WO2025069226A1 - Medicine containing pemafibrate - Google Patents

Abstract

The problem addressed is to provide a medicine containing pemafibrate that can be provided to a patient with renal dysfunction.　Provided is a medicine containing pemafibrate or a salt thereof or a solvate thereof as an active ingredient that is for administration to patients with renal dysfunction who require treatment by pemafibrate.

Description

Medicines containing pemafibrate

The present invention relates to a medicine containing pemafibrate.

Pemafibrate (chemical name: (2R)-2-[3-({1,3-benzoxazol-2-yl[3-(4-methoxyphenoxy)propyl]amino}methyl)phenoxy]butanoic acid) or its salts or solvates are compounds that have PPARα activation activity and are known to be useful in the prevention and treatment of diseases such as dyslipidemia (Patent Document 1).

Yokote et al. have investigated the safety and efficacy of pemafibrate in patients with chronic kidney disease (Non-Patent Document 1). In this report, pemafibrate was administered at 0.2-0.4 mg/day, and the blood concentration of pemafibrate in patients with kidney disease was measured.
However, pemafibrate is still contraindicated, along with other fibrate drugs such as fenofibrate and bezafibrate, for patients with renal dysfunction such as those with serum creatinine levels of 2.5 mg/dL or more or creatinine clearance of less than 40 mL/min, due to concerns that it may cause rhabdomyolysis (Non-Patent Documents 2, 3, 4). In the report by Yokote et al., the blood concentration of pemafibrate after long-term administration in patients with kidney disease was not fully confirmed, and it was not clarified whether the blood concentration would increase to the extent that it could cause rhabdomyolysis. In addition, in sustained-release preparations, the drug is administered in a large amount at one time and is absorbed over a long period of time, so that if accidentally overdosed, there is a high possibility of serious side effects and poisoning compared to immediate-release preparations (Non-Patent Document 5). For this reason, more careful administration is required. In addition, rhabdomyolysis has been reported in cases where other fibrate drugs were used in combination with HMG-CoA reductase inhibitors in patients with renal dysfunction (Non-Patent Document 6).

International Publication No. 2005/023777

Int J Mol Sci. 2019 Feb; 20(3):706. Package insert "Palmodia (registered trademark) Tablets 0.1 mg", Kowa Company, Ltd., revised May 2021 (10th edition) Package insert "Tricor (registered trademark) tablets 53.3 mg / Tricore (registered trademark) tablets 80 mg", ASKA Pharmaceutical Co., Ltd., revised July 2023 (3rd edition) Package insert "Bezatol (registered trademark) SR tablets 100 mg / Bezatol (registered trademark) SR tablets 200 mg", Kissei Pharmaceutical Co., Ltd., revised March 2023 (1st edition) Yakushin No. 1, No. 5, "Guidelines for the design and evaluation of sustained-release preparations (oral preparations)", March 11, 1988 Pharmaceutical interview form "Palmodia (registered trademark) Tablets 0.1 mg", Kowa Company, Ltd., revised in *2021 (12th edition)

The object of the present invention is to provide a medicine containing pemafibrate that can be provided to patients with renal dysfunction.

In order to achieve the above object, the inventors conducted extensive research and discovered that administration of pemafibrate for 12 weeks to patients with renal dysfunction did not result in clinically problematic blood concentrations, regardless of the level of renal dysfunction or whether or not a statin was used concomitantly, and thus completed the present invention.

