Methods for treating subcutaneous lipodymaturia and lymphatic disorders

Abstract

A method for treating lipodymere in patients requiring treatment of lipodymere is described, comprising the step of administering a therapeutically effective dose of a selective LTA4H inhibitor. A method for treating subcutaneous lymphatic dysfunction-related abnormalities or subcutaneous lymphatic diseases in patients requiring treatment of subcutaneous lymphatic dysfunction-related abnormalities or subcutaneous lymphatic diseases is also described, comprising the step of administering a therapeutically effective dose of a selective LTA4H inhibitor. Furthermore, a method for preventing lymphodymere or reducing the risk of developing it is described for patients requiring prevention of lymphodymere or reduction of the risk of developing it.

Description

[Technical Field]

[0001] Related applications This application claims the benefit of U.S. Provisional Application No. 63 / 472,050, filed on 9 June 2023. The entire contents of the above-mentioned referenced application are incorporated herein by reference. [Background technology]

[0002] Background of the Invention Liposomal edema is a chronic condition that is estimated to affect about 10% of women (Kruppa et al. (2020)). The condition is characterized by bilateral fat deposits in the extremities that persist despite diet and exercise (Kruppa et al.; Escobedo et al. (2017)). Liposomal edema is also associated with painful subcutaneous adipose tissue (SAT), which is morphologically abnormal, including the presence of hypertrophic adipocytes (Poojari et al. (2022)). Ultrasonographic examination of SAT in patients with lipodyma reveals abnormal ultrasound-detectable fascial surfaces (e.g., loss or blurring of the distinction between interfascial planes in adipose tissue) and changes in echogenicity compared to normal patients (Ibarra et al. (2018); Iker et al. (2019)). The fascial blurring is thought to be due to edema in the tissue (Ibarra et al.). Bilancini et al. demonstrated that lipodymia is consistently associated with functional changes in lymphovascular structure. Using dynamic imaging, they showed that patients suffering from lipodymia have abnormal lymphoscintigraphy patterns with delayed lymphatic flow, similar to the changes seen in patients with lymphedema. Thus, lipodymia is a lipopathy associated with functional changes in the lymphatic system (Escobedo et al. (2017); Poojari et al. (2022); Kruppa et al.). Lymphidynastic dysregulation has been described as both a consequence and a causative factor of lipodymia and adipose tissue enlargement (Poojari et al. (2022)).

[0003] Liposomal edema is often misdiagnosed as obesity and lymphedema. Lymphedema, which affects as many as 200 million people worldwide, is also associated with lymphatic system dysfunction and abnormal subcutaneous adipose tissue (SAT). Lymphedema is caused by relative lymphatic dysfunction and is characterized by prominent dermatopathology that increases limb circumference, fibrosis, inflammation, and the risk of recurrent skin infections. Similar to lipedema, lymphedema is associated with abnormal distribution of subcutaneous fat in the limbs (Escobedo et al. (2017)). Ultrasonography of affected tissue in lymphedema patients shows changes in echogenicity of the skin and SAT, blurring of the intermediate surface between subcutaneous fat and skin, and loss of distinction between fascial lines compared to normal patients (Iker et al. (2019); Suehiro et al. (2013)).

[0004] The need for pharmaceutical treatment of abnormal adipose tissue in patients with lipedema and lymphedema remains in this field. [Overview of the Initiative]

[0005] Summary of the Invention This invention is at least in part based on the finding that treatment with acebilustat resulted in early, significant ultrasound-detectable skin changes in the affected limbs of patients with secondary lymphedema. Specifically, as shown in the examples and figures, acebilustat reduced skin thickness, subcutaneous thickness, limb volume, water content, and subcutaneous echogenicity of the affected limb as observed by ultrasound. The reduced skin thickness and subcutaneous echogenicity suggest that acebilustat may target inflammation and excess water content in the affected tissue. These findings are relevant to the tissue changes observed in lipedema and lymphedema.

[0006] The present invention includes a method for treating lipodymetabolism in a subject requiring treatment for lipodymetabolism, comprising the step of administering acevirstat or another selective LTA4H inhibitor in a therapeutically effective dose. Patients suffering from lipodymetabolism may, for example, suffer from combined pathologies, such as stage IV lipodymetabolism, also known as lipopolymphedema. In a specific aspect, the method comprises the step of administering acevirstat. In a further aspect, pain, bruising and / or capillary fragility are reduced after treatment with acevirstat; for example, pain, bruising and / or capillary fragility are reduced for a period of 6 months or less or 3 months or less after treatment with acevirstat.

[0007] Also described herein is a method for treating a subcutaneous lymphatic dysfunction-related abnormality or subcutaneous lymphatic disease in a patient requiring treatment for such abnormality or subcutaneous lymphatic disease, comprising the step of administering a therapeutically effective dose of acevirstat or another selective LTA4H inhibitor to the patient. In one aspect, the patient suffers from lipedema. In another aspect, the patient suffers from lymphedema. The patient suffering from lymphedema may be suffering from a complex pathology, such as stage IV lipedema, also known as adipose lymphedema. In yet another aspect, the patient suffers from lower extremity lymphedema. In yet another aspect, the patient suffers from upper extremity lymphedema. In a further aspect, the present invention relates to a method for treating a subcutaneous lymphatic dysfunction-related abnormality or subcutaneous lymphatic disease in a patient suffering from lymphedema, wherein the subcutaneous thickness of the affected area (the area affected by the subcutaneous lymphatic dysfunction-related abnormality or subcutaneous lymphatic disease) is reduced by at least about 10% compared to baseline within 3 months or less after administration of acevirstat.

[0008] In a further aspect, the present invention is a method for reducing the subcutaneous thickness of a lymphedematous area in a patient suffering from lymphedema, the method comprising administering a therapeutically effective dose of acevirstat to the patient, wherein the subcutaneous thickness is reduced by at least about 10% compared to baseline within 6 months or less after administration of acevirstat. In a further aspect, the subcutaneous thickness is reduced by at least about 10% within 3 months or less after administration of acevirstat. In a further embodiment, the subcutaneous thickness is reduced by at least about 15% or at least about 20% compared to baseline within 6 months or less after administration of acevirstat. In a further aspect, the subcutaneous thickness is reduced by at least about 15% or at least about 20% compared to baseline within 3 months or less after administration of acevirstat.

[0009] In one aspect, the present invention is a method for treating a subcutaneous lymphatic dysfunction-related disorder or subcutaneous lymphatic disease or lymphedema in a patient requiring treatment for subcutaneous lymphatic dysfunction-related disorder or subcutaneous lymphatic disease or lymphedema, the method comprising administering to the patient a therapeutically effective dose of acevirstat or another selective LTA4H inhibitor, the patient further being treated by a surgical intervention such as lymphovenous anastomosis (LVA), vascularized lymph node transplantation (VLNT), and artificial lymph node transplantation. In one aspect, lymphedema is upper limb lymphedema. In a further aspect, lymphedema is lower limb lymphedema. In one aspect, acevirstat is administered.

[0010] The present invention further includes a method for preventing or reducing the risk of lymphedema in a patient, comprising the step of administering an effective dose of acevirstat or another selective LTA4H inhibitor to the patient, who is in need of prevention of lymphedema or reduction of the risk of developing it. In some aspects, acevirstat is administered. In some examples, patients who are in need of prevention of lymphedema or reduction of the risk of developing it may be cancer patients and patients who have undergone or are undergoing lymph node dissection or radiation therapy as part of cancer treatment, for example. In some embodiments, acevirstat is administered in conjunction with another prophylactic intervention, such as LVA or artificial lymph node transplantation.

[0011] In a further embodiment, the present invention includes a method for promoting lymphangiogenesis and / or lymphatic repair in a patient requiring such promotion, comprising the step of administering an effective dose of acevirstat or another selective LTA4H inhibitor to the patient. In one aspect, acevirstat is administered. For example, a patient requiring promotion of lymphangiogenesis and / or lymphatic repair is a patient at risk of developing lymphedema, such as a cancer patient or a patient undergoing or having undergone lymph node dissection or radiation therapy (e.g., as part of cancer treatment). In a further aspect, a patient requiring promotion of lymphangiogenesis and / or lymphatic repair is a patient who has received a prosthetic lymph node; in one aspect, treatment with acevirstat increases lymph proliferation and repair to and from the prosthetic lymph node. In a further aspect, the present invention relates to a method for promoting lymphatic vascular formation and / or lymphatic repair to an artificial lymph node in a patient who has received an artificial lymph node implantation, the method comprising the step of administering an effective amount of acevirstat to the patient.

[0012] The present invention also includes a method for treating lymphedema in a patient requiring treatment for lymphedema, wherein the subcutaneous echogenicity of the affected (lymphedematous) area is increased compared to normal (i.e., lymphedema is characterized by increased subcutaneous echogenicity of the affected area compared to normal), and the method comprises the step of administering to the patient an effective dose of acevirstat or another selective LTA4H inhibitor, the echogenicity of which is determined by ultrasound. In one aspect, the method further comprises the step of determining skin structural characteristics by ultrasound. In one aspect, acevirstat is administered.

[0013] The present invention further includes a method for treating lymphedema in a patient requiring treatment for lymphedema, wherein the lymphedema is characterized by an affected area or tissue having a skin echogenicity to subcutaneous echogenicity ratio smaller than the control ratio, and the method comprises administering to the patient an effective dose of acevirstat or another selective LTA4H inhibitor, the echogenicity being determined by ultrasound. In one aspect, the method further comprises determining skin structural characteristics by ultrasound. In one aspect, acevirstat is administered.

[0014] The present invention also includes a method for identifying patients who are responsive to treatment for lymphedema, the method being: i. A step of determining the skin echogenicity and subcutaneous echogenicity of the affected area or tissue using ultrasound; ii. A step of calculating the ratio of skin echogenicity to subcutaneous echogenicity in the affected area or tissue; iii. The process of identifying a patient as responsive to treatment when the ratio of affected areas is smaller than the ratio of the control; and iv. The procedure includes administering acevirstat or another selective LTA4H inhibitor to a patient identified as responsive to treatment. At some point, acevirstat is administered.

[0015] A method for identifying lymphedema patients who are responsive to treatment with acevirstat is also disclosed herein, the method being: i. A step of determining the skin echogenicity and subcutaneous echogenicity of the affected area or tissue using ultrasound; ii. A step of calculating the ratio of skin echogenicity to subcutaneous echogenicity in the affected area or tissue; iii. The process of identifying a patient as responsive to treatment when the ratio of affected areas is smaller than the ratio of the control; and iv. The procedure includes administering acevirstat to patients identified as responsive to treatment.

[0016] The present invention also includes a method for treating lymphedema in patients requiring treatment for lymphedema, the method being: i. A step of determining the skin echogenicity and subcutaneous echogenicity of the affected (lymphedematous) area or affected (lymphedematous) tissue at baseline using ultrasound, and calculating the ratio of skin echogenicity to subcutaneous echogenicity at baseline; ii. The step of administering acevirstat or another selective LTA4H inhibitor to the patient at an initial daily dose for, for example, for at least about 3 months, at least about 4 months, at least about 5 months, at least about 6 months, at least about 9 months, or at least about 1 year; iii. A step of determining the skin echogenicity and subcutaneous echogenicity of the affected area or tissue by ultrasound after treatment, and calculating the ratio of skin echogenicity to subcutaneous echogenicity after treatment; and iv. The procedure includes continuing administration of acevirstat or another selective LTA4H inhibitor at an initial daily dose if the post-treatment ratio is greater than the baseline ratio, or increasing the daily dose of acevirstat to an increased daily dose if the post-treatment ratio is not greater than the baseline ratio. At some point, acevirstat is administered.

[0017] In certain embodiments, the method includes administering to a patient an effective amount of aselastat. For example, aselastat can be administered at least once a day, such as orally. In one embodiment, the method includes orally administering to a patient aselastat at a total daily dose of about 200 mg or less, about 150 mg or less, about 100 mg or less, about 50 mg or less, about 50 mg to about 100 mg, about 100 mg or about 50 mg. BRIEF DESCRIPTION OF THE DRAWINGS

[0018] BRIEF DESCRIPTION OF THE DRAWINGS [Figure 1] Figures 1A, 1B, and 1C are graphs showing the skin thickness (mm) over time of the affected (lymphedematous) limb measured at baseline, 3 months, and 6 months after aselastat treatment for 10 or 11 patients as shown. Skin thickness was measured with calipers. A significant decrease in skin thickness was observed as early as about 3 months after aselastat treatment (p < 0.0001). [Figure 2] Figures 2A, 2B, and 2C are graphs showing the same data as above as the percent change over time of skin thickness (compared to baseline) measured at baseline, 3 months, and 6 months after aselastat treatment for 10 or 11 patients as shown. At 6 months, a 43% decrease in skin thickness was observed (mean for 10 patients; p < 0.0001). [Figure 3] Figures 3A, 3B, and 3C are graphs showing the volume (% change) of the limb over time measured at baseline, 3 months, and 6 months after aselastat treatment for 6 - 11 patients as shown. At 6 months, a 6.7% decrease in limb volume was observed (mean for 6 patients; p < 0.03). [Figure 4] Figures 4A, 4B, and 4C are graphs showing the bioimpedance (mOhm) of the affected limb over time (after aselastat treatment, at baseline, 3 months, and 6 months). Bioimpedance is a measure of water content, and higher bioimpedance corresponds to lower water content. [Figure 5] Figures 5A, 5B, and 5C are graphs showing the same data as changes in bioelectrical impedance over time (compared to baseline). At 6 months (Figure 5C), significantly higher bioelectrical impedance (corresponding to lower water content) was observed (p<0.01). [Figure 6A] Figures 6A and 6B show skin ultrasound images of a patient with right leg lymphedema before treatment (Figure 6A; left) and 3 months after treatment with acevirstat (Figure 6B; right). At 6 months (6 months of acevirstat treatment), subcutaneous thickness decreased by more than 20.2%, skin thickness decreased by 3.7%, and total thickness decreased by 17.6%. [Figure 6B] Figures 6A and 6B show skin ultrasound images of a patient with right leg lymphedema before treatment (Figure 6A; left) and 3 months after treatment with acevirstat (Figure 6B; right). At 6 months (6 months of acevirstat treatment), subcutaneous thickness decreased by more than 20.2%, skin thickness decreased by 3.7%, and total thickness decreased by 17.6%. [Figure 7] Figure 7 shows ultrasound images of a different patient from those in Figures 6A and 6B, illustrating subcutaneous thickness before treatment (left) and 6 months after treatment with acevirstat (right). A 15.2% decrease in subcutaneous thickness was observed 6 months after treatment. [Figure 8] Figure 8 shows a graph of the LymVAS total status score, a tool used to assess patients' quality of life at 3 and 6 months after acevirstat treatment. A significant improvement in the LymVAS quality of life status score was observed as early as 3 months after acevirstat treatment. [Figure 9] Figure 9 shows a graph of the LymVAS total change score, a tool used to assess changes in patients' quality of life at 3 and 6 months after acevirstat treatment. A significant improvement in the LymVAS total change score was observed as early as 3 months after acevirstat treatment. [Modes for carrying out the invention]

[0019] Detailed description of the invention Preferred embodiments of the present invention are described below.

[0020] As used herein, the words “a” and “an” mean to include one or more unless otherwise specified. For example, the term “an additional therapeutic agent” includes both a single additional therapeutic agent and a combination of two or more additional therapeutic agents. In another example, “upper limb” is intended to include one or both arms.

[0021] When the dosage or amount range of a drug or active ingredient (e.g., acevirstat) is described as "between" the lower limit and "between" the upper limit of the range, it is understood that the range is intended to include both the lower and upper limits, as well as the dosages between the lower and upper limits. For example, "a dosage of approximately 50 mg to approximately 100 mg" is understood to include the lower limit of the range of approximately 50 mg, the upper limit of the range of approximately 100 mg, and dosages in between, such as approximately 75 mg. Similarly, "a dosage of approximately 50 mg or less" is intended to include the dosage of approximately 50 mg and dosages less than approximately 50 mg.

