Pharmaceutical uses of KL1333

Abstract

This provides pharmaceutical applications for KL1333. [Solution] The following uses are provided: i) KL1333 for use in the treatment of mitochondrial diseases or mitochondrial disease-related disorders, such as fatigue syndrome or disease-related fatigue, or muscle weakness associated with mitochondrial disease; ii) KL1333 for use in a drug administration plan for the treatment of one or more of fatigue, muscle weakness, and mitochondrial disease; iii) Use of the blood lactate (mM) / pyruvate (mM) ratio as a biomarker of the therapeutic effect of KL1333, wherein a decrease in the ratio indicates that the treatment is effective.

Description

[Technical Field]

[0001] This invention relates to the pharmaceutical use of KL1333 in the treatment of mitochondrial diseases or diseases / conditions related to mitochondrial diseases. Furthermore, this invention relates to the treatment of fatigue or muscle weakness. [Background technology]

[0002] Fatigue and muscle weakness are often associated with or caused by specific diseases.

[0003] Mitochondria are vital organelles that produce most of the energy required by the human body in the form of adenosine triphosphate (ATP) via the electron transport chain. Primary mitochondrial diseases generally develop as a result of dysfunction in the electron transport chain, leading to impaired mitochondrial energy production and excessive production of reactive oxygen species (ROS). Hundreds of types of primary mitochondrial diseases are known, including mitochondrial encephalomyopathy, lactic acidosis, stroke-like seizure syndrome (MELAS), Leber's hereditary optic neuropathy, red ragged fiber-myoclonus epilepsy syndrome, and Leigh syndrome. Primary mitochondrial diseases present with a variety of symptoms depending on the type of organ affected, and while they were previously considered clinical syndromes, in recent years they have been viewed as a disease spectrum caused by gene deficiencies that affect mitochondrial function. It is estimated that 125 people per 1,000,000 live population suffer from primary mitochondrial disease. The clinical manifestations of primary mitochondrial disease exhibit a broad phenotypic spectrum, including life-threatening conditions such as organ failure, respiratory and circulatory arrest, intracranial hemorrhage, leukemia / lymphoma, myocardial ischemia, intestinal obstruction, and immunodeficiency, as well as a wide range of other debilitating conditions.

[0004] Currently, there are no approved drugs for primary mitochondrial disease. Therefore, there is a need to identify drug substances that are effective against mitochondrial disease and / or against disorders or diseases associated with mitochondrial disease. [Overview of the Initiative] [Problems that the invention aims to solve]

[0005] KL1333 is a novel compound currently under development for primary mitochondrial diseases. KL1333 acts as a substrate for NAD(P)H:dehydrogenase [quinone]1 (NQO1), and by utilizing nicotinamide adenine dinucleotide (reduced form; NADH) as a cofactor, it transfers two electrons to KL1333, thereby reducing nicotinamide adenine dinucleotide (oxidized form; NAD + It produces ATP. KL1333 directly promotes ATP production by transferring these electrons to the mitochondrial electron transport chain. Furthermore, NAD + By increasing its levels, it activates mitochondrial biosynthetic pathways such as sirtuin 1 (SIRT1), 5'-adenosine monophosphate-activated protein kinase (AMPK), and peroxisome proliferator-activated receptor γ coactivator 1α (PGC-1α), thereby improving mitochondrial function.

[0006] In preclinical models, KL1333 has been shown to increase mitochondrial energy output and have long-term beneficial effects on energy metabolism. Clinical trials reported herein have shown that KL1333 reduces fatigue and enhances muscle function. [Means for solving the problem]

[0007] This invention relates to the following: i) KL1333 for use in the treatment of fatigue, including fatigue syndrome and disease-related fatigue. ii) KL1333 for use in strengthening muscle function in cases of disease-related muscle weakness, etc. iii) KL1333 for use in a drug administration plan for the treatment of one or more of fatigue, muscle weakness and mitochondrial disease, The aforementioned drug administration plan, i) To obtain a steady-state blood KL1333 concentration in subjects with fatigue, muscle weakness, or mitochondrial disease, administer KL1333 in the range of 25-150 mg, for example, 25-100 mg of KL1333 daily for 2-10 days. ii) Measuring the concentration of KL1333 in blood or plasma, preferably in plasma, as AUC (area under the curve), Cmin, or Ctrough, to determine whether the AUC is less than 3,000 h·ng / mL, the Cmin is 65 ng / mL or less, or the Ctrough is 130 ng / mL or less, and iii) By adjusting the daily dose to obtain steady-state blood or plasma KL1333 concentrations corresponding to an AUC of at least 3,000 h·ng / mL, a Cmin of at least 65 ng / mL, and / or a Ctrough of at least 130 ng / mL, preferably corresponding steady-state plasma KL1333 concentrations, on day 10 after dose adjustment, an AUC of at least 3,500 h·ng / mL, a Cmin of at least 77 ng / mL, and / or a Ctrough of at least 162 ng / mL. Obtain; obtain an AUC of at least 4,000 h·ng / mL, a Cmin of at least 88 ng / mL, and / or a Ctrough of at least 196 ng / mL; obtain an AUC of at least 4,500 h·ng / mL, a Cmin of at least 100 ng / mL, and / or a Ctrough of at least 228 ng / mL; or obtain an AUC in the range of 4,000 to 12,000 h·ng / mL, a Cmin in the range of 88 to 275 ng / mL, and / or a Ctrough in the range of 196 to 333 ng / mL. KL1333, including. iv) Use of the blood lactate (mM) / pyruvate (mM) ratio as a biomarker for the therapeutic effect of KL1333, wherein a decrease in the lactate / pyruvate ratio indicates that the treatment is effective. v) Use of serum niacinamide and / or xanthine as an initial response biomarker for the therapeutic effect of KL1333, wherein an increase in the ratio of niacinamide concentration and / or xanthine concentration has been shown to indicate therapeutic efficacy, and the ratio of niacinamide concentration and / or xanthine concentration is (serum concentration on the day of the test) / (serum concentration at the start of treatment). [Modes for carrying out the invention]

[0008] In conclusion, the blood lactate / pyruvate ratio, niacinamide, and xanthine can be used as biomarkers for the therapeutic effect of KL1333 in patients with primary mitochondrial disease. Based on this, it was found that patients who showed the greatest decrease in fatigue scores on the daily fatigue scale on day 10 of KL1333 treatment also had a low serum lactate / pyruvate ratio (Figure 10).

[0009] In this description, "Cmin" refers to the lowest blood or plasma concentration at a steady state, and "Ctrough" refers to the blood or plasma concentration immediately before the next administration. Plasma concentration measurement is preferred.