That is, the present invention provides the following [Aspect 1] to [Aspect 60].
[Aspect 1]
A pharmaceutical agent comprising pemafibrate or a salt thereof, or a solvate thereof as an active ingredient, for administration to a patient with renal dysfunction who requires treatment with pemafibrate.
[Aspect 2]
2. The medicament of aspect 1, wherein the medicament is not administered as part of a clinical trial.
[Aspect 3]
The pharmaceutical composition according to aspect 1 or 2, which is a sustained release formulation.
[Aspect 4]
The pharmaceutical agent according to any one of Aspects 1 to 3, wherein the patient has renal dysfunction with a serum creatinine level of 2.5 mg/dL or more or a creatinine clearance of less than 40 mL/min.
[Aspect 5]
The medicament according to any one of Aspects 1 to 4, wherein the medicament is used in combination with a statin.
[Aspect 6]
The pharmaceutical agent according to any one of aspects 1 to 5, wherein the patient has a last measured estimated glomerular filtration rate (eGFR) of less than 45 mL/min/1.73 ^m2 as of 3 days prior to treatment with pemafibrate, and the patient has been receiving a statin since before the start of treatment with pemafibrate.
[Aspect 7]
The pharmaceutical according to any one of aspects 1 to 6, wherein the patient has an estimated glomerular filtration rate (eGFR) of less than 30 mL/min/1.73 ^m2 .
[Aspect 8]
A pharmaceutical agent according to any one of aspects 1 to 7, wherein the patient has a fasting serum triglyceride level of less than 200 mg/dL prior to initiation of treatment with pemafibrate.
[Aspect 9]
The pharmaceutical agent according to any one of aspects 1 to 7, wherein the patient has a fasting serum triglyceride level of less than 150 mg/dL prior to initiation of treatment with pemafibrate.
[Aspect 10]
Treatment with pemafibrate has been shown to improve the following conditions: hyperlipidemia, hypertriglyceridemia, hypercholesterolemia, high HDL cholesterolemia, dyslipidemia, diabetes, diabetic complications, peripheral arterial disease, inflammation, glaucoma, age-related macular degeneration, optic atrophy, external ophthalmoplegia, retinitis pigmentosa, heart disease, arteriosclerosis, chronic obstructive pulmonary disease (COPD), cancer cachexia, muscular dystrophy, amyotrophic lateral sclerosis (ALS), spinal muscular atrophy (SMA), spinal-bulbar muscular atrophy, hypotonia, muscle weakness, severe cramps, severe fatigue, rhabdomyolysis, fatigue, hyperkalemia, myopathy, sarcopenia, convulsions, myoclo 10. The pharmaceutical according to any one of Aspects 1 to 9, which is for the treatment of one or more selected from the group consisting of chronic obstructive pulmonary disease, ataxia, stroke-like symptoms, decreased intelligence, migraine, psychiatric symptoms, dystonia, myelopathy, non-alcoholic steatohepatitis, primary biliary cirrhosis, hepatic failure, Fanconi syndrome, renal tubular dysfunction, glomerular lesions, myoglobinuria, exocrine insufficiency, sideroblastic anemia, pancytopenia, sensorineural hearing loss, diarrhea, constipation, hypohidrosis, hirsutism, short stature, hypocalcemia, impaired consciousness, encephalopathy, vomiting induced by hunger or infection, frequent vomiting, delayed mental or motor development, poor weight gain, respiratory abnormalities, recurrent Reye-like syndrome, and hypoproteinemia.
[Aspect 11]
The pharmaceutical agent according to any one of Aspects 1 to 10, wherein the patient is not suffering from hyperlipidemia.
[Aspect 12]
Treatment with pemafibrate has been shown to improve the following conditions: hypercholesterolemia, high HDL cholesterol, dyslipidemia, diabetes, diabetic complications, peripheral arterial disease, inflammation, glaucoma, age-related macular degeneration, optic atrophy, external ophthalmoplegia, retinitis pigmentosa, heart disease, arteriosclerosis, chronic obstructive pulmonary disease (COPD), cancer cachexia, muscular dystrophy, amyotrophic lateral sclerosis (ALS), spinal muscular atrophy (SMA), spinal-bulbar muscular atrophy, hypotonia, muscle weakness, severe cramps, severe fatigue, rhabdomyolysis, easy fatigability, hyperkalemia, myopathy, sarcopenia, convulsions, myoclonus, ataxia, stroke. 12. The pharmaceutical composition according to any one of Aspects 1 to 9 or 11, which is for the treatment of one or more symptoms selected from: renal failure, myoglobinuria, exocrine insufficiency, sideroblastic anemia, pancytopenia, sensorineural hearing loss, diarrhea, constipation, hypohidrosis, hirsutism, short stature, hypocalcemia, impaired consciousness, encephalopathy, hunger- or infection-induced vomiting, frequent vomiting, delayed mental or motor development, poor weight gain, respiratory abnormalities, recurrent Reye-like syndrome, and hypoproteinemia.
[Aspect 13]
The pharmaceutical agent according to any one of Aspects 1 to 12, which is administered at 0.1 to 0.2 mg/day as pemafibrate.
[Aspect 14]
1. Use of pemafibrate, or a salt thereof, or a solvate thereof, for the manufacture of a medicament for administration to a patient with renal impairment in need of treatment with pemafibrate.
[Aspect 15]
15. The use according to aspect 14, wherein the medicament is not administered as part of a clinical trial.
[Aspect 16]
The use according to aspect 14 or 15, wherein the medicament is a sustained release formulation.
[Aspect 17]
The use according to any one of aspects 14 to 16, wherein the patient has renal dysfunction as indicated by a serum creatinine level of 2.5 mg/dL or more or a creatinine clearance of less than 40 mL/min.
[Aspect 18]
18. The use according to any of aspects 14 to 17, wherein the medicament is used in combination with a statin.
[Aspect 19]
The use according to any one of aspects 14 to 18, wherein the patient has a last measured estimated glomerular filtration rate (eGFR) of less than 45 mL/min/1.73 ^m2 3 days prior to treatment with pemafibrate, and the patient is receiving a statin prior to initiating treatment with pemafibrate.
[Aspect 20]
20. The use according to any of aspects 14 to 19, wherein the patient has an estimated glomerular filtration rate (eGFR) of less than 30 mL/min/1.73 ^m2 .
[Aspect 21]
21. The use according to any of aspects 14 to 20, wherein the patient has a fasting serum triglyceride level of less than 200 mg/dL prior to initiation of treatment with pemafibrate.
[Aspect 22]
21. The use according to any of aspects 14 to 20, wherein the patient has a fasting serum triglyceride level of less than 150 mg/dL prior to initiation of treatment with pemafibrate.
[Aspect 23]
Treatment with pemafibrate has been shown to improve the following conditions: hyperlipidemia, hypertriglyceridemia, hypercholesterolemia, high HDL cholesterolemia, dyslipidemia, diabetes, diabetic complications, peripheral arterial disease, inflammation, glaucoma, age-related macular degeneration, optic atrophy, external ophthalmoplegia, retinitis pigmentosa, heart disease, arteriosclerosis, chronic obstructive pulmonary disease (COPD), cancer cachexia, muscular dystrophy, amyotrophic lateral sclerosis (ALS), spinal muscular atrophy (SMA), spinal and bulbar muscular atrophy, hypotonia, muscle weakness, severe cramps, severe fatigue, rhabdomyolysis, fatigue, hyperkalemia, myopathy, sarcopenia, convulsions, myoclonus, and cerebrovascular disease. 23. The use according to any one of aspects 14 to 22, which is for the treatment of one or more symptoms selected from: chronic obstructive pulmonary disease, chronic myocardial infarction, ataxia, stroke-like symptoms, decreased intelligence, migraine, psychiatric symptoms, dystonia, myelopathy, non-alcoholic steatohepatitis, primary biliary cirrhosis, liver failure, Fanconi syndrome, renal tubular dysfunction, glomerular lesions, myoglobinuria, exocrine insufficiency, sideroblastic anemia, pancytopenia, sensorineural hearing loss, diarrhea, constipation, hypohidrosis, hirsutism, short stature, hypocalcemia, impaired consciousness, encephalopathy, hunger- or infection-induced vomiting, frequent vomiting, delayed mental or motor development, poor weight gain, respiratory abnormalities, recurrent Reye-like syndrome, and hypoproteinemia.
[Aspect 24]
24. The use according to any of aspects 14 to 23, wherein the patient is not suffering from hyperlipidemia.
[Aspect 25]
Treatment with pemafibrate has been shown to improve the following conditions: hypercholesterolemia, high HDL cholesterol, dyslipidemia, diabetes, diabetic complications, peripheral arterial disease, inflammation, glaucoma, age-related macular degeneration, optic atrophy, external ophthalmoplegia, retinitis pigmentosa, heart disease, arteriosclerosis, chronic obstructive pulmonary disease (COPD), cancer cachexia, muscular dystrophy, amyotrophic lateral sclerosis (ALS), spinal muscular atrophy (SMA), spinal-bulbar muscular atrophy, hypotonia, muscle weakness, severe cramps, severe fatigue, rhabdomyolysis, easy fatigability, hyperkalemia, myopathy, sarcopenia, convulsions, myoclonus, ataxia, stroke-like syndrome. 25. The use according to any one of aspects 14 to 22 or 24, which is for the treatment of one or more selected from symptoms, decreased intelligence, migraine, psychiatric symptoms, dystonia, myelopathy, non-alcoholic steatohepatitis, primary biliary cirrhosis, liver failure, Fanconi syndrome, renal tubular dysfunction, glomerular lesions, myoglobinuria, exocrine insufficiency, sideroblastic anemia, pancytopenia, sensorineural hearing loss, diarrhea, constipation, hypohidrosis, hirsutism, short stature, hypocalcemia, impaired consciousness, encephalopathy, hunger- or infection-induced vomiting, frequent vomiting, delayed mental or motor development, poor weight gain, respiratory abnormalities, recurrent Reye-like syndrome, and hypoproteinemia.
[Aspect 26]
The use according to any one of aspects 14 to 25, wherein the amount of pemafibrate administered is 0.1 to 0.2 mg/day.
[Aspect 27]
Pemafibrate or a salt thereof, or a solvate thereof, for administration to a patient with renal impairment in need of treatment with pemafibrate.
[Aspect 28]
28. The pemafibrate or a salt thereof, or a solvate thereof according to aspect 27, wherein the pemafibrate or a salt thereof, or a solvate thereof is not administered as part of a clinical trial.
[Aspect 29]
29. The pemafibrate or a salt thereof, or a solvate thereof according to aspect 27 or 28, which is a sustained release formulation.
[Aspect 30]
30. The pemafibrate or a salt thereof, or a solvate thereof according to any one of aspects 27 to 29, wherein the patient has renal dysfunction with a serum creatinine level of 2.5 mg/dL or more or a creatinine clearance of less than 40 mL/min.
[Aspect 31]
The pemafibrate or a salt thereof, or a solvate thereof according to any one of Aspects 27 to 30, wherein the pemafibrate or a salt thereof, or a solvate thereof is used in combination with a statin.
[Aspect 32]
The use of pemafibrate or a salt thereof, or a solvate thereof according to any one of aspects 27 to 31, wherein the patient has a last measured estimated glomerular filtration rate (eGFR) of less than 45 mL/min/1.73 ^m2 as of 3 days prior to treatment with pemafibrate, and the patient has been administered a statin prior to the start of treatment with pemafibrate.
[Aspect 33]
The pemafibrate or a salt thereof, or a solvate thereof according to any one of aspects 27 to 32, wherein the patient has an estimated glomerular filtration rate (eGFR) of less than 30 mL/min/1.73 ^m2 .
[Aspect 34]
The pemafibrate or a salt thereof, or a solvate thereof according to any one of Aspects 27 to 33, wherein the patient's fasting serum triglyceride level before initiation of treatment with pemafibrate is less than 200 mg/dL.
[Aspect 35]