[0022] When used herein in relation to a number or range, the term "about" allows for a degree of variability in a value or range that is, for example, within 10%, 5%, or 4%, or within 2%, or within 1% of the value or range.

[0023] The term "affected area" in relation to patients with lipodymetabolism refers to the anatomical portion of the patient that is lipodymetic. For example, in type III lipodymetabolism, the affected area may be the thigh or a portion thereof. In patients with lipodymetabolism, "affected tissue" refers to the tissue of a part of the patient's anatomy that is affected (lipodymetic). The terms "affected tissue," etc., can be used interchangeably with the terms "lipodymetic tissue" and "lipodymetic tissue," etc. For example, in type III lipodymetabolism, the affected tissue may be the subcutaneous tissue of the affected thigh region.

[0024] The term "affected area" in relation to lymphedema patients refers to a portion of the patient's anatomy that is lymphedematous. The affected area may be one or both arms, and / or one or both legs. In lymphedema patients, the terms "affected tissue," etc., refer to a portion of the patient's anatomy that is affected (lymphedematous). The term "affected tissue" can be used interchangeably with the terms "lymphedematous tissue" and "lymphedema tissue," etc. The term "tissue" includes the epifascial layer of the skin.

[0025] The term "affected tissue" refers to the subcutaneous tissue of patients exhibiting lymphatic disease and / or lymphatic dysfunction-related abnormalities in the subcutaneous tissue.

[0026] The echogenicity of a tissue is its ability to reflect or transmit ultrasound waves in relation to the surrounding tissue (Ihnatsenka et al. (2020)). Structures or tissues (or parts thereof) can be characterized as hyperechoic (white on an ultrasound image), hypoechoic (gray on an ultrasound image), and anechoic (black on an ultrasound image). For example, fat is mostly anechoic, while fascia and other connective tissue strands usually appear hyperechoic. Also, when there is an intermediate plane between two different structures (e.g., dermis and epidermis), the visible differences are usually clear, in contrast. As will be described in more detail herein, lipedema and lymphedema are associated with certain ultrasound changes, such as changes in echogenicity, compared to normal, unaffected tissue. For example, echogenicity can be measured in a specific region of interest (ROI) within the tissue.

[0027] The "skin-to-subcutaneous echogenicity ratio" is the ratio of the echogenicity of the dermis (or a target area within the dermis) to the echogenicity of the subcutaneous tissue (or a target area within the subcutaneous tissue). In some contexts, the skin-to-subcutaneous echogenicity ratio is the ratio of the echogenicity of the dermis (or a target area within the dermis) to the echogenicity of the subcutaneous adipose tissue (or a target area within the subcutaneous adipose tissue). The baseline skin-to-subcutaneous echogenicity ratio is determined in the same subject or a similar subject population before treatment is initiated. If the baseline skin-to-subcutaneous echogenicity ratio is determined using a similar subject population to the patient, the subject population may be composed of individuals suffering from the same disease and optionally or at the same stage or type as the patient. For example, for lipodeema, this may be the mean skin-to-subcutaneous echogenicity ratio of a population of patients suffering from similar lipodeema in type and / or stage as the patient. For lymphedema, this may be the ratio of the mean skin echogenicity to subcutaneous echogenicity of a population of patients suffering from lymphedema similar to the patient's lymphedema in terms of type. The subject population may be demographically similar, for example, in terms of age or sex. The skin echogenicity and subcutaneous echogenicity used to calculate the ratio may be measured / determined using the same ultrasound device (e.g., at baseline and / or after treatment).

[0028] The present invention relates to the use of acevirstat in patients diagnosed with, for example, lipedema and subcutaneous lymphatic disorders and / or subcutaneous lymphatic dysfunction-related abnormalities. Such subcutaneous lymphatic disorders are observed in most patients with lymphedema and lipedema in general. It is thought that acevirstat inhibits the enzymatic production of LTB4 in such patients, and as a result of this relaxation of molecular signaling, it may reverse the experience of abnormal fat distribution, loss of function, and / or impaired quality of life in such patients.

[0029] The present invention includes a method for treating a subcutaneous lymphatic dysfunction-related disorder or subcutaneous lymphatic disease in a patient requiring treatment of such disorder, comprising the step of administering a therapeutically effective dose of acevirstat to the patient. In one aspect, the subcutaneous tissue includes subcutaneous adipose tissue (SAT). In a further aspect, the subcutaneous tissue is SAT. In a further aspect, the subcutaneous tissue includes or consists of fibrous tissue. For example, a lymphatic dysfunction-related disorder may be an accumulation or deposition of SAT, inflammation of SAT, lipomegaly and / or hyperplasia, and / or fascial band distribution of SAT, or a combination thereof. In one aspect, a patient with a subcutaneous lymphatic dysfunction-related disorder or subcutaneous lymphatic disease suffers from lymphedema. In a further aspect, a patient with a subcutaneous lymphatic dysfunction-related disorder or subcutaneous lymphatic disease suffers from lipedema.

[0030] The present invention also includes a method for preventing or reducing the risk of subcutaneous lymphatic dysfunction-related abnormalities or subcutaneous lymphatic disease in a patient, comprising the step of administering a therapeutically effective dose of acevirstat to a patient at risk of subcutaneous lymphatic dysfunction-related abnormalities or subcutaneous lymphatic disease. In one aspect, subcutaneous tissue includes subcutaneous adipose tissue (SAT). In a further aspect, subcutaneous tissue is SAT. In a further aspect, subcutaneous tissue includes or consists of fibrous tissue. For example, lymphatic dysfunction-related abnormalities may be, for example, accumulation or deposition of SAT, inflammation of SAT, lipomegaly and / or hyperplasia, and / or disruption of the fascial bands of SAT, or a combination thereof. In one aspect, patients with subcutaneous lymphatic dysfunction-related abnormalities or subcutaneous lymphatic disease suffer from lymphedema. In a further aspect, patients with subcutaneous lymphatic dysfunction-related abnormalities or subcutaneous lymphatic disease suffer from lipedema.

[0031] The methods described herein may enhance the ultrasound characteristics of one or more symptoms, features, endpoints, or treated diseases (e.g., lipedema, lymphedema, subcutaneous lymphatic dysfunction-related abnormalities, or subcutaneous lymphatic disorders). The enhancement or change may be observed, for example, about 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 9 months, or 1 year or more after the initiation of treatment (e.g., administration of acevirstat or other LTA4H inhibitors). The enhancement or change may be observed, for example, within about 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 9 months, 1 year, or 2 years after the initiation of treatment (e.g., administration of acevirstat or other LTA4H inhibitors).

[0032] A method for preventing or reducing the risk of subcutaneous lymphatic dysfunction-related abnormalities or subcutaneous lymphatic disease in patients at risk of subcutaneous lymphatic dysfunction-related abnormalities or subcutaneous lymphatic disease can protect patients from developing subcutaneous lymphatic dysfunction-related abnormalities or subcutaneous lymphatic disease, or symptoms thereof, compared to, for example, the risk in patients without acevirstat administration, or can prevent patients from developing subcutaneous lymphatic dysfunction-related abnormalities or subcutaneous lymphatic disease, or symptoms thereof, or can reduce the risk of developing subcutaneous lymphatic dysfunction-related abnormalities or subcutaneous lymphatic disease, or symptoms thereof. The method includes a step of preventing or reducing the risk of lipedema or lymphedema in patients who require prevention or reduction of the risk of lipedema or lymphedema. In patients at risk of lipodymetabolism, methods for preventing lipodymetabolism or reducing its risk can protect patients from developing lipodymetabolism or its symptoms, prevent the development of lipodymetabolism or its symptoms, or reduce the risk of developing lipodymetabolism, compared to, for example, the patient's risk in the absence of acevirstat administration. In patients at risk of lymphedema, methods for preventing lymphedema or reducing its risk can protect patients from developing lymphedema or its symptoms, prevent the development of lymphedema or its symptoms, or reduce the risk of developing lymphedema, compared to, for example, the patient's risk in the absence of acevirstat administration.

[0033] When it is stated that a symptom or endpoint improved "for a period of X months or less" after administration of the activator, this is intended to include improvements in the symptom or endpoint determined at approximately X months after the initiation of activator treatment and improvements determined at less than X months after the initiation of acevirstat treatment. For example, a reduction in subcutaneous thickness such as "for a period of 6 months or less after administration of acevirstat" includes reductions in subcutaneous thickness measured at approximately 6 months after the initiation of acevirstat treatment and reductions measured at less than 6 months after the initiation of acevirstat treatment.

[0034] Liposomal edema is classified by stage (stages I-IV) and type (I-V). Stage I lipodema is characterized by normal skin texture over an enlarged subcutaneous tissue (Vyas et al., 2023). In stage 2, the skin has an uneven surface over a mass of subcutaneous tissue (ibid.). Stage 3 is more painful and is characterized by increased lipoede tissue and loss of skin elasticity (Poojari et al.). In stage 4, the patient also has lymphedema, which is called lipolymphedema. The types of lipodema are classified based on the affected anatomy. Type I includes a distribution of fat from the navel to the hip joint, including the pelvis and buttocks. Type II includes a distribution of fat from around the pelvis to the knee. Type III includes a distribution of fat from around the pelvis to the ankle, with a prominent cuff at the ankle. Type IV includes a distribution of fat from the shoulder to the wrist. Type V is rare and involves a distribution of fat extending from the knee or below the knee through the ankle. Patients may exhibit combinations of types of lipodyme. For example, patients with types II and IV, as well as patients with types II and IV, share common characteristics. The present invention also includes methods for treating stage 1, stage 2, stage 3 and / or stage 4 lipodyme. The present invention also includes methods for treating type I, type II, type III, type IV and / or V lipodyme and combinations thereof.

[0035] The treatments described herein may improve one or more symptoms, characteristics, endpoints, or ultrasound characteristics of a disease. Improvements or changes may be observed, for example, about 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 9 months, or 1 year or longer after the initiation of treatment (e.g., administration of acevirstat). Such improvements may be compared to those before the initiation of treatment (referred herein to as "baseline"). For example, treatment may reduce the severity of the disease and / or improve the histology and / or function and / or elasticity of the skin compared to baseline. In another example, treatment with acevirstat may reduce inflammation and / or pain and / or capillary fragility and / or bruising. In yet another example, treatment with acevirstat may increase lymphatic flow and / or improve vascular function and / or increase lymphatic drainage and / or reduce edema. In a further development, treatment results in an improvement in lymphatic symptoms compared to baseline, as indicated, for example, by lymphoscintigraphy and indocyanine green (ICG) lymphography. Lymphoscintigraphic findings in lipoede include intricate lymphatic vessels that slow the transport of radionuclides in the foot (Herbst et al. (2021)). Furthermore, treatment results in a reduction in the amount of fat or adipose in the affected area and / or structural changes in the adipose tissue in the affected area. In addition, as described herein, treatment may reduce the number or size of lipoede nodules.

[0036] As described above, treatment with acevirstat may reduce pain and / or bruising in patients with lipodymere. Symptoms of lipodymere include pain (e.g., pain on palpation), easy bruising, and cosmetic impairment. Lipodymere pain is also described as tenderness. The term “lipodymere pain” includes, for example, tenderness and discomfort in one or both arms, and / or pain / tenderness / discomfort in one or both legs. In some embodiment, as described herein, treatment with acevirstat reduces lipodymere pain. For example, lipodymere pain is reduced in the affected area for up to 6 months or up to 3 months after administration of acevirstat. Lipodymere pain may be measured by subjective pain scores, for example, as described in Smoot et al. (2015), J Cancer Surviv. 9: 287-304, the contents of which are explicitly incorporated herein by reference. Furthermore, in more detail, lipoedema-related contusions and / or hematoma formation are reduced in the affected area within 6 months or less or 3 months or less after administration of acevirstat.

[0037] Lipid edema is also associated with increased capillary fragility. In one aspect, treatment with acevir stat improves or reduces capillary fragility, as measured, for example, by vacuum aspiration (VSM), using Parrot's angiosterrometer, as described, for example, Szolnoky et al. (2017), Lymphology 50(4): 203-209. Capillary fragility is a tendency for capillary walls to rupture. Increased macrophage infiltration is observed in lipid edema tissue, and the infiltrating macrophages are mainly M2 polarized macrophages (Wolf et al. (2022)). In one aspect, treatment reduces the number of macrophages and / or the number of M2 polarized macrophages. In a further aspect, treatment may alter the macrophage composition. In a further aspect, treatment reduces the number of fibroblasts in lipid edema tissue.

[0038] As described above, in some patients, lipodymere is associated with a decrease in the visualization of the fascial band / surface of the affected subcutaneous tissue (e.g., subcutaneous adipose tissue) under ultrasound and / or changes in the echogenicity of the skin and / or subcutaneous tissue. In some cases, treatment with acevirstat results in changes on ultrasound in the affected (lipodymere) area or tissue compared to baseline. As used herein, “baseline” is the time before the initiation of treatment (e.g., acevirstat or other LTA4H inhibitors). Baseline echogenicity is determined in the same subject or a similar subject population (e.g., a group of patients suffering from similar types and / or stages of lipodymere) before treatment is initiated. Treatment with acevirstat may result in a decrease in subcutaneous echogenicity (e.g., echogenicity of the subcutaneous adipose tissue or the area of ​​interest in SAT) in the affected (lipodymere) area or tissue compared to baseline. For example, heterogeneity may be observed in subcutaneous adipose tissue with areas of increased echogenicity at baseline, and the echogenicity of one or more of these areas of interest decreases after treatment with acevirstat. In a further context, the treatments described herein result in improvement and / or visualization by ultrasound treatment of the fascial band of the subcutaneous adipose tissue in the affected area. Furthermore, the ratio of cutaneous echogenicity to subcutaneous echogenicity in adipose tissue increases after treatment with acevirstat or another selective LTA4H inhibitor compared to baseline.

[0039] Although the genetic components of the disease are not fully understood, lipodymere is an autosomal dominant disorder that is likely to be inherited. Patients treated with acevirstat may, for example, express biomarkers indicating lipodymere, and elevated levels of PF4 have been reported in patients with lipodymere and lymphedema (for example, as described in US20220107329, which is explicitly incorporated herein by reference). In a further context, patients treated may be carriers of genes associated with lipodymere. Such genes include, for example, the aldo-ketoreductase 1C1 (AKR1C1) mutation (e.g., Leu213Gln) associated with non-symptomatic primary lipodymere (Michelini et al. (2020)). Further genetic elements are described, for example, in Paolacci et al. (2019), Genetics of lipedema: new perspectives on genetic research and molecular diagnoses, Eur Rev Med Pharmacol Sci 23(13):5581-5594, the contents of which are explicitly incorporated herein by reference. The present invention also includes methods for preventing lipedema, reducing the risk of developing lipedema, or inhibiting the progression of lipedema in individuals who are, have been, or are being treated for lipedema, or in patients at risk of developing lipedema, such as patients expressing genetic markers associated with lipedema.

[0040] In some cases, patients are treated with surgery, such as lipoedema reduction surgery, in addition to the administration of acevirstat or other selective LTA4H inhibitors before and after surgery. In further cases, patients are further treated with compression therapy, physiotherapy, exercise therapy, functional lymphatic rehabilitation, and / or manual lymphatic drainage. In further cases, patients are treated with acevirstat in addition to additional activators selected from the group consisting of sympathomimetic agents (e.g., amphetamine or phentermine), metformin, resveratrol, diosmin, and selenium, or a combination thereof. Acevirstat or other selective LTA4H inhibitors may be administered before or after the administration of one or more additional activators. Such combination therapy includes the administration of a single drug formulation containing acevirstat or other selective LTA4H inhibitor and one or more additional activators, as well as the administration of acevirstat and each activator in its own separate drug formulation.

[0041] The present invention also includes a method for treating lipodymere in a patient requiring treatment for lipodymere, wherein the baseline subcutaneous echogenicity of the affected area or tissue (or area of ​​interest) is increased compared to normal, and the method comprises the step of administering an effective dose of acevirstat to the patient. In this context, “normal” echogenicity means the echogenicity of the same part of the anatomy or the corresponding area of ​​interest in an individual(s) not suffering from lipodymere, or in other words, in a normal individual or a population of normal individuals.

