5, or a peptide consisting of the amino acid sequence of SEQ ID NO: 5, wherein the cysteine ​​residue at position 14 and the cysteine ​​residue at position 19 form a disulfide bond; (f) A peptide consisting of the amino acid sequence of SEQ ID NO: 6, or a peptide consisting of the amino acid sequence of SEQ ID NO: 6, wherein the cysteine ​​residue at position 14 and the cysteine ​​residue at position 19 form a disulfide bond; (g) A peptide in any of (a) to (f) in which the disulfide bond is substituted with an ethylene group and which has adrenomedullin activity; (h) A peptide in any of (a) to (g) in which 1 to 15 amino acids are deleted, substituted, or added and which has adrenomedullin activity; (i) A peptide in any of (a) to (h) in which the C-terminus is amidated; and (j) A peptide in any of (a) to (h) in which a glycine residue is added to the C-terminus; It is more preferable that the peptide is selected from the group consisting of (peptide (A-1)).

[0047] As the above-mentioned peptide (A-1), the following are preferred: (a) a peptide consisting of the amino acid sequence of SEQ ID NO: 1, or a peptide consisting of the amino acid sequence of SEQ ID NO: 1 and having a disulfide bond formed between the cysteine residue at position 16 and the cysteine residue at position 21; (b) a peptide consisting of the amino acid sequence of SEQ ID NO: 2, or a peptide consisting of the amino acid sequence of SEQ ID NO: 2 and having a disulfide bond formed between the cysteine residue at position 16 and the cysteine residue at position 21; (c) a peptide consisting of the amino acid sequence of SEQ ID NO: 3, or a peptide consisting of the amino acid sequence of SEQ ID NO: 3 and having a disulfide bond formed between the cysteine residue at position 16 and the cysteine residue at position 21; (d) a peptide consisting of the amino acid sequence of SEQ ID NO: 4, or a peptide consisting of the amino acid sequence of SEQ ID NO: 4 and having a disulfide bond formed between the cysteine residue at position 16 and the cysteine residue at position 21; (e) a peptide consisting of the amino acid sequence of SEQ ID NO: 5, or a peptide consisting of the amino acid sequence of SEQ ID NO: 5 and having a disulfide bond formed between the cysteine residue at position 14 and the cysteine residue at position 19; (f) a peptide consisting of the amino acid sequence of SEQ ID NO: 6, or a peptide consisting of the amino acid sequence of SEQ ID NO: 6 and having a disulfide bond formed between the cysteine residue at position 14 and the cysteine residue at position 19; (i) a peptide in which the C-terminus of any of the peptides (a) to (f) is amidated; and (j) a peptide in which a glycine residue is added to the C-terminus of any of the peptides (a) to (f); It is more preferably a peptide selected from the group consisting of.

[0048] In the peptide (h) described above, the number of deleted, substituted, or added amino acid residues is preferably in the range of 1 to 12, more preferably in the range of 1 to 10, even more preferably in the range of 1 to 8, particularly preferably in the range of 1 to 5, and most preferably in the range of 1 to 3. A preferred peptide of (h) is a peptide in which any of the peptides (a) to (g) has a deletion of an amino acid at positions 1 to 15, 1 to 12, 1 to 10, 1 to 8, 1 to 5, or 1 to 3 from the N-terminus, and has adrenomedullin activity. A more preferred peptide of (h) is a peptide in which any of the peptides (a) to (d) has a deletion of an amino acid residue at positions 1 to 15, 1 to 10, or 1 to 5 from the N-terminus, and has adrenomedullin activity, or a peptide in which an amino acid residue at positions 1 to 13, 1 to 8, or 1 to 5 from the N-terminus, and has adrenomedullin activity. In the preferred peptides, one or more (e.g., 1 to 5, 1 to 3, or 1 or 2) amino acids may be further deleted, substituted, or added. By using the peptide (h) described above, the adrenomedullin activity of the peptide can be made substantially equivalent to that of native adrenomedullin. Furthermore, by using the peptide (h) described above, the peptide can sustainably express adrenomedullin activity in vivo.

[0049] Adrenomedullin or its derivative having adrenomedullin activity is particularly preferably a peptide having the amino acid sequence of SEQ ID NO: 1, wherein the cysteine ​​residue at position 16 and the cysteine ​​residue at position 21 form a disulfide bond, and the C-terminus is amidated.

[0050] (Salts of Adrenomedullin or its Derivatives) Adrenomedullin or its derivatives having adrenomedullin activity used as an active ingredient includes not only the compound itself but also its salts. When adrenomedullin or its derivatives having adrenomedullin activity are in the form of a salt, it is preferable that they are pharmaceutically acceptable salts. Counterions of salts of adrenomedullin or its derivatives having adrenomedullin activity are, but are not limited to, sodium ions, potassium ions, calcium ions, magnesium ions, or cations such as substituted or unsubstituted ammonium ions, or chloride ions, bromide ions, iodide ions, phosphate ions, nitrate ions, sulfate ions, carbonate ions, bicarbonate ions, perchlorate ions, formate ions, acetate ions, trifluoroacetate ions, propionate ions, lactate ions, maleate ions, hydroxymaleate ions, methylmaleate ions, fumarate ions, adipate ions, benzoate ions, 2-acetoxybenzoate ions Anions such as p-aminobenzoate ion, nicotinate ion, cinnamate ion, ascorbate ion, pamoate ion, succinate ion, salicylate ion, bismethylenesalicylate ion, oxalate ion, tartrate ion, malate ion, citrate ion, gluconate ion, aspartate ion, stearate ion, palmitate ion, itaconicate ion, glycolate ion, glutamate ion, benzenesulfonate ion, cyclohexylsulfamate ion, methanesulfonate ion, ethanesulfonate ion, isethionate ion, benzenesulfonate ion, p-toluenesulfonate ion, or naphthalenesulfonate ion are preferred. When adrenomedullin or a derivative thereof having adrenomedullin activity is in the form of a salt with the above counterion, the adrenomedullin activity of the compound can be made substantially equivalent to that of natural adrenomedullin.