The use of pemafibrate or a salt thereof, or a solvate thereof according to any one of aspects 27 to 33, wherein the patient's fasting serum triglyceride level before initiation of pemafibrate treatment is less than 150 mg/dL.
[Aspect 36]
Treatment with pemafibrate has been shown to improve the following conditions: hyperlipidemia, hypertriglyceridemia, hypercholesterolemia, high HDL-cholesterolemia, dyslipidemia, diabetes, diabetic complications, peripheral arterial disease, inflammation, glaucoma, age-related macular degeneration, optic atrophy, external ophthalmoplegia, retinitis pigmentosa, heart disease, arteriosclerosis, chronic obstructive pulmonary disease (COPD), cancer cachexia, muscular dystrophy, amyotrophic lateral sclerosis (ALS), spinal muscular atrophy (SMA), spinal-bulbar muscular atrophy, hypotonia, muscle weakness, severe cramps, severe fatigue, rhabdomyolysis, fatigue, hyperkalemia, myopathy, sarcopenia, convulsions, myoclonus, ataxia, stroke-like syndrome 36. The use of pemafibrate or a salt thereof, or a solvate thereof according to any one of aspects 27 to 35, which is for the treatment of one or more of the following conditions: vomiting induced by hunger or infection, decreased intelligence, migraine, psychiatric symptoms, dystonia, myelopathy, non-alcoholic steatohepatitis, primary biliary cirrhosis, liver failure, Fanconi syndrome, renal tubular dysfunction, glomerular lesions, myoglobinuria, exocrine insufficiency, sideroblastic anemia, pancytopenia, sensorineural hearing loss, diarrhea, constipation, hypohidrosis, hirsutism, short stature, hypocalcemia, impaired consciousness, encephalopathy, fasting or infection-induced vomiting, frequent vomiting, delayed mental or motor development, poor weight gain, respiratory abnormalities, recurrent Reye-like syndrome, and hypoproteinemia.
[Aspect 37]
The use of pemafibrate or a salt thereof, or a solvate thereof according to any one of Aspects 27 to 36, wherein the patient is not suffering from hyperlipidemia.
[Aspect 38]
Treatment with pemafibrate has been shown to improve the following conditions: hypercholesterolemia, high HDL cholesterol, dyslipidemia, diabetes, diabetic complications, peripheral arterial disease, inflammation, glaucoma, age-related macular degeneration, optic atrophy, external ophthalmoplegia, retinitis pigmentosa, heart disease, arteriosclerosis, chronic obstructive pulmonary disease (COPD), cancer cachexia, muscular dystrophy, amyotrophic lateral sclerosis (ALS), spinal muscular atrophy (SMA), spinal-bulbar muscular atrophy, hypotonia, muscle weakness, severe cramps, severe fatigue, rhabdomyolysis, fatigue, hyperkalemia, myopathy, sarcopenia, convulsions, myoclonus, ataxia, stroke-like symptoms, decreased intelligence, migraines, 38. The use of pemafibrate or a salt thereof, or a solvate thereof according to any one of aspects 27 to 35 or 37, for treating one or more conditions selected from psychiatric symptoms, dystonia, myelopathy, non-alcoholic steatohepatitis, primary biliary cirrhosis, hepatic failure, Fanconi syndrome, renal tubular dysfunction, glomerular lesions, myoglobinuria, exocrine insufficiency, sideroblastic anemia, pancytopenia, sensorineural hearing loss, diarrhea, constipation, hypohidrosis, hirsutism, short stature, hypocalcemia, impaired consciousness, encephalopathy, fasting/infection-induced vomiting, frequent vomiting, delayed mental/motor development, poor weight gain, respiratory abnormalities, recurrent Reye-like syndrome, and hypoproteinemia.
[Aspect 39]
Pemafibrate or a salt thereof, or a solvate thereof according to any one of Aspects 27 to 38, which is administered at 0.1 to 0.2 mg/day as pemafibrate.
[Aspect 40]
A method for treating a disease requiring treatment with pemafibrate, comprising administering to a patient suffering from renal dysfunction an effective amount of pemafibrate, a salt thereof, or a solvate thereof.
[Aspect 41]
The method of treatment according to aspect 40, wherein pemafibrate or a salt thereof or a solvate thereof is not administered as part of a clinical trial.
[Aspect 42]
42. The method of treatment according to aspect 40 or 41, wherein the compound is administered as a sustained release formulation.
[Aspect 43]
The method according to any one of aspects 40 to 42, wherein the patient has renal dysfunction with a serum creatinine level of 2.5 mg/dL or more or a creatinine clearance of less than 40 mL/min.
[Aspect 44]
The method of treatment according to any one of Aspects 40 to 43, wherein pemafibrate or a salt thereof, or a solvate thereof is used in combination with a statin.
[Aspect 45]
45. The method of any one of aspects 40 to 44, wherein the patient has a last measured estimated glomerular filtration rate (eGFR) of less than 45 mL/min/1.73 ^m2 as of 3 days prior to treatment with pemafibrate, and the patient is receiving a statin prior to initiating treatment with pemafibrate.
[Aspect 46]
46. A method of treatment according to any of aspects 40 to 45, wherein the patient has an estimated glomerular filtration rate (eGFR) of less than 30 mL/min/1.73 ^m2 .
[Aspect 47]
47. The method of treatment according to any of aspects 40 to 46, wherein the patient has a fasting serum triglyceride level of less than 200 mg/dL prior to initiation of pemafibrate treatment.
[Aspect 48]
47. The method of treatment according to any of aspects 40 to 46, wherein the patient has a fasting serum triglyceride level of less than 150 mg/dL prior to initiation of pemafibrate treatment.
[Aspect 49]
Diseases requiring treatment with pemafibrate include hyperlipidemia, hypertriglyceridemia, hypercholesterolemia, high HDL cholesterolemia, dyslipidemia, diabetes, diabetic complications, peripheral arterial disease, inflammation, glaucoma, age-related macular degeneration, optic atrophy, external ophthalmoplegia, retinitis pigmentosa, heart disease, arteriosclerosis, chronic obstructive pulmonary disease (COPD), cancer cachexia, muscular dystrophy, amyotrophic lateral sclerosis (ALS), spinal muscular atrophy (SMA), spinal and bulbar muscular atrophy, hypotonia, muscle weakness, severe cramps, severe fatigue, rhabdomyolysis, easy fatigue, hyperkalemia, myopathy, sarcopenia, convulsions, myoclonus, and pulmonary embolism. 49. The method according to any one of aspects 40 to 48, wherein the disease is one or more diseases selected from the group consisting of chronic kidney disease, ataxia, stroke-like symptoms, decreased intelligence, migraine, psychiatric symptoms, dystonia, myelopathy, non-alcoholic steatohepatitis, primary biliary cirrhosis, liver failure, Fanconi syndrome, renal tubular dysfunction, glomerular lesions, myoglobinuria, exocrine insufficiency, sideroblastic anemia, pancytopenia, sensorineural hearing loss, diarrhea, constipation, decreased sweating, hirsutism, short stature, hypocalcemia, impaired consciousness, encephalopathy, vomiting induced by hunger or infection, frequent vomiting, delayed mental and motor development, poor weight gain, respiratory abnormalities, recurrent Reye-like syndrome, and hypoproteinemia.
[Aspect 50]
A method of treatment according to any one of aspects 40 to 49, wherein the patient is not suffering from hyperlipidemia.
[Aspect 51]
Diseases requiring treatment with pemafibrate include hypercholesterolemia, high HDL cholesterolemia, dyslipidemia, diabetes, diabetic complications, peripheral arterial disease, inflammation, glaucoma, age-related macular degeneration, optic atrophy, external ophthalmoplegia, retinitis pigmentosa, heart disease, arteriosclerosis, chronic obstructive pulmonary disease (COPD), cancer cachexia, muscular dystrophy, amyotrophic lateral sclerosis (ALS), spinal muscular atrophy (SMA), spinal-bulbar muscular atrophy, hypotonia, muscle weakness, severe cramps, severe fatigue, rhabdomyolysis, easy fatigue, hyperkalemia, myopathy, sarcopenia, convulsions, myoclonus, ataxia, and cerebral 51. The method according to any one of aspects 40 to 48 or 50, wherein the disease is one or more selected from stroke-like symptoms, intellectual disability, migraine, psychiatric symptoms, dystonia, myelopathy, non-alcoholic steatohepatitis, primary biliary cirrhosis, liver failure, Fanconi syndrome, renal tubular dysfunction, glomerular lesions, myoglobinuria, exocrine insufficiency, sideroblastic anemia, pancytopenia, sensorineural hearing loss, diarrhea, constipation, hypohidrosis, hirsutism, short stature, hypocalcemia, impaired consciousness, encephalopathy, hunger- or infection-induced vomiting, frequent vomiting, delayed mental or motor development, poor weight gain, respiratory abnormalities, recurrent Reye-like syndrome, and hypoproteinemia.
[Aspect 52]
The method of any one of Aspects 40 to 51, wherein pemafibrate is administered at 0.1 to 0.2 mg/day.
[Aspect 53]
The pharmaceutical agent according to any one of Aspects 1 to 13, wherein pemafibrate, or a salt thereof, or a solvate thereof is administered for 53 weeks or longer.
[Aspect 54]
The use according to any one of aspects 14 to 26, wherein pemafibrate or a salt thereof, or a solvate thereof is administered for 53 weeks or more.
[Aspect 55]
The pemafibrate or a salt thereof, or a solvate thereof according to any one of aspects 27 to 39, wherein the pemafibrate or a salt thereof, or a solvate thereof is administered for 53 weeks or more.
[Aspect 56]
A method of treatment according to any one of Aspects 40 to 52, wherein pemafibrate or a salt thereof, or a solvate thereof is administered for 53 weeks or more.
[Aspect 57]
54. The medicament according to any one of aspects 1 to 13 or 53, wherein the patient is undergoing treatment with one or more selected from anion exchange resins, intestinal cholesterol transporter inhibitors, nicotinic acid derivatives, polyunsaturated fatty acids and salts or esters of polyunsaturated fatty acids, PCSK9 inhibitors, MTP (microsomal triglyceride transfer protein) inhibitors, Apo CIII inhibitors, CETP (cholesteryl ester transfer protein) inhibitors, ACL (ATP citrate lyase) inhibitors, probucol and salts of probucol, and mipomersen and salts of mipomersen.
[Aspect 58]
55. The use according to any of aspects 14 to 26 or 54, wherein the patient is undergoing treatment with one or more selected from anion exchange resins, intestinal cholesterol transporter inhibitors, nicotinic acid derivatives, polyunsaturated fatty acids and salts or esters of polyunsaturated fatty acids, PCSK9 inhibitors, MTP (microsomal triglyceride transfer protein) inhibitors, Apo CIII inhibitors, CETP (cholesteryl ester transfer protein) inhibitors, ACL (ATP citrate lyase) inhibitors, probucol and salts of probucol, and mipomersen and salts of mipomersen.
[Aspect 59]
56. The use of pemafibrate or a salt thereof, or a solvate thereof according to any one of aspects 27 to 39 or 55, wherein the patient is undergoing treatment with one or more selected from anion exchange resins, intestinal cholesterol transporter inhibitors, nicotinic acid derivatives, polyunsaturated fatty acids and salts or esters of polyunsaturated fatty acids, PCSK9 inhibitors, MTP (microsomal triglyceride transfer protein) inhibitors, Apo CIII inhibitors, CETP (cholesteryl ester transfer protein) inhibitors, ACL (ATP citrate lyase) inhibitors, probucol and salts of probucol, and mipomersen and salts of mipomersen.
[Aspect 60]
57. The method of any of aspects 40-52 or 56, wherein the patient is undergoing treatment with one or more selected from anion exchange resins, intestinal cholesterol transporter inhibitors, nicotinic acid derivatives, polyunsaturated fatty acids and salts or esters of polyunsaturated fatty acids, PCSK9 inhibitors, MTP (microsomal triglyceride transfer protein) inhibitors, Apo CIII inhibitors, CETP (cholesteryl ester transfer protein) inhibitors, ACL (ATP citrate lyase) inhibitors, probucol and salts of probucol, and mipomersen and salts of mipomersen.

