Methods of treating sporadic cerebral small vessel disease

Abstract

The present disclosure provides a method for treating a patient diagnosed with sporadic small vessel disease with a therapeutically effect amount of a rho kinase inhibitor, including fasudil or hydroxyfasudil or a pharmaceutically acceptable salt thereof such as fasudil hydrochloride hemihydrate. Further disclosed are the dosages used for the treatment.

Description

[0001] Methods of Treating Sporadic Cerebral Small Vessel Disease

[0002] Background of the Invention

[0003] Cerebral small vessel disease (SVD) is a disease of the small vessels of, principally the white matter, of the brain. SVD is associated with an increased risk of stroke, cognitive decline and ultimately dementia (Sharrief 2023).

[0004] Small vessel disease accounts for approximately 22% of ischemic stroke, and disease burden increases the risk of recurrent stroke (Sharrief 2023). In addition to clinically recognized strokes, infarctions due to SVD may be “silent” and undetected until revealed later by imaging manifesting at the characteristic white matter hyperintensities (WMH). It is estimated that 10% to 20% of adults have evidence of such silent infarctions. These lesions are also associated with an increased risk of other neurologic, neuropsychiatric, and cognitive symptoms.

[0005] Age is the most common nonmodifiable risk factor for SVD (Sharrief 2023). Almost 100% of adults aged 90 and older have evidence of SVD. Modifiable risk factors include hypertension, obstructive sleep apnea, diabetes mellitus, hyperlipidemia, and tobacco use. SVD is often attributed to these risk factors, but at most these risk factors can explain no more than about two percent of the lesion burden seen with imaging (Backhouse 2023). This apparent disconnect is enhanced by the fact that risk factor modification clinical trials so far have had, at most, limited effects on preventing recurrent stroke, cognitive decline, and WMH progression. Moreover, while the extent of WMHs appear to have a dose dependent effect on cognition, the risk of experiencing cognitive decline varies wildly with WMH burden.

[0006] It is becoming increasingly clear that early-life conditions may affect SVD (Backhouse 2023). These include prenatal nutrition, and cognitive ability, education, and socioeconomic status in childhood. Explanations for such effects may include differences in brain resilience and reserve, access to cognitive, social, and economic resources, and health behaviors.

[0007] SVD is often discovered on MRI incidentally in asymptomatic patients. Patients may present with mild signs or symptoms of neurocognitive dysfunction mistakenly attributed to normal aging. Clinical presentations can include acute stroke syndromes, various subjective cognitive impairments, mild cognitive impairment, dementia, mood or behavioral disturbances, gait dysfunction, movement disorders, and a general decline in function.

[0008] SVD is characterized by loss of smooth muscle cells from the tunica media of the blood vessels, lipohyalinosis, the development of microatheroma, and segmental arterial disorganization. These changes contribute to lacunar infarcts and large ischemic and hemorrhagic strokes, as well as other radiographic changes.

[0009] While the pathologic findings of SVD are clear, the cause or causes of the pathology underlying SVD is not well understood. Multiple molecular defects in vessel wall-glia constituents have been identified. These include endothelium, pericytes, smooth muscle, basement membrane, extracellular matrix, microglia, oligodendrocytes and astrocytes (Blair 2021). These defects are thought to lead to functional vascular defects. These include compromised blood-brain barrier (BBB) function (increased permeability), impaired vasoreactivity, altered pulsatility and defective perivascular interstitial fluid clearance. How these defects relate to each other and lead to the pathological and clinical manifestations of SVD are largely unknown. The absence of effective therapies reflects the lack of understanding of the disease processes.

[0010] Various general terms are used to describe the white matter changes found in neuroimaging SVD, including leukoaraiosis, white matter disease, leukoencephalopathy, and white matter hypcrintcnsitics, among others (Sharricf 2023). The STandards for Reporting and Imaging of Small Vessel Disease (STRIVE) guideline define WMHs, recent small subcortical infarcts, lacunes, cerebral microbleeds, enlarged perivascular spaces, and brain atrophy which are common features of SVD detected through neuroimaging (Duering 2023).

[0011] Categories of SVD have been proposed based on etiopathogenic features: 1) Arteriolosclerosis, 2) Sporadic and hereditary cerebral amyloid angiopathy (CAA), 3) Inherited or genetic SVD distinct from CAA, 4) Inflammatory and immunologically mediated SVD, 5) Venous collagenosis, and 6) Other SVD (Inoue 2023).

[0012] Summary of the Invention

[0013] In one embodiment, a patient with sporadic SVC is treated with fausidil or its metabolite hydroxyfaudil (M3) or a pharmacologically acceptable salt thereof. In one embodiment, the sporadic SVD patient does not have dementia.

[0014] In another embodiment, the sporadic SVD patient has mild cognitive impairment.

[0015] In one embodiment, the sporadic SVD patient does not have Binswanger’s disease. In another embodiment, the sporadic SVD patient does not have Alzheimer’s disease.

[0016] Patients treatable according to the invention will generally be at least 40 years old, though exact treatment age will depend on the appearance of at least one sign or symptom of SVD, such as a cerebral microbleed or a lacunar infarction, especially when risk factors are present. In certain embodiments, treatment will begin when patients are between 40 and 80 years old and may continue as long as treatment is effective. In other embodiments, treated patients may be 50-80 years old or 60-70 years old.

[0017] In another embodiment, the sporadic SVD patient is a younger adult patient aged 35-55 with vascular risk factors. In a specific embodiment, the younger adult patient smokes tobacco.

[0018] In a further embodiment, the sporadic SVD patient treated with fasudil or hydroxyfasudil has a Fazekas score of > 1. In a specific embodiment, the sporadic SVD patient has a Fazekas score of 1 to 3.

[0019] In another embodiment, the sporadic SVD patient has evidence of at least one microbleed and / or at least one lacunar stroke.

[0020] In a further embodiment, the sporadic SVD patient reports experiencing apathy, or reduction in processing speed or behavioral changes. In a specific embodiment, at least one family member of the patient reports that the patient has experienced apathy, or reduction in processing speed or behavioral changes.

[0021] In a further embodiment, the sporadic SVD patient has decreased executive function.

[0022] In one embodiment, the sporadic SVD patient has reduced processing speed as demonstrated by a timed neurocognitive test.

[0023] In a specific embodiment, the sporadic SVD patient does not have memory deficits. In a specific embodiment, the sporadic SVD patient does exhibit memory deficits. In specific embodiment, the memory deficits arc in in working memory and / long-tcrm memory.

[0024] In a further embodiment, the sporadic SVD patient has no sign of motor dysfunction.

[0025] In one embodiment the sporadic SVD patient either does not have hypertension or has wellmanaged hypertension.

[0026] In one embodiment, the sporadic SVD patient is not treated with fasudil or hydroxyfasudil if there is evidence of a recent stroke.

[0027] In another embodiment, the sporadic SVD patient treated with fasudil is obese and / or has a body mass index of 30 or higher.

[0028] In another embodiment, the sporadic SVD patient will not be treated following a diagnosis of acute stroke.

[0029] In another embodiment the sporadic SVD patient will not be treated with fasudil or hydroxyfasudil for at least 30 days following the first symptoms of a stroke. In a further embodiment, the patient will not treated with fasudil until 60 or even 90 days following the stroke.

[0030] In one embodiment, fasudil or hydroxyfasudil treatment of sporadic SVD improves a symptom of SVD.

[0031] In a specific embodiment, fasudil or hydroxyfasudil treatment improves arteriolosclerosis.

[0032] In another specific embodiment, fasudil or hydroxyfasudil treatment reduces the number and / or intensity of white matter hyperintensities (WMH) and / or lacunar infarcts. In a specific embodiment, the improvement is reflected by an improved (decreased) Fazekas score.