[0051] (Solvates of Adrenomedullin or its Salts) Adrenomedullin or its derivatives having adrenomedullin activity used as an active ingredient includes not only the compound itself but also solvates of the compound or its salts. When adrenomedullin or its derivatives having adrenomedullin activity, or its salts, are in the form of a solvate, it is preferable that they are pharmaceutically acceptable solvates. The solvents that can form a solvate with the compound or its salts are not limited to, but are preferably organic solvents such as water, methanol, ethanol, 2-propanol (isopropyl alcohol), dimethyl sulfoxide (DMSO), acetic acid, ethanolamine, acetonitrile, or ethyl acetate. When adrenomedullin or its derivatives having adrenomedullin activity, or its salts, are in the form of a solvate with the solvent, the adrenomedullin activity of the compound can be made substantially equivalent to that of natural adrenomedullin.

[0052] Adrenomedullin or its derivatives having adrenomedullin activity used as an active ingredient include individual enantiomers and diastereomers of the compound, as well as mixtures of stereoisomers of the compound, such as racemates.

[0053] (Methods of Use of This Therapeutic Agent) This therapeutic agent encompasses both the use of the active ingredient "adrenomedullin or a derivative thereof having adremedullin activity, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof" (adrenomedullin, etc.) alone, and the use of a pharmaceutical agent containing adremedullin, etc. as an active ingredient together with a pharmaceutically acceptable carrier. Although not limited to these, one preferred embodiment more specifically encompasses both the use of a pharmaceutical agent consisting of adremedullin, etc. as a single active ingredient, and the use of a pharmaceutical composition containing adremedullin, etc. as a single active ingredient together with one or more pharmaceutically acceptable carriers (both embodiments are collectively referred to as "this pharmaceutical agent"). In addition to adrenomedullin, the pharmaceutical composition may also contain, depending on the form of the composition, one or more pharmaceutically acceptable media (e.g., a solvent such as sterile water or a solution such as physiological saline), excipients, binders, vehicles, solubilizers, preservatives, stabilizers, disintegrants, disintegration inhibitors, swelling agents, lubricants, surfactants, emulsifiers, oily liquids (e.g., vegetable oil), suspending agents, buffers, analgesics, antioxidants, sweeteners, and / or flavoring agents.

[0054] The dosage form of this therapeutic agent is not particularly limited, and may be any preparation for intravenous administration. Examples of preparations for intravenous administration include injectable preparations such as sterile solutions or suspensions with water or other pharmaceutically acceptable liquids. Additives that can be mixed with the injectable preparation are not limited to, but include, for example, vehicles such as isotonic solutions containing physiological saline, glucose or other adjuvants (e.g., D-sorbitol, D-mannitol, or sodium chloride), solubilizers such as alcohols (e.g., ethanol or benzyl alcohol), esters (e.g., benzyl benzoate), and polyalcohols (e.g., propylene glycol or polyethylene glycol), nonionic surfactants such as polysorbate 80 or polyoxyethylene hydrogenated castor oil, oily solutions such as sesame oil or soybean oil, buffers such as phosphate buffer or sodium acetate buffer, analgesics such as benzalkonium chloride or procaine hydrochloride, stabilizers such as human serum albumin or polyethylene glycol, preservatives, and antioxidants. The prepared injectable drugs are typically filled into suitable containers (e.g., vials or ampoules) and stored in appropriate conditions until use.

[0055] The active ingredients in this therapeutic agent, such as adremedullin, are derived from adremedullin, a naturally occurring bioactive peptide. As shown in the examples below, the safety of adremedullin has been confirmed in clinical trials, even in its application to hereditary cerebral small vessel disease. Therefore, this therapeutic agent can be applied to a variety of "subjects" requiring treatment for hereditary cerebral small vessel disease. These subjects may be humans or non-human mammals (e.g., warm-blooded animals such as pigs, dogs, cattle, rats, mice, guinea pigs, rabbits, chickens, sheep, cats, monkeys, baboons, or chimpanzees). Human patients are more preferable.

[0056] When administering this therapeutic agent to a target, particularly a human patient, the precise dosage and administration method can be ultimately determined by the attending physician, taking into account many factors such as the target's age, sex, the exact state (e.g., severity) of the symptoms, disease, and / or disorder to be prevented or treated, and the route of administration. Therefore, in this therapeutic agent, the active ingredient, adremedullin, etc., is administered to the target in a therapeutically effective dosage and administration method (e.g., dosage and route of administration). Such a therapeutically effective dosage and administration method, for example, when administering this therapeutic agent intravenously to a human patient, is preferably performed at a rate in the range of 1.0 to 20.0 ng of active ingredient / kg body weight / min, more preferably in the range of 6.0 to 18.0 ng of active ingredient / kg body weight / min, and even more preferably in the range of 15.0 ng of active ingredient / kg body weight / min, in terms of adremedullin equivalent. The drug is preferably administered continuously for 4 to 12 hours per day, more preferably for 6 to 10 hours, and even more preferably for 8 hours. However, administration may be performed intermittently if necessary. Furthermore, the drug is preferably administered continuously for 7 to 21 days, more preferably for 10 to 18 days, and even more preferably for 14 days. However, administration may be performed intermittently if necessary. By administering the drug to humans according to the above dosage and administration method, hereditary cerebral small vessel disease can be treated without causing undesirable side effects.

[0057] (Concomitant use with other therapeutic drugs) While this therapeutic agent is useful alone for the treatment of hereditary cerebral small vessel disease, it is not excluded from use in combination with other drugs that are expected to be useful as therapeutic drugs for hereditary cerebral small vessel disease, at the discretion of the medical community. In this case, this therapeutic agent may be provided and used in the form of a single drug containing adremedullin and one or more other drugs, or it may be provided and used in the form of a combination drug or kit containing multiple formulations in which adremedullin and one or more other drugs are separately formulated. In the case of a combination drug or kit, each formulation can be administered simultaneously or separately (for example, sequentially).