The present invention makes it possible to provide new preventive and/or therapeutic options for patients with renal dysfunction.

FIG. 1 shows the relationship between eGFR and pharmacokinetic parameters (AUCτ, C _Max ).

In this specification, pemafibrate means (2R)-2-[3-({1,3-benzoxazol-2-yl[3-(4-methoxyphenoxy)propyl]amino}methyl)phenoxy]butanoic acid, which has the following chemical formula (A):

The compound can be produced, for example, according to the method described in Patent Document 1. It can also be formulated according to the method described in the literature. Furthermore, a formulation containing pemafibrate has been approved in Japan as a hyperlipidemia treatment agent, "Palmodia (registered trademark) tablets," and these "Palmodia tablets" can also be used.

In one embodiment of the present invention, a salt and/or solvate of pemafibrate can also be used. The salt and solvate can be produced by a conventional method. There are no particular limitations on the salt of pemafibrate as long as it is pharma- ceutically acceptable, and examples of the salt include alkali metal salts such as sodium salt and potassium salt; alkaline earth metal salts such as calcium salt and magnesium salt; organic base salts such as ammonium salt and trialkylamine salt; mineral acid salts such as hydrochloride and sulfate; and organic acid salts such as acetate. Examples of solvates of pemafibrate or its salt include hydrates and alcohol solvates (e.g., ethanol solvates).

In one aspect of the present invention, a pharmaceutical agent is provided that contains pemafibrate or a salt thereof, or a solvate thereof as an active ingredient, and is intended for administration to a patient with renal dysfunction who requires treatment with pemafibrate.

In one aspect of the present invention, there is provided a use of pemafibrate or a salt thereof, or a solvate thereof, for the manufacture of a medicament for administration to a patient with renal impairment in need of treatment with pemafibrate.

In one aspect of the present invention, there is provided pemafibrate or a salt thereof, or a solvate thereof for administration to a patient with renal impairment who requires treatment with pemafibrate.

In one aspect of the present invention, there is provided a method for treating a disease requiring treatment with pemafibrate, comprising administering to a patient with renal dysfunction an effective amount of pemafibrate or a salt thereof, or a solvate thereof.

In one aspect of the present invention, pemafibrate or a salt thereof or a solvate thereof can be formulated into a pharmaceutical formulation such as a tablet, capsule, granule, powder, lotion, ointment, injection, or suppository using other pharmaceutically acceptable carriers. These preparations can be manufactured by known methods. In one aspect of the present invention, a pharmaceutical formulation containing pemafibrate or a salt thereof or a solvate thereof can be administered orally or parenterally, with oral administration being preferred.

In one embodiment of the present invention, pemafibrate or its salt or solvate thereof can be made into an immediate release formulation. In this specification, the term "immediate release formulation" refers to a formulation in which the release of the active ingredient from the formulation is not specifically controlled. An example of the "immediate release formulation" is the commercially available "Palmodia (registered trademark) tablets".
In one embodiment of the present invention, pemafibrate or a salt thereof, or a solvate thereof may be made into a sustained release formulation. In this specification, the term "sustained release formulation" refers to a formulation in which the release rate, release time, and release site of the active ingredient from the formulation are adjusted for the purpose of reducing the number of administrations or reducing side effects. The sustained release formulation may be manufactured by various known methods. The controlled release formulation may be of any of the reservoir type, matrix type, osmotic pump type, and ion exchange type. It may also be of the multiple unit type. As the formulation base for controlled release, for example, as described in Saishin Pharmaceutical Science, Hirokawa Shoten Co., Ltd., published on February 25, 2006, 7th edition, ethyl acrylate-methacrylic acid copolymer, aminoalkyl methacrylate copolymer, ethyl cellulose, carnauba wax, stearyl alcohol, shellac, hydroxypropyl methylcellulose, hydroxypropyl cellulose, silicone, ethylene-vinyl acetate copolymer, polylactic acid, polylactic acid-glycolic acid, chitin, chitosan, gelatin, collagen, albumin, phospholipids, and/or cyclodextrin may be used. Alternatively, commercially available products such as "Palmodia (registered trademark) XR tablets" may be used.

