PROPHYLACTIC OR THERAPEUTIC AGENT FOR NON-ALCOHOLIC STEATOHEPATITIS IN HUMANS
20230015691 · 2023-01-19
Assignee
Inventors
Cpc classification
A61P1/16
HUMAN NECESSITIES
A61K31/538
HUMAN NECESSITIES
International classification
Abstract
The present invention aims to provide a prophylactic agent or therapeutic agent for human non-alcoholic steatohepatitis (NASH), the agent being capable of (i) reducing body weight, (ii) changing the amount of HA, the amount of PIIINP, and the amount of TIMP-1, in serum, and changing the amount of sVCAM-1 in plasma, or (iii) reducing liver stiffness. The object is achieved by a prophylactic agent or therapeutic agent for human non-alcoholic steatohepatitis (NASH), including: the 1,4-benzoxazine compound represented by Formula (I) or a pharmaceutically acceptable salt thereof as an effective component; and a pharmaceutically acceptable carrier; the agent being capable of (i) reducing body weight, (ii) changing the amount of HA, the amount of PIIINP, and the amount of TIMP-1, in serum, and changing the amount of sVCAM-1 in plasma, or (iii) reducing liver stiffness.
Claims
1-6. (canceled)
7. A method of prevention or treatment of human non-alcoholic steatohepatitis, comprising: administering a prophylactically or therapeutically effective amount of the 1,4-benzoxazine compound represented by the following Formula (I): ##STR00015## or a pharmaceutically acceptable salt thereof to a subject in need of the prevention or treatment; the method being capable of reducing body weight.
8. A method of prevention or treatment of human non-alcoholic steatohepatitis, comprising: administering a prophylactically or therapeutically effective amount of the 1,4-benzoxazine compound represented by the following Formula (I): ##STR00016## or a pharmaceutically acceptable salt thereof to a subject in need of the prevention or treatment; the method being capable of changing one or more selected from the group consisting of the amount of HA, the amount of PIIINP, and the amount of TIMP-1, in serum, and the amount of sVCAM-1 in plasma.
9. A method of prevention or treatment of human non-alcoholic steatohepatitis, comprising: administering a prophylactically or therapeutically effective amount of the 1,4-benzoxazine compound represented by the following Formula (I): ##STR00017## or a pharmaceutically acceptable salt thereof to a subject in need of the prevention or treatment; the method being capable of reducing liver stiffness.
10-12. (canceled)
13. The method according to claim 7, the method of prevention or treatment of human non-alcoholic steatohepatitis is a method of prevention of human non-alcoholic steatohepatitis, the method being capable of suppressing progression from non-alcoholic simple fatty liver to non-alcoholic steatohepatitis.
14. The method according to claim 7, the method being capable of suppressing progression from non-alcoholic steatohepatitis to non-alcoholic liver fibrosis.
15. The method according to claim 7, the method being capable of suppressing progression from non-alcoholic steatohepatitis to liver cancer.
16. The method according to claim 8, the method of prevention or treatment of human non-alcoholic steatohepatitis is a method of prevention of human non-alcoholic steatohepatitis, the method being capable of suppressing progression from non-alcoholic simple fatty liver to non-alcoholic steatohepatitis.
17. The method according to claim 8, the method being capable of suppressing progression from non-alcoholic steatohepatitis to non-alcoholic liver fibrosis.
18. The method according to claim 8, the method being capable of suppressing progression from non-alcoholic steatohepatitis to liver cancer.
19. The method according to claim 9, the method of prevention or treatment of human non-alcoholic steatohepatitis is a method of prevention of human non-alcoholic steatohepatitis, the method being capable of suppressing progression from non-alcoholic simple fatty liver to non-alcoholic steatohepatitis.
20. The method according to claim 9, the method being capable of suppressing progression from non-alcoholic steatohepatitis to non-alcoholic liver fibrosis.