[0058] Other embodiments disclosed by the present invention are described below. (1) Another embodiment disclosed by the present invention is "[B] A method for treating hereditary cerebral small vessel disease, comprising administering a therapeutically effective amount of adrenomedullin or a derivative thereof having adrenomedullin activity, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof, to a subject requiring administration" (Embodiment B). Hereinafter, this will also be referred to as "the treatment method". More specifically, the following embodiments are given. [B-1] The treatment method according to [B] above, wherein the hereditary cerebral small vessel disease is a disease selected from CADASIL, CARASIL, pseudoxanthoma elastica, cerebral small vessel disease due to heterozygous HTRA1 mutation, PADMAL, CARASAL, COL4A1 / COL4A2-associated cerebral small vessel disease, RVCL-S, Fabry disease, MELAS, and MELAS-like syndrome due to POLG1 mutation. [B-2] The treatment method described in [B] above, wherein the hereditary cerebral small vessel disease is CADASIL. [B-3] The treatment method described in [B] to [B-2] above, wherein the treatment for hereditary cerebral small vessel disease is improvement of cerebral blood flow in the cerebral white matter. [B-4] The treatment method described in [B-3] above, wherein the improvement of cerebral blood flow is improvement of circulatory impairment of cerebral blood flow. [B-5] The treatment method described in [B-4] above, wherein the circulatory impairment of cerebral blood flow is a decrease in cerebral blood flow. [B-6] The treatment method described in [B] to [B-5] above, wherein the treatment for hereditary cerebral small vessel disease is treatment for cognitive impairment in hereditary cerebral small vessel disease. [B-7] The treatment method described in [B-6] above, wherein the treatment for hereditary cerebral small vessel disease is improvement and / or suppression of the progression of cognitive impairment in hereditary cerebral small vessel disease. [B-8] The treatment method described in [B-6] or [B-7] above, wherein the cognitive impairment is early cognitive impairment in hereditary cerebral small vessel disease. [B-9] The treatment method described in [B-8] above, wherein the early cognitive impairment is executive function disorder. [B-10] The treatment method described in [B] to [B-5] above, wherein the treatment of hereditary cerebral small vessel disease is treatment of ischemic pathology in the cerebral white matter. [B-11] The treatment method described in [B-10] above, wherein the ischemic pathology in the cerebral white matter is cerebral white matter lesion. [B-12] The treatment method described in any of [B] to [B-11] above, which is administered to humans.[B-13] The treatment method described in [B-12] above, wherein adrenomedullin, etc., is administered intravenously at a rate of 1.0 to 20.0 ng / kg body weight / min as adrenomedullin, continuously for 4 to 12 hours per day for 7 to 21 days. [B-14] The treatment method described in [B-13] above, wherein adrenomedullin, etc., is administered intravenously at a rate of 15 ng / kg body weight / min as adrenomedullin, continuously for 8 hours per day for 14 days.

[0059] In Embodiment B, details regarding the target diseases of "this treatment method," such as hereditary cerebral small vessel disease, cerebral blood flow disorders, cognitive impairment, and ischemic conditions, can be found in the description above for the target diseases of the therapeutic agent in Embodiment A. Details regarding the adremedullin, etc., administered in "this treatment method" can be found in the description above for the adremedullin, etc., in the therapeutic agent in Embodiment A. Details regarding the manner of use of adremedullin, etc., in "this treatment method" (nature of treatment, dosage form, target recipients, dosage and administration, etc.) can be found in the description above for the therapeutic agent in Embodiment A. The therapeutic effective dose refers to a dose sufficient to produce a therapeutic effect for the target disease of adremedullin, etc.

[0060] (2) Another embodiment disclosed by the present invention is "[C] Adrenomedullin or a derivative thereof having adremedullin activity, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof, for use in the treatment of hereditary cerebral small vessel disease" (Embodiment C). Hereinafter, this will also be referred to as "the Adrenomedullin, etc." More specifically, the following embodiments are given: [C-1] The Adrenomedullin, etc. described in [C] above, wherein the hereditary cerebral small vessel disease is a disease selected from CADASIL, CARASIL, pseudoxanthoma elastica, cerebral small vessel disease due to heterozygous HTRA1 mutation, PADMAL, CARASAL, COL4A1 / COL4A2-associated cerebral small vessel disease, RVCL-S, Fabry disease, MELAS, and MELAS-like syndrome due to POLG1 mutation. [C-2] Hereditary cerebral small vessel disease is CADASIL, and the adrenomedullin etc. described in [C] above. [C-3] Treatment of hereditary cerebral small vessel disease is improvement of cerebral blood flow in the cerebral white matter, and the adrenomedullin etc. described in [C] to [C-2] above. [C-4] Improvement of cerebral blood flow is improvement of circulatory impairment of cerebral blood flow, and the adrenomedullin etc. described in [C-3] above. [C-5] Circulatory impairment of cerebral blood flow is decreased cerebral blood flow, and the adrenomedullin etc. described in [C-4] above. [C-6] Treatment of hereditary cerebral small vessel disease is treatment of cognitive impairment in hereditary cerebral small vessel disease, and the adrenomedullin etc. described in [C] to [C-5] above. [C-7] Treatment of hereditary cerebral small vessel disease is improvement and / or suppression of progression of cognitive impairment in hereditary cerebral small vessel disease, and the adrenomedullin etc. described in [C-6] above. [C-8] Adrenomedullin, etc., as described in [C-6] or [C-7] above, where the cognitive impairment is early cognitive impairment in hereditary cerebral small vessel disease. [C-9] Adrenomedullin, etc., as described in [C-8] above, where the early cognitive impairment is executive function impairment. [C-10] Adrenomedullin, etc., as described in [C] to [C-5] above, where the treatment for hereditary cerebral small vessel disease is treatment for ischemic pathology in the cerebral white matter. [C-11] Adrenomedullin, etc., as described in [C-10] above, where the ischemic pathology in the cerebral white matter is cerebral white matter lesions.[C-12] Adrenomedullin, etc., as described in any of [C] to [C-11] above, for administration to humans. [C-13] Adrenomedullin, etc., as described in [C-12] above, for continuous intravenous administration at a rate of 1.0 to 20.0 ng / kg body weight / min, for 4 to 12 hours per day, for 7 to 21 days. [C-14] Adrenomedullin, etc., as described in [C-13] above, for continuous intravenous administration at a rate of 15 ng / kg body weight / min, for 8 hours per day, for 14 days.

[0061] In Embodiment C, details regarding the target diseases of "this adremedullin, etc.", such as hereditary cerebral small vessel disease, circulatory disorders of cerebral blood flow, cognitive impairment, and ischemic conditions, can be found in the description above for the target diseases of the therapeutic agent in Embodiment A. Details regarding the adremedullin, etc. administered in "this adremedullin, etc." can be found in the description above for the adremedullin, etc., of the therapeutic agent in Embodiment A. Details regarding the manner of use of the adremedullin, etc. in "this adremedullin, etc." (nature of treatment, form of use such as dosage form, target recipients, dosage and administration, etc.) can be found in the description above for the therapeutic agent in Embodiment A.