In this specification, "patients in need of treatment with pemafibrate" refers to patients suffering from one or more diseases whose symptoms may be eliminated or alleviated by administration of pemafibrate or a salt thereof, or a solvate thereof. Examples of such diseases include, but are not limited to, eye diseases such as glaucoma, age-related macular degeneration, optic atrophy, external ophthalmoplegia, and retinitis pigmentosa, angina pectoris, cardiovascular disease, coronary artery disease, cardiomyopathy, cardiac hypertrophy, cardiac dysfunction, myocardial infarction, dilated cardiomyopathy, pulmonary hypertension, conduction disorder, and Wolff-Parkinson-White syndrome, and heart diseases such as muscle atrophy diseases (muscular dystrophies (chromosomal recessive muscular dystrophies such as Duchenne muscular dystrophy and Becker muscular dystrophy, Fukuyama type, Ullrich type, merosin deficiency, integravir deficiency, and eosinophilic dysplasia), and other diseases. Congenital muscular dystrophies such as leukemia, Walker-Warburg syndrome, limb-girdle muscular dystrophy, Miyoshi muscular dystrophy, facioscapulohumeral muscular dystrophy, myotonic dystrophy, etc.), amyotrophic lateral sclerosis (ALS), spinal muscular atrophy (SMA) or spinal-bulbar muscular atrophy, etc.), hypotonia, muscle weakness, severe cramps, severe fatigue, rhabdomyolysis, easy fatigability, hyperkalemia, myopathy, sarcopenia and other skeletal muscle diseases, convulsions, myoclonus, ataxia, stroke-like symptoms, decreased intelligence, migraine, psychiatric disorders central nervous system disorders such as dystonia and myelopathy, liver disorders such as non-alcoholic fatty liver disease, primary biliary cirrhosis and liver failure, Fanconi syndrome, renal disorders such as tubular dysfunction, glomerular lesions and myoglobinuria, pancreatic disorders such as exocrine insufficiency, blood disorders such as sideroblastic anemia and pancytopenia, inner ear disorders such as sensorineural hearing loss, intestinal disorders such as diarrhea and constipation, skin disorders such as decreased sweating and hirsutism, endocrine disorders such as short stature and hypocalcemia, hypoproteinemia such as hypoalbuminemia, impaired consciousness, encephalopathy, vomiting induced by hunger or infection, frequent vomiting, mental and Examples of the symptoms include delayed motor development, poor weight gain, respiratory abnormalities, recurrent Reye-like syndrome, hyperlipidemia, hypertriglyceridemia, hypercholesterolemia (familial hypercholesterolemia (homozygous), familial hypercholesterolemia (heterozygous), hyper LDL-cholesterolemia, etc.), hyper HDL-cholesterolemia, dyslipidemia, diabetes, diabetic complications (diabetic nephropathy, diabetic retinopathy, etc.), peripheral arterial disease, arteriosclerosis, chronic obstructive pulmonary disease (COPD), cancer cachexia, and inflammation. In this specification, "treatment with pemafibrate" means administering pemafibrate or a salt thereof, or a solvate thereof to the above-mentioned "patient in need of treatment with pemafibrate" for the elimination or mitigation of symptoms of one or more diseases that may be eliminated or mitigated by administering pemafibrate or a salt thereof, or a solvate thereof.

In some embodiments, the patient is one in whom statins do not sufficiently reduce blood LDL cholesterol or who has restrictions on statin administration. Also included are patients for whom treatment with existing LDL-C-lowering drugs is not suitable, for example, patients for whom statin administration is restricted. Here, a patient in whom statins do not sufficiently reduce blood LDL-C is a patient in whom blood LDL-C is not sufficiently reduced even with statin administration. A patient for whom statin administration is restricted is a patient for whom statin administration is restricted due to contraindications such as muscle-related side effects or liver damage.

In some embodiments, the patient has hyperlipidemia. In some embodiments, the patient may have a fasting serum triglyceride level, e.g., greater than or equal to 250, 240, 230, 220, 210, 200, 190, 180, 170, 160, or 150 mg/dL prior to initiation of pemafibrate treatment.

In another embodiment, the patient does not suffer from hyperlipidemia. In another embodiment, the patient may have a fasting serum triglyceride level, e.g., less than 250, 240, 230, 220, 210, 200, 190, 180, 170, 160, or 150 mg/dL prior to initiation of pemafibrate treatment.

In one embodiment of the present invention, a "patient with renal dysfunction" is a patient with a serum creatinine level of 2.5 mg/dL or more or a creatinine clearance of less than 40 mL/min. In the present specification, creatinine clearance is calculated by ((urinary creatinine (mg/dL) x urine volume per minute (mL/min))/(serum creatinine (mg/dL)) x (1.73/body surface area ( ^m2 )).

In another embodiment, a "patient with renal impairment" is a patient with an estimated glomerular filtration rate (eGFR) of less than 60 mL/min/1.73 ^m2 , preferably less than 45 mL/min/1.73 ^m2 , more preferably less than 30 mL/min/1.73 ^m2 . In particular, a patient with an eGFR of less than 30 mL/min/1.73 ^m2 may be referred to as a patient with "severe renal impairment."
In this specification, eGFR may be calculated based on serum creatinine value or serum cystatin C value. When eGFR is calculated based on serum creatinine value, it is creatinine (mg/dL) ^-1.094 x age (years) ^-0.287 for men, and creatinine (mg/dL) -1.094 x age (years) ^-0.287 x 0.739 for women. When eGFR is calculated based on serum cystatin C value, it is [104 x cystatin C (mg/dL) ^-1.019 x 0.996 ^{age (years) ] -8 for men, and [104 x cystatin C (mg/dL) -1.019 x} 0.996 ^{age (years)} x 0.929] -8 for women. The choice of whether to use a serum creatinine level or a serum cystatin C level should be determined by those skilled in the art, taking into account the patient's condition, such as the patient's skeletal muscle mass, whether or not the patient has been administered drugs such as steroids or cyclosporine, and whether or not the patient has hypothyroidism.
In one embodiment, the "patient with renal dysfunction" is a patient with an estimated glomerular filtration rate (eGFR) calculated based on serum creatinine levels of less than 60 mL/min/1.73 ^m2 , preferably less than 45 mL/min/1.73 ^m2 , more preferably less than 30 mL/min/1.73 ^m2 . In particular, a patient with an eGFR of less than 30 mL/min/1.73 ^m2 may be referred to as a patient with "severe renal dysfunction". In another embodiment, the "patient with renal dysfunction" is a patient with an estimated glomerular filtration rate (eGFR) calculated based on serum cystatin C levels of less than 60 mL/min/1.73 ^m2 , preferably less than 45 mL/min/1.73 ^m2 , more preferably less than 30 mL/min/1.73 ^m2 . In particular, patients with an eGFR of less than 30 mL/min/1.73 ^m2 are sometimes referred to as patients with "severe renal dysfunction."

In a further embodiment, the patient may be undergoing dialysis treatment.

In some embodiments, pemafibrate or a salt thereof or a solvate thereof may be used in combination with a statin. The patient may have been administered a statin prior to the start of pemafibrate treatment. In some embodiments, the patient has an estimated glomerular filtration rate (eGFR) last measured less than 45 mL/min/1.73 m2 ³ days prior to the start of pemafibrate treatment, and the patient has been administered a statin prior to the start of pemafibrate treatment.
As used herein, "statin" refers to a hydroxymethylglutaryl-coenzyme A (HMG-CoA) reductase inhibitor, and examples thereof include atorvastatin, pravastatin, fluvastatin, lovastatin, pitavastatin, rosuvastatin, simvastatin, and salts thereof. The embodiment of the present invention using a statin includes an embodiment in which these statins are in the form of a solvate.

In some embodiments, the patient may also be receiving other therapeutic agents. Examples of other therapeutic agents include, but are not limited to, anion exchange resins such as cholestyramine, cholestimide, colesevelam, and salts thereof; intestinal cholesterol transporter inhibitors such as ezetimibe and salts of ezetimibe; nicotinic acid derivatives such as niacin, tocopherol nicotinate, tocopherol, niceritrol, nicomol, and salts thereof; omega-3 fatty acids and salts or esters of omega-3 fatty acids (icosapentic acid, salts of icosapentic acid, esters of icosapentic acid such as ethyl icosapentate, docosahexaenoic acid, salts of docosahexaenoic acid, esters of docosahexaenoic acid such as ethyl docosahexaenoate, etc.); and polyunsaturated fatty acids and salts or esters of polyunsaturated fatty acids. The therapeutic agent may be one or more selected from the group consisting of PCSK9 inhibitors such as levofloxacin, human anti-PCSK9 (proprotein convertase subtilisin/kexin type 9) monoclonal antibodies (evolocumab, alirocumab, etc.), MTP (microsomal triglyceride transfer protein) inhibitors such as lomitapide and salts of lomitapide such as lomitapide mesylate, Apo CIII inhibitors such as voranesorsen and salts of voranesorsen, CETP (cholesteryl ester transfer protein) inhibitors such as anacetrapib and salts of anacetrapib, ACL (ATP citrate lyase) inhibitors such as bempedoic acid and salts of bempedoic acid, probucol and salts of probucol, and mipomersen and salts of mipomersen. This embodiment also includes an embodiment in which these other therapeutic agents are solvated.

The effective amount and the number of administrations vary depending on the patient's weight, age, sex, symptoms, etc., but can be appropriately determined by a person skilled in the art. For example, in the case of a normal adult, pemafibrate can be administered at 0.05 to 0.8 mg per day in 1 to 3 divided doses, preferably 0.1 to 0.4 mg per day in 1 to 2 divided doses, more preferably 0.1 to 0.2 mg per day in 1 or 2 divided doses. For patients with eGFR less than 30 mL/min/1.73 ^m2 , administration may be started at a low dose or the administration interval may be extended. For patients with individual eGFR less than 30 mL/min, administration may be started at a low dose or the administration interval may be extended. The maximum dose for the patient may be up to 0.2 mg per day. When a sustained release formulation is administered to the patient, 0.2 mg per dose may be administered once per day.
In one aspect of the present invention, the administration period of pemafibrate or a salt thereof, or a solvate thereof can be set appropriately, and can be, for example, 12 weeks or more, 24 weeks or more, 36 weeks or more, 53 weeks or more, 60 weeks or more, 72 weeks or more, 96 weeks or more, or 104 weeks or more.