[0010] Regarding the reduction in the blood lactate (mM) / pyruvate (mM) ratio, which is an indicator of effective treatment, a reduction of at least 10% from the baseline value, for example, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, or at least 50%, indicates that the treatment is effective. The baseline value may be the value before treatment is started, or it may be the value after treatment has started but before the effectiveness of the treatment is observed over time.

[0011] The increase in serum niacinamide may be more than a twofold increase from the baseline value defined above, and may even be more than a threefold increase, for example.

[0012] The increase in xanthine in the serum may be an increase of 20% or more, for example, an increase of 25% or more or an increase of 30% or more.

[0013] KL-1333 is a drug substance with a molecular weight of 240.26 g / mol. KL-1333 is a crystalline powder that is light pink to reddish brown, non-hygroscopic, and hardly soluble in water. KL-1333 is produced through multiple chemical synthesis steps. Its molecular structure is shown by the following chemical formula.

Chemical formula

[0014] KL1333 has been shown to be a more potent substrate of NQO1 than another NQO1 active compound (i.e., idebenone) developed for primary mitochondrial diseases. In a cell model containing cells obtained from MELAS patients, KL1333 increases ATP; decreases ROS; decreases lactate; increases NAD + ; activates SIRT1, AMPK and PGC-1α; and improves the oxidative phosphorylation function of mitochondria.

[0015] In the clinical trial reported herein (KL1333 2018-102), 64 healthy volunteers and 8 patients with genetically confirmed mitochondrial disease were administered either KL1333 or placebo. No serious adverse events were observed in this study. Furthermore, no clear treatment-dependent or dose-dependent trends were observed in the mean or individual values ​​of the clinical chemistry, hematological, or urinalysis data of the subjects in this study. No clear treatment-dependent or dose-dependent trends were observed in vital sign measurements, 12-lead electrocardiograms, or physical examinations in this study. KL1333 was well tolerated when administered as a single oral dose of 25 mg to healthy subjects, with or without food. In healthy subjects, once-daily (QD) doses of 25-75 mg were well tolerated, and the 150 mg dose was also well tolerated. However, the 250 mg dose was poorly tolerated, as it resulted in gastrointestinal adverse events (TEAEs) during administration of the investigational drug. When the 150 mg daily dose of KL1333 was divided into twice-daily (BID) or three times-daily (TID) doses, it was better tolerated than the once-daily (QD) dose, and the frequency and severity of gastrointestinal adverse events decreased. In patients with primary mitochondrial disease, KL1333 was also well tolerated when administered orally at a 50 mg once-daily (QD) dose for 10 days. Clinical outcome evaluations in patients with primary mitochondrial disease in this study demonstrated that KL1333 is effective in treating fatigue and muscle weakness.

[0016] fatigue As described herein, KL1333 effectively acts on fatigue. Fatigue may be in the form of chronic fatigue syndrome, or it may be associated with other diseases such as mitochondrial diseases, including primary mitochondrial disease.

[0017] Fatigue is the feeling of being tired. Fatigue can occur suddenly or gradually. It is normal for fatigue to occur after prolonged physical or mental activity and to fully recover with rest. On the other hand, if fatigue persists, is severe, progressive, or occurs without a cause, it is a symptom of a pathological condition.

[0018] Physical fatigue is a temporary inability of muscles to maintain optimal physical performance, and it can become severe with strenuous exercise. Muscle fatigue can result from energy loss in the muscles, decreased efficiency of the neuromuscular junction, or reduced signals from the central nervous system. A central factor in fatigue is the increase in serotonin levels in the central nervous system. Physical fatigue can also be caused by neuromuscular disorders.

[0019] Mental fatigue is a temporary decline in maximum cognitive ability resulting from prolonged cognitive activity. Mental fatigue can manifest as somnolence, lethargy, or fatigue of selective attention.

[0020] Neurological fatigue can occur in patients with multiple sclerosis. Such patients often experience extreme malaise or fatigue.

[0021] Chronic fatigue is fatigue that persists for at least six consecutive months. Chronic fatigue is a symptom of various diseases and conditions. Some of the main diseases associated with fatigue include: i) Autoimmune diseases such as celiac disease, systemic lupus erythematosus, multiple sclerosis, Sjögren's syndrome, and spondyloarthritis, ii) Blood disorders such as anemia and hemochromatosis, iii) Cancer (also known as cancer fatigue), iv) Chronic fatigue syndrome (CFS), v) Substance use disorders, including alcohol use disorder, vi) Depression and other mental illnesses, vii) Developmental disorders such as autism spectrum disorder, viii) Eating disorders, ix) Endocrine or metabolic disorders such as diabetes, hypothyroidism, and Addison's disease, x) fibromyalgia, xi) Gulf War Syndrome, xii) heart failure; xiii) HIV, xiv) Idiopathic chronic fatigue (ICF), xv) Congenital metabolic disorders such as fructose malabsorption, xvi) Infectious diseases such as infectious mononucleosis and tuberculosis, xvii) irritable bowel syndrome, xviii) For example, kidney diseases such as acute renal failure and chronic renal failure, xix) Leukemia or lymphoma, xx) Liver failure, or liver disease such as hepatitis, xxi) Lyme disease, xxii) Neurological disorders such as narcolepsy, Parkinson's disease, post-orthostatic tachycardia syndrome, and post-concussion syndrome. xxiii) Physical trauma, and other conditions that cause pain, such as arthritis. xxiv) Sleep deprivation or sleep disorder, xxv) Satsuki disease, xxvi) Stroke, xxvii) thyroid disease; xxviii) Uremia, and xxix) Mitochondrial disease These are some examples.

[0022] Muscle weakness Muscle weakness is a lack of muscle strength. True muscle weakness is a primary symptom of various skeletal muscle diseases. Muscle weakness can also be neuromuscular fatigue, which can be classified into central or peripheral muscle fatigue depending on its cause. Central muscle fatigue manifests as overall energy depletion, while peripheral muscle fatigue manifests as a localized state of muscle dysfunction.

[0023] Muscle weakness is generally caused by lack of exercise, aging, or muscle injury. Furthermore, muscle weakness can occur in association with long-term illnesses, such as diabetes, heart disease, stroke, depression, fibromyalgia, chronic fatigue syndrome, polymyositis, inflammatory muscle disease, mitochondrial disease; and neuromuscular diseases such as muscular dystrophy, multiple sclerosis, Graves' disease, myasthenia gravis, and Guillain-Barré syndrome.