[0042] The present invention further includes a method for treating lipodymetabolism in a patient requiring treatment for lipodymetabolism, wherein the affected area (or portion thereof) has a baseline skin echogenicity to subcutaneous echogenicity ratio smaller than the control ratio, and the method comprises the step of administering an effective dose of acevirstat to the patient, the echogenicity being determined by ultrasound. The "control ratio" is the mean skin echogenicity to subcutaneous echogenicity ratio of a population of normal individuals. If, at some point, the ratio (e.g., at baseline) is at least 5%, 10%, 15%, or 20% lower than the control ratio, treatment is initiated or the patient is administered acevirstat.

[0043] In patients requiring treatment for lipodymere, methods for treating lipodymere are also included, and these methods include: A step of determining the baseline skin echogenicity and subcutaneous echogenicity of the affected (lipidedematous) area or tissue using ultrasound, and calculating the baseline ratio of skin echogenicity to subcutaneous echogenicity; The process of administering acevirstat to the patient at an initial daily dose; and A step of determining the skin echogenicity and subcutaneous echogenicity of the affected area or tissue after treatment using ultrasound, and calculating the ratio of post-treatment skin echogenicity to subcutaneous echogenicity; The procedure includes continuing administration of acevirstat at the initial daily dose if the post-treatment ratio is greater than the baseline ratio, or increasing the daily dose of acevirstat to the increased daily dose if the post-treatment ratio is not greater than the baseline ratio. The initial daily dose is the daily dose at the start of treatment and / or the daily dose at the time of measurement of skin echogenicity and subcutaneous echogenicity. The increased daily dose is a daily dose greater than the initial daily dose.

[0044] Skin echogenicity and subcutaneous echogenicity can be determined after treatment, for example, at least about 1 month, at least about 2 months, at least about 3 months, at least about 4 months, at least about 5 months, at least about 6 months, at least about 9 months, at least about 1 year, at least about 18 months, or at least about 2 years after initiation of acevirstat administration. If the ratio does not increase (at the time it is measured, e.g., 6 months after initiation of treatment), the administration regimen may be modified, for example, the total daily dose may be increased.

[0045] Acevirstat or other selective LTA4H inhibitors may be administered to patients in addition to existing therapeutic regimens or standard of care. Standard of care for lipodymere includes, but is not limited to, exercise (e.g., postural and muscle strengthening exercises), gait training, neuromuscular re-education, diaphragmatic breathing to increase lymphatic flow, manual therapy, compression garments, air compression devices, soft tissue fluidization (e.g., to reduce pain and inflammation), manual lymphatic drainage, and surgery. Treatment for lipodymere may also include the administration of drugs selected from the group consisting of sympathomimetic agents, metformin, resveratrol, diosmin, and selenium, or combinations thereof; therefore, acevirstat or other LTA4H inhibitors may be administered to patients in addition to drugs selected from the group consisting of sympathomimetic agents, metformin, resveratrol, diosmin, and selenium, or combinations thereof. For example, sympathomimetic agents are selected from the group consisting of amphetamines and phentermines. In a further context, acevirstat or other LTA4H inhibitors are administered to patients being treated with glucagon-like peptide (GLP-1) agonists, such as, but not limited to, dulaglutide, exenatide, semaglutide, liraglutide, terzepatide, and lixisenatide.

[0046] In yet another aspect, acevirstat or other selective LTA4H inhibitors are administered in combination with one or more additional activators useful for the prevention or treatment of lipedema. In some of these embodiments, acevirstat or other selective LTA4H inhibitors are administered with different LTB4 inhibitors. For example, the different LTB4 inhibitors may be from the BLT1 / BLT2 antagonist class of LTB4 inhibitors. In further examples, acevirstat or other selective LTA4H inhibitors are administered in combination with sympathomimetic agents (e.g., amphetamine or phentermine), metformin, resveratrol, diosmin, and selenium.

[0047] Regarding lipodymere, treatment may begin, for example, at any stage of the condition and may continue until or beyond the point at which the patient's condition stabilizes or reverses to a non-symptomatic state. Treatment using the method of the present invention may be initiated, for example, after the onset of any clinically apparent lipodymere, for example, after the onset of stage 1. Treatment using the method of the present invention may also be initiated after the onset of stage 2 lipodymere. Treatment using the method of the present invention may also be initiated, for example, after the onset of stage 3 lipodymere. Treatment may also be initiated in patients who are at risk of developing lipodymere but before the onset of lipodymere.

[0048] Those skilled in the art will understand that the methods of the present invention are applicable to the treatment and prevention of lipodymere, including its signs and symptoms, such as those related to the following clinical indicators of lipodymere. Some clinical indicators may be used to diagnose lipodymere and to monitor the effectiveness of treatments, such as treatment using the compositions and methods of the present invention. The present invention provides a method for determining the efficacy of lipodymere treatment in a subject requiring lipodymere treatment by (a) measuring an endpoint of a clinical indicator in a patient, where the endpoint is measured after treatment has started; (b) comparing the endpoint of the clinical indicator to a baseline or reference, where the baseline or reference is measured in the same subject or a similar subject population before treatment has started; and (c) determining the efficacy of the lipodymere treatment based on the comparison step. Analysis of clinical indicators may include changes in ultrasound; reduction of subcutaneous adipose tissue; structural changes in subcutaneous adipose tissue, reduction of edema or swelling, reduction of pain, reduction of bruising, reduction of capillary fragility, and / or changes in the structure and function of lymph.

[0049] In some embodiments of the present invention, for example, in the treatment of patients with established diseases, improvement of the structure of adipose tissue in the affected area provides a convenient method for evaluating the success of the treatment. In some embodiments, the treatments provided herein are effective when, after a period of time from the start of treatment (e.g., about 2 weeks, about 1 month, about 2 months, about 3 months, about 4 months, about 5 months, about 6 months or more), a reduction in fat deposits or a change in the structure of adipose tissue (as measured by ultrasound) is observed in at least one affected area compared to at least one affected area before the start of treatment.

[0050] The present invention also encompasses methods for treating lymphatic dysfunction-related abnormalities or lymphatic disorders of the subcutaneous tissue in patients with lymphedema. A method for treating lymphedema using acevirstat is described, for example, in WO2023 / 107608 (PCT application number PCT / US22 / 52230; title “Methods of Treating Lymphedema”), the contents of which are expressly incorporated herein by reference. Similarly, a method for treating lymphedema using the LTA4H inhibitor ubenimex is described, for example, in U.S. Patent No. 10,500,178, the contents of which are expressly incorporated herein by reference. As used herein, lymphedema is edema of one or more areas of the body due to genetically determined lymphatic dysfunction (primary lymphedema) or obstruction, obstruction, or dysfunction of lymphatic vessels (secondary or acquired lymphedema). Symptoms and signs may include varying degrees of thickening, fibrous, or non-pitting edema in one or more areas of the body. In one phase, the patient suffers from primary lymphedema. In another phase, the patient suffers from secondary lymphedema. And in yet another phase, the lymphedema is cryptogenic lymphedema.

[0051] Primary lymphedema is constitutive and relatively less common than secondary forms. They vary in phenotype and patient age at presentation. While the methods of the present invention are applicable to these primary forms of lymphedema, it will be understood by those skilled in the art that treatment may be more effective in some forms other than others due to different disease etiologies. Primary forms of lymphedema include, but are not limited to, Milroy's disease, Mage's disease, (primary lymphedema), lymphedema trichiasis, lymphedema Tarda, and other genetic syndromes with prominent lymphedema, such as Turner syndrome and Henecum syndrome. Congenital lymphedema, for example, appears at birth or within a few months thereafter and may be due to lymphoid malformation or hypoplasia. Milroy's disease is an autosomal dominant familial form of congenital lymphedema resulting from a mutation in the FLT4 gene and associated with hypoproteinemia due to protein-losing enteropathy caused by edema and sometimes diarrhea and / or lymphangiectasia of the intestines. Lymphedema with trichiasis is an autosomal dominant familial form of primary lymphedema caused by a mutation in the transcription factor gene (FOXC2), resulting in excessive eyelashes (trichiasis) and edema of the legs, arms, and sometimes face. Lymphedema Tarda develops after the age of 35. Both familial and sporadic forms exist; the genetic criteria for both are unknown. Clinical findings are similar to those of primary lymphedema, but may be less severe. Hereditary lymphedema type II (Meige's disease, primary lymphedema) develops in most individuals around or shortly after puberty. This is the most common type of primary lymphedema. In addition to lymphedema of the limbs, other areas of the body, such as the arms, face, and larynx, may be affected. Some individuals may develop yellow nails. Lymphedema is prominent in several other genetic syndromes, including Turner syndrome; yellow nail syndrome, characterized by pleural effusion, chronic lung disease, lymphedema, and yellow nails; and Hennecum syndrome, a rare congenital syndrome of systemic lymphatic abnormalities, facial deformities, and intellectual disability. The methods and compositions of the present invention may be used to treat subcutaneous lymphatic dysfunction-related abnormalities or subcutaneous lymphatic disorders in patients suffering from any of these primary lymphedemas and their symptoms.

[0052] Secondary (acquired) lymphedema is considerably more common than primary lymphedema. It is generally caused by surgery (especially lymph node dissection, typically for staging and treatment of cancer), radiation therapy (especially axillary or groin), trauma, lymphatic obstruction due to tumors, increased white blood cell count due to leukemia, infection, venous hypertension (venous lymphedema), and, in developing countries, lymphophilia or any condition or treatment that restricts or reduces lymphatic flow. In some aspects, the methods described herein are used to treat secondary lymphedema. In further aspects, the methods described herein are used to treat secondary lymphedema in cancer patients (e.g., patients who have been treated for cancer or are being treated for cancer). Furthermore, in even further aspects, the methods described herein are used to treat secondary lymphedema resulting from non-cancerous causes (e.g., in patients who have not been treated for cancer or were not treated for cancer).

[0053] In one embodiment, the method includes the treatment of subcutaneous lymphatic dysfunction-related abnormalities or subcutaneous lymphoid disorders in patients with established secondary lymphedema, for example, as a result of cancer treatment. It is estimated that more than 15% of breast cancer survivors experience secondary lymphedema. Surgical removal of lymph nodes or therapeutic radiation of lymph nodes increases the risk of lymphedema. After axillary intervention, 15%–30% of breast cancer survivors experience clinically relevant lymphedema, but other types of cancer and their associated treatments can also cause secondary lymphedema. The prevalence of lymphedema associated with other malignancies (cancers) was as follows: soft tissue sarcoma 30%, lower extremity melanoma 28%, gynecological cancers 20%, genitourinary cancers 10%, and head and neck cancers 50%. Lymphedema can also occur due to increased lymph production in patients with other causes of chronic venous insufficiency, congestive heart failure, and venous hypertension. The method of the present invention is applicable to the treatment of subcutaneous lymphatic dysfunction-related abnormalities or subcutaneous lymphatic disorders in any of the patients with secondary lymphedema. In one context, the lymphedema is upper extremity lymphedema. In one context, the patient develops upper extremity lymphedema after breast cancer treatment (referred herein to as breast cancer treatment-related upper extremity lymphedema). In a further context, the lymphedema is associated with head and neck cancer. In yet another context, the lymphedema is lower extremity lymphedema. In yet another context, the lymphedema is lymphedema of the head, neck, and torso.

[0054] The basic sign of acquired lymphedema is soft tissue edema, graded into four stages. The term “established lymphedema” can generally refer to any of stages 1-3 of the disease, without limitation, including more advanced stages of the disease, such as stages 2 and 3, where structural changes in the affected tissue are observed. In stage 0, the affected area is physically normal, but lymphatic insufficiency may be indicated by clinical evaluation. In stage 1, the edema is sunken, and the affected area often returns to normal after elevation of the affected limb(s). In stage 2, the edema is sunken, and chronic soft tissue inflammation causes structural changes in the tissue with sunken edema. In stage 3, due to large, chronic soft tissue structural changes, the edema is thickened and irreversible.

[0055] In patients undergoing surgery and / or at risk of developing lymphedema, treatment may be initiated, for example, immediately after surgery, or within one week or one to three days after surgery (for example, an initial dose may be administered). Treatment may also be initiated after, immediately after, or within one week of the completion of surgical wound healing. In further contexts, treatment may be initiated one to three days after radiotherapy or cancer treatment, or before the onset or diagnosis of stage 0 lymphedema. Treatment may also be initiated after the onset or diagnosis of stage 0 lymphedema, or after the onset or diagnosis of clinically apparent lymphedema.

[0056] In patients suffering from lymphedema, treatment with acevirstat may also reduce pain in patients with lymphedema. In addition to swelling, lymphedema is associated with localized pain (referred to herein as “lymphedema pain”). Pain is also described as tenderness and / or discomfort. The term “lymphedema pain” includes tenderness and discomfort, e.g., pain / tenderness / discomfort in one or both arms and / or pain / tenderness / discomfort in one or both legs. In some aspects, treatment with acevirstat as described herein reduces lymphedema pain. For example, lymphedema pain is reduced in the affected area within 6 months or less or 3 months or less after administration of acevirstat. In some aspects, pain is reduced by at least about 5%, 10%, 15%, or 20% within 6 months or less or 3 months or less after administration of acevirstat. Lymphedema pain is described, for example, in Smoot et al. (2015), J Cancer Surviv. 9: As described on pages 287-304, it can be measured, for example, by a subjective pain score.

[0057] As discussed herein, lymphedema and lipedema produce tissue changes that are visible by ultrasound. One such change is the appearance of "cobblestoning," or cobblestone formation in the tissue. In some embodiments, treatment with acevirstat as described herein improves or reduces the appearance of cobblestone formation visible by ultrasound.

[0058] In some cases, treatment with acevirstat results in changes on ultrasound of the affected (lymphedematous) area or tissue compared to baseline. Lymphedema in some patients is associated with decreased visualization of the fascial bands / surfaces of the affected subcutaneous tissue (e.g., subcutaneous adipose tissue) and / or changes in echogenicity of the skin and / or subcutaneous tissue under ultrasound. Treatment with acevirstat may result in decreased subcutaneous echogenicity (e.g., subcutaneous adipose tissue or echogenicity of the area of ​​interest) of the affected (lymphedematous) area or tissue compared to baseline. In further cases, the treatments described herein result in improved fascial bands and / or ultrasound visualization of the subcutaneous adipose tissue in the affected area. In some cases, the ratio of skin echogenicity to subcutaneous echogenicity is increased after treatment compared to baseline.

[0059] The present invention also includes a method for treating lymphedema in a patient, wherein the subcutaneous echogenicity of the affected area or tissue of the patient is increased compared to normal, and the method includes the step of administering an effective dose of acevirstat to the patient. In this context, “normal” echogenicity means the echogenicity of the same part of anatomy in an individual (one or more) that does not suffer from lymphedema and / or the echogenicity of an area (e.g., limb) or tissue opposite to the affected area (or limb) or tissue. For example, if a patient suffers from lymphedema in their right leg, “normal” echogenicity may be determined by ultrasound treatment of the patient’s unaffected (non-lymphedematous) left leg.

[0060] The present invention also relates to a method for treating lymphedema in a patient, wherein the affected area or tissue of the patient has a skin echogenicity to subcutaneous echogenicity ratio smaller than the control ratio, and the method comprises the step of administering an effective dose of acevirstat to the patient, the echogenicity being determined by sonication. The "control ratio" is either the control ratio which is the mean skin echogenicity to subcutaneous echogenicity ratio of a population of normal individuals, or the control ratio which is the skin echogenicity to subcutaneous echogenicity ratio of the patient's tissue on the opposite side of the affected (lymphedematous) area or tissue. In some cases, acevirstat is administered to the patient if the ratio is at least 5%, 10%, 15%, or 20% lower than the control ratio.