In one embodiment of the present invention, pemafibrate or its salts or solvates thereof are not used in clinical trials. In this specification, "clinical trials" refers to clinical trials that have been notified to the authorities having jurisdiction over a country or region. In the case of Japan, the "competent authorities" is the Pharmaceuticals and Medical Devices Agency as of the filing date of this application.

The present invention will be explained in more detail below with reference to examples, but these examples are not intended to limit the present invention.

Example 1: Post-marketing clinical trial of pemafibrate in patients with renal impairment . Purpose of the study: To investigate the pharmacokinetics and safety of Palmodia tablets (this drug, immediate-release tablets) at 0.2 mg/day (twice a day) administered for 12 weeks to patients with dyslipidemia and high TG (triglyceride) levels who have renal impairment, and to verify that the degree of renal impairment does not have a clinically significant effect on the pharmacokinetics of pemafibrate, thereby obtaining information that can serve as a basis for reviewing the precautions for use.
Study design: Multicenter, placebo-controlled, randomized, double-blind, parallel-group comparative study. Enrollment criteria: (1) Dyslipidemic patients aged 20 years or older at the time of consent. (2) Male or postmenopausal female. (3) Subjects with fasting serum TG of 150 mg/dL or higher in the screening test. (4) Subjects who meet any of the following criteria: 1) Subjects with eGFR of less than 30 mL/min/1.73 ^m2 at the time of screening and not receiving hemodialysis treatment (Group A).
2) Those undergoing hemodialysis treatment (Group B)
3) Those with eGFR ≥ 30mL/min/ ^1.73m2 and < 60mL/min/ ^1.73m2 at the time of screening and not undergoing hemodialysis treatment (Group C)
Exclusion criteria (abstract)
(1) Patients with severe liver disorder, liver cirrhosis, or biliary obstruction. (2) Patients with gallstones. (3) Pregnant women or women who may be pregnant. (4) Those who are taking or need to take drugs prohibited in this study continuously during the study period. (5) Those who have undergone kidney transplantation.

Study Method: Within each of the following groups, subjects were randomly assigned to either the Palmodia tablet group or the placebo group in a 3:1 ratio.
Group A: 8 patients with severe renal impairment (non-dialysis patients) Group B: 4 patients with severe renal impairment (dialysis patients) Group C: 8 patients with mild to moderate renal impairment (non-dialysis patients) The treatment period was 12 weeks, and Palmodia tablets or placebo were orally administered at a dose of 1 tablet twice a day, morning and evening, for 12 weeks.
Evaluation items
Pharmacokinetics Primary endpoint: Pharmacokinetic parameters of unchanged pemafibrate at 12 weeks of treatment: AUC _0- τ (area under the concentration-time curve from time 0 to τ hours between doses)
Safety Evaluation items (excerpts)
・Side effects
Efficacy Changes (rate or amount of change) from baseline values (values at week 0 of the treatment period) at each measurement point for evaluation items and lipid-related test items

Main study results [Pharmacokinetics]
The geometric mean ratios of AUC _0- τ in the severe renal impairment group to the mild to moderate renal impairment group (control group) and their 90% confidence intervals at 12 weeks are shown in the following Table 1, and no increase in exposure was observed even in subjects with severe renal impairment. In addition, as shown in Figure 1, no tendency was observed for AUC _0- τ or C _max (maximum blood concentration) to increase with the concomitant use of a statin.

The plasma pharmacokinetic parameters were as shown in Table 2 below.

[Safety]
The incidence rates of side effects, serious side effects, and side effects leading to discontinuation of administration are shown in Table 3 below.

Regarding side effects, one patient in the C group receiving Palmodia tablets showed a positive urine myoglobin level, leading to discontinuation of the drug. No serious side effects were observed.
[Effectiveness]
The change rate from baseline in fasting serum TG from 4 weeks into the treatment period to 4 weeks after the end of administration was as shown in Table 4 below.

Example 2: Pemafibrate sustained-release tablet "Palmodia XR Tablet"
The formulation is a film-coated tablet, which is a multiple-unit sustained-release formulation containing 0.2 or 0.4 mg of the active pharmaceutical ingredient per tablet. The formulation contains microcrystalline cellulose (granules), hydrated silicon dioxide, hypromellose, methacrylic acid copolymer L, ethyl cellulose, magnesium stearate, D-mannitol, microcrystalline cellulose, crospovidone, hydroxypropyl cellulose, titanium oxide, triethyl citrate, light anhydrous silicic acid, yellow ferric oxide, and carnauba wax as excipients.

Example 3: Domestic Phase II study of pemafibrate sustained-release tablets (CR-01 study, CTD5.3.1.1-1, conducted from September to December 2019)
A 12-group, two-period crossover study was conducted in 60 patients with dyslipidemia and high TG levels, in which subjects were orally administered 0.4 or 0.8 mg/day of Palmodia XR Tablets (this drug, extended-release tablets) or 0.2 mg/day of Palmodia Tablets (existing product, immediate-release tablets) for 4 weeks (no washout period) (Table 5 below). The PK (pharmacokinetic) parameters of this drug at 4 weeks after the start of administration for each dose are shown in Table 6 below. In addition, the geometric mean ratios [90% CI (confidence interval)] of _Cmax and _AUC0-24h (area under the plasma concentration-time curve from 0 to 24 hours after administration) of this drug when administered after a meal to when administered under fasting conditions were 1.124 [0.840, 1.503] and 1.097 [0.879, 1.370], respectively, for Palmodia XR Tablets 0.4 mg/day.

Based on the PK data obtained in the Phase II study (CR-01 study), the geometric mean ratios [95% CI] of the AUC _0-24h of the drug when administered with Palmodia XR tablets at 0.4 mg/day and 0.8 mg/day to the AUC 0-12h (area under the plasma concentration-time curve from 0 to 12 hours after administration) of the drug when administered with Palmodia tablets at 0.2 mg/day, corrected for differences in the number of administrations _{per day} and single dose, were calculated. The results were: when comparing Palmodia tablets 0.2 mg/day with Palmodia XR tablets 0.4 mg/day, the exposure was 0.863 [0.797, 0.934] and 0.870 [0.788, 0.960] when administered under fasting conditions and after a meal, respectively; when comparing Palmodia tablets 0.2 mg/day with Palmodia XR tablets 0.8 mg/day, the exposure was 0.879 [0.812, 0.952] and 1.035 [0.940, 1.139] when administered under fasting conditions and after a meal, respectively; there was no significant difference in the exposure to the drug between Palmodia XR tablets and Palmodia tablets at any dose. Regarding the correction of the AUC _0-12h of the drug when administered with Palmodia tablets at 0.2 mg/day, the AUC _0-24h when administered with Palmodia XR tablets and the AUC _0-12h when administered with Palmodia tablets are both AUCs that reflect the elimination of the drug from the blood per administration. Taking into consideration that in the CR-01 study, Palmodia XR tablets were administered once daily whereas Palmodia tablets were administered twice daily, and that the daily dose of Palmodia XR tablets was twice (4 mg/day) or four times (8 mg/day) compared to Palmodia tablets (2 mg/day), the AUC _0-12h of the drug when administered with Palmodia tablets at 0.2 mg/day was set at 4 or 8 times, respectively.

Example 4: Verification study (ER-02 study, CTD5.3.5.1-1, implementation period March to September 2021)
A randomized, double-blind, parallel-group comparative study was conducted at 11 facilities nationwide to investigate the non-inferiority of Palmodia XR Tablets (this drug, extended-release tablets) 0.2 mg/day and 0.4 mg/day to Palmodia Tablets (existing product, immediate-release tablets) 0.2 mg/day in patients with dyslipidemia and high TG levels (target number of cases: 345 (115 in each group)).
The subjects were dynamically assigned to one of the following groups: Palmodia XR Tablet 0.2 mg/day group, Palmodia XR Tablet 0.4 mg/day group, or Palmodia Tablet 0.2 mg/day group, based on factors such as facility, sex, timing of taking the investigational drug (fasting or after a meal), and whether or not they were taking a statin concomitantly. After a screening period of up to 8 weeks, during the treatment period of 12 weeks, Palmodia XR Tablet 0.2 or 0.4 mg was orally administered once a day after breakfast, or Palmodia Tablet 0.1 mg per dose, twice a day after breakfast and dinner, and the investigational drug was administered at a fixed timing (fasting or after a meal) throughout the study period according to the instructions of the investigator (subinvestigator). The provisions for concomitant medication were the same as those for the CR-01 study (see the section "Example 3: Domestic Phase II Study").

The main inclusion criteria were patients aged 20 years or older with dyslipidemia who met the following criteria:
- Fasting serum TG of 200 mg/dL or more for two consecutive measurements at screening - Fasting serum TG of 1000 mg/dL or less at screening Of the 356 randomized cases (119 cases in the Palmodia XR tablets 0.2 mg/day group, 119 cases in the Palmodia XR tablets 0.4 mg/day group, 118 cases in the Palmodia tablets 0.2 mg/day group; the same order below), 355 cases (118 cases, 119 cases, 118 cases) were administered the investigational drug and were included in the safety analysis population, excluding one case in the Palmodia XR tablets 0.2 mg/day group who requested to withdraw consent and discontinue. Of these, 353 cases (117 cases, 119 cases, 117 cases) with at least one evaluable piece of data during the 4, 8, or 12 week treatment period were included in the FAS (largest analysis population), and as a result of examining the differences, Palmodia XR tablets 0.4 and 0.8 mg/day were repeatedly administered to dyslipidemic patients with high TG levels for 4 weeks.