[0033] In yet another embodiment, fasudil or hydroxyfasudil reduces intracerebral microbleeds or hemorrhages.

[0034] In another embodiment, fasudil or hydroxyfasudil reduces cerebral amyloid angiopathy (CAA). In a further embodiment, fasudil or hydroxyfasudil treatment improves cognition, as assessed by the MMSE or MoCA. In another embodiment, treatment improves a mood or behavioral symptom

[0035] In another embodiment, fasudil or hydroxyfasudil treatment improves gait dysfunction or improve movement disorders.

[0036] In one embodiment, the fasudil or hydroxyfasudil is orally administered to the patient in a dose of between 70 to 240 mg / kg per day.

[0037] In another embodiment, the fasudil or hydroxyfasudil is administered as fasudil hydrochloride hemihydrate.

[0038] In a further embodiment, the fasudil or fasudil hydrochloride hemihydrate is orally administered to the patient in a dose of between 90 to 180 mg / kg per day.

[0039] In other embodiments, the fasudil or fasudil hydrochloride hemihydrate is administered twice per day (BID) or three times per day (TID) in an immediate-release tablet.

[0040] Detailed Description

[0041] The invention relates to using a rho kinase inhibitor to treat sporadic forms of small vessel disease (SVD) in human patients. SVD is a chronic, progressive vascular disease affecting arterioles, capillaries, and small veins that supply white matter of the brain. SVD causes strokes, gait disturbances, depression, cognitive impairment, and dementia.

[0042] The following definitions pertaining to SVD have been adopted by the SVD medical community in the Standards for Reporting Vascular Changes on Neuroimaging (Duering 2023) and will be used in accordance with these definitions herein. Patients treated according to the invention will have one or more of these imaging abnormalities.

[0043] Recent small subcortical infarct. Neuroimaging evidence of a recent infarction in the territory of one perforating arteriole, with imaging features and clinical symptoms consistent with a lesion occurring within the previous few — i.e., around 3 — weeks Lacune (of presumed vascular origin) Round or ovoid, subcortical, fluid filled (similar signal to CSF) cavity up to 15 mm in diameter that is likely to be end tissue damage from a recent small subcortical infarct, small subcortical hemorrhage, incidental diffusion-weighted- imaging-positive lesion, or end-stage cavitation in a white matter hyperintensity.

[0044] White matter hyperintensity (of presumed vascular origin). Signal abnormality of variable size in the white matter that is hyperintense on T2-weighted images, such as fluid- attenuated inversion recovery (FLAIR), without cavitation (signal different from CSF). Lesions in the subcortical grey matter or brainstem are not included into this category unless explicitly stated — where deep grey matter and brainstem hyperintensities are included as well, the collective name should be subcortical hyperintensities.

[0045] Perivascular space. Fluid-filled space, which follows the typical course of a vessel penetrating the brain through grey or white matter; has signal intensity similar to CSF on all sequences; has a round, ovoid, or linear shape (depending on the slice direction) with a diameter commonly not exceeding 2 mm when imaged perpendicular to the course of the vessel.

[0046] Cerebral microbleed. Small (usually 2-5 mm or sometimes 10 mm in size) areas of signal void with associated blooming artifact on T2* or other MRI sequences sensitive to susceptibility effects.

[0047] Cortical superficial siderosis. Thin areas of hypointensity on T2*, or other MRI sequences sensitive to susceptibility effects, in or overlying the superficial cortex, which can be confined to one gyrus and adjacent sulci, or occasionally more widespread affecting several brain regions.

[0048] Brain atrophy. Brain volume loss, not related to a specific macroscopic focal injury such as trauma or infarction; thus, the focal injury is not included in this measure unless explicitly stated.

[0049] Summary small vessel disease score. A grouping of accepted small vessel disease markers that serves to summarize small vessel disease brain burden into a single index, score, or unitary construct.

[0050] Cortical cerebral microinfarct. Small lesions appearing hypointense on Tl-weighted, hyperintense on T2-weighted or FLAIR, and isointense on T2*-weighted MRI, operationally defined to be strictly cortical and with an upper size limit of 4 mm. Certain patients treatable according to the invention will have evidence of one or more micro bleeds and / or one or more lacunar strokes. In one embodiment, the patients to be treated according to the disclosed methods will have at least one white matter hyperintensity on imaging. In some embodiments, the white lesions will be graded as having mild (punctate), moderate (some confluence) or severe white matter disease (large confluent areas). In an embodiment, the imaging is performed using MRI.

[0051] MRI white matter burden is typically assessed according to the Fazekas score and treatable patients will have a minimum score of 1, 2 or 3 according to the following grading:

[0052] Periventricular white matter (PVWM)

[0053] 0 = absent

[0054] 1 = “caps” or pencil-thin lining

[0055] 2 = smooth “halo”

[0056] 3 = irregular periventricular signal extending into the deep white matter

[0057] Deep white matter (DWM)

[0058] 0 = absent

[0059] 1 = punctate foci

[0060] 2 = beginning confluence

[0061] 3 = large confluent areas

[0062] In one embodiment, only the deep white matter scale is applied, for a maximum score of 3. In another embodiment, the full score is used, the patients will have a Fazekas score of 4, 5 or even 6.

[0063] In another embodiment, the two scales are presented separately. Thus, patients may have a

[0064] PVWM score of 0, 1, 2 or 3 and a DWM score of 0, 1, 2 or 3, but both scores may not be 0. In a specific embodiment, exemplary scores, denoting PVWM:DWM, include 1 :1 , 0:2, 1 :2 and the like. In general, a Fazckas score of 1, 2, or 3 may refer cither to the PVWM or the DWM score.

[0065] In another embodiment, sporadic SVD patients with white lesions are graded using the Lesion Segmentation Tool (LST) (applied-statistics.de / lst.html). This method automatically segments white matter signal abnormalities in the form of hyperintensities in the T2- weighted fluid- attenuated inversion recovery (FLAIR) MRI sequence. (Schmidt 2011). In a specific embodiment, the proposed cut-off value to classify low and high Fazekas WMSA burden is 0.00496 for LST. (Cedres 2020).

[0066] In yet another embodiment, sporadic SVD patients with white lesions are evaluated using FreeSurfer software (surfer.nmr.mgh.harvard.edu) (Fischl 2012). This method is increasingly used to automatically segment WMSA in the form of hypointensities in the Tl-weighted MRI sequence. Hypointense WMSA seems to be related to poorer white matter integrity as compared to hyperintense white matter signal abnormalities. In a specific embodiment, the proposed cut-off value to classify low and high Fazekas WMSA burden is 0.00321 for FreeSurfer WMSA.

[0067] (Cedres 2020).

[0068] In an embodiment, the sporadic SVD patient may show evidence of cerebral hemodynamic dysfunction, such as abnormally reduced cerebrovascular reactivity, or regional or global cerebral hypoperfusion. In another embodiment, the patient may show evidence of abnormally increased vascular myogenic tone. In a further embodiment, the patient typically will have elevated rho kinase activity. In one embodiment, the ROCK2 activity is elevated.

[0069] Forms of sporadic SVD. Sporadic pathologic valiants treatable according to the invention include SVD due to arteriolosclerosis, sporadic cerebral amyloid angiopathy (CAA), inflammatory and immunologically mediated SVD, venous collagenosis, and other sporadic SVD.