[0062] Another embodiment disclosed by the present invention is "[D] Use of adrenomedullin or a derivative thereof having adrenomedullin activity, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof, in the manufacture of a pharmaceutical product for the treatment of hereditary cerebral small vessel disease" (Embodiment D). Hereinafter, this will also be referred to as "the use." More specifically, the following embodiments are given: [D-1] The use according to [D] above, wherein the hereditary cerebral small vessel disease is a disease selected from CADASIL, CARASIL, pseudoxanthoma elastica, cerebral small vessel disease due to heterozygous HTRA1 mutation, PADMAL, CARASAL, COL4A1 / COL4A2-associated cerebral small vessel disease, RVCL-S, Fabry disease, MELAS, and MELAS-like syndrome due to POLG1 mutation. [D-2] The use according to [D] above, wherein the hereditary cerebral small vessel disease is CADASIL. [D-3] Use as described in [D] to [D-2] above, where the treatment of hereditary cerebral small vessel disease is improvement of cerebral blood flow in the cerebral white matter. [D-4] Use as described in [D-3] above, where improvement of cerebral blood flow is improvement of circulatory impairment of cerebral blood flow. [D-5] Use as described in [D-4] above, where circulatory impairment of cerebral blood flow is decreased cerebral blood flow. [D-6] Use as described in [D] to [D-5] above, where the treatment of hereditary cerebral small vessel disease is treatment of cognitive impairment in hereditary cerebral small vessel disease. [D-7] Use as described in [D-6] above, where the treatment of hereditary cerebral small vessel disease is improvement and / or suppression of the progression of cognitive impairment in hereditary cerebral small vessel disease. [D-8] Use as described in [D-6] or [D-7] above, where cognitive impairment is early cognitive impairment in hereditary cerebral small vessel disease. [D-9] Use as described in [D-8] above, where early cognitive impairment is executive function impairment. [D-10] Use as described in [D] to [D-5] above, where the treatment of hereditary cerebral small vessel disease is the treatment of an ischemic condition in the cerebral white matter. [D-11] Use as described in [D-10] above, where the ischemic condition in the cerebral white matter is a cerebral white matter lesion. [D-12] Use as described in any of [D] to [D-11] above, where it is administered to humans.[D-13] A pharmaceutical product for intravenous administration of adrenomedullin or a derivative thereof having adrenomedullin activity, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof, as adrenomedullin, at a rate of 1.0 to 20.0 ng / kg body weight / min, continuously for 4 to 12 hours per day for 7 to 21 days, as described in [D-12] above. [D-14] A pharmaceutical product for intravenous administration of adrenomedullin or a derivative thereof having adrenomedullin activity, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof, as adrenomedullin, at a rate of 15 ng / kg body weight / min, continuously for 8 hours per day for 14 days, as described in [D-13] above.

[0063] In Embodiment D, details regarding the target diseases of "this use," such as hereditary cerebral small vessel disease, cerebral blood flow disorders, cognitive impairment, and ischemic conditions, can be found in the description above for the target diseases of the therapeutic agent in Embodiment A. Details regarding the adremedullin, etc., administered in "this use," can be found in the description above for the adremedullin, etc., in the therapeutic agent in Embodiment A. Details regarding the manner of use of adremedullin, etc., in "this use" (nature of treatment, dosage form and other forms of use, target recipients, dosage and administration, etc.), can be found in the description above for the manner of use of the therapeutic agent in Embodiment A.

[0064] The present invention will be described in more detail below using examples, but this will not limit the scope of the invention.

[0065] Example 1: Efficacy of adrenomedullin administration for various symptoms in patients with autosomal dominant (overt) cerebral arteriovenous disease (CADASIL) accompanied by subcortical infarction and leukoencephalopathy This clinical trial was conducted according to the following protocol. [I-1: Test drug] (a) Active ingredient: Generic name: Human synthetic adrenomedullin (hereinafter also referred to as "hu-adrenomedullin") It is a peptide consisting of the amino acid sequence of Sequence ID No. 1, with the C-terminus being amidated, and two cysteine ​​residues in the amino acid sequence forming a disulfide bond and a ring structure. The peptide sequence is shown below.

[0066] Tyr-Arg-Gln-Ser-Met-Asn-Asn-Phe-Gln-Gly-Leu-Arg-Ser-Phe-Gly-Cys-Arg-Phe-Gly-Thr-Cys-Thr-Val-Gln-Lys-Leu-Ala-His-Gln-Ile-Tyr-Gln-Phe-Thr-Asp-Lys-Asp-Lys-Asp-Asn-Val-Ala-Pro-Arg-Ser-Lys-Ile-Ser-Pro-Gln-Gly-Tyr (SEQ ID NO: 1) (In the above, a disulfide bond is formed between Cys16 and Cys21, and the C-terminal Tyr is amidated.)

[0067] (b) Dosage form, content and properties: Dosage form and content: An injectable preparation (lyophilized) containing 500 μg of hu adrenomedullin per vial, to be dissolved before use. Properties: Before dissolution; a white mass or powder. After dissolution; a colorless liquid. (c) Preparation: 1) Dissolution method: Using a 10 mL syringe and a 21 G needle, 10 mL of Japanese Pharmacopoeia (JP) physiological saline was taken, and the JP physiological saline was gently injected along the wall of one vial of the investigational drug, taking care not to create bubbles. Since the lyophilized investigational drug dissolves rapidly, after stirring slowly, it was confirmed that the solution was completely clear. Administration was started within 4 hours at room temperature from the time it was removed from storage, such as a constant temperature cabinet.

[0068] 2) Dilution method: Dissolve each of the two vials of investigational drug in 10 mL of Japanese Pharmacopoeia (JP) physiological saline. Take 10 mL from each of the two vials into a 30 mL syringe, and add 10 mL of JP physiological saline to make a total volume of 30 mL.

[0069] [I-2: Subjects] The subjects were patients who met the prescribed selection criteria, such as having given written consent to participate in the clinical trial, having a NOTCH3 gene mutation confirmed by genetic testing, and being diagnosed with CADASIL, and who did not violate the prescribed exclusion criteria, such as being unable to undergo cognitive function testing (e.g., hearing loss, blindness, severe cognitive impairment with an MMSE-J score of less than 10). There were 60 subjects at the time of study planning (59 at the time of analysis).