21. The method according to claim 9, the method being capable of suppressing progression from non-alcoholic steatohepatitis to liver cancer.
22. The method according to claim 8, wherein the subject is with one or more conditions selected from the group consisting of having diabetes, having hypertension and with a BMI of not less than 30; and the administering the compound decreases the amount of PIIINP in serum.
23. The method according to claim 8, wherein the subject is with one or more conditions selected from the group consisting of having diabetes and having hypertension; and the administering the compound decreases the amount of sVCAM-1 in plasma.
Description
BRIEF DESCRIPTION OF THE DRAWINGS
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MODE FOR CARRYING OUT THE INVENTION
[0053] The present invention is described below in detail.
[0054] In the present description, any “fiber/fibre” generated in a living body is referred to as “fiber”.
[0055] The term “non-alcoholic simple fatty liver” used in the present description means a disease showing only fat deposition in hepatocytes.
[0056] The term “non-alcoholic steatohepatitis (NASH)” used in the present description means a disease showing not only fat deposition, but also findings similar to those of alcoholic hepatitis (such as inflammation, hepatic necrosis, ballooning degeneration, and/or fibrosis).
[0057] The term “non-alcoholic liver fibrosis” used in the present description means a disease showing not only advanced fibrosis in the liver tissue, but also excessive production and/or accumulation of collagen and/or another/other component(s) of the extracellular matrix.
[0058] The term “non-alcoholic liver cirrhosis” used in the present description means a disease in which the hepatic lobule structure is modified due to advanced fibrosis.
[0059] One aspect of the present invention relates to a prophylactic agent or therapeutic agent for human non-alcoholic steatohepatitis (NASH), comprising:
[0060] the 1,4-benzoxazine compound represented by the following Formula (I):
##STR00012##
or a pharmaceutically acceptable salt thereof, as an effective component; and
[0061] a pharmaceutically acceptable carrier;
the agent being capable of reducing body weight.
[0062] The 1,4-benzoxazine compound represented by the Formula (I) (which may be referred to as “Compound (I) in the present description) contained as an effective component in the prophylactic agent or therapeutic agent of the present invention is a known compound described in Patent Document 3. Compound (I) may be used for a pharmaceutical use either in the free form, or in the form of a pharmaceutically acceptable salt thereof.
[0063] Examples of the pharmaceutically acceptable salt include salts with an acid, such as inorganic acid salts (including hydrochloric acid salt, sulfuric acid salt, phosphoric acid salt, and hydrobromic acid salt), and organic acid salts (including acetic acid salt, fumaric acid salt, oxalic acid salt, citric acid salt, methanesulfonic acid salt, benzenesulfonic acid salt, tosic acid salt, and maleic acid salt). Other examples of the pharmaceutically acceptable salt include salts with a base, such as alkali metal salts (including sodium salt and potassium salt) and alkaline earth metal salts (including calcium salt).
[0064] Compound (I) or the pharmaceutically acceptable salt thereof includes any of the inner salts and adducts thereof, and the solvates and hydrates thereof.
[0065] Compound (I) is known to show crystal polymorphism (Patent Document 4). The Compound (I) used for the prophylactic agent or therapeutic agent of the present invention may be any of the crystal polymorphs.
[0066] The prophylactic agent or therapeutic agent of the present invention may be orally or parenterally administered to a human. Examples of the parenteral administration include intravenous administration, intramuscular administration, subcutaneous administration, intraorgan administration, intranasal administration, intradermal administration, ocular instillation, intracerebral administration, rectal administration, vaginal administration, intraperitoneal administration, and intralesional administration.
[0067] The dosage form of the prophylactic agent or therapeutic agent of the present invention is not limited. Examples of the dosage form include tablets, pills, granules, capsules, powders, injection solutions, inhalants, solutions, emulsions, and suppositories.