[0070] Arteriolosclerotic SVD is the most common, characterized by hyaline thickening of vessel walls (< 150 pm in diameter) without association with lipid-containing cells, intramural inflammation, and amyloid or fibrinoid necrosis. Lesions show smooth muscle cell loss from the tunica media and deposits of fibro-hyaline material and collagens in vessel walls. The Vascular Cognitive Impairment Neuropathology Guidelines (VCING) system has been widely used to evaluate the severity of artcriolosclcrosis in a semiquantitative manner; 0 = Normal, 1 = Mid thickening of the vessel media with mid fibrosis, 2 = Partial loss of smooth muscle cells in the media with moderate hyaline fibrosis, and 3 = Complete loss of smooth muscle cells in the media with severe hyaline fibrosis and lumen stenosis. Arteriosclerotic patients treatable according to the invention will have a VCING score of 1, 2 or 3. (Skrobot 2016).

[0071] CAA is characterized by the progressive accumulation of amyloid-0 (A0) in leptomeningeal arteries, penetrating arterioles, and capillaries. A0 deposits begin at the basement membrane between smooth muscle cell layers and develop into circumferential transmural deposits. Vessel integrity loss caused by A0 deposits can lead to spontaneous lobar intracerebral hemorrhage. A0 also disrupts the vascular extracellular matrix layers, causing luminal obstruction, leading to parenchymal ischemia. CAA categorization based heavily on intracerebral hemorrhage status divides cases in “definite CAA”, “probable CAA with supporting pathological evidence”, “probable CAA”, or “possible CAA” under the Boston criteria version 2.0 (Charidimou 2022). The following table summarizes the Boston criteria.

[0072] Notes: ICH = intracerebral hemorrhage; TFNEs = Transient focal neurologic episodes; cSAH = cerebral subarachnoid hemorrhage; CI = cognitive impairment; MRI = magnetic resonance imaging; CMB = cerebral microbleed; cSS = cortical superficial siderosis; CSO-PVS = visible perivascular spaces in the centrum semioval e; WMH-MS = white matter hyperintensities in a multispot pattern.

[0073] Sporadic SVD patients treatable according to the invention may have definite CAA, probable CAA with supporting pathological evidence, probable CAA, or possible CAA.

[0074] Inflammatory and immunologically mediated SVD is characterized by excess immune cell infiltration into the vessel walls (vasculitis) due to systemic and vascular inflammation during infection, autoimmune diseases, and rare immunological diseases. High neutrophil count is associated with increased risk for enlarged perivascular spaces. Plasma C-reactive protein (CRP) or interleukin 6 (IL-6) levels are positively correlated with the presence of WMHs. Sporadic SVD patients treatable according to the invention may have inflammatory and / or immunologically mediated SVD with evidence of vasculitis. They may have elevated neutrophil counts, plasma C-reactive protein (CRP) and / or interleukin 6 (IL-6) levels. Immune mediated SVD can be associated with systemic lupus erythematosus, Sjogren’s syndrome-associated vasculitis; Behcet’s vasculitis. Venous collagenosis is noninflammatory thickening of venous walls mainly composed of collagen I and III in white matter regions along lateral ventricles. Venous collagenosis is associated with leukoaraiosis severity or periventricular white matter ischemia. Only increased venous, but not arterial, collagen predicts of high WMH burden. Sporadic SVD patients treated according to the invention may show evidence of venous collagenosis, especially in the white matter along the lateral ventricles.

[0075] Sporadic SVD may also result as a side effect of radiotherapy. It may result in arteritis, intracranial aneurysm, cavernous malformation, mineralizing microangiopathy. Microbleeds, microinfarcts, or white matter lesions are frequently observed in follow-up after cranial irradiation. Patients treatable according to the invention may have SVD as a result of radiotherapy. In one aspect of the invention, patient undergoing radiotherapy are treated prior to any evidence of SVD in order to prevent SVD development.

[0076] Certain infections and / or inflammation can also cause SVD including meningovascular neurosyphilis; viral infections such as varicella-zoster virus, cytomegalovirus, hepatitis B and C, and HIV; fungi, schistosomiasis; oral infections such as gingivitis / periodontis; and cerebral malaria. Over expression of fibrillar collagen type- III as well as strong immunoreactivity of the basement membrane component collagen type-IV in vascular smooth muscle cells were marked to be associated with non-amyloid microangiopathy and associated with WMHs.

[0077] In certain embodiments of the invention, the treated patient has no evidence of memory deficits. In another embodiment, the patient may have mild or moderate vascular cognitive impairment (VCI). Patients with vascular dementia (VaD) would typically be excluded. Mild VCI is impairment in at least one cognitive domain, and mild to no impairment in instrumental activities of daily living (IADL) or basic activities of daily living ADL, respectively (independent of the motor / sensory sequelae of the vascular event). VaD (aka major VCI) is clinically significant deficits of sufficient severity in at least one cognitive domain (deficits may be present in multiple domains) and severe disruption to lADLs / ADLs (independent of the motor / sensory sequelae of the vascular event). IADLS arc those activities that allow an individual to live independently in a community; the major domains of IADLs include cooking, cleaning, transportation, laundry, and managing finances. In contrast with IADLS, ADLs are necessary for basic functional living; the major domains of ADLs arc feeding, dressing, bathing, and walking.

[0078] In another embodiment, the patient may have decreased executive function or reduced processing speed. In a specific embodiment, the patient with cognitive decline an impaired working memory is male. In a further embodiment, the patient may have memory deficits, including in working memory and long-term memory.

[0079] In certain embodiments, a patient who reports they have experienced apathy, reduced processing speed or behavioral changes is treated. Similarly, in other embodiments, a patient who has at least one family member report that the patient has experienced apathy, a reduction in processing speed or behavioral changes. In an embodiment, the patient does not exhibit wandering as wandering is not a typical symptom of the patients for whom treatment is contemplated. The invention specifically contemplates that the treated patient either does not have hypertension or has well-managed hypertension.

[0080] In some embodiments, patients exhibit acute stroke symptoms, various subjective cognitive impairments, mild cognitive impairment, mood or behavioral disturbances, gait dysfunction, movement disorders, and / or a general decline in function. It is contemplated that patients with intact motor function (no dysfunction) are treatable and that treatment may prevent motor dysfunction.

[0081] In another embodiment, the SVD patient does not have Alzheimer’s disease.

[0082] In a further embodiment, the SVD patient does not have Binswanger’s disease.

[0083] In one embodiment, the SVD patient has kidney disease or decreased glomerular filtration. In a specific embodiment, the eGFR is below 60 mL / min / 1.73 nr.

[0084] In one embodiment, the white matter lesions are in the thalamus.

[0085] In another embodiment, the small SVD patient has epilepsy, including seizures. In a specific embodiment, the epilepsy is temporal lobe epilepsy. In one embodiment, the epilepsy is late- onset epilepsy. In a further embodiment, the sporadic SVD patient has an infection. In a specific embodiment, the infection is HIV.

[0086] Genetic SVD. There are certain SVD variants of genetic origin. Genetic SVD is not within the scope of the disclosed method of treatment. For example, patients having antiphospholipid Antibody Syndrome (APS), CADASIL (cerebral autosomal-dominant arteriopathy with subcortical infarcts and leukoencephalopathy), CARASIL (cerebral autosomal recessive arteriopathy with subcortical infarcts and leucoencephalopathy), cerebrotendinous xanthomatosis, Ehlers-Danlos syndrome, Fabry disease, familial hemiplegic migraine, fibromuscular dysplasia, giant cell (temporal) arteritis, hereditary hemorrhagic telangiectasia (Osler- Weber-Rendu syndrome), homocystinuria, Marfan syndrome, MELAS (Mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes), Moyamoya disease, pseudoxanthoma elasticum, reversible cerebral vasoconstriction syndromes, sickle cell anemia, ingle-gene disorders, or polygenic conditions, Sneddon syndrome (SS), Susac’s Syndrome and Vasculopathy associated with ADA2 mutations are not treatable according to the invention.