[0024] Mitochondrial disease KL1333 is used for the prevention or treatment of mitochondrial diseases, particularly those caused by complex I deficiency, or for the treatment of one or more symptoms associated with mitochondrial disease (e.g., fatigue and muscle weakness). Mitochondrial diseases are selected from the following: • Alpers disease (progressive infant poliodystrophy) Amyotrophic lateral sclerosis (ALS) ·autism • Birth syndrome (fatal infant cardiomyopathy) Beta-oxidation deficiency • Bioenergy metabolism deficiency Carnitine-acylcarnitine deficiency Carnitine deficiency Creatine deficiency syndromes (cerebral creatine deficiency syndrome (CCDS)) including guanidinoacetate methyltransferase deficiency (GAMT deficiency), L-arginine-glycine amidinotransferase deficiency (AGAT deficiency), and SLC6A8-related creatine transporter deficiency (SLC6A8 deficiency). Coenzyme Q10 deficiency • Complex I deficiency (NADH dehydrogenase (NADH-CoQ reductase) deficiency) • Complex II deficiency (succinate dehydrogenase deficiency) • Complex III deficiency (ubiquinone-cytochrome C oxidoreductase deficiency) • Complex IV deficiency / COX deficiency (Cytochrome C oxidase deficiency is caused by a deficiency in Complex IV of the respiratory chain) • Complex V deficiency (ATP synthase deficiency) COX deficiency ·CPEO (Chronic Progressive External Ophthalmoplegia Syndrome) • CPT I deficiency • CPT II deficiency • Friedreich's ataxia (FRDA or FA) Glutaric aciduria type II • KSS (Kerns-Sayer Syndrome) Lactic acidosis • LCAD (Long-chain acyl-CoA dehydrogenase deficiency) ·LCHAD • Leigh disease or Leigh syndrome (subacute necrotizing cerebrospinal fluid disorder) • LHON (Leber's hereditary optic neuropathy) Luft disease • MCAD (Medium-chain acyl-CoA dehydrogenase deficiency) • MELAS (Mitochondrial Encephalomyopathy, Lactic Acidosis, Stroke-like Attack Syndrome) • MERRF (Red rag fiber myoclonus epileptic disorder) • MIDD (Maternally inherited diabetes mellitus and hearing loss) • MIRAS (Mitochondrial Recessive Ataxia Syndrome) • Mitochondrial cell disease Mitochondrial DNA deficiency • Mitochondrial encephalopathy, including encephalomyopathy and cerebrospinal cord disorders. Mitochondrial myopathy • MNGIE (Nervous Gastrointestinal Encephalomyopathy) • NARP (Neurogenic Ataxia Retinitis Pigmentosa) • Neurodegenerative diseases associated with Parkinson's disease, Alzheimer's disease, or Huntington's disease Pearson syndrome • Pyruvate carboxylase deficiency • Pyruvate dehydrogenase deficiency ·POLG mutation • Respiratory chain defect • SCAD (Short-chain acyl-CoA dehydrogenase deficiency) • SCHAD (short-chain L-3-hydroxyacyl-CoA dehydrogenase (SCHAD) deficiency, also known as 3-hydroxyacyl-CoA dehydrogenase deficiency (HADH)) • VLCAD (Very Long Chain Acyl-CoA Dehydrogenase Deficiency) ·Diabetes • Acute starvation Endotoxemia ·Sepsis • Systemic Inflammatory Response Syndrome (SIRS) • Multiple organ failure

[0025] Based on information available on the United Mitochondrial Disease Foundation (www.umdf.org) website, some of the aforementioned diseases are described in more detail below.

[0026] Complex I deficiency: Inside mitochondria are groups of proteins (complexes I-IV) that transport electrons along four chain reactions, contributing to energy production. This chain reaction is known as the electron transport chain. A fifth group of proteins (complex V) produces large amounts of ATP. The electron transport chain and ATP synthase work together to form the respiratory chain, and this entire process is known as oxidative phosphorylation, or OXPHOS.

[0027] Complex I, the first step in this chain reaction, is the most common site of mitochondrial abnormalities, accounting for one-third of all respiratory chain deficiencies. Complex I deficiency is a progressive neurodegenerative disorder that is commonly found at birth or in early childhood, causing a variety of clinical symptoms in organs and tissues that require particularly high energy levels, such as the brain, heart, liver, and skeletal muscle. Many specific mitochondrial diseases, such as Leber's hereditary optic neuropathy (LHON), MELAS, MERRF, and Leigh syndrome (LS), are associated with Complex I deficiency. MELAS stands for Mitochondrial Encephalomyopathy, Lactic Acidosis, Stroke-like Seizure Syndrome, and MERRF stands for Red Ragged Fiber Myoclonus Epilepsy Syndrome.

[0028] Leber's hereditary optic neuropathy (LHON) is characterized by blindness that typically develops between the ages of 27 and 34. This blindness can occur simultaneously in both eyes, or sequentially in one eye at a time (blindness usually begins in one eye, followed on average by blindness in the other eye two months later). Other symptoms, such as cardiac abnormalities and neurological complications, may also occur.

[0029] Complex I deficiency primarily has three subtypes. i) Fatal multiple system disease of infants - characterized by hypotonia, growth retardation, heart disease, lactic acidosis, and respiratory failure. ii) Myopathy (muscle disease) - Beginning in childhood or adulthood and characterized by weakness or exercise intolerance. iii) Mitochondrial encephalomyopathy (brain and muscle disorders) - Beginning in childhood or adulthood, symptoms include a combination of symptoms ranging in degree, such as ophthalmoplegia, retinopathy of pigmentosum (retinitis pigmentosa with blindness), hearing loss, sensory neuropathy (nerve damage including sensory organs), seizures, dementia, ataxia (abnormal muscle coordination), and involuntary movements. This form of Complex I deficiency can lead to Leigh syndrome and MELAS.

[0030] Most cases of complex I deficiency are caused by autosomal recessive inheritance (a combination of defective nuclear genes inherited from both the mother and father). While complex I deficiency can be maternally inherited or occur sporadically, these are infrequent. The gene deficiency is found in mitochondrial DNA.

[0031] Treatment: As with all mitochondrial diseases, there is currently no cure for complex I deficiency. Various potentially effective treatments include metabolic therapies such as riboflavin, thiamine, biotin, coenzyme Q10, carnitine, and ketogenic diets. Treatment for complex I deficiency in the form of lethal infant multisystem disease has been unsuccessful.

[0032] The clinical course and prognosis of patients with complex I deficiency vary considerably depending on the specific gene deficiency, age of onset, involved organs, and other factors.