[0068] In cases of a solid preparation, examples of the pharmaceutically acceptable carrier that may be used include excipients, lubricants, binders, and disintegrators. In cases of a liquid preparation, examples of the carrier that may be used include solvents, solubilizers, suspending agents, isotonic agents, and buffers. When necessary, other additives (for example, an antiseptic) may also be added.
[0069] Specific examples of the carrier include binders such as gelatin, corn starch, tragacanth gum, and gum arabic; excipients such as starch and crystalline cellulose; swelling agents such as alginic acid; injection solvents such as water, ethanol, and glycerin; and adhesives such as rubber adhesives and silicone adhesives.
[0070] The prophylactic agent or therapeutic agent of the present invention can be expected to show only low toxicity and low side effects, and is an excellent pharmaceutical. Thus, the prophylactic agent or therapeutic agent of the present invention can be safely administered to a human. The human is preferably a human in need of prevention or treatment of non-alcoholic steatohepatitis (NASH).
[0071] The human preferably has, but does not necessarily need to have, a Body Mass Index (which may be referred to as “BMI”) of not less than 30. It is well known that BMI can be calculated by measuring the body height and the body weight by known methods.
[0072] The human is preferably a human complicated with another/other disease(s) and/or the like (including diseases, disorders, symptoms, and signs, in the present description). Examples of the other disease(s) include diabetes, hyperglycemia, hypertension, obesity, glucose intolerance, insulin resistance, metabolic syndrome, and dyslipidemia (hyperlipidemia). The other disease(s) is/are preferably diabetes and/or hypertension.
[0073] Compound (I) or the pharmaceutically acceptable salt thereof as an effective component of the prophylactic agent or therapeutic agent of the present invention is effective for prevention or treatment of human non-alcoholic steatohepatitis (NASH), and has an action that reduces the body weight of the human.
[0074] The “reduction of the body weight” means that administration of Compound (I) or the pharmaceutically acceptable salt thereof to a human results in a lower body weight of the human relative to that in a case where it is not administered. The human body weight can be measured with a body weight scale or the like.
[0075] In the present description, the “treatment” includes curing of a disease or the like (such as the entire pathological conditions, or one or more pathological conditions), improvement of the disease or the like, and suppression of an increase in the severity of the disease or the like. The “therapeutically effective amount” means a dose of the therapeutic agent of the present invention, which dose is sufficient for achieving such an object.
[0076] The “prevention” in the present description includes prevention of development of a disease or the like, and slowing of development of the disease or the like. The “prophylactically effective amount” means a dose of the prophylactic agent of the present invention, which dose is sufficient for achieving such an object.
[0077] The total amount of Compound (I) or the pharmaceutically acceptable salt thereof in the total amount of the prophylactic agent or therapeutic agent of the present invention may be appropriately set depending on the dosage form, administration method, carrier, and/or the like. It is usually not less than 0.01% (w/w), preferably not less than 0.05% (w/w), more preferably not less than 0.1% (w/w), but is usually not more than 99% (w/w), preferably not more than 90% (w/w), more preferably not more than 85% (w/w).
[0078] The dose of the prophylactic agent or therapeutic agent of the present invention is appropriately set depending on the subject to whom the agent is to be administered, the administration route, the age of the subject, the sex of the subject, symptoms, severity of the symptoms, the dosage form, the usage, and/or the like. The dose is not limited as long as the prophylactic effect or therapeutic effect on non-alcoholic steatohepatitis (NASH) can be produced in the subject to whom the agent is administered. In any case, the agent may be administered once daily, or dividedly a plurality of times daily. In a specific example for oral administration to an adult patient (with a body weight of about 40 kg to 80 kg, for example, 60 kg), the daily dose in terms of the total amount of Compound (I) or the pharmaceutically acceptable salt thereof is usually not less than 0.1 mg, preferably not less than 0.5 mg, more preferably not less than 1 mg, but is usually not more than 50 mg, preferably not more than 40 mg, more preferably not more than 30 mg.