[0061] In patients requiring treatment for lymphedema, methods for treating lymphedema are also included, and such methods are: A step of determining the skin echogenicity and subcutaneous echogenicity of the affected area or tissue at baseline using ultrasound, and calculating the baseline ratio of skin echogenicity to subcutaneous echogenicity; The process of administering acevirstat to the patient at an initial daily dose; and A process of determining the skin echogenicity and subcutaneous echogenicity of the affected area or tissue after treatment using ultrasound, and calculating the ratio of skin echogenicity to subcutaneous echogenicity after treatment; The procedure includes continuing administration of acevirstat at the initial daily dose if the post-treatment ratio is greater than the baseline ratio, or modifying the dose of acevirstat if the post-treatment ratio is not greater than the baseline ratio. Skin echogenicity and subcutaneous echogenicity are determined at least about 1 month, at least about 2 months, at least about 3 months, at least about 4 months, at least about 5 months, at least about 6 months, at least about 9 months, at least about 1 year, at least about 18 months, or at least about 2 years after the start of acevirstat administration. If the ratio does not increase (at the time it is measured, e.g., 6 months after the start of treatment), the dose regimen may be modified, e.g., the total daily dose may be increased.

[0062] In other embodiments, the present invention relates to a method for treating lymphatic dysfunction-related abnormalities or lymphatic disorders of the subcutaneous tissue, wherein the patient has lymphedema (stages 0-3) as a result of cancer treatment, such as surgery or radiotherapy, or other therapies or treatments that damage the lymphatic system, and the method comprises the step of administering an effective dose of acevirstat. In some embodiments, the individual is treated by surgery as a result of cancer diagnosis and treatment. Other surgical procedures affecting lymph nodes also make lymphedema treatable according to the present invention. In such embodiments, treatment with acevirstat may be initiated before surgery, immediately after surgical wound healing, or after some or further substantial wound healing, but before the patient is diagnosed with stage 0 lymphedema, for example, at a point after surgical wound healing, such as 3-14 days after surgery. In further embodiments, the patient has been treated with radiotherapy, and the patient may subsequently undergo surgery for cancer treatment. In this embodiment, treatment with acevirstat may be initiated before, during, or after radiotherapy, or after some or more substantial wound healing has occurred as described above, but may be initiated at a post-radiation point, such as before the patient is diagnosed with stage 0 lymphedema.

[0063] The present invention encompasses a method for treating subcutaneous lymphatic dysfunction-related abnormalities, subcutaneous lymphatic disease, or lymphedema in patients suffering from subcutaneous lymphatic dysfunction-related abnormalities, subcutaneous lymphatic disease, or lymphedema, the patients having undergone, for example, lymph node dissection or radiotherapy as part of cancer treatment, and the method comprises the step of administering an effective dose of acevirstat.

[0064] The present invention also includes a method for treating a subcutaneous lymphatic dysfunction-related abnormality or subcutaneous lymphatic disease in a patient who requires treatment for such abnormality or subcutaneous lymphatic disease, the patient suffering from upper limb lymphedema (e.g., arm lymphedema) after, for example, cancer surgery and / or radiotherapy, and the method comprises the step of administering an effective dose of acevirstat to the patient. For example, a patient may suffer from upper limb lymphedema after breast cancer surgery and / or radiotherapy. Arm or upper limb lymphedema may be caused by disruption of the axillary lymphatic system due to surgery or radiotherapy, resulting in fluid accumulation in the subcutaneous tissue of the arm.

[0065] The present invention further includes a method for treating a subcutaneous lymphatic dysfunction-related abnormality or subcutaneous lymphatic disease in a patient who is in need of treatment for a subcutaneous lymphatic dysfunction-related abnormality or subcutaneous lymphatic disease, the patient suffering from lower extremity lymphedema (e.g., lymphedema of the leg). In one example, the patient suffering from lower extremity lymphedema is not a cancer patient.

[0066] In some embodiments, the present invention is a method for treating subcutaneous lymphatic dysfunction-related abnormalities, subcutaneous lymphatic diseases, or lymphedema in patients requiring treatment (e.g., after lymph node dissection), comprising the step of administering an effective dose of acevirstat in combination with a surgical intervention intended to treat or alleviate the condition. Non-limiting examples of surgical interventions used to treat lymphedema include lymphovenous anastomosis (LVA) (also referred to in the literature as lymphovenous bypass or LVB), vascularized lymph node transplantation (VLNT), and artificial lymph node implantation. LVA is used to treat lymphedema and improve physical symptoms and quality of life (Jonis et al. (2024), Nature Scientific Reports 14: 2238). In some aspects, the present invention relates to a method for treating subcutaneous lymphatic dysfunction-related abnormalities, subcutaneous lymphatic diseases, or lymphedema, comprising the step of administering acevirstat in combination with LVA. Artificial lymph nodes are implantable devices designed to maintain lymphatic flow after lymph node dissection surgery (see, for example, Duran-Aguilar et al. (2022), Healthcare (Basel) 10(1): 68; U.S. Patents 8,101,195, 9,234,175, 8,030,070, JP2004255110A, JP2012036151A, U.S.2006171988A and JP2006129839A). In one aspect, the present invention is a method for treating subcutaneous lymphatic dysfunction-related abnormalities, subcutaneous lymphatic diseases, or lymphedema, comprising the step of administering acevirstat to a patient who has had an artificial lymph node implanted. VLNT involves the transport of lymphatic drainage from a functional lymph node to an area of ​​the body where the lymphatic drainage is damaged or affected. In one aspect, the present invention is a method for treating lymphedema, comprising the step of administering acevirstat in combination with VLNT.

[0067] The present invention further includes a method for preventing or reducing the risk of subcutaneous lymphatic dysfunction-related abnormalities, subcutaneous lymphatic diseases, or lymphedema in a patient, comprising the step of administering an effective dose of acevirstat to the patient, who is in need of prevention or reduction of the risk of subcutaneous lymphatic dysfunction-related abnormalities, subcutaneous lymphatic diseases, or lymphedema. Patients who are in need of prevention or reduction of the risk of subcutaneous lymphatic dysfunction-related abnormalities, subcutaneous lymphatic diseases, or lymphedema are patients at risk of developing lymphedema, for example, patients who have experienced surgery (e.g., lymph node dissection for staging and treatment of cancer), radiotherapy (especially axillary or groin), trauma, lymphatic obstruction due to tumor, increased leukocytes for leukemia, infection, venous hypertension (venous lymphedema), filariasis (in developing countries), or any condition or treatment that restricts or reduces lymphatic flow. In a particular aspect, the present invention is a method for preventing or reducing the risk of subcutaneous lymphatic dysfunction-related abnormalities, subcutaneous lymphatic disease, or lymphedema in patients who are or have been undergoing lymph node dissection or radiotherapy, for example, as part of cancer treatment. The method comprises the steps of administering acevirstat after surgery or radiotherapy and optionally administering acevirstat before the commencement of surgery or radiotherapy. Regarding surgical procedures, subcutaneous lymphatic dysfunction-related abnormalities, subcutaneous lymphoid disorders, or lymphedema may develop in a delayed manner, for example, more than one year after surgery, or for example, one to five years after surgery (Cemal et al. (2013), J Am Coll Surg 213(4): 543-551). The method may include administration of acevirstat after surgery (e.g., lymph node dissection), for example, within a few hours or one week after surgery, and administration of acevirstat may be continued until the risk of subcutaneous lymphatic dysfunction-related abnormalities, subcutaneous lymphoid disorders, or lymphedema is significantly reduced, for example, acevirstat may be administered for at least six months, at least one year, at least 18 months, at least two years, at least 30 months, at least three years, at least four years, at least five years, at least six years or more after surgery. The method may optionally include administration of acevirstat before surgery.Treatment with acevirstat may reduce the risk of developing subcutaneous lymphatic dysfunction-related abnormalities, subcutaneous lymphatic disease, or lymphedema compared to the absence of acevirstat treatment. In some cases, administration of acevirstat after surgery reduces the risk of developing lymphedema by at least approximately 5%, 10%, 15%, 20%, 25%, 30%, 40%, 45%, or 50% or more compared to the absence of acevirstat treatment. Methods for preventing or reducing the risk of subcutaneous lymphatic dysfunction-related abnormalities, subcutaneous lymphatic disease, or lymphedema include steps to reduce the severity of subcutaneous lymphatic dysfunction-related abnormalities, subcutaneous lymphatic disease, or lymphedema, or any of these symptoms. For example, such methods include steps to reduce the severity of lymphedema that develops compared to the risk in patients without acevirstat administration. For example, the method includes steps to reduce the risk of a patient developing stage 1, 2, or 3 lymphedema.

[0068] In some embodiments, the present invention provides a method for preventing or reducing the risk of subcutaneous lymphatic dysfunction-related abnormalities, subcutaneous lymphatic disease, or lymphedema in patients requiring prevention or reduction of the risk of subcutaneous lymphatic dysfunction-related abnormalities, subcutaneous lymphatic disease, or lymphedema, comprising the step of administering an effective amount of acevirstat in combination with another prophylactic intervention, e.g., pharmaceutical treatment or prophylactic surgical intervention (e.g., after lymph node dissection), the method comprising the step of administering an effective amount of acevirstat. For example, the method may prevent or reduce the risk of subcutaneous lymphatic dysfunction-related abnormalities, subcutaneous lymphatic disease, or lymphedema in patients after surgery (e.g., lymph node dissection), including the administration of acevirstat and further prophylactic interventions after surgery. Non-limiting examples of prophylactic surgical interventions include lymphovenous anastomosis (LVA) (also referred to in the literature as lymphovenous bypass or LVB) and artificial lymph node implantation. LVA is used prophylactically in cancer patients to reduce the risk of lymphedema (Deldar et al. (2023), Ann Surg Open 4(2): e278). In some cases, the administration of acevirstat in addition to prophylactic LVA may reduce the risk of developing lymphedema compared to the absence of acevirstat treatment. Lymph nodes are implantable devices designed to maintain lymphatic flow after lymph node dissection surgery (see, for example, Duran-Aguilar et al. (2022), Healthcare (Basel) 10(1): 68; U.S. Patents 8,101,195, 9,234,175, and 8,030,070). In some cases, administration of acevirstat in combination with the implantation of lymph nodes may reduce the risk of developing lymphedema compared to the absence of acevirstat treatment.

[0069] In patients at risk of lymphedema due to surgery, radiotherapy, or cancer treatment, treatment may be initiated, for example, immediately after the start of surgery, radiotherapy, or cancer treatment, within one week, or one to three days later (e.g., an initial dose may be administered), or before the start of surgery, radiotherapy, or cancer treatment. Treatment may also be initiated after surgical wound healing is complete, or immediately after the start of radiotherapy or cancer treatment, within one week, or one to three days later. In some cases, acevirstat is administered before surgery and continued after surgery as described above.

[0070] The present invention also includes methods for preventing or inhibiting the progression of lymphedema in individuals who are being treated for, have been treated for, or are being treated for cancer but have not yet developed lymphedema. The present invention may also be implemented in other prophylactic forms, such as after successful treatment. Some patients may be treated according to the present invention and achieve complete or significantly complete recovery and may not benefit from further treatment. However, other patients may benefit from continued administration of acevir stat or other selective LTA4H inhibitors after treatment has successfully prevented disease recurrence. Thus, for the prophylactic purpose of lymphedema prevention, after treatment according to the method of the present invention, the composition of the affected patient's skin, e.g., the skin of the limbs, remains substantially normal, consistent with successful treatment. After prophylactic treatment according to the method of the present invention, the volume of tissues, e.g., upper limbs, lower limbs, etc., should be stable over time compared to a control group in the absence of treatment. The time to observe the treatment benefit may be about one week, about two weeks, about three weeks, about one month, about two months, about three months, about four months, or longer. In some embodiments, the volume and / or structure of affected or at-risk tissue, i.e., lymphedematous tissue, is measured or otherwise assayed or evaluated at various points in time, for example, at least at initiation and at several designated endpoints for testing. In some embodiments, the structure of affected tissue is assayed by skin thickness measurement or histological evaluation, and the absence of lymphedema can be confirmed by serial measurement of limb bioelectrical impedance. The effect on the lymphatic system can also be evaluated, for example, using lymphoscintigraphy and / or indocyanine green lymphography. In some embodiments, the structure of affected tissue after treatment is similar to or more closely similar to the structure of unaffected tissue.

[0071] The present invention also includes a method for promoting lymphangiogenesis and / or lymphatic repair in a patient requiring promotion of lymphangiogenesis and / or lymphatic repair, comprising the step of administering an effective dose of acevirstat to the patient. Such patients include those at risk of subcutaneous lymphatic dysfunction-related abnormalities, subcutaneous lymphatic diseases, or lymphedema, such as those who have undergone surgery (e.g., lymph node dissection for staging and treatment of cancer), radiotherapy (particularly axillary or groin), trauma, lymphatic obstruction due to tumor, leukocytosis for leukemia, infection, venous hypertension (venous lymphedema), filariasis (in developing countries), or any condition or treatment that restricts or reduces lymphatic flow. In one aspect, the present invention is a method for promoting lymphangiogenesis and / or lymphatic repair in a patient at risk of developing lymphedema, the patient having or having undergone node dissection or radiotherapy. In a further context, the patient is implanted with artificial lymph nodes; in a further context, treatment with acevirstat increases lymphatic proliferation and repair to and from the artificial lymph nodes. In a further context, the present invention is a method for promoting lymphatic vascular formation and / or lymphatic repair to the artificial lymph nodes in a patient who has been implanted with artificial lymph nodes, the method comprising the step of administering an effective dose of acevirstat to the patient. As described above, the treatment may be initiated, for example, immediately after surgery, radiotherapy or cancer treatment, within one week or one to three days later (for example, an initial dose may be administered). The treatment may also be initiated after surgical wound healing is complete, or immediately after, within one week or one to three days after the initiation of radiotherapy or cancer treatment. In a further context, the administration of acevirstat is administered before surgery and continues after surgery as described above. In a further context, the method further comprises the administration of retinoic acid. While not wanting to be constrained by theory, acevirstat promotes lymphangiogenesis by reducing inflammation and / or enhancing Notch signaling and VEGFR3 expression. By reducing LTB4, acevirstat may allow for the resumption of normal signaling in both of these pathways.

[0072] Acevirstat and other LTA4H inhibitors are described, for example, in U.S. Patent No. 7,737,145, U.S. Patent No. 9,820,974 and U.S. Patent Application Publication 20100210630A1, the contents of which are incorporated herein by reference. The chemical name of acevirstat is 4-{[(1S,4S)-5-({4-[4-oxazol-2-ylphenoxy]phenyl}methyl)-2,5-diazabicyclo[2.2.1]heptan-2-yl]methyl}benzoic acid (also known as CTX-4430). Acevirstat is a potential inhibitor of leukotriene A4 hydrolase (LTA4H), the rate-limiting enzyme in the production of leukotriene B4 (LTB4).

[0073] The present invention involves administering an effective dose of acevirstat (also known as CTX-4430) to a human patient. In one aspect, acevirstat is administered orally. The compound and methods for its preparation are described in detail in U.S. Patent No. 7,737,145, U.S. Patent No. 9,820,974 and U.S. Patent Application Publication 20100210630A1, the contents of which are incorporated herein by reference. Acevirstat has the following chemical structure: [ka]

[0074] In vitro, acevirstat showed an IC50 rate of 6.3 ng / mL for LTB4 production. 50 It inhibits the epoxide hydrolase enzyme activity of LTA4H. In human whole blood tested at Exovivo, acevirstat showed an approximate IC of 30.8 ng / mL. 50 It inhibits LTB4 production. Acevirstat 48 ng / mL has also been shown to reduce neutrophil swarming by 80% in vitro in response to factors present in human cystic fibrosis (CF) sputum. In pharmacodynamic studies in humans, acevirstat reduced neutrophil swarming by an estimated in vivo EC of 93 ng / mL. 50It inhibits LTB4 production. In CF patients, sputum leukocytes decreased by only 31% from baseline in all treated subjects (50 or 100 mg doses) and by only 60% from baseline in the 100 mg acevirstat group. Sputum neutrophils decreased by only 34% in all treated patients (50–100 mg doses) and by only 65% ​​in the 100 mg group. In a recent Phase II trial in adult patients with CF, acevirstat showed promise in reducing the rate of lung deterioration over a 48-week course of treatment without evidence of an increased risk of infection (as described, e.g., in U.S. Patent No. 10,898,484; its contents are expressly incorporated herein by reference). This effect was most pronounced in patients with the initial disease.