[0033] Complex III deficiency: The symptoms of this disease mainly include four subtypes. i) The child presents with fatal infantile encephalomyopathy, congenital lactic acidosis, hypotonia, dystrophy-like posture, seizures, and coma. Generally, red, ragged fibers are seen in the muscle tissue. ii) Encephalomyopathy that develops in the later stages (childhood to adulthood): Frailty, short stature, ataxia, dementia, hearing loss, sensory neuropathy, retinitis pigmentosa, and pyramidal tract signs are observed in various combinations. Generally, red, ragged fibers are seen. Lactic acidosis may also be present. iii) Myopathy accompanied by exercise intolerance that develops into fixed muscle weakness. Generally, red, ragged fibers are observed. Lactic acidosis may also be present. iv) Infant histiocytic cardiomyopathy

[0034] Complex IV deficiency / COX deficiency: The symptoms of this disease mainly include two types. 1. Encephalomyopathy: Typically normal for the first 6-12 months of life, but subsequently exhibiting developmental regression, ataxia, lactic acidosis, optic nerve atrophy, ophthalmoplegia, nystagmus, dystonia, pyramidal tract signs, and respiratory distress. Seizures are frequent. Leigh syndrome may develop. 2. Myopathy: Two main variants: 1. Fatal infant myopathy: This develops shortly after birth and is accompanied by hypotonia, weakness, lactic acidosis, red rag fibers, respiratory failure, and kidney problems. 2. Benign infant myopathy: This develops shortly after birth and is accompanied by hypotonia, weakness, lactic acidosis, red rag fibers, and respiratory problems, but (if the affected child survives) it improves spontaneously.

[0035] KSS (Kerns-Sayer Syndrome): KSS is a slowly progressive multisystem mitochondrial disease that often begins with ptosis (drooping of the upper eyelid). Eventually, symptoms appear in other eye muscles, leading to paralysis of eye movement. Retinal degeneration typically results in decreased vision in dimly lit environments.

[0036] KSS has three main characteristics. • It usually develops before the age of 20, but it can also develop in infancy or adulthood. • It causes a specific type of ophthalmoplegia (called chronic progressive extraocular palsy (CPEO)). • Degeneration of the retina leads to the abnormal deposition of pigment substances (colored substances) (retinitis pigmentosa).

[0037] Furthermore, one or more of the following conditions are indicated: • Blockage of electrical signals from the heart (cardiac conduction system disorder) • Increased cerebrospinal fluid protein • Inability to coordinate movements (ataxia)

[0038] Furthermore, KSS patients may experience problems such as hearing loss, dementia, renal dysfunction, and muscle weakness. Endocrine abnormalities such as growth retardation, short stature, and diabetes may also be present.

[0039] KSS is a rare disease. KSS is usually caused by a single large deletion (deletion) of genetic material in mitochondrial DNA (mtDNA), rather than in nuclear DNA. Deletions usually occur spontaneously, and there are more than 150 different types. Mutations can be transmitted maternally, but this is infrequent.

[0040] As with all mitochondrial diseases, there is no cure for KSS.

[0041] Treatment is determined based on the type of symptoms and the organs involved, and may include coenzyme Q10, insulin for diabetes, cardiac medications, and a cardiac pacemaker that may be life-saving. Surgical intervention for ptosis may be considered, but should be performed by a specialist in ophthalmic surgery.

[0042] KSS progresses slowly, and the prognosis varies depending on the severity. Generally, death occurs within 30-40 years, and death may be due to organ failure.

[0043] Leigh disease or Leigh syndrome (subacute necrotizing cerebrospinal fluid disorder): Symptoms: convulsions, hypotonia, fatigue, nystagmus, decreased reflexes, difficulty eating and swallowing, respiratory distress, decreased motor function, ataxia.

[0044] Causes: pyruvate dehydrogenase deficiency, complex I deficiency, complex II deficiency, complex IV / COX deficiency, NARP.

[0045] Leigh disease is a progressive neurometabolic disorder that typically develops in infancy or childhood, often following a viral infection, but can also develop in adolescence or adulthood. It is characterized by the presence of necrotic lesions (dead or dying tissue) in the brain, particularly the midbrain and brainstem, as seen on MRI.

[0046] Children with Leigh disease often appear normal at birth, and symptoms typically begin between a few months and two years of age, although the onset can be significantly earlier or later. Early symptoms include loss of basic skills such as sucking, head control, walking, and talking. These symptoms may be accompanied by other problems such as tantrums, loss of appetite, vomiting, and seizures. There may be periods of rapid decline in some functions and periods of temporary recovery in others. Affected children may eventually develop complications affecting the heart, kidneys, vision, and respiratory system.

[0047] There are various deficiencies that cause Leigh disease. These deficiencies include pyruvate dehydrogenase (PDHC) deficiency and respiratory chain enzyme deficiencies, namely complex I deficiency, complex II deficiency, complex IV deficiency, and complex V deficiency. Depending on the type of deficiency, the mode of inheritance can be X-linked dominant (a deficiency on the X chromosome, and the disease usually affects only males), autosomal recessive (inherited from both the father and mother), or matrilineal (inherited only from the mother). In addition, it can occur spontaneously without being inherited.

[0048] There is no cure for Leigh disease. Treatment typically involves the use of various vitamins and nutritional supplements, but these are often combined as a "cocktail" therapy and only have partial effects. Various sources suggest that thiamine, coenzyme Q10, riboflavin, biotin, creatine, succinate, and idebenone may be used. The application of experimental therapies such as dichloroacetate (DCA) is also being attempted in some hospitals. Depending on the case, a special diet may be prescribed, which should be monitored by a dietitian with extensive knowledge of metabolic diseases.

[0049] The prognosis for Leigh disease is poor. Depending on the type of deficiency, patients typically only live for a few years to mid-adolescence. Patients diagnosed with Leigh-like syndrome or those who remain asymptomatic into adulthood tend to survive longer.

[0050] MELAS (Mitochondrial Encephalomyopathy, Lactic Acidosis, Stroke-like Syndrome): Symptoms: short stature, seizures, stroke-like episodes with focal neurological impairment, recurrent headaches, cognitive regression, disease progression, and red, ragged fibers.

[0051] Cause: Mitochondrial DNA point mutation: A3243G (most common) MELAS-related conditions include mitochondrial myopathy (muscle weakness), encephalopathy (diseases of the brain and central nervous system), lactic acidosis (accumulation of products from anaerobic respiration), and stroke-like episodes (hemiplegia, partial blindness, or other neurological abnormalities).

[0052] MELAS is a progressive neurodegenerative disease that typically develops between the ages of 2 and 15, but it can also develop in infancy or even later in adulthood. Early symptoms may include stroke-like episodes, seizures, migraines, and recurrent vomiting.

[0053] Patients typically appear normal in infancy, but are generally short in stature. Symptoms are rare in infancy and may include growth retardation, learning disabilities, or attention deficit disorder. Motor intolerance, leg weakness, hearing loss, and diabetes may be present before the onset of a stroke-like episode.

[0054] Stroke-like episodes, often accompanied by seizures, are characteristic symptoms of MELAS, causing hemiplegia, vision loss, and localized neurological impairment. These episodes gradually accumulate, often leading to a combination of varying degrees of motor skill impairment (speech, movement, and feeding), sensory impairment (blindness and reduced vital sensation), and mental deficits (dementia). Furthermore, MELAS patients may present with other symptoms such as muscle weakness, peripheral nerve dysfunction, diabetes, hearing loss, heart and kidney problems, and digestive disorders. Lactate typically accumulates at high levels in the blood, cerebrospinal fluid, or both.