[0087] Fasudil

[0088] The disclosed methods contemplate the administration of the rho kinase (ROCK) inhibitor fasudil or its metabolite M3 in the treatment of sporadic forms of cerebral small vessel disease (SVD). Two mammalian ROCK homologs arc known, R0CK1 (aka ROKf), Rho-kinasc 0, or pl60ROCK) and R0CK2 (aka ROKa) (Nakagawa 1996). In humans, the genes for both R0CK1 and ROCK2 are located on chromosome 18. The two ROCK isoforms share 64% identity in their primary amino acid sequence, whereas the homology in the kinase domain is even higher (92%) (Jacobs 2006; Yamaguchi 2006). Both ROCK isoforms are serine / threonine kinases and have a similar structure.

[0089] The isoquinoline derivative fasudil was the first small molecule ROCK inhibitor developed by Asahi Chemical Industry (Tokyo, Japan). The characteristic chemical structure of fasudil consists of an isoquinoline ring, connected via a sulphonyl group to a homopiperazine ring. Fasudil is a potent inhibitor of both ROCK isoforms. In vivo, fasudil is subjected to hepatic metabolism to its active metabolite hydroxyfasudil (aka, M3). Other examples of isoquinolinc derived ROCK inhibitors include dimcthylfasudil, ripasudil, Y-27632, and Y-39983.

[0090] Fasiidij Hydroxyfesiidil

[0091] The oral administration of fasudil, in contrast to intravenous, results in nearly 100% conversion to M3, whereas intravenous administration results in a mixture of the parent fasudil and the metabolite M3. While both fasudil and M3 are potent ROCK inhibitors, they do not have the same specificity on the two different ROCK isoforms and they do not have the same specificity against off-target kinases, like protein kinase G. Thus, the administration of intravenous fasudil is not predictive of the administration of oral fasudil. Moreover, rodents metabolize oral fasudil differently from humans and they are exposed to a mixture of fasudil and M3 after oral administration. In other words, oral fasudil in rodents mimics intravenous fasudil in humans, but is different from oral fasudil in humans.

[0092] Fasudil has been reported to have a number of potentially beneficial effects in conditions of the CNS, although there is no Level 1 evidence of treatment effect in any condition, meaning any potential medical application remains speculative.

[0093] The hemodynamic effects of fasudil are mediated by two principal mechanisms. It inhibits calcium-independent, ROCK-mediated phosphorylation of myosin light chain phosphatase, a principal player in vascular myogenic tone. Thus, in situations where ROCK activity is elevated, it can provide an additional vasodilatory response on top of vasodilators that rely on calcium mobilization (e.g., CO, NO, PDE inhibitors, calcium channel blockers). In addition, ROCK elevation is often responsible for endothelial dysfunction by inhibiting the expression and activity of endothelial nitric oxide synthase. Hence, fasudil can improve both the vasodilatory signal coming from the endothelium and the dynamics of the response by the vascular smooth muscle cells.

[0094] As used herein, unless clearly specified, the term fasudil means the free base, salts, hydrates, ion pairs, polymorphs and metabolites thereof, such as hydroxyfasudil (aka, M3), also including the free base, salts, hydrates, polymorphs and ion pairs of metabolites. Specific dosing information refers to fasudil hydrochloride hemihydrate and molar equivalents of other forms or metabolites.

[0095] Dosage and Administration

[0096] In accordance with the treatment methods, a therapeutically effective amount of fasudil or a pharmaceutically acceptable salt thereof, such as fasudil hydrochloride hemihydrate, for administration one or more times a day may comprise from about 10 mg to about 1000 mg.

[0097] Fasudil, hydroxyfasudil, or fasudil hydrochloride hemihydrate, for example, is suitably administered in a daily amount of about 10 mg to about 500 mg, about 10 mg to about 400 mg, about 10 mg to about 200 mg, about 10 mg to about 100 mg, about 20 mg to about 10 mg.

[0098] One dosing regimen involves the treatment with 25, 30, 40, 60 or 80 mg of fasudil, hydroxyfasudil, or fasudil hydrochloride hemihydrate three times per day using an immediate- release formulation, for a total daily dose of 70 to 240 mg per day. Most preferred dosing exceeds a daily dose of 70 mg, with most preferred ranges for daily dosing being 90 to 240 mg administered in two or three equal amounts during the day.

[0099] A particularly preferred daily dose is 180 mg / day administered 60 mg TID immediate release tablets. Fasudil and its salts and derivatives is most preferably administered orally in accordance with the foregoing using an immediate release formulation. In another embodiment, fasudil is administered in a dose of 240 mg / day administered 80 mg TID immediate-release tablets.

[0100] Another embodiment involves the treatment with 90-360 mg of fasudil, hydroxyfasudil, or fasudil hydrochloride hemihydrate once per day in an extended-release dosage form. Treatment with an extended-release total daily dose of 90 mg fasudil, hydroxyfasudil, or fasudil hydrochloride hemihydrate once per day is preferred. In one embodiment, the fasudil, hydroxyfasudil, or fasudil hydrochloride hemihydrate is administered to the patient in a dose from about 90 to 240 mg / day as an immediate release formulation.

[0101] In another embodiment, the fasudil , hydroxyfasudil, or fasudil hydrochloride hemihydrate is administered to the patient in an extended-release formulation, wherein the maximum plasma concentration and area under the curve in plasma over 24 hours do not exceed by more than 15% what is obtained using a dosing regimen of 70 to 240 mg / day as an immediate release formulation.

[0102] Methods of administering compositions according to the invention would generally be continued for at least one day. Some preferred methods treat for up to 30 days or up to 60 days or even up to 90 days or even more. Treatment for more than 60 days is preferred and treatment for at least 6 months is particularly preferred. The precise duration of treatment will depend on the patient’s condition and response to treatment.

[0103] Pharmaceutical Compositions

[0104] In a preferred embodiment, fasudil is administered in an oral dosage form. Pharmaceutical compositions of fasudil or its salts or hydrates for oral administration may be in the form of tablets or capsules and may be immediate-release formulations or may be controlled- or ex tended- release formulations, which may contain pharmaceutically acceptable excipients, such as com starch, mannitol, povidone, magnesium stearate, talc, cellulose, methylcellulose, carboxymethylcellulose and similar substances. The oral pharmaceutical composition comprising fasudil or a salt or hydrate thereof may comprise one or more pharmaceutically acceptable excipients, which are known in the art.

[0105] Formulations also include oral films, orally disintegrating tablets, effervescent tablets and granules or beads that can be sprinkled on food or mixed with liquid as a slurry or poured directly into the mouth to be washed down.

[0106] In one embodiment, the fasudil is administered in a taste-masked oral formulation. An example of a bitterness masker that can bind a rho kinase inhibitor is an ion exchange resin, for example, as disclosed in U.S. Application Serial Nos. 18 / 171,007; 18 / 171,070; and 18 / 171,077. In another embodiment, the fasudil is orally administered in the form of liposomes.

[0107] Pharmaceutical compositions containing fasudil, or salts or hydrates thereof can be prepared by any method known in the art of pharmaceutics. In general, such preparatory methods include the steps of bringing fasudil or a pharmaceutically acceptable salt or hydrate thereof into association with a carrier or excipient, and / or one or more other accessory ingredients, and then, if necessary and / or desirable, shaping, and / or packaging the product into a desired single- or multi-dose unit.

[0108] Pharmaceutical compositions can be prepared, packaged, and / or sold in bulk, as a single unit dose, and / or as a plurality of single unit doses. As used herein, a “unit dose” is a discrete amount of the pharmaceutical composition comprising a predetermined amount of the active ingredient. The amount of the active ingredient is generally equal to the dosage of the active ingredient which would be administered to a subject and / or a convenient fraction of such a dosage such as, for example, one-half or one-third of such a dosage.