[0075] In some cases, the effective dose of orally administered acevirstat may be about 200 mg or less. Therefore, the present invention encompasses oral administration of about 200 mg or less of acevirstat to a patient. In some cases, a patient is administered about 200 mg of acevirstat; for example, chronic oral administration (e.g., longer than about 1 day, at least about 1 week, at least about 2 weeks, at least about 3 weeks, at least about 1 month, at least about 2 months, at least about 3 months, at least about 4 months, at least about 5 months or at least about 6 months or 24 weeks and / or throughout the patient's treatment). The present invention also encompasses oral administration of about 100 mg of acevirstat to the patient; for example, chronic oral administration (e.g., longer than about 1 day, at least about 1 week, at least about 2 weeks, at least about 3 weeks, at least about 1 month, at least about 2 months, at least about 3 months, at least about 4 months, at least about 5 months or at least about 6 months or 24 weeks and / or throughout the patient's treatment). The present invention also includes the administration of approximately 50 mg of acevirstat to the patient; for example, chronic oral administration (e.g., for at least about 1 week, at least about 2 weeks, at least about 3 weeks, at least about 1 month, at least about 2 months, at least about 3 months, at least about 4 months, at least about 5 months or at least about 6 months or about 24 weeks and / or throughout the patient's treatment). Acevirstat may be administered, for example, in doses of approximately 50 mg every 12 or 24 hours (or once or twice a day) or in doses of approximately 100 mg every 12 or 24 hours (or once or twice a day). In some cases, acevirstat is administered in doses of approximately 100 mg every 24 hours (or once a day). The total daily dose of acevirstat may be approximately 200 mg or less, approximately 100 mg or less, or approximately 50 mg or less. The total daily dose of acevirstat is approximately 100 mg to 200 mg, for example, it could be as low as 150 mg. The total daily dose of acevirstat is also approximately 50 mg to 100 mg, for example, it could be as low as 75 mg. In some cases, the dose of acevirstat is administered at a dose of approximately 25 mg once or twice daily, or at a dose of approximately 25 to 50 mg once or twice daily.Acevirstat can be administered with or without food.

[0076] In some contexts, an effective dose of acevirstat or other selective LTA4H hydrolase inhibitor is administered in an effective dose, which is less than the dose that provides maximum inhibition of LTA4H epoxide hydrolase activity. In some cases, an effective dose may provide at least about 50%, at least about 60%, at least about 70%, at least about 80%, or at least about 85% inhibition of LTA4H epoxide hydrolase activity, for example, at least about 50%, at least about 60%, at least about 70%, at least about 80%, or at least about 85% inhibition of LTB4 production. For example, human pharmacodynamic studies have shown that a 50 mg dose of acevirstat provides 63% or more LTB4 inhibition, a 100 mg dose of acevirstat provides about 74% or more LTB4 inhibition, a 150 mg dose provides about 82% or more LTB4 inhibition, and a 200 mg dose of acevirstat provides about 85% or more LTB4 inhibition.

[0077] In further stages, acevirstat or other selective LTA4 hydrolase inhibitors are administered topically.

[0078] The present invention also includes a method by which acevirstat or other selective LTA4 hydrolase inhibitors are administered by pulsatile administration or by which acevirstat is contained in a pulsatile-release pharmaceutical composition. Pulsatile administration involves the administration or release of an activator or drug after a predetermined period of no release or delay time. Thus, pulsatile administration may involve rapid and complete delivery of the drug after a period of no drug release. For example, the concentration of the activator or drug in plasma is reduced to less than about 50% inhibition of LTA4H activity or less than about 50% of LTB4 production before the next dose is administered. Acevirstat or other selective LTA4H inhibitors may also be administered in controlled-release, sustained-release, and / or delayed-release modes. Acevirstat or other selective LTA4H inhibitors may also be administered in controlled-release formulations, such as sustained-release and / or delayed-release formulations. "Controlled-release" means a drug-containing formulation or its unit dose form using a controlled-release formulation in which the release of the drug is not immediate, i.e., the administration does not result in the immediate release of all the drug administered into the absorption pool. The term is used interchangeably with “non-immediate release,” as defined in Remington: The Science and Practice of Pharmacy, Nineteenth Ed. (Easton, Pa.: Mack Publishing Company, 1995). Generally, controlled-release formulations include sustained-release and delayed-release formulations. “Sustained-release” and “extended-release” refer to drug formulations that provide a gradual release of the drug over an extended period of time, typically resulting in a substantially constant blood level of the drug over the extended period, though not always. “Delayed-release” refers to drug formulations that provide a measurable time delay after administration to the patient before the drug is released from the formulation into the patient's body.

[0079] Treatment may include administering the same dose and / or regimen throughout the patient's treatment. The regimen may also include an initial dose(s) of acevirstat or other selective LTA4H inhibitor, followed by maintenance therapy comprising one or more maintenance doses, where one or more maintenance doses differ from the initial dose. For example, one or more maintenance doses may be less than the initial dose and / or less frequently than the initial regimen. In another example, one or more maintenance doses may be more than the initial dose and / or more frequently than the initial regimen.

[0080] The present invention encompasses methods for treating subcutaneous lymphatic dysfunction-related abnormalities or lymphatic disorders in the subcutaneous tissue using a selective LTA4H inhibitor other than acevirstat. The present invention also encompasses methods for treating lipedema, comprising the step of administering a selective LTA4H inhibitor other than acevirstat. LTA4H is an epoxide hydrolase that produces LTB4 from LTA4. The present invention further encompasses methods for preventing or reducing the risk of subcutaneous lymphatic dysfunction-related abnormalities, subcutaneous lymphatic disorders or lymphedema in patients requiring prevention or reduction of the risk of such abnormalities, subcutaneous lymphatic disorders or lymphedema, comprising the step of administering a selective LTA4H inhibitor other than acevirstat. Since LTB4 is a pro-inflammatory mediator, inhibition of LTA4H activity inhibits the production of pro-inflammatory LTB4. LTA4H is also an aminopeptidase that degrades the neutrophil chemoattractant tripeptide Pro-Gly-Pro (PGP) (Low et al. (2017), Scientific Reports 7, 44449 (2017). https: / / doi.org / 10.1038 / srep44449; its contents are expressed herein by reference). PGP accumulation is associated with pro-inflammatory effects. Therefore, LTA4H plays an important anti-inflammatory role in the degradation of PGP, a role that is paradoxical to its pro-inflammatory epoxide hydrolase activity. This invention is at least in part based on the finding that treatment with acevirstat resulted in skin and adipose tissue changes, such as ultrasound changes in the affected area. A selective LTA4H inhibitor is a drug or compound that exhibits higher selectivity for LTA4H than other aminopeptidase enzymes and / or higher selectivity for LTA4H's epoxide hydrolase activity than for LTA4H's aminopeptidase activity. In the context of LTA4 inhibitors, selectivity refers to the ability to inhibit. For example, an LTA4H inhibitor has an IC rating for epoxide hydrolase inhibition. 50 IC regarding aminopeptidase activity 50When the value is lower than the epoxide hydrolase activity of LTA4H, it is more selective for LTA4H's aminopeptidase activity than for LTA4H's aminopeptidase activity. In another example, LTA4H inhibitors are compared with IC for LTA4H inhibitors. 50 IC for other aminopeptidases 50When the threshold is lower than [value], it is more selective than other aminopeptidases for inhibiting LTA4H. A selective LTA4H inhibitor that is more selective than LTA4H aminopeptidase activity for LTA4H epoxide hydrolase activity inhibits LTB4 production with minimal effect on PGP degradation. Acevirstat is a selective LTA4H inhibitor that is more selective than LTA4H aminopeptidase activity for LTA4H epoxide hydrolase activity and more selective than aminopeptidase inhibition for LTA4H inhibition. Specifically, acevirstat has two times the priority over aminopeptidase activity for inhibiting epoxide hydrolase activity (Bhatt et al. (2017), Seminars in Immunology 33: 65-73; its contents are expressly incorporated herein by reference). Specifically, Bhatt et al. teach that acevirstat exhibits a 2x functional selectivity (12 nM) for LTA4H epoxide hydrolase compared to LTA4H aminopeptidase (27 nM), and is highly selective for LTA4H compared to other metalloenzymes. In contrast, several other LTA4H inhibitors, such as SC567461A (Searle / Pharmacia), DG-051 (DeCODE Pharmaceuticals), and JNJ-40929837 (Johnson and Johnson), have similar capabilities in inhibiting LTB4 production and PGP degradation, and may therefore have pro-inflammatory effects by causing PGP accumulation. Such inhibitors are referred to herein as “non-selective LTA4H inhibitors.” Ubenimex is a non-selective LTA4H inhibitor and a broad-spectrum aminopeptidase inhibitor (Bhatt et al. (2017); Inoi et al. (1995), Anticancer Res. 15(5B): 2081-2087; its contents are expressly incorporated herein by reference).

[0081] IC of LTA4H epoxide hydrolase activity 50can be measured using methods known in the art, for example, the LTA4 hydrolase homologous time-resolved fluorescence assay described in, for example, U.S. Patent Nos. 7,737,145 and 10,202,362, the contents of which are hereby expressly incorporated by reference. The hydrolase homologous time-resolved fluorescence assay is a two-step assay that measures the hydrolysis of LTA4 to LTB4 by analyzing the amount of LTB4 produced. The first step involves the enzymatic conversion of LTA4 to LTB4, and the second step involves the quantification of LTB4 formed by the homologous time-resolved fluorescence assay. LTA4H epoxide hydrolase activity can also be measured in a whole blood assay, for example, using human whole blood, using the methods described in Penning, T. D. et al., J. Med. Chem. (2000), 43(4): 721-735 and U.S. Patent No. 7,737,145, the contents of each of which are hereby expressly incorporated by reference. In the whole blood assay, inhibitor compounds are tested for their ability to inhibit LTB4 release upon stimulation with calcium ionophore, and the LTB4 levels in the supernatant are measured by ELISA. LTA4H epoxide hydrolase activity can also be measured according to the method described in Low et al. (2017). For LTA4H aminopeptidase activity, IC 50This can be measured using methods known in the art, for example, the methods described in Kull et al., The Journal of Biological Chemistry 274(49): 34683-34690, the methods described in U.S. Patent No. 10,202,362, and / or the methods described in Low et al. (2017), the contents of which are expressly incorporated herein by reference. Other methods for measuring LTA4H epoxide hydrolase activity and / or LTA4H peptidase activity are described, for example, Askonas, LJ, et al., The Journal of Pharmacology and Experimental Therapeutics 2002, 300(2): 577-582; Penning, TD, J. Med. Chem. 2000, 43(4): 721-735; Kull, F. et al., The Journal of Biological Chemistry 1999, 274 (49): 34683-34690, the contents of which are explicitly referenced herein.

[0082] The present invention includes a method for treating subcutaneous lymphatic dysfunction-related disorders or lymphatic disorders in the subcutaneous tissue, comprising the step of administering an effective dose of a selective LTA4H inhibitor to a patient who requires treatment for subcutaneous lymphatic dysfunction-related disorders or lymphatic disorders in the subcutaneous tissue. The present invention also includes a method for treating lipedema, comprising the step of administering an effective dose of a selective LTA4H inhibitor to a patient who requires treatment for lipedema. The present invention further includes a method for preventing or reducing the risk of subcutaneous lymphatic dysfunction-related disorders, subcutaneous lymphatic disorders or lymphedema in a patient who requires prevention or reduction of the risk of such disorders, subcutaneous lymphatic disorders or lymphedema, comprising the step of administering a selective LTA4H inhibitor other than acevirstat. A selective LTA4H inhibitor may have at least about 1.5 times or at least about 2 times higher selectivity for the epoxide hydrolase activity of LTA4H than for the aminopeptidase activity of LTA4H. Selective LTA4H inhibitors may, additionally or alternatively, exhibit at least about 1.5 times, at least about 2 times, at least about 2.5 times, at least about 3 times, at least about 5 times, or at least about 10 times higher selectivity for LTA4H than other aminopeptidases. In yet another embodiment, an LTA4H inhibitor is at least about 2 times more selective for LTA4H than other aminopeptidases and is more than about 1.5 times more selective for epoxide hydrolase activity than the aminopeptidase activity of LTA4H. An LTA4H inhibitor may also be at least about 2.5 times, at least about 3 times, at least about 5 times, or at least about 10 times more selective for epoxide hydrolase activity than the aminopeptidase activity of LTA4H. In yet another embodiment, an LTA4H inhibitor is at least about 2 times more selective for LTA4H than other aminopeptidases and is more than about 2 times more selective for epoxide hydrolase activity than the aminopeptidase activity of LTA4H. Examples of selective LTA4H inhibitors include acevirstat. Other selective LTA4H inhibitors are described in Low et al., and include compounds containing a resveratrol core.Non-limiting examples of LTA4H inhibitors include, for example, cis-resveratrol, trans-resveratrol, isoflavone daidzein, and 7,8,4'-trihydroxyisoflavones. Further non-limiting examples of LTA4H inhibitors are shown in the table below. [Table 1] [Table 2] [Table 3]

[0083] In some aspects, an effective dose of acevirstat is administered to individuals with lipodymetabolism, such as established lipodymetabolism, for a period of time sufficient to reduce or reverse the histopathology of the affected (lipodymetabolous) tissue compared to an untreated control group or the patient's baseline. In some embodiments, an effective dose of acevirstat is administered to individuals with subcutaneous lymphatic dysfunction-related abnormalities or subcutaneous lymphoid disorders for a period of time sufficient to reduce or reverse the histopathology of the affected tissue compared to an untreated control group or the patient's baseline. As described above, the reduction or reversal of histopathology may be assessed by changes in ultrasound. Treatment may be continued as necessary to maintain the therapeutic benefit; if necessary, maintenance therapy may be maintained at the same dose and schedule as the previous treatment or may be achieved by converting to an alternative maintenance schedule, for example, with a lower dose or less frequent administration. In some embodiments, the treating physician may determine that the treatment is effective by verifying structural changes in the affected tissue. If visual examination alone is insufficient, the tissue may be assayed by any of the means described herein to verify the therapeutic benefit. Criteria for efficacy for lipedema and lymphedema are changes in ultrasound of the affected (lipedematous) area and / or a reduction in the amount of fat or adipose in the affected area and / or structural changes in the adipose tissue in the affected area. Further criteria for efficacy are improvements in lymphatic symptoms as indicated, for example, by lymphoscintigraphy and indocyanine green (ICG) lymphography. Further methods for determining whether the treatment is effective include lymphoscintigraphy, magnetic resonance lymphangiography and indocyanine green (ICG) lymphography.

[0084] In some embodiments, an effective dose of acevirstat or other selective LTA4H inhibitors is provided to individuals susceptible to subcutaneous lymphatic dysfunction-related abnormalities or subcutaneous lymphatic disorders. Such patients include, but are not limited to, individuals who have undergone surgery or radiation therapy for cancer (these patients are at risk of secondary lymphedema). In a further context, the lymphedema is secondary or acquired lymphedema. Furthermore, patients at risk of subcutaneous lymphatic dysfunction-related abnormalities or subcutaneous lymphatic disorders are female patients who have a family member with lipodymere and / or are carriers of genes associated with lipodymere.