[0070] [I-3: Dosage Plan] This clinical trial was conducted as a multicenter, single-arm, open-label, uncontrolled study (Phase II trial). As it was a single-arm study, subjects were not randomized to receive the investigational drug. (Investigational drug administration schedule) Days 1-14 (Investigational drug administration days 1-14): The investigational drug (15 ng / kg / min) was administered intravenously with physiological saline for 8 hours. Administration started in the morning.

[0071] [I-4: Evaluation Items] A. Effects on Cerebral White Matter (1) Effects on Cerebral Blood Flow MRI Arterial Spin Labeling (ASL) is a method that accurately evaluates cerebral blood flow by magnetically labeling arterial blood supplied to brain tissue at the level of the left and right carotid arteries and using this as a tracer. The rate of change in cerebral blood flow in the cerebral white matter, as evaluated by ASL, was assessed at 8 hours after the start of investigational drug administration on the first day, 15 days after administration, 28 days after administration, 90 days after administration, and 180 days after administration, compared to before administration of the investigational drug. (2) Effects on White Matter Integration Ability MRI diffusion-weighted imaging is a method that visualizes the diffusion motion of water molecules and detects disturbances in the course of nerve fibers in the cerebral white matter. Mean Diffusivity (MD) and Fractional Anisotropy (FA) are indicators of white matter integration ability in diffusion-weighted imaging. High MD and low FA values ​​indicate impaired neurotransmission in the white matter. The percentage changes in MD and FA were evaluated at 8 hours after the start of investigational drug administration on the first day, 15 days after administration, 28 days after administration, 90 days after administration, and 180 days after administration, compared to before administration of the investigational drug.

[0072] B. Effects on Cognitive Function (1) MoCA Test The MoCA is a cognitive function test that quickly and easily measures visuospatial and executive function, naming, memory, attention, repetition, word recall, abstract concepts, delayed recall, and orientation. The change in the total score of the Japanese version of the Montreal Cognitive Assessment (MoCA-J) at 15 days, 28 days, 90 days, and 180 days after the start of administration was evaluated compared to before administration of the investigational drug. (2) TMT Test The TMT (Trailmaking Test) is a test that quickly and easily measures working memory and processing ability. The change in completion time for TMT PART-A / PART-B at 15 days, 28 days, 90 days, and 180 days after the start of administration was evaluated compared to before administration of the investigational drug. (3) Wechsler Adult Intelligence Scale The Wechsler Adult Intelligence Scale is a test that measures working memory and processing speed quickly and easily using coding and digit span tasks. The change in Wechsler Adult Intelligence Scale (WAIS)-IV score at 15 days, 28 days, 90 days, and 180 days after the start of administration was evaluated compared to before administration of the investigational drug. (4) CDR Test The changes in Global Score, subscores such as memory, and Sum of Boxes Score were evaluated at 15 days, 28 days, 90 days, and 180 days after the start of administration, compared to before administration of the investigational drug. CDR (Clinical Dementia Rating) is a test that evaluates the severity of dementia. Global Score evaluates healthy individuals, suspected dementia (mild cognitive impairment), mild dementia, moderate dementia, and severe dementia based on scores from six items: memory, orientation, judgment and problem-solving ability, community activities, home and hobbies, and care situation, and makes an overall judgment. Sum of Boxes Score is the sum of subscores such as memory, and the change in Sum of Boxes Score from before administration indicates the therapeutic effect of the investigational drug on cognitive function.

[0073] C. Safety Evaluation Items: The presence or absence of serious adverse events for which a causal relationship could not be ruled out was evaluated.

[0074] [I-5: Evaluation Results] A. Effects on Cerebral White Matter (1) Effects on Cerebral Blood Flow The percentage change in cerebral blood flow in the cerebral white matter, as evaluated by ASL, compared to before administration of the investigational drug, during administration (8 hours after the start of investigational drug administration on the first day) / 15 days after the start of administration / 28 days after the start of administration / 90 days after the start of administration / 180 days after the start of administration (mean ± standard deviation, the same applies below) was 9.95 ± 31.72% (95% confidence interval of the mean: 1.54% to 18.37%) during administration (8 hours after the start of investigational drug administration on the first day) and 17.22 ± 32.09% (95% confidence interval of the mean) on 15 days after the start of administration. The 5% confidence interval was 8.63% to 25.81%, 16.98 ± 31.81% on day 28 of administration (mean 95% confidence interval: 8.46% to 25.49%), 5.88 ± 31.11% on day 90 of administration (mean 95% confidence interval: -2.45% to 14.21%), and 1.17 ± 33.49% on day 180 of administration (mean 95% confidence interval: -8.06% to 10.41%). Up to day 28 of administration, a significant change was observed where the mean 95% confidence interval exceeded 0%. The above evaluation results are shown in Figure 1. This effect of improving cerebral blood flow in the cerebral white matter was superior to the effect of improving cerebral blood flow in the cerebral cortex described below. Specifically, it exceeded the rate of change in cerebral blood flow in the cerebral cortex (during administration [8 hours after the start of investigational drug administration on the first day] 8.17 ± 23.62% [mean 95% confidence interval: 1.90% to 14.44%], 15 days after the start of administration 7.44 ± 20.58% [mean 95% confidence interval: 1.93% to 12.95%], 28 days after the start of administration 5.64 ± 23.47% [mean 95% confidence interval: -0.64% to 11.93%], 90 days after the start of administration -4.04 ± 19.98% [mean 95% confidence interval: -9.39% to 1.31%], 180 days after the start of administration -8.73 ± 18.74% [mean 95% confidence interval: -13.90% to -3.57%]). Such remarkable effects of adrenomedullin on improving cerebral blood flow in the cerebral white matter were effects that even those skilled in the art could never have predicted.