[0109] Relative amounts of the active ingredient, the pharmaceutically acceptable excipient, and / or any additional ingredients in a pharmaceutical composition of the invention will vary, depending upon the identity, size, and / or condition of the subject treated and further depending upon the route by which the composition is to be administered. The composition used in accordance with the methods of the present invention may comprise between 0.001 % and 100% (w / w) active ingredient.

[0110] Pharmaceutically acceptable excipients used in the manufacture of provided pharmaceutical compositions include inert diluents, dispersing and / or granulating agents, surface active agents and / or emulsifiers, disintegrating agents, binding agents, preservatives, buffering agents, lubricating agents, and / or oils. Excipients such as coloring agents, coating agents, sweetening, flavoring, and perfuming agents may also be present in the composition.

[0111] In certain embodiments, the pharmaceutical composition used in the methods of the present invention may comprise a diluent. Exemplary diluents include calcium carbonate, sodium carbonate, calcium phosphate, dicalcium phosphate, calcium sulfate, calcium hydrogen phosphate, sodium phosphate lactose, sucrose, cellulose, microcrystalline cellulose, kaolin, mannitol, sorbitol, inositol, sodium chloride, dry starch, cornstarch, powdered sugar, and mixtures thereof.

[0112] In certain embodiments, the pharmaceutical composition used in the methods of the present invention may comprise a granulating and / or dispersing agent. Exemplary granulating and / or dispersing agents include potato starch, corn starch, tapioca starch, sodium starch glycolate, clays, alginic acid, guar gum, citrus pulp, agar, bentonite, cellulose, and wood products, natural sponge, cation-exchange resins, calcium carbonate, silicates, sodium carbonate, cross-linked poly(vinyl-pyrrolidone) (crospovidone), sodium carboxymethyl starch (sodium starch glycolate), carboxymethyl cellulose, cross-linked sodium carboxymethyl cellulose (croscarmellose), methylcellulose, pregelatinized starch (starch 1500), microcrystalline starch, water insoluble starch, calcium carboxymethyl cellulose, magnesium aluminum silicate (VEEGUM), sodium lauryl sulfate, quaternary ammonium compounds, and mixtures thereof.

[0113] In certain embodiments, the pharmaceutical composition used in the methods of the present invention may comprise a binding agent. Exemplary binding agents include starch (e.g., cornstarch and starch paste), gelatin, sugars (e.g., sucrose, glucose, dextrose, dextrin, molasses, lactose, lactitol, mannitol, etc.), natural and synthetic gums (e.g., acacia, sodium alginate, extract of Irish moss, panwar gum, ghatti gum, mucilage of isapol husks, carboxymethylcellulose, methylcellulose, ethylcellulose, hydroxyethylcellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, microcrystalline cellulose, cellulose acetate, poly (vinyl-pyrrolidone), magnesium aluminum silicate ( VEEGUM. RTM.), and larch arabogalactan), alginates, polyethylene oxide, polyethylene glycol, inorganic calcium salts, silicic acid, polymethacrylates, waxes, water, alcohol, and / or mixtures thereof.

[0114] In certain embodiments, the pharmaceutical composition used in the methods of the present invention may comprise a preservative. Exemplary preservatives include antioxidants, chelating agents, antimicrobial preservatives, antifungal preservatives, antiprotozoan preservatives, alcohol preservatives, acidic preservatives, and other preservatives. In certain embodiments, the preservative is an antioxidant. In other embodiments, the preservative is a chelating agent.

[0115] In certain embodiments, the pharmaceutical composition used in the methods of the present invention may comprise an antioxidant. Exemplary antioxidants include alpha tocopherol, ascorbic acid, ascorbyl palmitate, butylated hydroxyanisole, butylated hydroxytoluene, monothioglyccrol, potassium metabisulfite, propionic acid, propyl gallate, sodium ascorbate, sodium bisulfite, sodium metabisulfite, and sodium sulfite.

[0116] In certain embodiments, the pharmaceutical composition used in the methods of the present invention may comprise a chelating agent. Exemplary chelating agents include ethylenediaminetetraacetic acid (EDTA) and salts and hydrates thereof (e.g., sodium edetate, disodium edetate, trisodium edetate, calcium disodium edetate, dipotassium edetate, and the like), citric acid and salts and hydrates thereof (e.g., citric acid monohydrate), fumaric acid and salts and hydrates thereof, malic acid and salts and hydrates thereof, phosphoric acid and salts and hydrates thereof, and tartaric acid and salts and hydrates thereof. Exemplary antimicrobial preservatives include benzalkonium chloride, benzethonium chloride, benzyl alcohol, bronopol, cetrimide, cetylpyridinium chloride, chlorhexidine, chlorobutanol, chlorocresol, chloroxylenol, cresol, ethyl alcohol, glycerin, hexetidine, imidurea, phenol, phenoxyethanol, phenylethyl alcohol, phenylmercuric nitrate, propylene glycol, and thimerosal.

[0117] In certain embodiments, the pharmaceutical composition may comprise a buffering agent together fasudil or salt or hydrate thereof. Exemplary buffering agents include citrate buffer solutions, acetate buffer solutions, phosphate buffer solutions, ammonium chloride, calcium carbonate, calcium chloride, calcium citrate, calcium glubionate, calcium gluceptate, calcium gluconate, D-gluconic acid, calcium glycerophosphate, calcium lactate, propanoic acid, calcium levulinate, pentanoic acid, dibasic calcium phosphate, phosphoric acid, tribasic calcium phosphate, calcium hydroxide phosphate, potassium acetate, potassium chloride, potassium gluconate, potassium mixtures, dibasic potassium phosphate, monobasic potassium phosphate, potassium phosphate mixtures, sodium acetate, sodium bicarbonate, sodium chloride, sodium citrate, sodium lactate, dibasic sodium phosphate, monobasic sodium phosphate, sodium phosphate mixtures, tromethamine, magnesium hydroxide, aluminum hydroxide, alginic acid, pyrogen-free water, isotonic saline, Ringer's solution, ethyl alcohol, and mixtures thereof.

[0118] In certain embodiments, the pharmaceutical composition used in the methods of the present invention may comprise a lubricating agent. Exemplary lubricating agents include magnesium stearate, calcium stearate, stearic acid, silica, talc, malt, glyceryl behanate, hydrogenated vegetable oils, polyethylene glycol, sodium benzoate, sodium acetate, sodium chloride, leucine, magnesium lauryl sulfate, sodium lauryl sulfate, and mixtures thereof.

[0119] In other embodiments, the pharmaceutical composition of containing fasudil or salt or hydrate thereof will be administered as a liquid dosage form. Liquid dosage forms for oral and parenteral administration include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups, and elixirs. In addition to the active ingredients, the liquid dosage forms may comprise inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (e.g., cottonseed, groundnut, corn, germ, olive, castor, and sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof. Besides inert diluents, the oral compositions can include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.

[0120] Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the active ingredient is mixed with at least one inert, pharmaceutically acceptable excipient or carrier such as sodium citrate or dicalcium phosphate and / or (a) fillers or extenders such as starches, lactose, sucrose, glucose, mannitol, and silicic acid, (b) binders such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone, sucrose, and acacia, (c) humectants such as glycerol, (d) disintegrating agents such as agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate, (e) solution retarding agents such as paraffin, (f) absorption accelerators such as quaternary ammonium compounds, (g) wetting agents such as, for example, cetyl alcohol and glycerol monostearate, (h) absorbents such as kaolin and bentonite clay, and (i) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof. In the case of capsules, tablets, and pills, the dosage form may include a buffering agent.