The FAS was the primary efficacy analysis population. Six subjects discontinued the study (3 subjects, 1 subject, and 2 subjects), and the reasons for discontinuation were withdrawal of consent/request to discontinue (3 subjects, 1 subject, and 0 subjects) and adverse events (0 subjects, 0 subjects, and 2 subjects).
The primary efficacy endpoint was the rate of change from baseline in TG at weeks 4, 8, and 12 of administration. The primary endpoint was to first evaluate the non-inferiority of the Palmodia XR Tablets 0.4 mg/day group to the Palmodia Tablets 0.2 mg/day group, and if non-inferiority was confirmed, to evaluate the non-inferiority of the Palmodia XR Tablets 0.2 mg/day group to the Palmodia Tablets 0.2 mg/day group, and if non-inferiority was confirmed, to confirm in turn that the point estimate of the Palmodia XR Tablets 0.4 mg/day group was lower than the point estimate of the Palmodia XR Tablets 0.2 mg/day group.
The rate of change from baseline in fasting serum TG at 4, 8, and 12 weeks of administration is shown in Table 7. The difference in the primary endpoint between the Palmodia XR Tablets 0.4 mg/day group and the Palmodia Tablets 0.2 mg/day group (difference in least squares means [95% CI]) was 0.00 [-4.79, 4.79]%, and the upper limit of 95% CI was below the pre-set non-inferiority limit (10%), demonstrating the non-inferiority of the Palmodia XR Tablets 0.4 mg/day group to the Palmodia Tablets 0.2 mg/day group.

In addition, the difference [95% CI] between the Palmodia XR Tablets 0.2 mg/day group and the Palmodia Tablets 0.2 mg/day group for the primary endpoint was 4.20 [-0.62, 9.02]%, and the upper limit of the 95% CI was below the pre-set non-inferiority limit (10%), demonstrating non-inferiority of the Palmodia XR Tablets 0.2 mg/day group to the Palmodia Tablets 0.2 mg/day group.
Furthermore, the point estimates for the primary endpoint in the Palmodia XR Tablets 0.4 mg/day group and the Palmodia XR Tablets 0.2 mg/day group were -48.00% and -43.80%, respectively, and the point estimate in the Palmodia XR Tablets 0.4 mg/day group was lower than the point estimate in the Palmodia XR Tablets 0.2 mg/day group.
If there were values from the two screening tests and at week 0 of the treatment period, the average of these was used as the baseline value, and if there was only a value at week 0 of the treatment period, this value was used as the baseline value. In addition, the non-inferiority limit was set at 10%, based on the validation study design of Palmodia tablets.

The secondary endpoints were the rate of change from baseline in fasting serum TC (total cholesterol), LDL-C (low-density lipoprotein cholesterol), HDL-C (high-density lipoprotein cholesterol), and non-HDL-C (lipoprotein cholesterol other than high-density lipoprotein cholesterol) at weeks 4, 8, and 12 of the treatment period, and the results are shown in Table 8 below.

Regarding safety, the occurrence of adverse events is as shown in Table 9 below.

No deaths were reported. Serious adverse events other than death were reported in two patients in the Palmodia XR Tablets 0.2 mg/day group (COVID-19, COVID-19 pneumonia) and one patient in the Palmodia Tablets 0.2 mg/day group (COVID-19), and a causal relationship to the study drug was denied in both cases. Adverse events leading to discontinuation of the study drug were reported in two patients in the Palmodia Tablets 0.2 mg/day group (dizziness, myalgia), and a causal relationship to the study drug was not denied in both cases, but the outcomes were recovery (dizziness) or relief (myalgia).

Example 5: Long-term administration study (ER-03 study, CTD5.3.5.2-1, 2, implementation period February 2021 to June 2022)
A randomized, open-label, parallel-group comparative study was conducted at 16 facilities nationwide to investigate the safety and efficacy of long-term administration of Palmodia XR tablets (this drug, extended-release tablets) in the morning or evening in patients with dyslipidemia and high TG levels (target number of cases: 110 (55 in each group)).
Subjects were dynamically assigned to either the Palmodia XR tablet morning group or the Palmodia XR tablet evening group, based on factors such as facility, sex, timing of taking the investigational drug (fasting or after a meal), and whether or not they were taking a statin concomitantly. After a screening period of 8 weeks or less, Palmodia XR tablets were orally administered once a day in the morning or evening during the 52-week treatment period. The starting dose was 0.2 mg/day, and if fasting serum TG was 150 mg/dL at any point during the period from 8 to 40 weeks of administration, the dose was increased to 0.4 mg/day after the end of the test at the next scheduled visit (12 to 44 weeks of administration, every 4 weeks). The timing of taking the investigational drug (fasting or after a meal) was instructed by the principal investigator (subinvestigator) to be consistent throughout the study period for each subject. The regulations for concomitant medication were the same as those for the CR-01 study (see the section "Example 3: Domestic Phase II Study").

The main inclusion criteria were patients aged 20 years or older with dyslipidemia who met the following criteria:
・Fasting serum TG at screening is 150 mg/dL or more for two consecutive times ・Fasting serum TG at screening is 1000 mg/dL or less All 121 randomized patients (61 patients in the morning group and 60 patients in the evening group, in the same order below) were administered the study drug and were included in the FAS and safety analysis population. FAS was the primary analysis population for efficacy. Seven patients (2 patients, 5 patients) discontinued after administration of the study drug, and the reason for discontinuation was adverse events (2 patients, 5 patients). The final dose of Palmodia XR tablets for the 121 patients who completed or discontinued the study was 0.2 mg/day: 39 patients (17 patients, 22 patients), 0.4 mg/day: 82 patients (44 patients, 38 patients).

The mean rate of change from baseline in fasting serum TG at the final evaluation and the time immediately prior to the final evaluation, which was the primary efficacy endpoint, is shown in Table 10 below. The final evaluation was at 52 weeks of treatment or at discontinuation. The mean values of the two screening tests and week 0 of the treatment period were used as the baseline value.

In addition, the rate of change from baseline for other lipid parameters at the time of the final evaluation and immediately prior thereto was as shown in Table 11 below. If values were available from the two screening tests and at week 0 of the treatment period, the average of these was used as the baseline value, and if only a value was available at week 0 of the treatment period, this value was used as the baseline value.

Regarding safety, the occurrence of adverse events was as shown in Table 12 below.

Adverse events leading to death were observed in one patient in the group receiving Palmodia XR tablets in the evening (myocardial infarction), but a causal relationship to the study drug was denied. Serious adverse events other than death were observed in five patients in the group receiving Palmodia XR tablets in the morning (carotid artery stenosis, retinal hemorrhage, colon cancer, arrhythmia, bladder cancer) and two patients in the group receiving Palmodia XR tablets in the evening (COVID-19, contusion), and a causal relationship to the study drug was denied except for arrhythmia. Adverse events leading to discontinuation of the study drug were observed in four patients in the group receiving Palmodia XR tablets in the evening (myalgia, aortic valve stenosis/asthenia/myalgia/abnormal sensation, eczema, increased blood CK (creatine kinase)), and a causal relationship to the study drug was not denied in any of the cases, and the outcomes were aortic valve stenosis not recovered, and the others recovered.

Example 6: Evaluation of rhabdomyolysis Rhabdomyolysis, an important identified risk of this drug, was evaluated. The occurrence of events related to rhabdomyolysis (rhabdomyolysis, myopathy) in the ER-02 and ER-03 studies is shown in the following Table 13, and no clear difference was observed between Palmodia XR Tablets (this drug, extended-release tablets) and Palmodia Tablets (existing product, immediate-release tablets).

Events related to rhabdomyolysis that led to discontinuation of the investigational drug were observed in one case (myalgia) in the Palmodia Tablet 0.2 mg/day group in the ER-02 study and in three cases (2 cases of myalgia, increased blood CK (creatine phosphokinase)) in the Palmodia XR Tablet group in the ER-03 study. A causal relationship to the investigational drug could not be denied in any case, but the events improved or recovered with no treatment or outpatient treatment.
In all clinical trials, no clinically significant changes were observed in laboratory test values related to rhabdomyolysis and renal dysfunction (blood CK, blood Cr (creatinine), and eGFR).
Furthermore, the presence or absence of renal impairment and the concomitant use of statins in subjects who experienced rhabdomyolysis-related events in the ER-02 and ER-03 studies are shown in the following Table 14. Although rhabdomyolysis-related events were observed in four patients with renal impairment who were concomitantly using statins, the events were mild (3 cases) or moderate (1 case), and all of them recovered. No tendency was observed for an increased risk of rhabdomyolysis in patients with renal impairment who were concomitantly using statins.

Example 7: Therapeutic evaluation of sustained-release tablets for patients with renal dysfunction. Administration of Palmodia XR tablets (this drug, sustained-release tablets) and Palmodia tablets (existing product, immediate-release tablets) to patients with renal dysfunction was examined. The incidence of adverse events by renal function in the ER-02 and ER-03 studies is shown in Table 15 below. Even in the subgroup of patients with renal dysfunction (eGFR less than 60 mL/min/1.73 ^m2 ), the incidence of adverse events was similar in the Palmodia XR tablet group and the Palmodia tablet group. Two patients with eGFR less than 30 mL/min/1.73 ^m2 were enrolled in the ER-03 study, and no deaths or serious adverse events other than death were observed in these two patients.

The present invention is useful as a medicine for preventing and/or treating diseases requiring treatment with pemafibrate.