[0055] MELAS is maternally inherited due to a defect in mitochondrial DNA. There are at least 17 mutations that can cause MELAS. The most frequently observed mutation to date is the A3243G mutation, which accounts for approximately 80% of all cases.

[0056] There is no cure or specific treatment for MELAS. Although its effectiveness has not been demonstrated in clinical trials, common treatments include metabolic therapy with CoQ10, creatine, phylloquinone, and other vitamins and nutritional supplements. Anticonvulsants and insulin may be needed for further symptom management. Moderate exercise under supervision may be beneficial in some patients with muscle dysfunction. Other treatments such as dichloroacetate (DCA) and menadione may be prescribed to selected cases, but these drugs are not routinely used due to the potential for adverse side effects.

[0057] The prognosis for MELAS is poor. Generally, the age of death ranges from 10 to 35 years, although some patients live longer. Death can be caused by progressive dementia and muscle weakness, or general emaciation due to complications in other organs such as the heart and kidneys.

[0058] MERRF (Red Ragged Fiber Myoclonus Epilepsy Syndrome) MERRF is a progressive multiple system syndrome that typically begins in childhood, but can also begin in adulthood. The rate of progression varies greatly. The onset and severity of symptoms can vary considerably among siblings affected by the disorder.

[0059] The classic features of MERRF include the following: Myoclonus (sudden, instantaneous muscle spasms) - the most characteristic symptom. • Epileptic seizures • Ataxia (incoordination disorder) • Red ragged fibers (a characteristic abnormality observed under microscopic examination of muscle biopsies from MERRF patients and other patients with mitochondrial diseases). Further symptoms include hearing loss, lactic acidosis (elevated blood lactate levels), short stature, exercise intolerance, dementia, cardiac defects, eye abnormalities, and speech disorders.

[0060] Sporadic cases of MERRF are rare, and the majority of cases are maternally inherited due to mitochondrial mutations. The most common mutation causing MERRF is A8344G, which accounts for over 80% of all cases. In addition, four other mitochondrial DNA mutations have been reported to cause MERRF. A mother's MERRF mutation is transmitted to all of her children, but some of them show no symptoms at all.

[0061] As with all mitochondrial diseases, there is no cure for MERRF. Treatment may include coenzyme Q10, L-carnitine, and various vitamins, often combined as a "cocktail" therapy. Anticonvulsants are usually needed to manage seizures. Other medications may be needed to control other symptoms.

[0062] The prognosis for MERRF varies considerably depending on the age of onset, the type and severity of symptoms, the organs involved, and other factors.

[0063] Maternally inherited diabetes mellitus and hearing loss (MIDD) MIDD is a mitochondrial disease characterized by maternally transmitted diabetes mellitus and sensorineural hearing loss. While the first symptoms can appear at any age, a definitive diagnosis is usually made in early adulthood. In most cases, hearing loss precedes diabetes. The severity of hearing loss varies, but it is sensorineural, bilateral, and progressive, more pronounced in the high-frequency range. Most patients present with pseudo-type 2 diabetes, exhibiting a normal or low body mass index. Pseudo-type 1 diabetes is observed in 20% of cases and may be associated with ketoacidosis. Diabetic retinopathy is less frequent in MIDD patients compared to classical diabetes. More than 80% of all cases develop the distinctive patterned macular dystrophy lesions characteristic of MIDD, although most cases are asymptomatic. Because highly metabolically active organs (muscle, cardiac muscle, kidneys, and brain) are frequently affected, myalgia, gastrointestinal symptoms, nephropathy, cardiomyopathy, and neuropsychiatric symptoms may occur. In most cases, MIDD is caused by a point mutation in the mitochondrial gene MT-TL1, which encodes mitochondrial tRNA for leucine. In rare cases, MIDD is caused by a point mutation in the MT-TE gene, which encodes mitochondrial tRNA for glutamate, or a point mutation in the MT-TK gene, which encodes mitochondrial tRNA for lysine.

[0064] Mitochondrial DNA deficiency: The symptoms of this disease mainly include three types. 1. Congenital myopathy: Neonatal weakness. Hypotonia requiring assisted breathing. Renal dysfunction may also be present. Severe lactic acidosis. Marked red, ragged fibers. Usually leads to death due to respiratory failure before the age of one. 2. Infant myopathy: After normal early development up to 1 year of age, weakness rapidly appears and worsens, leading to respiratory failure and usually death within a few years. 3. Liver damage: Enlarged liver and refractory liver failure, as well as myopathy. Severe lactic acidosis. Death usually occurs in the first year.

[0065] Friedreich's ataxia Friedreich's ataxia (FRDA or FA) is an autosomal recessive neurodegenerative and myocardial degeneration disorder caused by a decrease in the frataxin protein. Frataxin is important for the assembly of iron-sulfur clusters in the mitochondrial respiratory chain complex. The estimated prevalence of FRDA in the United States is 1 in 22,000–29,000 people (see www.nlm.nih.gov / medlineplus / ency / article / 001411.htm) to 1 in 50,000 people. The disease causes progressive loss of coordination of voluntary movements (ataxia) and cardiac complications. Symptoms usually begin in childhood and progressively worsen as the patient grows, eventually leading to wheelchair use due to motor impairment.

[0066] In addition to congenital disorders involving hereditary mitochondrial dysfunction, acquired mitochondrial dysfunction has also been suggested to contribute to disease, specifically to age-related neurodegenerative diseases such as Parkinson's disease, Alzheimer's disease, and Huntington's disease. The incidence of somatic mutations in mitochondrial DNA increases exponentially with age, indicating a general decline in respiratory chain activity in the elderly. Furthermore, mitochondrial dysfunction has been suggested to be involved in excitotoxicity, neuronal damage, and cerebrovascular events, including seizures, strokes, and ischemia.

[0067] General matters Any features and / or embodiments described herein in relation to the compounds described herein are to be interpreted as also applying to the methods described herein.

[0068] The following drawings and examples are provided to illustrate the present invention. These drawings and examples are for illustrative purposes only and should not be construed as limiting the invention. [Brief explanation of the drawing]

[0069] [Figure 1] The following data was obtained from NeuroQoL Short Form Fatigue. Wasting fatigue is considered the most important symptom to improve in patients with mitochondrial disease. The graph on the left shows the mean change in the KL1333 group and the placebo group; improvement was observed in the KL1333 group, but not in the placebo group. The graph in the center shows the correlation between effect size (change from baseline to day 10) and KL1333 exposure (shown as total AUC(0-τ)(h·ng / mL) or C(min) on day 10). The graph on the right shows the same data, but divides patients who received active treatment into low exposure and high exposure groups. These results indicate that the effectiveness of KL1333 was induced in patients treated with high exposure (in all patients, the total AUC(0-τ) value of KL1333 exceeded 4500 h·ng / mL or C(min) exceeded 100 ng / mL on day 10). In patients showing low efficacy, the exposure level was less than 3000 h·ng / mL or C(min) was less than 65 ng / mL on day 10. In the high-exposure KL1333 group, the change in NeuroQol fatigue score from baseline was statistically significantly greater than in the placebo group (Kruskal-Wallis test).