[0085] In the methods described herein, acevirstat may be administered to a patient with familiarity with their current treatment regimens or levels of treatment. Levels of treatment for lymphedema include, but are not limited to, diuretics, antibiotics, exercise, manual lymphatic drainage, compression bandages, and compression garments. The methods of the present invention may also involve the administration of a therapeutically effective dose of at least one further active agent other than an LTA4H inhibitor. The further agent may be selected from the group consisting of, for example, selective COX-1 inhibitors, selective COX-2 inhibitors, non-selective COX-1 / COX-2 inhibitors, coumarins, antihistamines, montelukast, and other related leukotriene inhibitors, antifibrotic compounds, diuretics, statins, mTOR inhibitors, and pirfenidone. In certain situations, additional agents may be selected from a group consisting of, for example, selective COX-1 inhibitors, selective COX-2 inhibitors, non-selective COX-1 / COX-2 inhibitors, coumarins, antihistamines, antifibrotic compounds, diuretics, statins, mTOR inhibitors, and pirfenidone. Non-selective COX-1 / COX-2 inhibitors include, but are not limited to, salicylic acid derivatives, e.g., aspirin, sodium salicylate, magnesium choline trisalicylate, salsalate, diflunisal, sulfasalazine, and olsalazine; para-aminophenol derivatives, e.g., acetaminophen, indole, and indene acetate, e.g., indomethac and sulindac; heteroaryl acetates, e.g., tolmetine, diclofenac, and ketelolac; arylpropionic acids, e.g., ibuprofen, naproxen, flurbiprofen, ketoprofen, fenoprofen, and oxaprozin; anthranilic acids (fenamate), e.g., mefanamic acid and meclofenamic acid; enolic acids, e.g., oxicam, e.g., piroxicam and meloxicam, and alkanones, e.g., nabumetone; and their pharmaceutically effective esters, salts, isomers, conjugates, and prodrugs. Furthermore, in more contexts, non-selective COX-1 / COX-2 inhibitors include propionic acid derivatives, such as ketoprofen. Examples of selective COX-2 inhibitors include celecoxib.Non-limiting examples of diuretics include furosemide, torasemide, and hydrochlorothiazide, recombinant angiotensin-converting enzyme-2, and acetylsalicylic acid. Examples of statins include atorvastatin, fluvastatin, lovastatin, pitavastatin, pravastatin, rosuvastatin, simvastatin, and / or ezetimibe / simvastatin combinations. Examples of mTOR inhibitors include rapamycin, everolimus, sirolimus, and rapalog. Non-limiting examples of antifibrotic agents include pirfenidone, transforming growth factor beta (TGFβ) inhibitors such as galunisertib, and connective tissue growth factor (CTGF) inhibitors such as FG-3019. Further activators may also be any other drugs and / or prelymphatic agents used in the treatment of lymphedema, such as retinoic acids (e.g., 9-cisretinoic acid). In another example, further activators are drugs, such as biologics or small molecules that target and / or inhibit anti-lymphatic growth factors or cytokines, for example, but not limited to, anti-TGF-β1 antibodies, anti-IFN-γ antibodies, anti-IL-4 antibodies, and anti-IL-13 antibodies. For example, further drugs may be antibodies (e.g., monoclonal antibodies) that target and / or inhibit anti-lymphatic growth factors or cytokines, for example, but not limited to, anti-TGF-β1 antibodies, anti-IFN-γ antibodies, anti-IL-4 antibodies, and anti-IL-13 antibodies. The antibodies may target one or more anti-lymphatic growth factors or cytokines, for example, but not limited to, dupilumab (a monoclonal antibody that inhibits IL-4 and IL-13) and pascolizumab (a humanized anti-IL-4 monoclonal antibody). Further drugs may also be pitrakinra, a human recombinant protein that is an antagonist of IL-4 and IL-13. It is understood that when acevirstat or other selective LTA4H inhibitors are administered co-administered with or in combination with at least one additional activator, acevirstat or other selective LTA4H inhibitors may be administered simultaneously with, before, or after the administration of one or more additional activators.For example, the initiation of acevirstat treatment may follow the initiation of treatment with additional activators. In another example, the initiation of treatment with additional activators may follow the initiation of acevirstat treatment. Such combination therapy includes the administration of a single drug-dose formulation containing acevirstat or other selective LTA4H inhibitors and one or more additional activators, as well as the administration of acevirstat and each activator in its own separate drug-dose formulation. When separate dose formulations are used, acevirstat and one or more additional activators may be administered at essentially the same time, i.e., simultaneously, or separately at different times, i.e., sequentially; and / or in the same treatment session and / or as part of the same treatment regimen; and / or as daily administration of acevirstat and daily administration of one or more additional activators. Combination therapy and concurrent administration are understood to include all of these regimens.

[0086] Acevirstat or other selective LTA4H inhibitors may be continued if the treatment is determined to be effective. As mentioned above, efficacy can be assessed by ultrasound. For example, in certain lymphedema patients, subcutaneous echogenicity in the affected area is increased compared to normal, and there is blurring of the intermediate surface between subcutaneous fat and skin (or lack of contrast between them) and / or loss of distinction of fascial lines. The efficacy of the treatment can be assessed by determining whether the subcutaneous echogenicity in the affected area decreased after treatment (compared to baseline), whether there is an increase in contrast between subcutaneous fat and skin, and / or whether there is an increase in visualization or distinction of fascial bands on ultrasound. In another example, the efficacy of the treatment in certain lipedema patients can be assessed by determining whether the subcutaneous echogenicity in the affected area decreased after treatment (compared to baseline), whether there is an increase in contrast between subcutaneous fat and skin, and / or whether there is an increase in visualization or distinction of fascial bands on ultrasound. The method may include maintaining, tapering, reducing, or discontinuing the dose of acevirstat or other selective LTA4H inhibitor in treatment when it is determined that the treatment is effective. The method may include increasing the dose of acevirstat or other selective LTA4H inhibitor in treatment when it is determined that the treatment is not effective or when it may be more effective if the dose is increased in daily doses or through changes in the dosing schedule. Alternatively, the method may include discontinuing treatment when it is determined that the treatment is not effective.

[0087] Regarding lymphedema, for example, treatment may begin at any point after the onset of stage 0 lymphedema, and for example, treatment may stabilize the patient's condition or reverse it to an asymptomatic state. Treatment according to the method of the present invention may begin, for example, after the onset of any clinically apparent lymphedema, for example, stage 1. Treatment according to the method of the present invention may also begin, for example, after the onset of stage 2 lymphedema. Treatment according to the method of the present invention may begin after the onset of stage 3 lymphedema. Treatment may also begin before the onset of stage 0 lymphedema, but after surgery, radiation therapy or other medical interventions that increase the risk of developing lymphedema.

[0088] Swelling, which may be associated with the progression of lymphedema, can be unilateral or bilateral and may worsen in warm weather, before menstruation, after physical exertion, and / or after the limb has been in a hanging position for a long time. The swelling may affect any part of the limb (isolated proximal or distal) or the entire limb, or the face, head and neck, torso, chest, or genitals; the swelling may limit the range of motion. Impairment and emotional distress may be significant, especially if the lymphedema is caused by medical or surgical procedures. Skin changes are common and include hyperkeratosis, hyperpigmentation, lichenification, vegetatives, papillomas, and fungal infections. The methods of the present invention include, for example, methods for treating any and all of these conditions and symptoms by administering acevirstat as described herein, but not limited to these.

[0089] Lymphangitis or cellulitis can develop when, for example, bacteria penetrate the skin barrier, which is impaired in lymphedema. Cellulitis in lymphedema may be characterized by only very subtle changes in the limb and can be difficult to diagnose or eradicate. Lymphangitis is frequently streptococcal, resulting in erysipelas; sometimes it is staphylococcal. The affected limb becomes red and feels hot; red streaks may spread proximally from the point of entry, and lymphadenopathy may develop. Rarely, the skin breaks down. Rarely, prolonged lymphedema can lead to lymphangiosarcoma (Stuart-Trives syndrome), usually in patients who have undergone mastectomy and those with filariasis. The methods of the present invention include methods for treating any and all of these conditions and symptoms by administration of acevirstat, for example, as described herein but not limited to. Without treatment, cell hyperproliferation, fat accumulation, and fibrosis promote progressive anatomical distortion and loss of function in the affected area. Furthermore, impaired transport of antigen-presenting cells in the lymphoid system hinders local immune surveillance of the lymphedematous area(s) to the afferent lymph nodes. This leads to chronic inflammation, infection, and skin hardening, which in turn results in further lymphatic vessel damage and deformation of the affected body part. In addition, there is a high degree of dysfunction due to physical factors such as reduced range of motion, increased extremity, increased pain, and decreased joint mobility, which impairs the ability to perform daily tasks. The methods of the present invention include methods for treating any and all of these conditions and symptoms by administering, for example, acevirstat or other selective LTA4H inhibitors described herein, but not limited to these.

[0090] Pathological skin changes associated with lymphedema include cellular changes in the layers of skin, glycoprotein accumulation, loss of elasticity, and an increase in the subcutaneous fat layer. The methods of the present invention include methods for treating any and all of these conditions and symptoms by administering, for example, acevirstat or other selective LTA4H inhibitors described herein, but not limited to these.

[0091] Therefore, those skilled in the art will understand that the methods of the present invention are applicable to the treatment and prevention of lymphedema, including its signs and symptoms, such as those associated with the following clinical signs of lymphedema. Some clinical signs may be used to diagnose lymphedema and to monitor the effectiveness of treatment, including treatment using the compositions and methods of the present invention. The present invention provides a method for determining the effectiveness of lymphedema treatment in a subject in need of lymphedema treatment by (a) measuring an endpoint of a clinical indicator in a patient, where the endpoint is measured after treatment has been initiated; (b) comparing the endpoint of the clinical indicator to a baseline or reference, where the baseline or reference is measured in the same subject or a similar subject population before treatment has been initiated; and (c) determining the effectiveness of lymphedema treatment based on the comparison step.

[0092] Analysis of clinical signs may include: skin thickness; changes in the volume of lymphedema in the legs / arms / hands; changes in fluid stagnation at shoulder / torso level; changes in extracellular fluid in the arms; changes in the thickness and reflexes of the skin (cutis) and subcutaneous tissue (subcutis) of the arms / shoulders / torso; changes in the elasticity of the skin and subcutaneous tissue of the arms; changes in the structure and function of the lymph; changes in venous circulation in the arms / torso; and measurement of the number of cellulitis episodes.

[0093] When imaging is used to diagnose lymphedema or to assess the disease state or progression, the most common modality for diagnosis is indirect radionuclide lymphoscintigraphy. This procedure uses appropriate radiolabeled tracers, for example 99m Tc-antimony sulfide colloid or 99mSubcutaneous injection of Tc-labeled human serum albumin is required. Criteria for diagnosing lymphatic dysfunction include: (1) delayed, asymmetric, or absent visualization of local lymph nodes; (2) asymmetric visualization of lymphatic channels; (3) collateral lymphatic channels; (4) cutaneous reflux; (5) interrupted vascular structures; and (6) visualization of lymph nodes of the deep lymphatic system. The presence of "cutaneous reflux" is considered abnormal. This is interpreted as indicating extravascular leakage of lymphatic fluid from lymphatic vessels into interstitial spaces as a result of lymphatic and / or venous hypertension. In addition to lymphoscintigraphy, magnetic resonance imaging and computed axial tomography have clinical utility. These imaging techniques allow for objective verification of structural changes caused by lymphedema. Recent advances in magnetic resonance approaches have improved the visualization of lymphatic abnormalities in both unenhanced and contrast-enhanced applications (see, e.g., Pankaj et al. (2013) World J Surg Oncol. 2013; 11: 237). As an alternative, bioelectrical impedance, which uses the frequency-dependent current flow properties to quantify changes in extracellular fluid, has been used to detect and monitor upper limb lymphedema (see Ridner et al. (2009) Lymphat Res Biol. 7(1): 11-15). In various embodiments, such techniques are used to monitor the progress of treatment in patients treated according to the invention or to identify patients who may benefit from such treatment. Imaging may also include indocyanine green (ICG) fluorescence lymphangiography, as described, e.g., Suami et al., BMC Cancer 19, 985 (2019). https: / / doi.org / 10.1186 / s12885-019-6192-1, the contents of which are explicitly incorporated herein by reference.

[0094] The effectiveness of treatment by the present invention is demonstrated by improvement in disease symptoms and pathology. The treated individual and medical practitioner may choose to assess success, monitor the course of treatment, and adjust dosage and timing based on any convenient signs.

[0095] In some embodiments of the present invention, the treatment of patients with established diseases (e.g., lymphatic dysfunction-related abnormalities or lymphatic diseases of the subcutaneous tissue), and the improvement of the structure of adipose tissue in the affected area, provides a convenient method for evaluating the success of the treatment. In some embodiments, the treatment provided herein is effective when, after a period of time from the start of treatment (e.g., 2 weeks, 1 month, 2 months, 3 months, 4 months, 5 months, 6 months or more), a reduction in fat deposits or a change in the structure of adipose tissue is observed in at least one affected area (as measured by ultrasound) compared to at least one affected area before the start of treatment.

[0096] In some aspects of the present invention, for example, in the treatment of patients with established lymphedema or lipedema, improvement of skin structure provides a convenient method for evaluating the success of treatment. For example, in lymphedema, skin thickness reflects structural changes in lymphedema. See, for example, Mellor et al., Breast J 2004; 10:496-503; Hacard et al. Skin Res Technol 2014; 20:274-81, which are specifically incorporated herein by reference. The present invention encompasses methods for reducing skin thickness associated with lymphedema. Skin thickness can be measured, for example, using a factory-calibrated subcutaneous fat (skinfold) calyx, e.g., Lange subcutaneous fat calyx, model EQ0014921. In a further aspect, a reduction in skin thickness or skin thickening is measured using ultrasound. In some embodiments, the treatments provided herein are effective if, after a period of time from the start of treatment (e.g., 2 weeks, 1 month, 2 months, 3 months, 4 months, 5 months, 6 months or more), there is a reduction in the thickness of the skin in at least one affected area (e.g., a limb) compared to the thickness of the skin in at least one affected area before the start of treatment. The reduction in skin thickness observed with successful treatment may be at least about 0.5 mm, about 1 mm, at least about 2.5 mm, at least about 5 mm, at least about 7.5 mm, at least about 10 mm, and may be at least about 12.5 mm, at least about 15 mm or more, compared to before the start of treatment (referred to herein as “baseline”) or at an early point in the treatment regimen. In further developments, skin thickening or skin thickness may decrease by at least approximately 5%, approximately 10%, approximately 15%, approximately 20%, approximately 25%, approximately 30%, approximately 35%, approximately 40%, approximately 45%, or more compared to before the initiation of treatment (referred to herein as “baseline”) or at an early point in the treatment regimen (e.g., 3 or 6 months after acevirstat treatment). Further measurements to determine the pathological modification of the skin structure may include, for example, DEXA scanning, direct biopsy, visual inspection, etc.Skin thickness and structure in the affected limb, such as the presence of hyperkeratosis, cutaneous collagen, and adipose deposits, can be monitored. In further instances, subcutaneous thickness is reduced by at least approximately 5%, 10%, 15%, or 20% compared to baseline, for example, 3 or 6 months (or less) after acevirstat treatment. In certain instances, subcutaneous thickness is reduced by at least approximately 10%, 15%, or 20% compared to baseline, 6 months after treatment with acevirstat. In further instances, subcutaneous thickness is reduced by at least approximately 5%, 10%, 15%, or 20% compared to baseline, for example, 3 or 6 months after acevirstat treatment. In certain instances, subcutaneous thickness is reduced by at least approximately 10%, 15%, or 20% compared to baseline, 6 months after treatment with acevirstat.

[0097] Baseline and post-treatment ultrasounds may be read or evaluated by, for example, a radiologist or specialist. In a further context, ultrasound reading and analysis may be automated. For example, ultrasound images may also be read or analyzed by computer systems such as ultrasound imaging software and / or ultrasound reporting software. In a further context, ultrasound images may be read or evaluated by artificial intelligence (AI) systems. In a further context, ultrasounds may be read or evaluated by radiologists or specialists and automated systems, such as computer systems or AI systems. For example, an AI system may include machine learning programs or deep learning. An AI system may include, but is not limited to, one or more algorithms programmed, trained and / or configured to evaluate ultrasound images, such as detecting or measuring skin thickness, subcutaneous thickness and / or subcutaneous echogenicity. In a certain context, an AI system may store images or measurements from baseline ultrasounds and compare them with post-treatment ultrasound images. In a further context, an automated computer or AI system may improve images, for example, by reducing noise and / or improving contrast. The use of AI in ultrasound examination is described, for example, in Kim 2021, Ultrasonography 40(3): 313-317 and Edwards et al. (2022), Ultrasound 30(4): 273-282, the content of which is explicitly incorporated herein by reference.