[0079] The dosing period of the prophylactic agent or therapeutic agent of the present invention is appropriately set depending on the subject to whom the agent is to be administered, the administration route, the age of the subject, the sex of the subject, symptoms, severity of the symptoms, the dosage form, the usage, and/or the like. The dosing period is not limited as long as the prophylactic effect or therapeutic effect on non-alcoholic steatohepatitis (NASH) can be produced in the subject to whom the agent is administered. In a specific example for oral administration to an adult patient (with a body weight of about 40 kg to 80 kg, for example, 60 kg), the dosing period regarding its lower limit is, for example, not less than 6 weeks, not less than 12 weeks, not less than 18 weeks, not less than 24 weeks, not less than 30 weeks, not less than 36 weeks, not less than 42 weeks, not less than 48 weeks, not less than 54 weeks, not less than 60 weeks, not less than 66 weeks, or not less than 72 weeks. Regarding the upper limit of the dosing period, the agent may be administered for the period used for prevention or treatment (including prognosis) of non-alcoholic steatohepatitis (NASH). Examples of the dosing period include, but are not limited to, the period until death, and a period of not more than 50 years, not more than 25 years, not more than 10 years, not more than 5 years, not more than 3 years, not more than 1.5 years, or not more than 72 weeks.
[0080] The prophylactic agent or therapeutic agent of the present invention can be produced by a known method. The prophylactic agent or therapeutic agent of the present invention may be molded into a sustained release formulation comprising the effective component.
[0081] The prophylactic agent or therapeutic agent of the present invention may be a prophylactic agent capable of suppressing progression from non-alcoholic simple fatty liver to non-alcoholic steatohepatitis.
[0082] The prophylactic agent or therapeutic agent of the present invention may be a prophylactic agent or therapeutic agent capable of suppressing progression from non-alcoholic steatohepatitis to non-alcoholic liver fibrosis.
[0083] The prophylactic agent or therapeutic agent of the present invention may be a prophylactic agent or therapeutic agent capable of suppressing progression from non-alcoholic steatohepatitis to liver cancer.
[0084] Another aspect of the present invention relates to a prophylactic agent or therapeutic agent for human non-alcoholic steatohepatitis (NASH), comprising:
[0085] the 1,4-benzoxazine compound represented by the following Formula (I):
##STR00013##
or a pharmaceutically acceptable salt thereof, as an effective component; and
[0086] a pharmaceutically acceptable carrier;
the agent being capable of changing the amount of HA, the amount of PIIINP, and the amount of TIMP-1, in serum, and changing the amount of sVCAM-1 in plasma.
[0087] Compound (I) or the pharmaceutically acceptable salt thereof as an effective component of the prophylactic agent or therapeutic agent of the present invention is effective for prevention or treatment of human non-alcoholic steatohepatitis (NASH), and has an action that changes one or more selected from the group consisting of the amount of HA, the amount of PIIINP, and the amount of TIMP-1, in serum, and the amount of sVCAM-1 in plasma, of the human.
[0088] The prophylactic agent or therapeutic agent of the present invention preferably has an action that changes the amount of HA, the amount of PIIINP, and the amount of TIMP-1, in serum, and the amount of sVCAM-1 in plasma.
[0089] Each change is an increase or a decrease, preferably a decrease.
[0090] The term “increasing the amount of HA in serum” means that administration of Compound (I) or the pharmaceutically acceptable salt thereof to a human results in a larger amount of HA in serum of the human relative to that in a case where it is not administered.
[0091] The term “decreasing the amount of HA in serum” means that administration of Compound (I) or the pharmaceutically acceptable salt thereof to a human results in a smaller amount of HA in serum of the human relative to that in a case where it is not administered.
[0092] The amount of HA in serum of a human can be measured by, for example, preparing serum from blood collected from the human according to a conventional method, and using a commercially available kit, as described later in Examples.