[0070] [Figure 2]The data obtained from the Daily Fatigue Impact Scale is shown. The graph on the left shows the change in mean values ​​in the KL1333 group and the placebo group, with the KL1333 group showing a greater improvement (reduction in fatigue during daily activities) than the placebo group. The graph on the right shows the correlation between effect size (change from baseline to day 10) and KL1333 exposure (shown as total AUC(0-τ)(h·ng / mL) on day 10).

[0071] [Figure 3] The data obtained from the 30-second stand-up test is shown. The 30-second stand-up test is a functional test strongly associated with patients with primary mitochondrial disease. The graph on the left shows the change in mean values ​​in the KL1333 group and the placebo group, with the KL1333 group showing greater improvement (increase in the number of stand-up repetitions) than the placebo group. The graph on the right shows the correlation between effect size (change from baseline to day 10) and KL1333 exposure (shown as total AUC(0-τ)(h·ng / mL) on day 10).

[0072] [Figure 4] This plot shows the time course of loose stool episodes in three cohorts. The Y-axis shows the severity of loose stools as assessed by the Bristol Stool Texture Chart, with grade 7 being the most severe. The experimental data showed that dividing the daily dose into twice-daily (BID) or three times-daily (TID) doses improved the frequency and severity of loose stool episodes.

[0073] [Figure 5]Healthy volunteers were treated with either KL1333 (n=36) or placebo (n=14) once daily for 9 days. Blood samples were collected to measure lactate and pyruvate concentrations, and the lactate / pyruvate ratio was calculated. Data for KL1333 administered at various doses, including 50 mg once daily (QD), 50 mg three times daily (TID), 75 mg once daily (QD), 75 mg twice daily (BID), 150 mg once daily (QD), and 250 mg once daily (QD), were compiled.

[0074] [Figure 6] Ten days after treatment with KL1333, higher plasma KL1333 concentrations were associated with lower blood lactate / pyruvate ratios. Healthy volunteers were treated with either KL1333 (n=36) or placebo (n=14) once daily for 9 days. Blood samples were collected to measure lactate and pyruvate concentrations, and the lactate / pyruvate ratio was calculated. Data on KL1333 at various doses were compiled from seven cohorts consisting of two placebo subjects and six KL1333 subjects treated with 25 mg once daily (QD), 50 mg once daily (QD), 50 mg three times daily (TID), 75 mg once daily (QD), 75 mg twice daily (BID), 150 mg once daily (QD), and 250 mg once daily (QD). In each cohort, the data was adjusted to the cohort mean.

[0075] [Figure 7] This shows the lactate / pyruvate ratio in patients with primary mitochondrial disease treated daily for 10 days with either 50 mg of KL1333 (n=6) or placebo (n=2).

[0076] [Figure 8] Serum niacinamide is an early biomarker indicating responsiveness to KL1333 treatment. Patients with primary mitochondrial disease were treated once daily (QD) with 50 mg of KL1333 (n=6) or placebo (n=2). Data are presented as the ratio of niacinamide concentration on day 2 to niacinamide concentration on day 1 in serum samples.

[0077] [Figure 9] Serum xanthine is an early biomarker indicating responsiveness to KL1333 treatment. Patients with primary mitochondrial disease were treated once daily (QD) with 50 mg of KL1333 (n=6) or placebo (n=2). Data are presented as the ratio of xanthine concentration on day 2 to xanthine concentration on day 1 in serum samples.

[0078] [Figure 10] This shows the correlation between fatigue scores on the Daily Fatigue Scale and the decrease in the blood lactate / pyruvate ratio after 10 days of treatment with 50 mg of KL1333 (black circle) or placebo (white circle).

[0079] [Figure 11]This graph shows the correlation between clinical outcomes and total Ctrough values ​​for KL1333. The upper left graph shows the correlation between effect size (change from baseline to day 10) assessed by the raw NeuroQoL Short Form Fatigue score and exposure (shown as total Ctrough (ng / mL) for KL1333 on day 10), and a statistically significant correlation was observed. The upper right graph shows the mean data, dividing patients who received active treatment into low-exposure and high-exposure groups. These results indicate that the effectiveness of KL1333 was induced in patients with high exposure (patients whose total AUCtrough value for KL1333 on day 10 exceeded 228 ng / ml). In patients with low effectiveness, the exposure on day 10 was less than 130 ng / ml. In the high-exposure KL1333 group, the change in NeuroQoL fatigue score from baseline was statistically significantly improved compared to the placebo group (Kruskal-Wallis test). The graph in the lower left shows the correlation between the effect size (change from day -1 to day 10) evaluated by the daily fatigue scale and the exposure level (shown as total Ctrough (ng / mL) of KL1333 on day 10), and a statistically significant correlation is observed. The graph in the upper left shows the correlation between the effect size (percentage change (%) from day -1 to day 10) evaluated by the 30-second stand-up test and the exposure level (shown as total Ctrough (ng / mL) of KL1333 on day 10). [Examples]

[0080] Example 1 - A double-blind, randomized, parallel-group, placebo-controlled Phase Ia / Ib multicenter study to evaluate the safety, tolerability, pharmacokinetics, and pharmacodynamics of KL1333 after single oral administration and repeated oral escalation in healthy subjects and patients with primary mitochondrial disease. The main purpose of this exam is, Evaluation of the safety and tolerability of single oral administration of KL1333 and repeated oral dose escalation of KL1333 in healthy individuals with or without food intake. Evaluation of the safety and tolerability of repeated oral administration of KL1333 in patients with mitochondrial disease. That is the case.

[0081] The second objective of this examination is, • Measurement of plasma pharmacokinetics (PK) of a single oral administration of KL1333 in healthy individuals (including the effect of food intake). • Measurement of plasma pharmacokinetics (PK) of repeated oral administration of KL1333 in healthy individuals and patients with mitochondrial disease. That is the case.

[0082] The purpose of this study is to explore the following: • Exploration of repeated-dose pharmacodynamics (PD) of KL1333 in healthy individuals and patients with mitochondrial disease using blood biomarkers. • Exploration of clinical outcome evaluation and patient-reported outcome evaluation after repeated oral administration of KL1333 to patients with mitochondrial disease. • Collection of blood samples for metabolomics analysis after repeated oral administration of KL1333 in healthy individuals and patients with mitochondrial disease. • Evaluation of the effects of KL1333 on electrocardiogram (ECG) parameters, including drug concentration-heart rate-corrected QT interval (QTc) analysis, in healthy individuals. • Collection of blood samples for NAD(P)H:dehydrogenase[quinone]1 genotyping from healthy individuals who received a single or repeated oral dose of KL1333, and from mitochondrial disease patients who received repeated oral doses of KL1333. That is the case.