[0098] In a further context, ultrasound refers to an automated or semi-automated ultrasound system that automatically scans limbs using, for example, an ultrasound transducer. In some contexts, the automated or semi-automated ultrasound system includes a computer system or an AI system.

[0099] In some embodiments, the change in the volume of the affected limb is measured as a criterion for treatment success, i.e., the volume decreases with successful treatment of lipedema and lymphedema. The volume can be measured by any of several methods in the art, e.g., circumferential measurement, water displacement volumetric measurement, etc. For example, the evaluator may use a standardized tape criterion for circumferential measurement taken every 2-6 cm, and calculate the volume by, for example, the cut cone method. Successful treatment can reduce or decrease the volume of a part of the body affected by lipedema (lipedema) or lymphedema (both fluid and tissue contents). In some cases, the volume decreases by about 1.5 times, about 2 times or more, i.e., compared to the volume before treatment, e.g., about 1.5 times, about 2 times or more, about 3 times or more, about 4 times or more, often about 5 times or more, about 10 times or more, about 15 times or more, and in some cases about 20 times or more, about 50 times or more. In other words, the volume decreases by approximately 50 milliliters or more, 100 milliliters or more, 200 milliliters or more, 300 milliliters or more, 400 milliliters or more, and 500 milliliters or more. In further stages, the volume decreases by at least approximately 5%, 10%, 15 or 20%, or more. In some cases, the volume recovers to the normal volume, i.e., the volume before the onset of lymphedema, for example, the volume of the unaffected bilateral tissue.

[0100] In some embodiments, serum LTB4 levels may be used for diagnosis, patient selection or grading for treatment, or monitoring the effectiveness of any disease or condition described herein. Reference values ​​for normal LTB4 may range from approximately 50 pg / mL or higher, to approximately 100 pg / mL or higher, to approximately 200 pg / mL or higher, to approximately 250 pg / mL or higher, and to approximately 300 pg / mL (depending on the assay type and format and individual laboratory implementation). Individuals with lymphedema may have elevated baseline levels of serum LTB4, where serum levels may range from approximately 500 pg / mL to approximately 1500 pg / mL, and up to approximately 1000 pg / mL or higher. In some cases, serum LTB4 levels in a sample obtained from a patient are measured, and if they exceed a predetermined threshold level, the patient is administered acevirstat or other selective LTB4H inhibitors. The treatment provided in the present invention may be determined to be effective if, after the initiation of treatment, the subject's endpoint LTB4 level decreases from the baseline LTB4 level. In other embodiments, the treatment provided in the present invention is effective if, after the initiation of treatment, the endpoint LTB4 level is about 2 times, about 3 times, about 4 times, about 5 times, about 10 times, or about 15 times lower than the baseline LTB4 level. For example, in some embodiments, higher or increased levels of LTB4 in a blood sample that are at least about 3 times, at least about 4 times, at least about 5 times, at least about 10 times, or at least about 15 times higher than the control value indicate that the patient requires treatment with the treatment of the present invention or that the patient may respond to the treatment of the present invention. Standard methods for assessing LTB4 levels are utilized. The method further includes administering an effective amount of acevirstat or other selective LTB4H inhibitor to a patient who has been determined to be likely to benefit from the treatment of the present invention, to require the treatment of the present invention, or to be likely to respond to the treatment of the present invention, thereby treating or preventing lymphedema in the patient.

[0101] As used herein, “therapeutic dose” or “effective dose” means an amount of compound or drug sufficient to perform, when administered to a mammal, preferably a human, the treatment of the disease or condition of interest in the mammal, preferably a human, as defined below. The amount of the compound of the present invention constituting the “therapeutic dose” or “effective dose” varies, for example, depending on the activity of the specific compound used; the metabolic stability and duration of action of the compound; the patient’s age, weight, general health, sex and diet; the mode and timing of administration; the rate of elimination; the drug combination; the severity of the particular disorder or condition; and the subject being treated, but can be conventionally determined by those skilled in the art with their own knowledge and interest in this disclosure. In any context, an effective or therapeutically effective dose of acevirstat or other selective LTA4H inhibitor is the amount that inhibits LTA4H or LTB4, and / or treats, inhibits or reduces the severity of a disease (lipedema or lymphedema), and / or inhibits or reduces the severity of subcutaneous lymphatic dysfunction-related abnormalities or subcutaneous lymphatic disorders, and / or reduces, and / or improves skin torgol, history and / or function or increases lymphatic flow, and / or improves vascular function, and / or reduces adipose tissue, and / or produces changes in ultrasound measurements.

[0102] "To treat" or "to treat," as used herein, preferably covers the treatment of lipoedeema, lymphedema, or lymphatic dysfunction-related abnormalities or lymphatic disorders of the subcutaneous tissue in humans, for example: (i) inhibiting or reducing the severity of a disease or condition or one or more of its symptoms, i.e., restricting or delaying the onset or progression of a disease or condition, inhibiting or reducing the severity of lymphatic dysfunction-related abnormalities or lymphatic disorders of the subcutaneous tissue, and / or reducing and / or improving cutaneous torgol, disease history and / or function, or increasing lymphatic flow and / or improving vascular function, and / or reducing adipose tissue and / or causing changes on ultrasound and / or alleviating or reducing one or more symptoms; (ii) reducing a disease or condition, i.e., causing a regression of a disease or condition or one or more of its symptoms; and / or (iii) stabilizing a disease or condition. "To treat" or "to treat" may include reducing the risk of progression of lipedema, lymphedema, and / or lymphatic dysfunction-related abnormalities or lymphatic disorders of the subcutaneous tissue.

[0103] As used herein, the terms “disease” and “condition” may be used interchangeably, or they may differ in that a particular disease or condition may not have known causative factors (i.e., the etiology is not yet at work), and therefore it is not recognized as a disease, but only as an undesirable condition or symptom, where more or less a particular set of symptoms has been identified by a clinician.

[0104] "Pharmaceutical composition" means a compound described herein, such as acevirstat or other selective LTA4H inhibitors and / or further therapeutic agents, and a formulation of a medium generally accepted in the art for the delivery of biologically active compounds to mammals, such as humans. Such a medium includes all pharmaceutically acceptable carriers, diluents, or excipients.

[0105] "Optional" or "optional" means that the event or situation described thereafter may or may not occur, and that the description includes examples of the event or situation occurring and examples of it not occurring.

[0106] "Pharmacologically acceptable excipients" include, but are not limited to, any adjuvants, carriers, excipients, flow enhancers, sweeteners, diluents, preservatives, pigments / colorants, flavor enhancers, surfactants, wetting agents, dispersants, suspending agents, stabilizers, isotonic agents, solvents, or emulsifiers approved, for example, by the U.S. Food and Drug Administration for use in humans or livestock animals.

[0107] The administration of compounds or drugs described herein includes the administration of pharmaceutically acceptable salts of such compounds or drugs, e.g., acetavirstat or other pharmaceutically acceptable salts of selective LTA4H inhibitors. The administration of compounds or drugs described herein (e.g., acetavirstat or other further therapeutic agents) or pharmaceutically acceptable salts thereof, in their pure form or in suitable pharmaceutical compositions, may be carried out by any acceptable form of administration of the agent to provide similar utility. As described herein, an exemplary form of administration for acetavirstat is oral administration. Pharmaceutical compositions described herein may be prepared by combining a compound or drug with a suitable pharmaceutically acceptable carrier, diluent or excipient, and may be formulated into preparations in solid, semi-solid, liquid or gaseous forms, e.g., tablets, capsules, powders, granules, ointments, solutions, suppositories, injections, inhalants, gels, microspheres and aerosols.

[0108] Routes of administration of such pharmaceutical compositions include, but are not limited to, oral, topical, transdermal, inhalation, parenteral, sublingual, rectal, vaginal, and nasal administration. The term parenteral, as used herein, includes subcutaneous, intravenous, intramuscular, intrasternal injection, or infusion techniques. The pharmaceutical compositions of the present invention are formulated such that the active ingredients contained herein are bioavailable upon administration of the composition to a patient. The composition administered to a subject or patient takes the form of one or more dosage units, where for example, a tablet may be a single dosage unit, and a container of the compound of the present invention in aerosol form may hold multiple dosage units. Practical methods for preparing such dosage forms are known or apparent to those skilled in the art; e.g., The Science and Practice of Pharmacy, 20 th See Edition (Philadelphia College of Pharmacy and Science, 2000). The administered composition contains a therapeutically effective amount of the compound or drug or a pharmaceutically acceptable salt thereof for the treatment of the disease or condition of interest in accordance with the teachings of the present invention in any event.

[0109] As described above, the pharmaceutical compositions described herein can be administered in a variety of different ways. Examples include the administration of compositions containing pharmaceutically acceptable carriers by oral, intranasal, rectal, topical, intraperitoneal, intravenous, intramuscular, subcutaneous, subdermal, transdermal, and intrasacral methods. Formulations suitable for parenteral administration, such as via intra-articular, intravenous, intramuscular, intradermal, intraperitoneal, and subcutaneous routes, include aqueous and non-aqueous sterile injection solutions that may contain antioxidants, buffers, and bacteriostatic agents, as well as solutions that make the formulation isotonic with the blood of the intended recipient, and aqueous and non-aqueous sterile suspensions that may contain suspensions, solubilizers, concentrators, stabilizers, and preservatives. Formulations suitable for intestinal administration, such as topical administration (e.g., solutions, lotions, creams, pastes, emulsions, suspensions, etc.), oral, rectal, vaginal, or inhalation, include capsules, liquid solutions, emulsions, suspensions, and elixirs. For example, when prepared for topical application, the composition may include a biocompatible organic solvent, such as isopropyl esters, such as isopropyl myristate and isopropyl palmitate; polar lipids, such as lecithin and phosphatidylcholine; surfactants, such as sodium doxate, sodium doxate benzoate, calcium doxate, tween 80, and polysorbate 80; water; and / or urea (present in a concentration of about 5-20% by mass of the final composition). In some examples, the topical formulation includes a skin penetration enhancer, such as SEPA 09. Examples of topical formulations can be found in U.S. Patents No. 5,654,337, 5,093,133, 5,210,099, 3,957,971, and 5,016,652, the full disclosure of which is incorporated herein by reference.

[0110] The components used to formulate pharmaceutical compositions are preferably of high purity and substantially free of potentially harmful contaminants (e.g., at least National Food (NF) grade, generally at least analytical grade, and more typically at least pharmaceutical grade). Furthermore, compositions intended for in vivo use are usually sterile. The resulting products are typically substantially free of any potentially toxic agents, particularly any endotoxins that may be present during the synthesis or purification process, to the extent that any given compound must be synthesized before use. Compositions for parenteral administration are also sterile and substantially isotonic and prepared under GMP conditions.

[0111] Pharmaceutical compositions may be in solid or liquid form. In one aspect, the carrier(s) are granular, so the composition may be, for example, in tablet or powder form. In another aspect, the composition may be in capsule-encapsulated powder or granule form. In another aspect, capsule-encapsulated powder or granule formulations may be opened and scattered in food or administered by gastric intubation. The carrier(s) may be liquid, and the composition may be, for example, an oral syrup, an injectable liquid, or an aerosol useful for, for example, inhalation administration. When intended for oral administration, pharmaceutical compositions may be in either solid or liquid form, where semi-solid, semi-liquid, suspension, and gel forms are included in the forms considered as either solid or liquid in this specification.

[0112] As solid compositions for oral administration, pharmaceutical compositions can be formulated in the form of powders, granules, compressed tablets, pills, capsules, chewing gum, wafers, etc. Such solid compositions typically contain one or more inert diluents or edible carriers. They may also contain: binders, e.g., carboxymethylcellulose, ethylcellulose, microcrystalline cellulose, tragacanth gum, or gelatin; excipients, e.g., starch, lactose, or dextrin; disintegrants, e.g., alginic acid, sodium alginate, Primogel, corn starch, etc.; lubricants, e.g., magnesium stearate or Sterotex; flow enhancers, e.g., colloidal silicon dioxide; sweeteners, e.g., sucrose or saccharin; flavoring agents, e.g., peppermint, methyl salicylate, or orange flavoring agents; and one or more colorants.

[0113] If the pharmaceutical composition is in the form of a capsule, such as a gelatin capsule, it may include a liquid carrier such as polyethylene glycol or oil, in addition to the types of materials described above.

[0114] Pharmaceutical compositions may be in the form of liquids, such as elixirs, syrups, solutions, emulsions, or suspensions. Liquids may be for delivery by oral administration or injection, as two examples. When intended for oral administration, the composition may contain, in addition to the compounds of the present invention, one or more sweeteners, preservatives, pigments / colorants, and flavor enhancers. Compositions intended for administration by injection may contain one or more surfactants, preservatives, wetting agents, dispersants, suspending agents, buffers, stabilizers, and isotonic agents.

[0115] The liquid pharmaceutical composition of the present invention, whether in solution, suspension or other similar form, may contain one or more of the following adjuvants: sterile diluents, e.g., water for injection, saline solution, preferably physiological saline, Ringer's solution, isotonic sodium chloride, or physiological saline; fixing oils, e.g., synthetic mono or diglycerides that can act as a solvent or suspension medium, polyethylene glycol, glycerin, propylene glycol, or other solvents; antimicrobial agents, e.g., benzyl alcohol or methylparaben; antioxidants, e.g., ascorbic acid or sodium bisulfite; chelating agents, e.g., ethylenediaminetetraacetic acid; buffers, e.g., acetates, citrates, or phosphates; and agents for adjusting isotonicity, e.g., sodium chloride or dextrose. Parenteral formulations may be sealed in glass or plastic ampoules, disposable syringes, or multi-dose vials. Physiological saline is a preferred adjuvant. The injectable pharmaceutical composition is preferably sterile.

[0116] The present invention will be illustrated by the following non-limiting embodiments. [Examples]

[0117] Example 1: Ultrasonographic skin changes after initial therapeutic LTB4 antagonism in lymphedema Lymphedema is a chronic disease characterized by the accumulation of excess fluid in interstitial spaces, resulting in localized edema. Currently, there is no treatment for this debilitating disease. The pathophysiology of lymphedema involves pro-inflammatory mediators such as leukotriene B4 (LTB4). Skin thickness and subcutaneous echogenicity are increased in chronic lymphedema. This study will investigate the use of acevirstat, a leukotriene A4 hydrolase (LTA4H) inhibitor and a rate-limiting step in leukotriene B4 (LTB4) synthesis. Work published in animal models supports LTB4 antagonism for reversing lymphedema and associated tissue changes.

[0118] HEAL is an ongoing single-center phase 2 trial of acevirstat in human upper limb lymphedema. The inventors present early ultrasound responses in participants who completed 3 months of a total 6-month exposure period. The primary endpoint of this trial includes quantitative analysis of dermal ultrasound skin changes.

[0119] Significant forearm skin changes were observed on ultrasound in subjects treated with acevirstat for 3 months. Specifically, dermal ultrasound of the forearm of subjects with stage II lymphedema 3 months after treatment showed a decrease in skin thickness and echogenicity compared to baseline. In addition, an increase in the boundary between the dermal-epidermal junction and the subcutaneous fascia was observed. Subcutaneous tissue echogenicity also decreased.

[0120] This case report provides evidence of significant ultrasound-detectable skin changes in the upper extremities of this partially treated subject. Acevirstat reduced skin thickness and subcutaneous echogenicity in a patient with upper extremity lymphedema. The reduction in skin thickness and subcutaneous echogenicity suggests that acevirstat may target inflammation and excess fluid content in the affected tissue, mirroring responses previously observed in preclinical models. These prior results confer great promise for the HEAL trial.