[0075] (2) Effect on white matter integration ability The percentage change in white matter MD (whole brain mean) (mean ± standard deviation, hereafter the same) as evaluated by MR diffusion tensor imaging during administration (8 hours after the start of investigational drug administration on the first day) / 15th day after the start of administration / 28th day after the start of administration / 90th day after the start of administration / 180th day after the start of administration, compared to before administration of the investigational drug, was -0.23 ± 2.89% during administration (8 hours after the start of investigational drug administration on the first day) (95% confidence interval of mean: -0.99% to 0.53 The results were as follows: %, day 15 of administration: -0.05±2.67% (mean 95% confidence interval: -0.74% to 0.65%), day 28 of administration: 0.07±2.99% (mean 95% confidence interval: -0.73% to 0.86%), day 90 of administration: -0.41±3.34% (mean 95% confidence interval: -1.28% to 0.47%), and day 180 of administration: -0.58±2.72% (mean 95% confidence interval: -1.32% to 0.15%). The above evaluation results are shown in Figure 2. The percentage change in white matter FA (whole brain mean) (mean ± standard deviation, hereafter the same) as assessed by MR diffusion tensor imaging during administration (8 hours after the start of investigational drug administration on the first day), on day 15, day 28, day 90, and day 180, compared to before administration of the investigational drug, was 2.05 ± 11.21% during administration (8 hours after the start of investigational drug administration on the first day) (95% confidence interval of the mean: The results were -0.90% to 5.00%, 0.67 ± 9.64% on day 15 of administration (mean 95% confidence interval: -1.84% to 3.18%), -0.97 ± 11.64% on day 28 of administration (mean 95% confidence interval: -4.06% to 2.12%), 2.39 ± 11.58% on day 90 of administration (mean 95% confidence interval: -0.66% to 5.43%), and -0.74 ± 3.22% on day 180 of administration (mean 95% confidence interval: -1.61% to 0.13%). These evaluation results are shown in Figure 3. In CADASIL, white matter integration ability is impaired over time, so MD increases and FA decreases. However, in patients who received adremedullin, there was no increase in MD or decrease in FA even 180 days after the start of administration, demonstrating an improvement in white matter damage.

[0076] B. Effects on cognitive impairment (1) MoCA test The change in the total MoCA score at 15 days, 28 days, 90 days, and 180 days after the start of administration was compared to the total MoCA score of 23.4 ± 5.3 (mean ± standard deviation, the same applies below) before administration of the investigational drug. At 15 days after the start of administration, the change was 1.1 ± 2.8 (95% confidence interval of the mean: 0.3 to 1.8), at 28 days after the start of administration, the change was 1.9 ± 2.5 (95% confidence interval of the mean: 1.3 to 2.6), at 90 days after the start of administration, the change was 1.4 ± 2.3 (95% confidence interval of the mean: 0.8 to 2.0), and at 180 days after the start of administration, the change was 1.8 ± 2.1 (95% confidence interval of the mean: 1.2 to 2.3). A significant increase was observed from 15 days after the start of administration up to 180 days, with the 95% confidence interval of the mean exceeding 0. In particular, the changes in the subscores of the MoCA (Abstract Concepts (Similarities) and Delayed Recall (Recall) at 15, 28, 90, and 180 days after administration, compared to before administration of the investigational drug, showed a significant increase with the mean 95% confidence interval exceeding 0 at all evaluation points. Table 2 below summarizes the above evaluation results. Figure 4 shows the changes described in Table 2 against the analysis time points.

[0077]

[0078] (2) TMT Test The mean change in completion time for TMT PART-A at day 15, day 28, day 90, and day 180 of administration, compared to the completion time of 67.7 ± 49.2 seconds (mean ± standard deviation, the same applies below) before administration of the investigational drug, was below 0 seconds at every point from day 15 to day 180 of administration. The change in completion time for TMT PART-A showed a significant decrease at day 28 of administration, at -6.4 ± 19.7 seconds (95% confidence interval of mean: -11.6 seconds to -1.1 seconds). Furthermore, compared to the completion time of 115.9 ± 84.6 seconds for TMT PART-B before administration of the investigational drug, the change in completion time showed a significant decrease: -9.7 ± 29.7 seconds (mean 95% confidence interval: -17.6 seconds to -1.9 seconds) on day 90 of administration and -9.5 ± 31.1 seconds (mean 95% confidence interval: -17.9 seconds to -1.1 seconds) on day 180 of administration. As described above, in TMT PART-B, which evaluates executive function, the mean 95% confidence interval of the change in completion time was below 0 on both day 90 and day 180 of administration, clearly demonstrating a significant improvement effect. Table 3 below shows an overview of the evaluation results for TMT PART-A, and Table 4 below shows an overview of the evaluation results for TMT PART-B. Furthermore, Figure 5 shows the changes listed in Table 3 against the analysis period, and Figure 6 shows the changes listed in Table 4 against the analysis period.

[0079]

[0080]

[0081] (3) Compared to the Wechsler Adult Intelligence Scale (WAIS-IV) score of 7.1 ± 3.9 (mean ± standard deviation, hereafter the same) before administration of the investigational drug, the change in score at day 15, day 90, and day 180 after administration showed a significant increase where the 95% confidence interval of the mean was above 0 at all time points from day 15 to day 180 after administration. Compared to the WAIS-IV score of 8.2 ± 3.3 before administration of the investigational drug, the change in score showed a significant increase where the 95% confidence interval of the mean was above 0 at all time points from day 15 to day 180 after administration, but a significant increase where the 95% confidence interval of the mean was above 0 was observed only at day 28 after administration. Table 5 below shows a summary of the evaluation results of the above WAIS-IV (code task age-adjusted standard score), and Table 6 below shows a summary of the evaluation results of the above WAIS-IV (code task age-adjusted standard score). Furthermore, Figure 7 shows the changes listed in Table 5 against the analysis period, and Figure 8 shows the changes listed in Table 6 against the analysis period.