[0083] Experimental design: This study is a double-blind, randomized, placebo-controlled single-dose and repeated-dose study conducted in the following four parts. Part A: Single-dose dose escalation studies (SADs) and the effects of food in healthy volunteers Part B: Repeated dose escalation study (MAD) in healthy volunteers Part C: Repeated dose escalation study (MAD) in patients with primary mitochondrial disease (PMD) Part D: Divided administration in healthy volunteers (administered twice or three times a day) These four parts will be discussed in detail below.

[0084] Part A: Part A includes randomized, single-dose, single-sequence, placebo-controlled trials. Eight healthy individuals are investigated in a single cohort (Group A1).

[0085] Within 28 days prior to the start of the first dose, potential participants were screened to assess their eligibility for enrollment in this study. Participants will participate in two treatment periods. Participants will be hospitalized at the Phase I clinical trial site from day 1 to day 3 of each treatment period (48 hours after administration). On days 4 and 5, participants will return to the clinical trial site for outpatient visits. There will be at least one 10-day drug-free period between each treatment period (between day 1 of treatment period 1 and day 1 of treatment period 2).

[0086] Six subjects will be randomized to receive 25 mg of KL1333, and two subjects will be randomized to receive a placebo. These subjects will receive the same treatment for both treatment periods. On day 1 of treatment period 1, subjects will receive a single oral dose of the investigational drug after fasting for at least 8 hours overnight. On day 1 of treatment period 2, subjects will receive a single oral dose of the investigational drug after consuming a standard high-fat breakfast. After reviewing safety, tolerability, and PK data, up to two additional dosing cohorts consisting of healthy controls may be added as needed to determine the clinical trial treatment to be conducted in Part B. Additional single-dose cohorts may be enrolled based on data obtained from Part A or Part B. If additional cohorts are required, each cohort will consist of eight subjects, six of whom will receive KL1333 and two will receive a placebo, and a single treatment period will be conducted. The dose level and dietary status for administering KL1333 to additional cohorts, if necessary, will be determined after reviewing the data from Part A and the available data from Part B. The dose level may be less than 25 mg or greater than 25 mg. However, the dose level must not exceed 600 mg. The estimated exposure after a single dose in subjects of Part A will be the area under the plasma concentration-time curve [AUC] from zero time to 24 hours post-administration, attributable to the total amount of KL1333. 0-24 The concentration must not exceed 51,800 ng·h / mL.

[0087] On the sixth day, or five days after the final dose, the patient will return for a follow-up outpatient visit.

[0088] Part B: Part B includes a randomized, repeated-dose, consecutive-group, placebo-controlled trial. Sixteen healthy participants will be investigated in two cohorts of eight participants each (Group B1 and Group B2). Part B may be initiated after the completion of the Part A1 trial and will be conducted at or below the dose administered in Part A.

[0089] Within 28 days prior to the initiation of the first dose, potential participants were screened to assess their eligibility for enrollment in this study. All participants participated in one treatment period and were hospitalized at the Phase I clinical trial site from day 1 to day 12 (48 hours after the final dose). On days 13 and 14, participants returned to the clinical trial site for outpatient visits.

[0090] On day 1, six participants will be randomized to receive KL1333 and two participants to receive placebo. The planned doses of KL1333 for groups B1 and B2, as determined from the preliminary study, will be 25 mg once daily (QD) for group B1 from days 1 to 10 and 50 mg once daily (QD) for group B2 from days 1 to 10. After reviewing the safety, tolerability, and PK data from Part A and the data being compiled in Part B, the dose level, administration frequency, and dietary status will be confirmed. Furthermore, before conducting each cohort study in Part B, a dose selection meeting will be held to review blinded data obtained from previous cohorts and make decisions regarding the transition to the next cohort. After reviewing the safety, tolerability, and PK data, up to three additional dosing cohorts consisting of healthy controls may be added as needed to further investigate the PK, safety, and tolerability of KL1333. If additional cohorts are required, each cohort will consist of eight subjects, with six subjects receiving KL1333 and two subjects receiving placebo. The dose level should not exceed 600 mg, and the estimated exposure after repeated once-daily dosing in subjects in Part B will be the AUC attributable to the total amount of KL1333. 0-24 The dose should not exceed 51,800 ng·h / mL. When increasing the dose in each cohort (between the last dose in one cohort and the first dose in the next cohort), there should be a gap of at least 6 days.

[0091] On the 15th day, or 5 days after the final dose, the patient will return for a follow-up outpatient visit.

[0092] Part C: Part C includes a randomized, repeated-dose, single-arm, placebo-controlled trial. Part of this trial will enroll a total of eight patients diagnosed with any mitochondrial disease. After the dose selection meeting to determine the dose for the last cohort of Part B has concluded, Part C may be initiated with a daily dose no higher than the highest dose that was well tolerated in Part B.

[0093] Within 75 days prior to the initiation of the first dose, potential test subjects will be screened to assess their eligibility for enrollment in this study. On days 1-2 and 10-11, patients will be admitted to the clinical trial site or stay at a hotel near the clinical trial site as recommended by the clinical trial site. On days 4 and 8, patients will return to the clinical trial site for outpatient visits. Patients will be randomized on day 1.

[0094] First, two patients will be administered medication: one will receive KL1333 and the other will receive a placebo. If no safety or tolerability issues are observed in these patients at their follow-up visit on day 4, the remaining six patients will be administered medication: five will receive KL1333 and one will receive a placebo, and they will be enrolled sequentially. If safety issues are observed after the completion of medication for the two sentinel lymphocyte patients, but the discontinuation criteria have not been met, the sponsor may add an intermediate cohort as needed for safety evaluation in the intermediate cohort. The medication schedule for the intermediate cohort will be the same as that of the planned cohort. The safety evaluation schedule for the intermediate cohort will, in principle, be the same as that of the planned cohort. The sponsor will decide whether or not to include safety evaluation in the intermediate cohort.

[0095] Patients are scheduled to receive the investigational drug once daily (QD) from days 1 to 10. After reviewing the safety, tolerability, and PK data from Part B, the dose level, frequency of administration, and dietary status will be confirmed, and fasting of the patient before administration will not be required unless it is deemed highly detrimental to the conduct of this study. When patients are hospitalized at the clinical trial site or return for outpatient visits, the investigational drug will be administered by the clinical trial site staff. On other days, patients will record their medication in a diary, and will also record any concomitant medications they are receiving. On the outpatient visit on day 10, the diary will be reviewed as part of the registration procedure to confirm compliance. Any clinical symptoms observed in patients while they are absent from the clinical trial site will be collected at the clinical trial site using standard adverse event (AE) reporting procedures.