[0093] The definitions and the measurement method described above similarly apply to the terms “changing the amount of PIIINP in serum”, “changing the amount of TIMP-1 in serum”, and “changing the amount of sVCAM-1 in plasma”.
[0094] To details of the present aspect, the above description on the prophylactic agent or therapeutic agent for human non-alcoholic steatohepatitis (NASH), comprising: the 1,4-benzoxazine compound represented by the above Formula (I) or a pharmaceutically acceptable salt thereof, as an effective component; and a pharmaceutically acceptable carrier; the agent being capable of reducing body weight, is applied.
[0095] Another aspect of the present invention relates to a prophylactic agent or therapeutic agent for human non-alcoholic steatohepatitis (NASH), comprising:
[0096] the 1,4-benzoxazine compound represented by the following Formula (I):
##STR00014##
or a pharmaceutically acceptable salt thereof, as an effective component; and
[0097] a pharmaceutically acceptable carrier;
the agent being capable of reducing liver stiffness.
[0098] Compound (I) or the pharmaceutically acceptable salt thereof as an effective component of the prophylactic agent or therapeutic agent of the present invention is effective for prevention or treatment of human non-alcoholic steatohepatitis (NASH), and has an action that reduces the liver stiffness of the human.
[0099] The “reduction of the liver stiffness” means that administration of Compound (I) or the pharmaceutically acceptable salt thereof to a human results in a lower liver stiffness of the human relative to that in a case where it is not administered.
[0100] The liver stiffness of a human can be measured using an apparatus such as Shear Wave Elastography or Fibro scan as described later in Examples.
[0101] To details of the present aspect, the above description on the prophylactic agent or therapeutic agent for human non-alcoholic steatohepatitis (NASH), comprising: the 1,4-benzoxazine compound represented by the above Formula (I) or a pharmaceutically acceptable salt thereof, as an effective component; and a pharmaceutically acceptable carrier; the agent being capable of reducing body weight, is applied.
EXAMPLES
[0102] The present invention is described below in more detail according to Examples. However, the scope of the present invention is not limited by these Examples. MT-3995, which was used in the following Examples, means the Compound (I).
[0103] [Test Protocol] [0104] Number of cases to be analyzed: 47 cases (placebo administration group: 23 cases; MT-3995 administration group: 24 cases) [0105] The subjects were selected according to the following criteria.
[0106] NAFLD activity score ≥4
[0107] Kleiner fibrosis classification: Stage 2 or Stage 3
[0108] ALT at 10 weeks before assignment and 2 weeks before assignment ≥60 [0109] Patient backgrounds are shown in Table 1.
[0110] [Table 1]