[0082]

[0083]

[0084] (4) CDR Test The mean change in the CDR Global Score compared to the value before administration of the investigational drug (0.33 ± 0.40, mean ± standard deviation) was below 0 at all time points from day 15 to day 180 after administration, with significant changes observed except on day 180. The breakdown of CDR Global Score before administration of the investigational drug was as follows: 0 (none) in 29 cases (49.2%), 0.5 (suspected) in 23 cases (39.0%), 1 (mild) in 6 cases (10.2%), 2 (moderate) in 1 case (1.7%), and 3 (severe) in 0 cases (0.0%). In the CDR Global Score and memory subscores, the percentage of patients who improved by one level compared to before administration of the investigational drug was highest on day 28 after administration. In the orientation subscore, the percentage of patients showing one-step and two-step improvement increased from day 15 to day 28 of administration. In the judgment and problem-solving subscore, the percentage of patients showing one-step improvement compared to before administration of the investigational drug remained unchanged from day 15 to day 180 of administration, but the percentage of patients showing a one-step deterioration gradually increased from day 15 to day 180 of administration. In the community activities, home life, and hobbies / interests subscore, the percentage of patients showing one-step improvement and a one-step deterioration gradually increased from day 15 to day 180 of administration. There was no change in the caregiving subscore. Compared to the CDR Sum of Boxes value of 1.50 ± 2.36 (mean ± standard deviation) before administration of the investigational drug, the mean change at day 15, day 28, day 90, and day 180 of administration was below 0 at all time points from day 15 to day 180, and a significant change was observed where the 95% confidence interval of the mean was below 0, except at day 180. Table 7 below shows an overview of the Global Score evaluation results, and Table 8 shows an overview of the Sum of Boxes evaluation results. Furthermore, Figure 9 shows the change in the values ​​listed in Table 7 against the analysis period, and Figure 10 shows the change in the values ​​listed in Table 8 against the analysis period.

[0085]

[0086]

[0087] 1) In various test items, it was shown that adrenomedullin not only suppressed but also improved cognitive decline in CADASIL patients over a long period of 180 days after administration. Previous studies have shown that cognitive function in CADASIL patients almost always deteriorates over time, so even those skilled in the art could not have predicted that adrenomedullin would continue to exert such a remarkable therapeutic effect over such a long period. 2) Furthermore, it was revealed that adrenomedullin administration resulted in a significant improvement in cognitive impairment at an early stage after administration. This excellent effect is thought to be because adrenomedullin was effective in treating executive function impairment, which is impaired early in CADASIL patients. This remarkable effect of adrenomedullin on "executive function impairment" in cognitive impairment could not have been predicted even by those skilled in the art.

[0088] C. Safety Assessment The safety of intravenous therapy with the investigational drug in patients with CADASIL was examined. Analysis was performed on 59 patients who were selected, and the following conclusions were reached. Adverse events occurred in 47 out of 59 patients (79.7%), totaling 109 events. By severity, mild adverse events occurred in 37 patients (62.7%), totaling 94 events, and moderate events occurred in 10 patients (16.9%), totaling 15 events, but there were no severe adverse events. Adverse events that could not be ruled out as being causally related to the investigational drug occurred in 38 patients (64.4%), totaling 58 events. By severity, mild events occurred in 31 patients (52.5%), totaling 48 events, and moderate events occurred in 7 patients (11.9%), totaling 10 events. There were no deaths throughout the trial period. One serious adverse event occurred in one patient (1.7%), totaling one event, but a causal relationship with the investigational drug was determined to be "unrelated". No adverse events occurred that led to discontinuation of administration. Therefore, it was confirmed that this investigational drug can be safely administered even when continuously administered intravenously for 8 hours at an infusion rate of 15 ng / kg body weight / min.

[0089] This application discloses, as one embodiment of the invention, a therapeutic agent for hereditary cerebral small vessel disease containing adrenomedullin or the like as an active ingredient, which is useful, for example, in the field of pharmaceuticals. This application is based on Japanese Patent Application No. 2024-206549 (filing date: November 27, 2024), the contents of which are entirely contained herein.

Claims

1. A therapeutic agent for hereditary cerebral small vessel disease, containing as an active ingredient adrenomedullin or a derivative thereof having adrenomedullin activity, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof.

2. The therapeutic agent according to claim 1, wherein the hereditary cerebral small vessel disease is a disease selected from CADASIL, CARASIL, pseudoxanthoma elastica, cerebral small vessel disease due to heterozygous HTRA1 mutation, PADMAL, CARASAL, COL4A1 / COL4A2-associated cerebral small vessel disease, RVCL-S, Fabry disease, MELAS, and MELAS-like syndrome due to POLG1 mutation.

3. The therapeutic agent according to claim 1, wherein the hereditary cerebral small vessel disease is CADASIL.

4. A therapeutic agent according to any one of claims 1 to 3, which is an agent for improving cerebral blood flow in the cerebral white matter in hereditary cerebral small vessel disease.

5. The therapeutic agent according to claim 4, wherein the improvement of cerebral blood flow is the improvement of circulatory disorders of cerebral blood flow.

6. The therapeutic agent according to claim 5, wherein the circulatory disorder of cerebral blood flow is a decrease in cerebral blood flow.

7. A therapeutic agent for the treatment of cognitive impairment in hereditary cerebral small vessel disease, as described in any one of claims 1 to 3.

8. The therapeutic agent according to claim 7, which is an agent for improving cognitive impairment and / or an agent for inhibiting its progression.

9. The therapeutic agent according to claim 8, wherein the cognitive impairment is early cognitive impairment in hereditary cerebral small vessel disease.

10. The therapeutic agent according to claim 9, wherein the early cognitive impairment is executive function impairment.

11. A therapeutic agent according to any one of claims 1 to 3, which is a therapeutic agent for ischemic conditions in the cerebral white matter in hereditary cerebral small vessel disease.

12. The therapeutic agent according to claim 11, wherein the ischemic pathology in the cerebral white matter is a cerebral white matter lesion.

13. The therapeutic agent according to any one of claims 1 to 3, wherein the adrenomedullin or a derivative thereof having adrenomedullin activity is a peptide selected from the group consisting of: (i) a peptide consisting of the amino acid sequence of adrenomedullin; (ii) a peptide consisting of the amino acid sequence of adrenomedullin, wherein two cysteine ​​residues in the amino acid sequence form a disulfide bond; (iii) a peptide in which the disulfide bond is substituted with an ethylene group and which has adrenomedullin activity; (iv) a peptide in which one to fifteen amino acid residues are deleted, substituted or added in any of the peptides from (i) to (iii) and which has adrenomedullin activity; (v) a peptide in which the C-terminus is amidated in any of the peptides from (i) to (iv); and (vi) a peptide in which a glycine residue is added to the C-terminus of any of the peptides from (i) to (iv).