Claims (60)

A medicine containing pemafibrate or a salt thereof, or a solvate thereof as an active ingredient, for administration to patients with renal dysfunction who require treatment with pemafibrate. The medicament of claim 1, wherein the medicament is not administered as part of a clinical trial. The pharmaceutical composition according to claim 1 or 2, which is a sustained release formulation. The pharmaceutical agent according to any one of claims 1 to 3, in which the patient has renal dysfunction with a serum creatinine level of 2.5 mg/dL or more or a creatinine clearance of less than 40 mL/min. The pharmaceutical agent according to any one of claims 1 to 4, which is used in combination with a statin. The pharmaceutical composition according to any one of claims 1 to 5, wherein the patient has an estimated glomerular filtration rate (eGFR) last measured 3 days prior to treatment with pemafibrate of less than 45 mL/min/1.73 ^m2 , and the patient has been administered a statin prior to the start of treatment with pemafibrate. The pharmaceutical composition according to any one of claims 1 to 6, wherein the patient's estimated glomerular filtration rate (eGFR) is less than 30 mL/min/1.73 ^m2 . The pharmaceutical agent according to any one of claims 1 to 7, in which the patient's fasting serum triglyceride level before the start of treatment with pemafibrate is less than 200 mg/dL. The pharmaceutical agent according to any one of claims 1 to 7, in which the patient's fasting serum triglyceride level before the start of treatment with pemafibrate is less than 150 mg/dL. Treatment with pemafibrate has been shown to improve the following conditions: hyperlipidemia, hypertriglyceridemia, hypercholesterolemia, high HDL cholesterolemia, dyslipidemia, diabetes, diabetic complications, peripheral arterial disease, inflammation, glaucoma, age-related macular degeneration, optic atrophy, external ophthalmoplegia, retinitis pigmentosa, heart disease, arteriosclerosis, chronic obstructive pulmonary disease (COPD), cancer cachexia, muscular dystrophy, amyotrophic lateral sclerosis (ALS), spinal muscular atrophy (SMA), spinal-bulbar muscular atrophy, hypotonia, muscle weakness, severe cramps, severe fatigue, rhabdomyolysis, fatigue, hyperkalemia, myopathy, sarcopenia, convulsions, myoclonus, and cerebrovascular disease. The pharmaceutical agent according to any one of claims 1 to 9, which is for the treatment of one or more of the following conditions: nausea, ataxia, stroke-like symptoms, decreased intelligence, migraine, psychiatric symptoms, dystonia, myelopathy, non-alcoholic steatohepatitis, primary biliary cirrhosis, liver failure, Fanconi syndrome, renal tubular dysfunction, glomerular lesions, myoglobinuria, exocrine insufficiency, sideroblastic anemia, pancytopenia, sensorineural hearing loss, diarrhea, constipation, decreased sweating, hirsutism, short stature, hypocalcemia, impaired consciousness, encephalopathy, vomiting induced by hunger or infection, frequent vomiting, delayed mental or motor development, poor weight gain, respiratory abnormalities, recurrent Reye-like syndrome, and hypoproteinemia. The pharmaceutical agent according to any one of claims 1 to 10, wherein the patient is not suffering from hyperlipidemia. Treatment with pemafibrate has been shown to improve the following conditions: hypercholesterolemia, high HDL cholesterolemia, dyslipidemia, diabetes, diabetic complications, peripheral arterial disease, inflammation, glaucoma, age-related macular degeneration, optic atrophy, external ophthalmoplegia, retinitis pigmentosa, heart disease, arteriosclerosis, chronic obstructive pulmonary disease (COPD), cancer cachexia, muscular dystrophy, amyotrophic lateral sclerosis (ALS), spinal muscular atrophy (SMA), spinal-bulbar muscular atrophy, hypotonia, muscle weakness, severe cramps, severe fatigue, rhabdomyolysis, fatigue, hyperkalemia, myopathy, sarcopenia, convulsions, myoclonus, ataxia, stroke-like syndrome. The pharmaceutical agent according to any one of claims 1 to 9 or 11, which is for the treatment of one or more of the following: symptoms, decreased intelligence, migraine, psychiatric symptoms, dystonia, myelopathy, nonalcoholic steatohepatitis, primary biliary cirrhosis, liver failure, Fanconi syndrome, renal tubular dysfunction, glomerular lesions, myoglobinuria, exocrine insufficiency, sideroblastic anemia, pancytopenia, sensorineural hearing loss, diarrhea, constipation, hypohidrosis, hirsutism, short stature, hypocalcemia, impaired consciousness, encephalopathy, vomiting induced by hunger or infection, frequent vomiting, delayed mental or motor development, poor weight gain, respiratory abnormalities, recurrent Reye-like syndrome, and hypoproteinemia. The pharmaceutical agent according to any one of claims 1 to 12, which is administered at a dose of 0.1 to 0.2 mg/day as pemafibrate. Use of pemafibrate, a salt thereof, or a solvate thereof in the manufacture of a medicine for administration to a patient with renal impairment who requires treatment with pemafibrate. The use of claim 14, wherein the medicament is not administered as part of a clinical trial. The use according to claim 14 or 15, wherein the pharmaceutical is a sustained release formulation. The use according to any one of claims 14 to 16, in which the patient has renal dysfunction with a serum creatinine level of 2.5 mg/dL or more or a creatinine clearance of less than 40 mL/min. The use according to any one of claims 14 to 17, wherein the medicine is used in combination with a statin. The use according to any one of claims 14 to 18, wherein the patient has a last measured estimated glomerular filtration rate (eGFR) of less than 45 mL/min/1.73 ^m2 3 days prior to treatment with pemafibrate, and the patient is receiving a statin prior to initiating treatment with pemafibrate. The use according to any one of claims 14 to 19, wherein the patient has an estimated glomerular filtration rate (eGFR) of less than 30 mL/min/1.73 ^m2 . The use according to any one of claims 14 to 20, wherein the patient has a fasting serum triglyceride level of less than 200 mg/dL prior to the start of treatment with pemafibrate. The use according to any one of claims 14 to 20, wherein the patient has a fasting serum triglyceride level of less than 150 mg/dL prior to the start of treatment with pemafibrate. Treatment with pemafibrate has been shown to improve the following conditions: hyperlipidemia, hypertriglyceridemia, hypercholesterolemia, high HDL cholesterolemia, dyslipidemia, diabetes, diabetic complications, peripheral arterial disease, inflammation, glaucoma, age-related macular degeneration, optic atrophy, external ophthalmoplegia, retinitis pigmentosa, heart disease, arteriosclerosis, chronic obstructive pulmonary disease (COPD), cancer cachexia, muscular dystrophy, amyotrophic lateral sclerosis (ALS), spinal muscular atrophy (SMA), spinal-bulbar muscular atrophy, hypotonia, muscle weakness, severe cramps, severe fatigue, rhabdomyolysis, fatigue, hyperkalemia, myopathy, sarcopenia, convulsions, myoclonus The use according to any one of claims 14 to 22, which is for the treatment of one or more of the following conditions: ataxia, stroke-like symptoms, intellectual impairment, migraine, psychiatric symptoms, dystonia, myelopathy, non-alcoholic steatohepatitis, primary biliary cirrhosis, liver failure, Fanconi syndrome, renal tubular dysfunction, glomerular lesions, myoglobinuria, exocrine insufficiency, sideroblastic anemia, pancytopenia, sensorineural hearing loss, diarrhea, constipation, hypohidrosis, hirsutism, short stature, hypocalcemia, impaired consciousness, encephalopathy, vomiting induced by hunger or infection, frequent vomiting, delayed mental or motor development, poor weight gain, respiratory abnormalities, recurrent Reye-like syndrome, and hypoproteinemia. The use according to any one of claims 14 to 23, wherein the patient is not suffering from hyperlipidemia. 　Treatment with pemafibrate has been shown to improve the following conditions: hypercholesterolemia, high HDL cholesterolemia, dyslipidemia, diabetes, diabetic complications, peripheral arterial disease, inflammation, glaucoma, age-related macular degeneration, optic atrophy, external ophthalmoplegia, retinitis pigmentosa, heart disease, arteriosclerosis, chronic obstructive pulmonary disease (COPD), cancer cachexia, muscular dystrophy, amyotrophic lateral sclerosis (ALS), spinal muscular atrophy (SMA), spinal-bulbar muscular atrophy, hypotonia, muscle weakness, severe cramps, severe fatigue, rhabdomyolysis, fatigue, hyperkalemia, myopathy, sarcopenia, convulsions, myoclonus, ataxia, stroke-like syndrome The use according to any one of claims 14 to 22 or 24, which is for the treatment of one or more of the following conditions: nausea, vomiting, decreased intelligence, migraine, psychiatric symptoms, dystonia, myelopathy, nonalcoholic steatohepatitis, primary biliary cirrhosis, liver failure, Fanconi syndrome, renal tubular dysfunction, glomerular lesions, myoglobinuria, exocrine insufficiency, sideroblastic anemia, pancytopenia, sensorineural hearing loss, diarrhea, constipation, hypohidrosis, hirsutism, short stature, hypocalcemia, impaired consciousness, encephalopathy, vomiting induced by hunger or infection, frequent vomiting, delayed mental or motor development, poor weight gain, respiratory abnormalities, recurrent Reye-like syndrome, and hypoproteinemia. The use according to any one of claims 14 to 25, wherein pemafibrate is administered at a dose of 0.1 to 0.2 mg/day. Pemafibrate or a salt thereof, or a solvate thereof, for administration to a patient with renal impairment who requires treatment with pemafibrate. The pemafibrate or its salt or its solvate according to claim 27, wherein the pemafibrate or its salt or its solvate is not administered as part of a clinical trial. The pemafibrate or its salt or solvate thereof according to claim 27 or 28, which is a sustained release formulation. The pemafibrate or a salt thereof, or a solvate thereof according to any one of claims 27 to 29, in which the patient has renal dysfunction with a serum creatinine level of 2.5 mg/dL or more or a creatinine clearance of less than 40 mL/min. The pemafibrate or its salt or its solvate according to any one of claims 27 to 30, wherein the pemafibrate or its salt or its solvate is used in combination with a statin. The patient has an estimated glomerular filtration rate (eGFR) last measured 3 days prior to treatment with pemafibrate of less than 45 mL/min/1.73 ^m2 , and the patient has been administered a statin prior to the start of treatment with pemafibrate. The pemafibrate or a salt thereof, or a solvate thereof according to any one of claims 27 to 31. The pemafibrate or its salt, or a solvate thereof according to any one of claims 27 to 32, wherein the patient's estimated glomerular filtration rate (eGFR) is less than 30 mL/min/1.73 ^m2 . The pemafibrate or a salt thereof, or a solvate thereof according to any one of claims 27 to 33, in which the patient's fasting serum triglyceride level before the start of treatment with pemafibrate is less than 200 mg/dL. The pemafibrate or a salt thereof, or a solvate thereof according to any one of claims 27 to 33, in which the patient's fasting serum triglyceride level before the start of treatment with pemafibrate is less than 150 mg/dL. Treatment with pemafibrate has been shown to improve the following conditions: hyperlipidemia, hypertriglyceridemia, hypercholesterolemia, high HDL cholesterolemia, dyslipidemia, diabetes, diabetic complications, peripheral arterial disease, inflammation, glaucoma, age-related macular degeneration, optic atrophy, external ophthalmoplegia, retinitis pigmentosa, heart disease, arteriosclerosis, chronic obstructive pulmonary disease (COPD), cancer cachexia, muscular dystrophy, amyotrophic lateral sclerosis (ALS), spinal muscular atrophy (SMA), spinal-bulbar muscular atrophy, hypotonia, muscle weakness, severe cramps, severe fatigue, rhabdomyolysis, fatigue, hyperkalemia, myopathy, sarcopenia, convulsions, myoclonus, ataxia, stroke-like symptoms , intellectual disability, migraine, psychiatric symptoms, dystonia, myelopathy, nonalcoholic steatohepatitis, primary biliary cirrhosis, liver failure, Fanconi syndrome, renal tubular dysfunction, glomerular lesions, myoglobinuria, exocrine insufficiency, sideroblastic anemia, pancytopenia, sensorineural hearing loss, diarrhea, constipation, hypohidrosis, hirsutism, short stature, hypocalcemia, impaired consciousness, encephalopathy, fasting/infection-induced vomiting, frequent vomiting, delayed mental/motor development, poor weight gain, respiratory abnormalities, recurrent Reye-like syndrome, and hypoproteinemia. The pemafibrate or a salt thereof, or a solvate thereof according to any one of claims 27 to 36, wherein the patient is not suffering from hyperlipidemia. 　Treatment with pemafibrate has been shown to improve the following conditions: hypercholesterolemia, high HDL cholesterolemia, dyslipidemia, diabetes, diabetic complications, peripheral arterial disease, inflammation, glaucoma, age-related macular degeneration, optic atrophy, external ophthalmoplegia, retinitis pigmentosa, heart disease, arteriosclerosis, chronic obstructive pulmonary disease (COPD), cancer cachexia, muscular dystrophy, amyotrophic lateral sclerosis (ALS), spinal muscular atrophy (SMA), spinal-bulbar muscular atrophy, hypotonia, muscle weakness, severe cramps, severe fatigue, rhabdomyolysis, fatigue, hyperkalemia, myopathy, sarcopenia, convulsions, myoclonus, ataxia, stroke-like symptoms, intellectual disability, migraine, and mental retardation. The pemafibrate or its salt or solvate thereof according to any one of claims 27 to 35 or 37, which is for the treatment of one or more of the following conditions: dystonia, myelopathy, non-alcoholic steatohepatitis, primary biliary cirrhosis, liver failure, Fanconi syndrome, renal tubular dysfunction, glomerular lesions, myoglobinuria, exocrine insufficiency, sideroblastic anemia, pancytopenia, sensorineural hearing loss, diarrhea, constipation, hypohidrosis, hirsutism, short stature, hypocalcemia, impaired consciousness, encephalopathy, vomiting induced by hunger or infection, frequent vomiting, delayed mental or motor development, poor weight gain, respiratory abnormalities, recurrent Reye-like syndrome, and hypoproteinemia. The pemafibrate or its salt or solvate thereof according to any one of claims 27 to 38, which is administered at 0.1 to 0.2 mg/day as pemafibrate. A method for treating a disease requiring treatment with pemafibrate, comprising administering a therapeutically effective amount of pemafibrate or a salt thereof, or a solvate thereof to a patient with renal dysfunction. The method of treatment according to claim 40, wherein pemafibrate or a salt thereof or a solvate thereof is not administered as part of a clinical trial. The method of treatment according to claim 40 or 41, which is administered as a sustained release formulation. The method of treatment according to any one of claims 40 to 42, wherein the patient has renal dysfunction with a serum creatinine level of 2.5 mg/dL or more or a creatinine clearance of less than 40 mL/min. The method of treatment according to any one of claims 40 to 43, wherein pemafibrate or a salt thereof, or a solvate thereof is used in combination with a statin. The method of any one of claims 40 to 44, wherein the patient has a last measured estimated glomerular filtration rate (eGFR) of less than 45 mL/min/1.73 ^m2 3 days prior to treatment with pemafibrate, and the patient is receiving a statin prior to initiation of treatment with pemafibrate. The method of any one of claims 40 to 45, wherein the patient has an estimated glomerular filtration rate (eGFR) of less than 30 mL/min/1.73 ^m2 . The method of any one of claims 40 to 46, wherein the patient's fasting serum triglyceride level before initiation of pemafibrate treatment is less than 200 mg/dL. The method of any one of claims 40 to 46, wherein the patient's fasting serum triglyceride level prior to the start of treatment with pemafibrate is less than 150 mg/dL. Diseases requiring treatment with pemafibrate include hyperlipidemia, hypertriglyceridemia, hypercholesterolemia, high HDL-cholesterolemia, dyslipidemia, diabetes, diabetic complications, peripheral arterial disease, inflammation, glaucoma, age-related macular degeneration, optic atrophy, external ophthalmoplegia, retinitis pigmentosa, heart disease, arteriosclerosis, chronic obstructive pulmonary disease (COPD), cancer cachexia, muscular dystrophy, amyotrophic lateral sclerosis (ALS), spinal muscular atrophy (SMA), spinal-bulbar muscular atrophy, hypotonia, muscle weakness, severe cramps, severe fatigue, rhabdomyolysis, easy fatigue, hyperkalemia, myopathy, sarcopenia, convulsions, myoclonic acidosis, and vasoconstriction. The method for treating any one of claims 40 to 48, wherein the disease is one or more diseases selected from the group consisting of rhonus, ataxia, stroke-like symptoms, intellectual impairment, migraine, psychiatric symptoms, dystonia, myelopathy, nonalcoholic steatohepatitis, primary biliary cirrhosis, liver failure, Fanconi syndrome, renal tubular dysfunction, glomerular lesions, myoglobinuria, exocrine insufficiency, sideroblastic anemia, pancytopenia, sensorineural hearing loss, diarrhea, constipation, hypohidrosis, hirsutism, short stature, hypocalcemia, impaired consciousness, encephalopathy, vomiting induced by hunger or infection, frequent vomiting, delayed mental or motor development, poor weight gain, respiratory abnormalities, recurrent Reye-like syndrome, and hypoproteinemia. The method of treatment according to any one of claims 40 to 49, wherein the patient is not suffering from hyperlipidemia. Diseases requiring treatment with pemafibrate include hypercholesterolemia, high HDL cholesterolemia, dyslipidemia, diabetes, diabetic complications, peripheral arterial disease, inflammation, glaucoma, age-related macular degeneration, optic atrophy, external ophthalmoplegia, retinitis pigmentosa, heart disease, arteriosclerosis, chronic obstructive pulmonary disease (COPD), cancer cachexia, muscular dystrophy, amyotrophic lateral sclerosis (ALS), spinal muscular atrophy (SMA), spinal-bulbar muscular atrophy, hypotonia, muscle weakness, severe cramps, severe fatigue, rhabdomyolysis, easy fatigue, hyperkalemia, myopathy, sarcopenia, convulsions, myoclonus, ataxia, and stroke. The method for treating one or more diseases selected from the group consisting of mild symptoms, intellectual disability, migraine, psychiatric symptoms, dystonia, myelopathy, nonalcoholic steatohepatitis, primary biliary cirrhosis, liver failure, Fanconi syndrome, renal tubular dysfunction, glomerular lesions, myoglobinuria, exocrine insufficiency, sideroblastic anemia, pancytopenia, sensorineural hearing loss, diarrhea, constipation, hypohidrosis, hirsutism, short stature, hypocalcemia, impaired consciousness, encephalopathy, vomiting induced by hunger or infection, frequent vomiting, delayed mental or motor development, poor weight gain, respiratory abnormalities, recurrent Reye-like syndrome, and hypoproteinemia. The method of treatment according to any one of claims 40 to 51, wherein pemafibrate is administered at 0.1 to 0.2 mg/day. The pharmaceutical agent according to any one of claims 1 to 13, wherein pemafibrate or a salt thereof or a solvate thereof is administered for 53 weeks or more. The use according to any one of claims 14 to 26, wherein pemafibrate or a salt thereof or a solvate thereof is administered for 53 weeks or more. The pemafibrate or its salt or its solvate according to any one of claims 27 to 39, wherein the pemafibrate or its salt or its solvate is administered for 53 weeks or more. The method of treatment according to any one of claims 40 to 52, in which pemafibrate or a salt thereof or a solvate thereof is administered for 53 weeks or more. The pharmaceutical agent according to any one of claims 1 to 13 or 53, wherein the patient is receiving treatment with one or more of the following: anion exchange resins, intestinal cholesterol transporter inhibitors, nicotinic acid derivatives, polyunsaturated fatty acids and salts or esters of polyunsaturated fatty acids, PCSK9 inhibitors, MTP (microsomal triglyceride transfer protein) inhibitors, Apo CIII inhibitors, CETP (cholesteryl ester transfer protein) inhibitors, ACL (ATP citrate lyase) inhibitors, probucol and salts of probucol, and mipomersen and salts of mipomersen. The use according to any one of claims 14 to 26 or 54, wherein the patient is undergoing treatment with one or more of the following: anion exchange resins, intestinal cholesterol transporter inhibitors, nicotinic acid derivatives, polyunsaturated fatty acids and salts or esters of polyunsaturated fatty acids, PCSK9 inhibitors, MTP (microsomal triglyceride transfer protein) inhibitors, Apo CIII inhibitors, CETP (cholesteryl ester transfer protein) inhibitors, ACL (ATP citrate lyase) inhibitors, probucol and salts of probucol, and mipomersen and salts of mipomersen. The pemafibrate or its salt or solvate thereof according to any one of claims 27 to 39 or 55, wherein the patient is receiving treatment with one or more of the following: anion exchange resins, intestinal cholesterol transporter inhibitors, nicotinic acid derivatives, polyunsaturated fatty acids and salts or esters of polyunsaturated fatty acids, PCSK9 inhibitors, MTP (microsomal triglyceride transfer protein) inhibitors, Apo CIII inhibitors, CETP (cholesteryl ester transfer protein) inhibitors, ACL (ATP citrate lyase) inhibitors, probucol and salts of probucol, and mipomersen and salts of mipomersen. The method of any one of claims 40 to 52 or 56, wherein the patient is receiving treatment with one or more of the following: anion exchange resins, intestinal cholesterol transporter inhibitors, nicotinic acid derivatives, polyunsaturated fatty acids and salts or esters of polyunsaturated fatty acids, PCSK9 inhibitors, MTP (microsomal triglyceride transfer protein) inhibitors, Apo CIII inhibitors, CETP (cholesteryl ester transfer protein) inhibitors, ACL (ATP citrate lyase) inhibitors, probucol and salts of probucol, and mipomersen and salts of mipomersen.

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