[0121] Some compositions of the invention relate to extended- or controlled-release formulations. These may be, for example, diffusion-controlled products, dissolution-controlled products, erosion products, osmotic pump systems or ionic resin systems. Diffusion-controlled products comprise a water-insoluble polymer which controls the flow of water and the subsequent egress of dissolved drug from the dosage from. Dissolution-controlled products control the rate of dissolution of the drug by using a polymer that slowly solubilizes or by microencapsulation of the drug - using varying thicknesses to control release. Erosion products control release of drug by the erosion rate of a carrier matrix. Osmotic pump systems release a drug based on the constant inflow of water across a semi permeable membrane into a reservoir which contains an osmotic agent. Ion exchange resins can be used to bind drugs such that, when ingested, the release of drug is determined by the ionic environment within the gastrointestinal tract.

[0122] Combination Therapy

[0123] The inventive methods can also employ fasudil in combination with one or more other vasoactive agents. These may be administered with fasudil in a single, fixed dose combination composition or fasudil and the other vasoactive agent may be administered as separate compositions but as part of a common treatment regimen. Exemplary other vasoactive agents include angiotensin converting enzyme (ACE) inhibitors, an angiotensin receptor blocker (ARB), calcium channel blockers (CCBs), phosphodiesterase (PDE) inhibitors and nitrates.

[0124] ARBs include, but are not limited to, valsartan, losartan, azilsartan, irbesartan, olmesartan, telmisartan, and fimasartan,

[0125] ACE inhibitors include, but are not limited to, alacepril, captopril, zofenopril, enalapril, ramipril, quinapril, perindopril, lisinopril, benazepril, imidapril, trandolapril, cilazapril, and fosinopril

[0126] CCBs include, but are not limited to, amlodipine, aranidipine, azelnidipine, bamidipine, benidipine, cilnidipine, clevidipine, efonidipine, felodipine, isradipine, lacidipine, lercanidipine, manidipine, nicardipine, nifedipine, nilvadipine, nimodipine, nisoldipine, nitrendipine, pranidipine, fendiline, gallopamil, verapamil and diltiazem.

[0127] PDEs include, but are not limited to, sildenafil, tadalafil, vardenafil, udenafil, avanafil, dipyridamole, amrinone, milrinone, enoximone, anagrelide, cilostazol and pimobendane.

[0128] Nitrates include, but are not limited to, amyl nitrite, glyceryl trinitrate, isosorbide mononitrate (with or without hydralazine), nitroglycerin and pentaerythritol tetranitrate. Diuretics are also commonly used as anti -hypertensive agents.

[0129] The inventive methods can also employ fasudil in combination with one or more other cognitive agents such as the cholinesterase inhibitors (e.g., donepezil, galantamine, rivastigmine) or memantine.

[0130] The inventive methods can also employ fasudil in combination with one or more other antimigraine agents including beta-blockers, triptans including sumatriptan, naratriptan, zolmitriptan, rizatriptan, acetaminophen with codeine or hydrocodone, morphine, tramadol, propranolol, amitriptyline, pizotifen, acetazolamide, and simple analgesics such as aspirin, acetaminophen, and ibuprofen.

[0131] Assessing Outcomes of Fasudil Treatment

[0132] The following measures may be used to assess patients treated with fasudil or M3 according to the disclosure. A patient will typically have a deficit in one or more of these assessments prior to treatment. Treatment will generally improve performance on at least one of these assessments. Typical improvements are in 5%, 10%, 15%, 20%, or 25% or more. Other improvements can be mor descriptive, such as severe may become moderate or moderate may become mild or mild may become asymptomatic. In some cases, assessment scores or categories will stabilize or the rate of deterioration is slowed relative to expectation or control patients.

[0133] One of ordinary skill in the art will be familiar with these measures and others that are useful in assessing patient deficits and outcomes of treatment. The invention contemplates improvements in one or more of the below assessments with fasudil or M3 treatment.

[0134] Imaging. In one embodiment, patients with SVD can be monitored he MRI and other imaging described above. White matter burden, as assessed by MRI, increases over time, and is linked with cognitive and functional decline.

[0135] In an embodiment, patients treated according to the invention may be seen to have a slowing of the rate of white matter lesion accumulation. Treated patients may also experience a reduction in the frequency of lacunar strokes and other cerebral ischemic events relative to their own clinical history or relative to an untreated cohort. In another embodiment, patients with white lesions may be diagnosed or monitored using diffusion tensor imaging, which measures water diffusion inside and outside cerebral lesions. Diffusion-tensor imaging detects ultrastructural tissue damage even in areas that appear normal in conventional MRI. The mean diffusivity was found to be the main predictor of clinical progression in patients with SVD. (REF).

[0136] Other methods of assessment commonly used by providers include CT angiography,

[0137] Neuropsychological and disability assessments. The Modified Rankin Scale is a disability scale often used in patients with small vessel disease. It is a seven-point scale (0-6), ranging from no symptoms to dead:

[0138] 0 - No symptoms.

[0139] 1 - No significant disability. Able to carry out all usual activities, despite some symptoms.

[0140] 2 - Slight disability. Able to look after own affairs without assistance, but unable to carry out all previous activities.

[0141] 3 - Moderate disability. Requires some help, but able to walk unassisted.

[0142] 4 - Moderately severe disability. Unable to attend to own bodily needs without assistance, and unable to walk unassisted.

[0143] 5 - Severe disability. Requires constant nursing care and attention, bedridden, incontinent.

[0144] 6 - Dead.

[0145] The Barthel Index can also be used to monitor disease progression. Barthel Index is a 100-point scale that measures activities of daily living. A score of 100 is fully independent. Feeding (0-10 points), bathing (0-5 points), grooming (0-5 points), dressing (0-10 points), bowel control (0-10 points), bladder control (0-10 points), toilet use (0-10 points), transfers (bed to chair and back) (0-15 points), mobility on level surfaces (0-15 points), and stairs (0-10 points).

[0146] Tests of working memory useful for assessing outcomes also include the Digit Span test, which involves the immediate recall of digit strings, forwards and backwards (WAIS-III 1997). The Wechsler Memory Scale III (WMS-III 1997) or WMS-IV can also be used. The memory indices arc: Auditory Immediate, Visual Immediate, Immediate Memory, Auditory Delayed, Visual Delayed, Auditory Recognition Delayed, General Memory and Working Memory.

[0147] Long term memory tests on the WMS include the Logical Memory test and the Visual Reproduction test. The Logical Memory test measures the immediate and delayed recall of short stories. It can also be used to monitor disease progression. The Visual Reproduction test measures the immediate and delayed reproduction of line drawings.

[0148] The Brief Memory and Executive Test (BMET) is a cognitive screening tool designed and previously validated to be sensitive to the cognitive deficit seen in sporadic SVD. (Brookes 2015). The test comprises 8 tasks (domains) that provide measures that form 2 subscales and an overall score. The first subscale, Executive Functioning and Processing Speed, is calculated using the tasks Letter-Number Matching, Motor Sequencing, Letter Sequencing, and Number- Letter Sequencing. The second subscale, Orientation and Memory, is made up of the Orientation, 5-item Repetition, 5-item Recall, and 5-item Recognition tasks. The measures from each task are transformed into scales that have a maximum of 2, giving a maximum total of 8 on each subscale and 16 overall. These scorings are age-adjusted, with each measure adjusted for the age of the participant.

[0149] Processing speed in SVD patients can be assessed by the BIRT Memory and Information Processing Battery, the Digit Symbol Substitution Test (DSST), and the Grooved Pegboard test. The BIRT involves the timed cancellation of the second highest of five two-digit numbers (Coughlan 2007). The DSST is a timed transcoding test (WAIS-III 1997). The Grooved Pegboard involves picking up, rotating and placing small pegs while being timed (Matthews 1964, Dawson 2010). The DSST is a paper-and-pencil cognitive test presented on a single sheet of paper that requires a subject to match symbols to numbers according to a key located on the top of the page. The subject copies the symbol into spaces below a row of numbers. The number of correct symbols within the allowed time, usually 90 to 120 seconds, constitutes the score.