TABLE-US-00001 TABLE 1 Patient backgrounds Placebo MT-3995 Total Number of subjects*.sup.1 23 24 47 Sex (male)*.sup.1 13 (56.5) 12 (50.0) 25 (53.2) Age (years old)*.sup.2 53.0 (31-75) 52.0 (40-67) 53.0 (31-75) Fifty years old or older*.sup.1 13 (56.5) 14 (58.3) 27 (57.4) Body weight (kg)*.sup.2 76.70 (51.8-100.5) 81.10 (45.6-108.3) 78.20 (45.6-108.3) BMI (kg/m.sup.2)*.sup.2 29.31 (21.8-36.3) 30.21 (21.7-39.8) 29.73 (21.7-39.8) Complication*.sup.1 Diabetes 8 (34.8) 12 (50.0) 20 (42.6) Dyslipidemia 13 (56.5) 15 (62.5) 28 (59.6) Hypertension 12 (52.2) 16 (66.7) 28 (59.6) SBP (mmHg)*.sup.2 130.0 (115-159) 136.0 (110-155) 130.0 (110-159) DBP (mmHg)*.sup.2 84.0 (66-98) 85.5 (65-98) 85.0 (65-98) ALT (U/L) 90.0 (64-168) 102.5 (49-174) 93.0 (49-174) ALT (U/L) >90*.sup.1 11 (47.8) 14 (58.3) 25 (53.2) *.sup.1Number of subjects (% ratio) *.sup.2Median (Minimum value-Maximum value) [0111] Pre-observation period (number of weeks): 10 weeks [0112] Administration period (number of weeks): 72 weeks [0113] Post-observation period (number of weeks): 8 weeks [0114] Dosage and administration: MT-3995 administration group=once daily, 10 mg; placebo group=once-daily administration
Example 1: Body Weight Change
[0115] Table 2 and
[0116] [Table 2]
TABLE-US-00002 TABLE 2 Average amount of change in the body weight after the assignment Change from baseline/Weight (kg) Placebo MT-3995 Visit Mean (SD) (n) Mean (SD) (n) Week 12 0.13 (1.68) 23 −1.39 (1.55) 24 Week 24 −0.80 (2.02) 23 −1.73 (2.09) 24 Week 36 −0.51 (2.01) 22 −1.88 (2.99) 22 Week 48 −0.63 (2.43) 21 −2.15 (3.23) 22 Week 60 −0.86 (2.55) 21 −2.23 (3.25) 22 Week 72 −0.78 (2.55) 21 −2.21 (3.10) 22
Example 2: Change in Serum Hyaluronic Acid Level
[0117] Table 3 and
[0118] Throughout the treatment period, the serum hyaluronic acid level in the placebo group was higher than the level observed at the beginning of the administration. On the other hand, throughout the treatment period, the serum hyaluronic acid level in the MT-3995 group was lower than the level observed at the beginning of the administration. At Weeks 24, 48, and 72 after the beginning of the administration, the serum hyaluronic acid level in the MT-3995 administration group was significantly lower than the level in the placebo group.
[0119] [Table 3]
TABLE-US-00003 TABLE 3 Average amount of change in the serum hyaluronic acid level after the assignment Change from baseline/Hyaluronic Acid (ng/mL) Placebo MT-3995 Visit LS Mean (95% Cl) (n) LS Mean (95% Cl) (n) Week 12 17.65 (−31.59, 66.89) 23 −31.87 (−80.13, 16.39) 24 Week 24 8.78 (−18.00, 35.56) 23 −39.02 (−65.34, −12.69) 24 Week 48 20.06 (−21.08, 61.21) 21 −47.23 (−87.58, −6.87) 22 Week 72 15.67 (−11.65, 42.99) 21 −32.02 (−58.74, −5.31) 22
Example 3: Change in Serum PIIINP Level
[0120] Table 4-1 and
[0121] Throughout the treatment period, the serum PIIINP value in the placebo group did not largely change from the value observed at the beginning of the administration. However, throughout the treatment period, the serum PIIINP value in the MT-3995 group was lower than the value observed at the beginning of the administration. At Weeks 12, 24, and 48 after the beginning of the administration, the serum PIIINP level in the MT-3995 administration group was significantly lower than the level in the placebo group.