14. Adrenomedullin or a derivative thereof having adrenomedullin activity is as follows: (a) A peptide consisting of the amino acid sequence of SEQ ID NO: 1 below (single letter in parentheses): TyrArgGlnSerMetAsnAsnPheGlnGly LeuArgSerPheGlyCysArgPheGlyThrCysThrValGlnLysLeuAlaHisGlnIle TyrGlnPheThrAspLysAspLysAspAsn ValAlaProArgSerLysIleSerProGln GlyTyr (SEQ ID NO: 1) (YRQSMNNNFQG LRSFGCRFGT CTVQKLAHQI (b) A peptide consisting of the amino acid sequence YQFTDKDKDN VAPRSKISPQ GY or SEQ ID NO: 1, wherein the cysteine ​​residue at position 16 and the cysteine ​​residue at position 21 form a disulfide bond; (b) A peptide consisting of the amino acid sequence of SEQ ID NO: 2 (single letter notation in parentheses) below: TyrArgGlnSerMetAsnAsnPheGlnGly LeuArgSerPheGlyCysArgPheGlyThrCysThrValGlnLysLeuAlaHisGlnIleTyrGlnPheThrAspLysAspLysAspGlyValAlaProArgSerLysIleSerProGlnGlyTyr (SEQ ID NO: 2) A peptide consisting of the amino acid sequence (YRQSMNNNFQG LRSFGCRFGT CTVQKLAHQI YQFTDKDKDG VAPRSKISPQ GY) or SEQ ID NO: 2, wherein the cysteine ​​residue at position 16 and the cysteine ​​residue at position 21 form a disulfide bond;(c) A peptide consisting of the amino acid sequence of Sequence ID No. 3 below (single letter in parentheses): TyrArgGlnSerMetAsnAsnPheGlnGly ProArgSerPheGlyCysArgPheGlyThrCysThrValGlnLysLeuAlaHisGlnIle TyrGlnPheThrAspLysAspLysAspGlyValAlaProArgSerLysIleSerProGln GlyTyr (Sequence ID No. 3) (YRQSMNNNFQG PRSFGCRFGT CTVQKLAHQI YQFTDKDKDG VAPRSKISPQ GY) or a peptide consisting of the amino acid sequence of SEQ ID NO: 3, wherein the cysteine ​​residue at position 16 and the cysteine ​​residue at position 21 form a disulfide bond; (d) a peptide consisting of the amino acid sequence of SEQ ID NO: 4 below (single letter notation in parentheses): TyrArgGlnSerLeuAsnAsnPheGlnGly LeuArgSerPheGlyCysArgPheGlyThrCysThrValGlnLysLeuAlaHisGlnIle TyrHisPheThrAspLysAspLysAspGlySerAlaProArgSerLysIleSerProGlnGlyTyr (SEQ ID NO: 4) (YRQSLNNFQG LRSFGCRFGT A peptide consisting of the amino acid sequence CTVQKLAHQI YHFTDKDKDG SAPRSKISPQ GY) or SEQ ID NO: 4, wherein the cysteine ​​residue at position 16 and the cysteine ​​residue at position 21 form a disulfide bond;(e) A peptide consisting of the amino acid sequence of Sequence ID No. 5 below (single letter in parentheses): TyrArgGlnSerMetAsnGlnGlySerArg SerThrGlyCysArgPheGlyThrCysThr MetGlnLysLeuAlaHisGlnIleTyrGln PheThrAspLysAspLysAspGlyMetAla ProArgAsnLysIleSerProGlnGlyTyr (Sequence ID No. 5) (YRQSMNQGSR STGCRFGTCT MQKLAHQIYQ FTDKDKDGMA PRNKISPQGY) or a peptide consisting of the amino acid sequence of SEQ ID NO: 5, wherein the cysteine ​​residue at position 14 and the cysteine ​​residue at position 19 form a disulfide bond; (f) a peptide consisting of the amino acid sequence of SEQ ID NO: 6 (single letter in parentheses) below: TyrArgGlnSerMetAsnGlnGlySerArg SerAsnGlyCysArgPheGlyThrCysThr PheGlnLysLeuAlaHisGlnIleTyrGln LeuThrrAspLysAspLysAspGlyMetAla ProArgAsnLysIleSerProGlnGlyTyr (SEQ ID NO: 6) (YRQSMNQGSR SNGCRRFGTCT FQKLAHQIYQ A therapeutic agent according to any one of claims 1 to 3, wherein the peptide is selected from the group consisting of: (LTDKDKDGMA PRNKISPQGY) or the amino acid sequence of Sequence ID No. 6, wherein the cysteine ​​residue at position 14 and the cysteine ​​residue at position 19 form a disulfide bond; (g) a peptide in any of the peptides (a) to (f) in which the disulfide bond is substituted with an ethylene group and which has adrenomedullin activity; (h) a peptide in any of the peptides (a) to (g) in which 1 to 15 amino acid residues are deleted, substituted, or added and which has adrenomedullin activity; (i) a peptide in any of the peptides (a) to (h) in which the C-terminus is amidated; and (j) a peptide in any of the peptides (a) to (h) in which a glycine residue is added to the C-terminus.

15. The therapeutic agent according to any one of claims 1 to 3, wherein the adrenomedullin or a derivative thereof having adrenomedullin activity is a peptide having the amino acid sequence of SEQ ID NO: 1, wherein the cysteine ​​residue at position 16 and the cysteine ​​residue at position 21 form a disulfide bond, and the C-terminus is amidated.

16. A therapeutic agent according to any one of claims 1 to 3, which is administered to humans.

17. The therapeutic agent according to claim 16, for intravenous administration of adrenomedullin or a derivative thereof having adrenomedullin activity, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof, as adrenomedullin, at a rate of 1.0 to 20.0 ng / kg body weight / min, continuously for 4 to 12 hours per day for 7 to 21 days.

18. The therapeutic agent according to claim 17, for intravenous administration of adrenomedullin or a derivative thereof having adrenomedullin activity, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof, as adrenomedullin, at a rate of 15 ng / kg body weight / min, continuously for 8 hours per day for 14 days.

19. A method for treating hereditary cerebral small vessel disease, comprising administering a therapeutically effective amount of adrenomedullin or a derivative thereof having adrenomedullin activity, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof, to a subject requiring administration.

20. Adrenomedullin or derivatives thereof having adremedullin activity, or pharmaceutically acceptable salts thereof, or pharmaceutically acceptable solvates thereof, for use in the treatment of hereditary cerebral small vessel disease.

21. Use of adrenomedullin or a derivative thereof having adrenomedullin activity, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof, in the manufacture of a pharmaceutical product for the treatment of hereditary cerebral small vessel disease.

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