[0150] The DSST measures a range of cognitive operations. DSST may prove to be a practical and effective method for use in clinical practice to detect decrements in cognitive processing over time. Good performance on the DSST requires intact motor speed, attention, and visuoperceptual functions, including scanning and the ability to write or draw (i.e., basic manual dexterity). Performance might also be affected by associative learning. For example, if pairings arc rapidly learned following the first few trials, performance speed will improve because the subject will not need to refer to the key to check the accuracy of each pairing. The decision to consciously engage in this learning strategy to improve performance speed calls for the executive functions of planning and strategizing. Working memory, another executive function, is likely required to hold in mind the task rules and for the continual updating of required symbol-digit pairs. SVD patients treatable according to the invention typically score approximately 1 SD below normal on the DSST.

[0151] Symbol coding paradigms comparable to the DSST (with different symbols) are included as subtests in the Brief Assessment of Cognition in Schizophrenia and the Repeatable Battery for the Assessment of Neuropsychological Status. The Symbol Digit Modalities Test uses essentially the same method, except in reverse; instead of drawing symbols that match digits, the subject is required to write the matching digit in the blank.9 This version of the coding paradigm has the advantage that it can be easily altered to allow oral responses in disorders that affect motor functioning. Computerized tests offer another option for monitoring change over time, for example the Cambridge Neuropsychological Test Auto-mated Battery developed by Cambridge Cognition, Cognigram, a version of the Cogstate Brief Battery, and THINC-IT (a freely available computerized test). (Jaeger 2018)

[0152] Executive Function in sporadic SVD patients can be tested using the Trail Making Test (the entire test or each individual part A or B), the DSST, the SL- Verbal Fluency test and the modified Wisconsin Card-Sorting Test. (Bondi 1983). The Trail Making Test involves sequencing alternating letters and numbers using pen and paper (Tombaugh 2004); eatspeakthink.com / wp- content / uploads / 2018 / 06 / IowaTrailMaking.pdf). The SL- Verbal Fluency tests the ability of the subject to generate words beginning with certain letters in a certain period of time (Delis 2001). The modified Wisconsin Card-Sorting Test involves asking the subject to sort a set of cards without instructions; they are given feedback on their performance and then adapt their strategy (Nagahama 2003). It tests the flexibility and the ability to learn the rules of the game. The Stroop test can also assess executive function. It assesses the reaction to conflicting stimuli, just as the word red written in blue letters. Gross cognitive assessments can also be used to assess sporadic SVD, including the Mini-Mental State Examination (MMSE) and Montreal Cognitive Assessment (MoCA). The maximum score for the MMSE is 30. A score of 25 or higher is classed as normal. If the score is 24 or below, the result is usually considered to be abnormal, indicating possible cognitive impairment. In one embodiment, the patient may be selected for treatment based on their MMSE, and / or their MMSE will improve with treatment according to the invention. In another embodiment, the patients have a maximum MMSE score of 23. In another embodiment, patients have a minimum MMSE score of 15.

[0153] The maximum score for the MoCA is 30. A score of 26 or higher is classed as normal. If the score is below 26, the result is usually considered to be abnormal, indicating possible cognitive impairment. In one embodiment, the patient may be selected based on their MoCA and / or their MoCA will improve with treatment according to the invention. A score of 18-25 is considered mild cognitive impairment (MCI). Treatable patients will preferably have MCI. A score of 10- 17 is considered moderate cognitive impairment and treatable patients may have moderate cognitive impairment. A score below 10 is considered to be dementia and the invention does not contemplate treating such patients. See, mocacognition.com

[0154] Vascular assessments. In addition, patients may show improvements upon treatment with fasudil or M3 on hemodynamic parameters, such are cerebrovascular reactivity (the ability of the blood vessels to dilate and constrict in response to stimuli) or cerebral hypoperfusion.

[0155] Improvements may also be seen in blood vessel patency. In another embodiment, patients with hypertension may improve (lower blood pressure or return to normal).

[0156] In a further embodiment, coronary symptoms including revealed diffuse vessel wall irregularities, vascular thickening, and mixed non-calcified / calcified coronary lesions with intermediate stenosis will improve with treatment.

[0157] Caregiver assessment. Caregiver assessments also can be used to monitor progression of SVD patients. NPI-O. In one Embodiment, the patient having sporadic small vessel disease treated with the ROCK inhibitor such as fasudil to is assessed using the Neuropsychiatric Inventory Questionnaire (NPI-Q). The NPI-Q is designed to be a self-administered questionnaire completed by informants about patients for whom they care. Each of the twelve NPI-Q domains contains a survey question that reflects cardinal symptoms of that domain. Initial responses to each domain question are “Yes”(present) or “No” (absent). Thus, a total score of 36 points would indicate maximum severity in all parameters considered.

[0158] If the response to the domain question is “No,” the informant goes to the next question. If “Yes,” the informant then rates both the Severity of the symptoms present within the last month on a 3- point scale and the associated impact of the symptom manifestations on them (i.e. Caregiver Distress) using a five-point scale. The NPI-Q provides symptom Severity and Distress ratings for each symptom reported, and total Severity and Distress scores reflecting the sum of individual domain scores. The NPI-Q Distress ratings have a maximum score of 60 (a score of 5 on all questions).

[0159] Example 1

[0160] Eighty patients diagnosed SVD are recruited. Patients with no apparent WMH on imaging are excluded. Patients with a non-neurological comorbidity or who use medication that could adversely affect cognition are also excluded. Patients have a maximum MMSE score of 23 and a minimum MMSE score of 15. Patients have maximum MoCA score of 25 and a minimum of 10. Cohorts of 20 patients arc treated orally with fasudil or placebo in a dose escalating manner.

[0161] Each group is randomized 10 patients each to placebo or drug and treated for 60 days. At the end of 30 days, based on assessment of adverse event, the next cohort with a higher dose is begun. At the end of 60 days, patients will be assessed for efficacy and safety and will be re-randomized into the next higher dose in the absence of dose-limiting side effects. Oral dosing using 10 mg immediate release tablets starts with the first cohort at 60 mg per day (administered in 3 equal doses throughout the day), the second cohort at 90 mg per day (administered in 3 equal doses throughout the day), the third cohort at 180 mg per day (administered in 3 equal doses throughout the day) and the fourth cohort at the maximum planned dose is 240 mg per day (administered in 3 equal doses throughout the day). No effect in cognition is observed with the 60 mg dose at 60 days, whereas each of the other doses show improvements at 60 days versus control. When the first cohort is escalated to 90 mg per day, a difference in cognition between treated and control in that cohort is observed. Cognition improves in a dose-dependent manner across all doses as measured by the MMSE or the MoCA. Patients generally improve by a minimum of 2-3 points on either the MMSE or the MoCA at their optimally effective dose. A dose-dependent increase in creatinine, indicating possible kidney dysfunction is seen. Only 50% of the subjects who are escalated to the 180 mg per day dose are also escalated to the 240 mg dose and 25% of patients treated with 240 mg daily are dose-reduced due to elevated creatinine levels.

[0162] It is determined that the optimal dose for improving cognition in sporadic SVD patients is between 90 mg and 180 mg per day. It is further expected that other biomarkers and imaging markers including reduction in WMH volume, lacunar infarcts, microbleeds, diffusion tensor imaging metrics, cerebral blood flow, and cerebrovascular reactivity will improve upon fasudil treatment.

[0163] Example 2

[0164] Eighty patients diagnosed SVD are recruited. Patients with no apparent WMH on imaging are excluded. Patients with a non-neurological comorbidity or who use medication that could adversely affect cognition are also excluded. Patients have a minimum deficit on the DSST of a half standard deviation below normal (as assessed by normative data based on age, maximum education, etc.) and a maximum deficit of 1.5 standard deviations below normal. The DSST is administered 3-5 times per assessment in order to reduce variability and any learning effects.