[0122] [Table 4-1]
TABLE-US-00004 TABLE 4-1 Average amount of change in the serum PIIINP level after the assignment Change from baseline/PIIINP (ng/mL) Placebo MT-3995 Visit LS Mean (95% Cl) (n) LS Mean (95% Cl) (n) Week 12 0.591 (−1.121, 2.303) 23 −2.192 (−3.874, −0.510) 24 Week 24 1.469 (−1.062, 3.999) 23 −3.124 (−5.605, −0.643) 24 Week 48 −0.457 (−2.270, 1.356) 21 −3.987 (−5.756, −2.218) 22 Week 72 −1.664 (−3.489, 0.161) 21 −3.930 (−5.714, −2.146) 22
[0123] A stratified analysis was carried out for the subjects based on the presence or absence of complication with diabetes. The results are shown in Table 4-2 and
[0124] [Table 4-2]
TABLE-US-00005 TABLE 4-2 Average amount of change in the serum PIIINP level after the assignment Change from baseline/PIIINP (ng/mL) Placebo M-3995 non-DM DM non-DM DM Visit Mean (n) Mean (n) Mean (n) Mean (n) Week 12 −0.03 15 1.23 8 −2.34 12 −2.45 12 Week 24 0.67 15 2.45 8 −4.19 12 −2.47 12 Week 48 −0.45 15 −0.40 8 −3.14 12 −4.92 12 Week 72 −1.84 15 −0.79 8 −2.89 12 −5.00 12
[0125] Further, a stratified analysis was carried out for the subjects based on the presence or absence of complication with hypertension. The results are shown in Table 4-3 and
[0126] [Table 4-3]
TABLE-US-00006 TABLE 4-3 Average amount of change in the serum PIIINP level after the assignment Change from baseline/PIIINP (ng/mL) Placebo MT-3995 non-HP HP non-HP HP Visit Mean (n) Mean (n) Mean (n) Mean (n) Week 12 0.61 11 0.23 12 −1.69 8 −2.75 16 Week 24 1.42 11 1.16 12 −2.71 8 −3.64 16 Week 48 −0.11 11 −0.79 12 −1.89 8 −5.26 16 Week 72 −1.89 11 −1.15 12 −2.13 8 −4.98 16
[0127] Further, an analysis was carried out after dividing the subjects into patients with a BMI of not less than 30 and patients with a BMI of less than 30. The results are shown in Table 4-4 and
[0128] [Table 4-4]
TABLE-US-00007 TABLE 4-4 Average amount of change in the serum PIIINP level after the assignment Change from baseline/PIIINP (ng/mL) Placebo MT-3995 BMI < 30 BMI ≥ 30 BMI < 30 BMI ≥ 30 Visit Mean (n) Mean (n) Mean (n) Mean (n) Week 12 −0.76 15 2.61 8 −2.33 12 −2.46 12 Week 24 0.78 15 2.25 8 −3.86 12 −2.79 12 Week 48 −0.35 15 −0.61 8 −2.58 12 −5.24 12 Week 72 −2.67 15 0.72 8 −2.40 12 −5.24 12
Example 4: Change in Serum TIMP-1 Level
[0129] Table 5 and
[0130] The placebo group showed serum TIMP-1 values higher than the value observed at the beginning of the administration, until Week 24 after the beginning of the treatment. The TIMP-1 value decreased thereafter. However, the MT-3995 administration group showed serum TIMP-1 values lower than the value observed at the beginning of the administration, from Week 24 after the beginning of the treatment. Throughout the period of the clinical trial, this group showed values lower than the values in the Placebo group.
[0131] [Table 5]
TABLE-US-00008 TABLE 5 Average amount of change in the serum TIMP-1 level after the assignment Change from baseline/TIMP-1 (ng/mL) Placebo MT-3995 Visit LS Mean (95% Cl) (n) LS Mean (95% Cl) (n) Week 12 4.1 (−11.6, 19.8) 23 2.4 (−12.3, 17.1) 24 Week 24 11.0 (−11.3, 33.3) 23 −7.2 (−28.6, 14.2) 24 Week 48 −12.3 (−30.2, 5.6) 21 −22.4 (−39.3, −5.5) 22 Week 72 −20.8 (−41.4, −0.1) 21 −25.8 (−45.5 −6.0) 22
Example 5: Change in Plasma sVCAM-1 Level
[0132] Table 6-1 and
[0133] The placebo group showed almost the same plasma sVCAM values as the value observed at the beginning of the administration, until Week 48 after the beginning of the treatment. However, at Week 72, the value was lower than the value observed at the beginning of the administration.