[0121] Example 2: Initial data on the treatment of lymphedema with acevir stat in Extended Access Program (EAP) patients. The primary arm of the study was the HEAL clinical trial (NCT05203835), which is described above and WO2023107608 (the contents of which are explicitly incorporated herein by reference), and was designed to investigate the response of unilateral upper limb (arm) lymphedema between the pharmacological treatment of lymphedema with oral placebo and oral acevirstat. This example describes initial data from an expanded access program, including patients with lymphedema of any non-cancerous cause, patients with genetic vascular conditions, and patients with lipedema and obesity.

[0122] Figures 1A–1C and 2A–2C show a dramatic reduction in skin thickness 3 and 6 months after treatment with acevirstat. Figure 2C shows a 43% reduction in skin thickness observed 6 months after treatment with acevirstat. Figure 3C shows a 6.7% reduction in limb volume after 6 months, and Figure 5C shows significantly lower water content in the affected limb after 6 months after treatment with acevirstat. Figures 6A–6B are ultrasound images of the skin of a patient with right leg lymphedema before treatment (Figure 6A) and 3 months after treatment with acevirstat. At 6 months, subcutaneous thickness was reduced by more than 20.2%, skin thickness by 3.7%, and total thickness by 17.6%. Finally, Figure 7 shows a 15.2% reduction in subcutaneous thickness observed at 6 months (in a different patient from those in Figures 6A and 6B). Overall, these results demonstrate significant changes in skin thickness, subcutaneous thickness, and subcutaneous space in lymphedema patients after treatment with acevirstat.

[0123] We also assessed quality of life indicators in 11 EAP patients using LymVAS, a tool for inquiring about the experiences of lymphedema patients, based on experience and practice from previous lymphedema trials. LymVAS uses a sliding visual analog scale in which the patient moves a slider along a line to indicate the degree of response to a question. LymVAS has two sections: 1. The state domain measures the patient's state at a given time (the question is in the format of: "How are you feeling today?") and 2. The change (or Δ) domain measures the change in the patient's experience after the start of treatment (the question is in the format of: "How have you changed since the start of treatment?"). Figures 8 and 9 show significant improvements in LymVAS quality of life state scores and change scores 3 months after acevirstat treatment, and that these improvements were maintained for 6 months post-treatment.

[0124] Example 3: Treatment of Expanded Access Program (EAP) patients with acevir stat for lipedema The purpose of this expanded access trial is to provide early access to treatment with acevirstat for individuals with lipedema who are resistant to conventional treatments and to evaluate the safety of acevirstat in patients with lipedema. Patients with a clinical diagnosis of lymphedema for ≥6 months will be included in the trial. Patients with upper limb lymphedema or a history of currently active cancer or cancer will be excluded. Acevirstat will be administered once daily at a dose of 100 mg for 12 months. The primary outcomes to be tested will be changes in cutaneous thickness and composition of the affected area as measured by ultrasound. Secondary outcomes will include changes in skin thickness as measured by calipas, changes in limb volume as measured by ultrasound, quantitative changes in subcutaneous tissue thickness and structure, quality of life, and pain.

[0125] References [Table 4]

[0126] While the present invention is particularly shown and described in relation to its preferred embodiments, it will be understood by those skilled in the art that various modifications in form and detail can be made in the present invention without departing from the scope of the invention as encompassed in the appended claims.

[0127] The patents and scientific documents referenced herein establish knowledge available to those skilled in the art. All U.S. patents and published or unpublished U.S. patent applications cited herein are incorporated by reference. All published foreign patents and patent applications cited herein are incorporated by reference. All other published references, documents, manuscripts and scientific documents cited herein are incorporated by reference. All relevant teachings in all patents, published applications and references cited herein are incorporated by reference in their entirety.

Claims

1. A method for treating lipodymetabolism in a patient requiring treatment for lipodymetabolism, comprising the step of administering a therapeutically effective dose of acevirstat to the patient requiring treatment for lipodymetabolism.

2. The method according to claim 1, wherein the patient is suffering from type I lipedema.

3. The method according to claim 1, wherein the patient is suffering from type II lipedema.

4. The method according to claim 1, wherein the patient is suffering from type III lipedema.

5. The method according to claim 1, wherein the patient is suffering from type IV lipedema.

6. The method according to claim 3, wherein the patient is suffering from type II and IV lipedema.

7. The method according to claim 4, wherein the patient is suffering from type III and IV lipedema.

8. The method according to claim 1, wherein the lipodyme is stage I lipodyme.

9. The method according to claim 1, wherein the lipodyme is stage II lipodyme.

10. The method according to claim 1, wherein the lipodyme is stage III lipodyme.

11. The method according to claim 1, wherein the lipodyme is stage IV lipodyme (lipid lymphedema).

12. The method according to any one of claims 1 to 11, wherein the treatment results in a reduction of adipose tissue in the affected area.

13. The method according to any one of claims 1 to 11, wherein the treatment reduces inflammation in the affected tissue.

14. The method according to any one of claims 1 to 11, wherein the treatment results in a reduction in the number of macrophages and / or the number of M2 polarized macrophages.

15. The method according to any one of claims 1 to 11, wherein the treatment results in improved ultrasound visualization of the fascial band of the subcutaneous adipose tissue in the affected area.

16. The method according to any one of claims 1 to 11, wherein lymphatic drainage is increased.

17. The method according to any one of claims 1 to 11, wherein, when measured by ultrasound, the subcutaneous echogenicity of the affected tissue is reduced in the patient after treatment.

18. The method according to any one of claims 1 to 11, wherein the ratio of skin echogenicity to subcutaneous echogenicity in the affected area is increased in the patient compared to the ratio measured before treatment.

19. The method according to claim 1, wherein the patient is further treated by compression therapy, physiotherapy, exercise therapy, functional lymphatic rehabilitation and / or manual lymphatic drainage.

20. The method according to claim 1, wherein the patient is further treated by lipomegaly reduction surgery.

21. The method according to claim 1, wherein the patient is treated with a further agent selected from the group consisting of sympathomimetic agents, metformin, resveratrol, diosmin, and selenium.

22. The method according to claim 21, wherein the sympathetic nerve stimulant is selected from the group consisting of amphetamines and phentermines.

23. The method according to any one of claims 1 to 22, wherein acevirstat is administered orally.

24. The method according to claim 23, wherein the daily dose of acevirstat is approximately 200 mg / day or less.

25. The method according to claim 23, wherein the daily dose of acevirstat is approximately 100 mg / day or less.

26. The method according to claim 23, wherein the daily dose of acevirstat is approximately 75 mg / day or less.

27. The method according to claim 23, wherein the daily dose of acevirstat is approximately 50 mg / day or less.

28. The method according to claim 26 or 27, wherein acevirstat is administered twice a day.

29. The method according to any one of claims 24 to 27, wherein acevirstat is administered once a day.

30. The method according to any one of claims 1 to 22, wherein acevirstat is administered locally.

31. A method for treating a subcutaneous lymphatic dysfunction-related abnormality or subcutaneous lymphatic disease in a patient requiring treatment of a subcutaneous lymphatic dysfunction-related abnormality or subcutaneous lymphatic disease, comprising the step of administering a therapeutically effective dose of acevirstat to the patient.

32. The method according to claim 31, wherein the subcutaneous tissue is subcutaneous adipose tissue (SAT).

33. The method according to claim 31, wherein the subcutaneous tissue is fibrous tissue.

34. The method according to claim 32, wherein the abnormality is selected from the group consisting of accumulation or deposition of SAT, inflammation of SAT and destruction of the SAT fascia, or a combination thereof.

35. The method according to claim 32, wherein ultrasound visualization of the fascial band in the affected SAT is improved after treatment.

36. A method according to any one of claims 31 to 35, wherein the patient is suffering from lymphedema.

37. The method according to claim 36, wherein the lymphedema is primary lymphedema.

38. The method according to claim 36, wherein the lymphedema is secondary lymphedema.

39. The method according to claim 36, wherein the lymphedema is subclinical lymphedema.

40. The method according to claim 36, wherein the lymphedema is upper limb lymphedema.

41. The method according to claim 36, wherein the lymphedema is lower limb lymphedema.

42. The method according to claim 36, wherein the lymphedema is head, neck, and torso lymphedema.

43. The method according to any one of claims 36 to 42, wherein, when measured by ultrasound, the subcutaneous echogenicity of the affected area decreases after treatment.

44. The method according to any one of claims 36 to 43, wherein, when measured by ultrasound, the skin echogenicity of the affected area increases after treatment.

45. The method according to any one of claims 36 to 42, wherein the ratio of skin echogenicity to subcutaneous echogenicity in the affected area is increased in the patient compared to the ratio measured before treatment.

46. The method according to claim 38, wherein the patient has previously undergone surgery and / or radiotherapy for cancer.

47. The method according to claim 46, wherein the cancer is a solid tumor.

48. The method according to any one of claims 31 to 46, wherein the subcutaneous thickness of the affected area is reduced by at least about 10% compared to baseline for a period of 3 months or less after administration of acevirstat.

49. The method according to claim 48, wherein the subcutaneous thickness is reduced by at least about 20% within 3 months or less after administration of acevirstat.

50. The method according to any one of claims 31 to 46, wherein the subcutaneous thickness of the affected area is reduced by at least about 10% compared to baseline for a period of 6 months or less after administration of acevirstat.

51. The method according to claim 50, wherein the subcutaneous thickness of the affected area is reduced by at least about 10% compared to baseline for a period of three months or less after administration of acevirstat.

52. A method according to any one of claims 31 to 35, wherein the patient is suffering from lipedema.

53. The method according to claim 52, wherein, when measured by ultrasound, the subcutaneous echogenicity of the affected area is reduced in the patient after treatment.

54. The method according to claim 52, wherein the ratio of skin echogenicity to subcutaneous echogenicity in the affected area is increased in the patient after treatment compared to the ratio measured before treatment.

55. The method according to claim 52, wherein the affected area has a skin echogenicity to subcutaneous echogenicity ratio smaller than that of the control.

56. The method according to any one of claims 31 to 55, wherein acevirstat is administered orally.

57. The method according to claim 56, wherein the daily dose of acevirstat is approximately 200 mg / day or less.

58. A method for treating lymphedema in a patient requiring treatment for lymphedema, wherein the lymphedema is characterized by increased subcutaneous echogenicity in the affected area compared to normal, The method includes the step of administering an effective amount of acevirstat to the patient, A method in which echo intensity is determined by ultrasound.

59. A method for treating lymphedema in a patient requiring treatment for lymphedema, wherein the lymphedema is characterized by an affected area having a skin echogenicity to subcutaneous echogenicity ratio smaller than that of the control. The method includes the step of administering an effective amount of acevirstat to the patient, A method in which echo intensity is determined by ultrasound.

60. The method according to claim 59, wherein the affected area has a skin echogenicity to subcutaneous echogenicity ratio that is at least 10% lower than that of the control.

61. The method according to claim 59 or 60, wherein the control ratio is the mean skin echogenicity to subcutaneous echogenicity ratio of a population of normal individuals, or the control ratio is the skin echogenicity to subcutaneous echogenicity ratio of the patient's tissue on the opposite side of the affected area.

62. A process of determining the skin echogenicity and subcutaneous echogenicity of the affected area of ​​a patient using ultrasound; A step of calculating the ratio of skin echogenicity to subcutaneous echogenicity in the affected area; A step of identifying a patient as responsive to treatment when the ratio of affected areas is smaller than the ratio of control areas; and The procedure includes administering acevirstat to patients identified as responsive to treatment, A method for identifying patients who are responsive to treatment for lymphedema.

63. The method according to claim 62, wherein acevirstat is administered to the patient when the ratio is at least 10% lower than the control ratio.

64. The method according to claim 62 or 63, wherein the control ratio is the mean skin echogenicity to subcutaneous echogenicity ratio of a population of normal individuals, or the control ratio is the skin echogenicity to subcutaneous echogenicity ratio of patient tissue on the opposite side of the affected area.

65. The method according to any one of claims 59 to 64, wherein acevirstat is administered orally.

66. The method according to claim 65, wherein the daily dose of acevirstat is approximately 200 mg / day or less.

67. The method according to claim 65, wherein the daily dose of acevirstat is approximately 100 mg / day or less.

68. A method for treating lymphedema in patients who require treatment for lymphedema, A step of determining the skin echogenicity and subcutaneous echogenicity of the affected area of ​​the patient at baseline using ultrasound, and calculating the baseline ratio of skin echogenicity to subcutaneous echogenicity; The process of administering acevirstat to the patient; and A step of determining the skin echogenicity and subcutaneous echogenicity of the affected area after treatment using ultrasound, and calculating the ratio of skin echogenicity to subcutaneous echogenicity after treatment; The process involves either continuing administration of acevirstat at the initial daily dose if the post-treatment ratio is greater than the baseline ratio, or modifying the daily dose of acevirstat to an increased dose if the post-treatment ratio is not greater than the baseline ratio. Methods that include...

69. The method according to claim 68, wherein skin echogenicity and subcutaneous echogenicity are determined at least about one month after the start of administration of acevirstat.

70. The method according to claim 69, wherein skin echogenicity and subcutaneous echogenicity are determined at least about two months after the start of administration of acevirstat.

71. The method according to claim 70, wherein skin echogenicity and subcutaneous echogenicity are determined at least about three months after the start of administration of acevirstat.

72. The method according to any one of claims 68 to 71, further comprising the step of increasing the dose of acevirstat if the ratio after treatment is not greater than the ratio at baseline.

73. The method according to any one of claims 68 to 71, wherein acevirstat is administered orally.

74. The method according to claim 73, wherein the initial daily dose of acevirstat is approximately 100 mg / day or less.

75. The method according to claim 74, wherein the initial daily dose of acevirstat is approximately 75 mg / day or less.

76. A method for preventing or reducing the risk of subcutaneous lymphatic dysfunction-related abnormalities or subcutaneous lymphatic disease in patients at risk of subcutaneous lymphatic dysfunction-related abnormalities or subcutaneous lymphatic disease, comprising the step of administering a therapeutically effective dose of acevirstat to patients at risk of subcutaneous lymphatic dysfunction-related abnormalities or subcutaneous lymphatic disease.

77. The method according to claim 76 for preventing lymphedema or reducing the risk of lymphedema.

78. The method according to either claim 76 or 77, wherein the patient has or has undergone lymph node dissection or radiotherapy.

79. The method according to claim 78, wherein the patient has undergone or is undergoing lymph node dissection as part of cancer treatment.

80. The method according to claim 78, wherein acevirstat is administered in combination with a prophylactic intervention selected from lymphovenous anastomosis (LVA) and artificial lymph node implantation.

81. The method according to any one of claims 77 to 80, wherein administration of acevirstat reduces the risk of developing lymphedema by at least about 10% compared to the risk in the absence of acevirstat administration.

82. A method for reducing the subcutaneous thickness of a lymphedematous area in a patient suffering from lymphedema, the method comprising administering a therapeutically effective dose of acevirstat to the patient, wherein the subcutaneous thickness of the lymphedematous area is reduced by at least about 10% compared to baseline within 6 months or less after administration of acevirstat.

83. The method according to claim 82, wherein the subcutaneous thickness is reduced by at least about 10% within 3 months or less after administration of acevirstat.

84. The method according to claim 82, wherein the subcutaneous thickness is reduced by at least about 15%.

85. The method according to claim 84, wherein the subcutaneous thickness is reduced by at least about 15% for a period of three months or less after administration of acevirstat.

86. The method according to claim 83, wherein the subcutaneous thickness is reduced by at least about 20% after administration of acevirstat.

87. The method according to claim 87, wherein the subcutaneous thickness is reduced by at least about 20% for a period of three months or less after administration of acevirstat.

88. The method according to any one of claims 82 to 87, wherein the lymphedematous area is the upper limb.

89. The method according to any one of claims 82 to 87, wherein the lymphedema area is the lower limb.

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