[0165] Cohorts of 20 patients are treated orally with fasudil or placebo in a dose escalating manner. Each group is randomized 10 patients each to placebo or drag and treated for 60 days. At the end of 30 days, based on assessment of adverse event, the next cohort with a higher dose is begun.

[0166] At the end of 60 days, patients will be assessed for efficacy and safety and will be re-randomized into the next higher dose in the absence of dose-limiting side effects. Oral dosing using 10 mg immediate release tablets starts with the first cohort at 60 mg per day (administered in 3 equal doses throughout the day), the second cohort at 90 mg per day (administered in 3 equal doses throughout the day), the third cohort at 180 mg per day (administered in 3 equal doses throughout the day) and the fourth cohort at the maximum planned dose is 240 mg per day (administered in 3 equal doses throughout the day). Drug effects are assessed by measuring the DSST 3-5 times approximately 2 hours after the first and then again approximately 2 hours after dosing just prior to the next dose escalation or at the last treatment.

[0167] No effect in cognition is observed with the 60 mg dose at 60 days, whereas each of the other doses show improvements at 60 days versus control. When the first cohort is escalated to 90 mg per day, a difference in cognition between treated and control in that cohort is observed.

[0168] DSST performance improves in a dose-dependent manner across all doses. Patients generally improve by a minimum of 0.5 standard deviations or more at their optimally effective dose. A dose-dependent increase in creatinine, indicating possible kidney dysfunction is seen. Only 50% of the subjects who are escalated to the 180 mg per day dose are also escalated to the 240 mg dose and 25% of patients treated with 240 mg daily are dose-reduced due to elevated creatinine levels.

[0169] It is determined that the optimal dose for improving cognition in sporadic SVD patients is between 90 mg and 180 mg per day. It is further expected that other biomarkers and imaging markers including reduction in WMH volume, lacunar infarcts, microbleeds, diffusion tensor imaging metrics, cerebral blood flow, and cerebrovascular reactivity will improve upon fasudil treatment.

[0170] List of References

[0171] Backhouse E. et al., Cerebral small vessel disease: early life antecedents and long-term implications for the brain, aging, stroke and dementia. Hypertension. 2023; 80:00-00. DOI: 10.1161 / HYPERTENSIONAHA.122.19940.

[0172] Blair GW et al., Imaging neurovascular, endothelial and structural integrity in preparation to treat small vessel diseases. The INVESTIGATE-SVDs study protocol. Part of the SVDs ©Target project. Cereb Circ Cogn Behav. 2021; 26:2: 10020. Doi 10.1016 / j.cccb.2021.100020. eCollection 2021. Bondi MW, Monsch AU, Butters N, Salmon DP. Utility of a modified version of the Wisconsin Card Sorting Test in the detection of dementia of the Alzheimer’s type. Clinical Neuropsychol. 1993;7:161-170.

[0173] Brookes RL et al., The Brief Memory and Executive Test (BMET) for detecting vascular cognitive impairment in small vessel disease: a validation study. BMC Medicine. 2015; 13: 51.

[0174] Cedres N et al., Predicting Fazekas scores from automatic segmentations of white matter signal abnormalities. Aging (Albany NY). 2020 Jan 12; 12(1): 894-901.

[0175] Charidimou A et al., The Boston criteria version 2.0 for cerebral amyloid angiopathy: a multicentre, retrospective, MRI-neuropathology diagnostic accuracy study. Lancet Neurol. 2022 Aug;21(8):714-725.

[0176] Coughlan, A, K., Oddy, M, J., & Crawford, J. R. BIRT Memory and Information Processing Battery (BMIPB). 2007. London: Brain Injury Rehabilitation Trust.

[0177] Dawson JD et al., Neuropsychological Predictors of Driving Errors in Older Adults. J. Am Ger Soc. 2010; 58(6): 1090-96.

[0178] Dueling M., Epub 2023 May 23. Neuroimaging standards for research into small vessel diseaseadvances since 2013.

[0179] Inoue Y et al., Pathophysiology and probable etiology of cerebral small vessel disease in vascular dementia and Alzheimer's disease. Mol Neurodegener. 2023 Jul 11 ; 18(1 ):46.

[0180] Jaeger J. Digit Symbol Substitution Test: The case for sensitivity over specificity in neuropsychological testing. Journal of Clinical Psychopharmacology, 38(5), 513-519.

[0181] Nagahama Y et al., Factor structure of a modified version of the Wisconsin card sorting test: an analysis of executive deficit in Alzheimer's disease and mild cognitive impairment. Dement Geriatr Cogn Disord. 2003 ; 16(2): 103- 12.

[0182] Sharrief et al., Diagnosis and Management of Cerebral Small Vessel Disease. 2023; Continuum (Minneap Minn) ;29(2):501-518. Lancet Neurol. 2023 Jul;22(7):602-618.

[0183] Skrobot OA et al., Vascular cognitive impairment neuropathology guidelines (VONG): the contribution of cerebrovascular pathology to cognitive impairment. Brain 2016. 139: 2957-69.

[0184] Tombaugh TN, Trail Making Test A and B: Normative data stratified by age and education. Archives of Clin Neuropsych. 2004; 19(2): 203-14.

[0185] All references listed throughout are incorporated by reference herein in their entireties. \\

Claims

Claims1. A method of treating sporadic cerebral small vessel disease (SVD), comprising treating a patient diagnosed with sporadic small vessel disease with a therapeutically effect amount of a rho kinase inhibitor.

2. The method according to claim 1, wherein the rho kinase inhibitor is fasudil or hydroxyfasudil (M3), or a pharmacologically acceptable salt thereof.

3. The method according to claims 1 or 2, wherein the patient does not have dementia.

4. The method according to claim 1 or 2, wherein the patient has mild cognitive impairment.

5. The method according to any one of the preceding claims, wherein the patient does not have Binswanger’s disease or Alzheimer’s disease.

6. The method according to any one of the preceding claims, wherein the patient has a Fazekas score of > 1.

7. The method according to any one of the preceding claims, wherein the patient has evidence of at least one micro bleed and / or at least one lacunar stroke.

8. The method according to any one of the preceding claims, wherein the patient reports experiencing apathy, or reduction in processing speed or behavioral changes.

9. The method according to any one of the preceding claims wherein the at least one family member of the patient reports that the patient has experienced apathy, or reduction in processing speed, or behavioral changes.

10. The method according to claim 8, wherein the patient has reduced processing speed as demonstrated by a timed neurocognitive test.

11. The method according to claim 8, wherein the patient has decreased executive function.1 . The method according to any one of the preceding claims, wherein the patient docs not have memory deficits.

13. The method according to claim 1, wherein the patient has memory deficits.

14. The method according to claim 13, wherein the memory deficits are in in working memory and / long-term memory.

15. The method according to any one of the preceding claims, wherein the patient either does not have hypertension or has well-managed hypertension.

16. The method according to claim 1, wherein the patient has no sign of motor dysfunction.

17. The method according to claim 1, wherein the SVD patient has probable, possible, or definite cerebral amyloid angiopathy (CAA).

18. The method according to any one of the preceding claims, wherein the fasudil is orally administered to the patient in a dose of between 70 to 240 mg / kg per day.

19. The method according to claim 17, wherein the fasudil is fasudil hydrochloride hemihydrate.

20. The method according to claims 17 or 18, wherein the fasudil or fasudil hydrochloride hemihydrate is orally administered to the patient in a dose of between 90 to 180 mg / kg per day.

21. The method according to any one of claims 17 to 19, wherein the fasudil or fasudil hydrochloride hemihydrate is administered twice per day (BID) or three times per day (TID) in an immediate-release tablet.

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