[0134] On the other hand, the MT-3995 group showed lower plasma sVCAM values from Week 24 after the beginning of the administration, and showed the maximum value at Week 72. Based on comparison between the groups, the plasma sVCAM value in the MT-3995 administration group was lower than the value in the placebo group at Week 24, Week 48, and Week 72.
[0135] [Table 6-1]
TABLE-US-00009 TABLE 6-1 Average amount of change in the plasma sVCAM-1 level after the assignment Change from baseline/sVCAM-1 (ng/mL) Placebo MT-3995 Visit Mean (SD) (n) Mean (SD) (n) Week 12 8.3 (136.2) 23 13.8 (121.5) 24 Week 24 −3.4 (124.3) 23 −43.8 (137.3) 24 Week 48 −0.1 (121.8) 21 −44.7 (159.3) 22 Week 72 −33.7 (147.0) 21 −74.7 (182.9) 22
[0136] A stratified analysis was carried out for the subjects based on the presence or absence of complication with diabetes. The results are shown in Table 6-2 and
[0137] [Table 6-2]
TABLE-US-00010 TABLE 6-2 Average amount of change in the plasma sVCAM-1 level after the assignment Change from baseline/sVCAM-1 (ng/mL) Placebo MT-3995 non-DM DM non-DM DM Visit Mean (n) Mean (n) Mean (n) Mean (n) Week 12 12.87 15 −0.13 8 34.25 12 −6.58 12 Week 24 8.80 15 −26.38 8 −40.58 12 −47.08 12 Week 48 5.47 15 −14.00 8 −26.64 12 −62.73 12 Week 72 −24.87 15 −55.83 8 −37.18 12 −112.27 12
[0138] Further, a stratified analysis was carried out for the subjects based on the presence or absence of complication with hypertension. The results are shown in Table 6-3 and
[0139] [Table 6-3]
TABLE-US-00011 TABLE 6-3 Average amount of change in the plasma sVCAM-1 level after the assignment Change from baseline/sVCAM-1 (ng/mL) Placebo MT-3995 non-HP HP non-HP HP Visit Mean (n) Mean (n) Mean (n) Mean (n) Week 12 34.55 11 −15.67 12 30.13 8 5.69 16 Week 24 17.09 11 −22.25 12 −43.38 8 −44.06 16 Week 48 −32.82 11 35.90 12 0.13 8 −70.29 16 Week 72 −58.91 11 −6.00 12 −48.75 8 −89.57 16
Example 6: Change in Liver Stiffness
[0140] The liver stiffness after the assignment was measured using Shear Wave Elastography or Fibro scan. Table 7 and
[0141] According to the measurement by either measurement apparatus, the liver stiffness in the placebo group was found to have been unchanged throughout the treatment period. However, throughout the treatment period, the liver stiffness in the MT-3995 group was lower than the value observed at the beginning of the administration.
[0142] [Table 7]
TABLE-US-00012 TABLE 7 Average amount of change in the liver stiffness (Shear Wave Elastography) after the assignment Change from baseline/Liver stiffness (kPa) Placebo MT-3995 Visit Mean (SD) (n) Mean (SD) (n) Week 12 0.02 (2.61) 5 −4.57 (2.48) 3 Week 24 0.64 (5.38) 5 −5.63 (3.23) 3 Week 48 0.02 (3.61) 5 −4.90 (4.38) 2 Week 72 0.70 (4.61) 5 −6.00 (5.23) 2
[0143] [Table 8]
TABLE-US-00013 TABLE 8 Average amount of change in the liver stiffness (Fibro scan) after the assignment Change from baseline/Liver stiffness (kPa) Placebo MT-3995 Visit Mean (SD) (n) Mean (SD) (n) Week 12 −0.31 (3.06) 15 −0.49 (2.24) 14 Week 24 −0.05 (4.01) 15 0.30 (2.82) 14 Week 48 0.87 (3.61) 12 −1.05 (3.67) 13 Week 72 0.53 (3.48) 12 −1.41 (3.97) 14