[0096] On the 15th day, or 5 days after the final dose, the patient returns for a follow-up outpatient visit.

[0097] Part D: Part D includes randomized, repeated-dose, placebo-controlled trials. Sixteen healthy participants will be surveyed in two cohorts of eight participants each (Group D1 and Group D2). Part D will begin after the completion of Part B, and multiple Part D groups may be conducted in parallel.

[0098] Within 35 days prior to the start of the first dose, potential participants will be screened to assess their eligibility for enrollment in this study. All participants will participate in one treatment period and will be hospitalized at the Phase I clinical trial site from day 1 to day 12 (48 hours after the final dose). On days 13 and 14, participants will return to the clinical trial site for outpatient visits.

[0099] On day 1, six subjects will be randomized to receive KL1333 and two subjects to receive a placebo. From days 1 to 10, the KL1333 dose will be 75 mg twice daily (BID) for the D1 group and 50 mg three times daily (TID) for the D2 group, with only one dose on day 10.

[0100] On the 15th day, or 5 days after the final dose, the patient will return for a follow-up outpatient visit.

[0101] The investigational drug, its dosage, and method of administration: Investigational drug: Encapsulated tablets containing 25 mg or 100 mg of KL1333 were used, along with corresponding placebo tablets. The placebo tablets were identical to the investigational drug in appearance, shape, and weight.

[0102] The KL1333 formulation is an immediate-release tablet intended for oral administration.

[0103] Proposed dose levels for Part A: 25 mg of KL1333 or placebo, administered once under fasting conditions and once under fed conditions.

[0104] The proposed dose levels for Part B are 25 mg or 50 mg of KL1333 or placebo once daily (QD) for 10 days. Based on the data from Part A of this study and the interim data being compiled for Part B, the dose levels, administration frequency, and dietary status for Part B will be determined in consultation with the sponsor.

[0105] Patients in Part C will receive either KL1333 or placebo once daily (QD) for 10 days. Based on the data from Part B of this study, the dose level, frequency of administration, and dietary status for Part C will be determined in consultation with the sponsor.

[0106] Dosage levels for Part D: Administer 75 mg of KL1333 or placebo twice daily (BID) for 10 days, or 50 mg of KL1333 or placebo three times daily (TID) for 10 days, with only one dose on day 10. The first doses on days 1 and 7, and the dose on day 10, should be administered on a fasted state. All other doses can be administered regardless of food intake.

[0107] The dose level should not exceed 600 mg, and in any cohort and any subject in this study, the estimated exposure is due to the total amount of KL1333, calculated using an improved biological analytical method capable of measuring KL1333 as the sum of the KL1333 parent drug, the glucuronide-deconjugated KL1333 metabolite, and the sulfated KL1333 metabolite. 0-24 Therefore, it must not exceed 51,800 ng·h / mL.

[0108] Endpoint: Pharmacokinetics: To analyze the plasma concentration of KL1333, blood samples are collected and PK parameters are determined by non-compartmental analysis.

[0109] The PK parameters for Part A include the following: AUC from zero time to infinite time (AUC 0-∞ ) AUC0-24 · AUC from zero time to the final measurable time (AUC 0-tlast ) · C max · C max Time (T max ) · Apparent plasma terminal elimination half-life (t 1 / 2 ) · Mean residence time (MRT) · Apparent total plasma clearance (CL / F) · Apparent terminal-phase volume of distribution (V z / F)

[0110] The PK parameters in parts B to D include the following. · AUC 0-∞ (only on day 1) · AUC over one dosing interval (AUC 0-τ ; days 1 and 10) · Transient change parameter (TCP; AUC 0-τ / AUC 0-∞ ) · C max · Minimum plasma concentration (C min ) · T max · t 1 / 2 · MRT on days 1 and 10 · CL / F on days 1 and 10 · V on days 1 and 10 z / F · Accumulation ratio (RA 0-τ ) based on AUC AUC ) · Accumulation ratio (RA max ) based on C Cmax ) · Peak / trough ratio (PTR)

[0111] Calculate other PK parameters if appropriate.

[0112] Pharmacodynamics: The evaluation of blood biomarkers in Parts B through D includes the following: • Nicotinamide adenine dinucleotide (oxidized form; NAD) + ) / Concentration and ratio of nicotinamide adenine dinucleotide (reduced form; NADH) • Fibroblast Growth Factor 21 (FGF21) • Growth and differentiation factor 15 (GDF15) • Lactic acid / pyruvic acid concentrations and their ratios

[0113] The evaluation of blood biomarkers in Part C includes the following: ·glucose • Concentration and ratio of glycated albumin / albumin

[0114] Part C of the clinical outcome assessments and patient-reported outcome assessments include the following: ·Newcastle Mitochondrial Disease Adult Scale ·Clinician Global Impression • Patient Global Impression - Improvement • Daily Fatigue Impact Severity ·Quality of Life in Neurological Disorders Fatigue Short Form • 30-second rise test

[0115] Results - Efficacy in patients with primary mitochondrial disease Patient-based outcome evaluation after repeated oral administration of KL1333 to patients with mitochondrial disease. Six patients with genetically confirmed primary mitochondrial disease received aggressive treatment with 50 mg of KL1333 once daily for 10 days. Two patients received a placebo.

[0116] Figure 1 shows the results obtained from the following three main clinical outcome assessments in patients with primary mitochondrial disease. Each data point represents the change in the mean value from baseline to the last day of medication (day 10). ·Quality of Life in Neurological Disorders Fatigue Short Form • Daily Fatigue Scale (D-FIS) • 30-second stand-up test (a test of muscle strength)

[0117] The graph below shows the same data, but divides patients who received active treatment into low-exposure and high-exposure groups. These results indicate that the efficacy of KL1333 was induced in patients treated with high exposure (in all patients, on day 10, the total AUC(0-τ) of KL1333 exceeded 4500 h·ng / mL, C(min) exceeded 100 ng / mL, and / or Ctrough exceeded 228 ng / mL). In patients showing low efficacy, on day 10, the exposure was less than 3000 h·ng / mL, C(min) was less than 65 ng / mL, and / or Ctrough was less than 130 ng / mL.

[0118] The results are shown in Figures 1-3. These results indicate that in patients treated with KL1333, compared to placebo, i) Significant improvement in fatigue, ii) Significant improvement in muscle strength and iii) Strong efficacy response These effects were observed, and it was shown that all of these effects were obtained by administering a dose of 50 mg once daily for just 10 days.

[0119] Figure 1 shows data obtained from NeuroQoL Short Form Fatigue. Wasting fatigue is considered the most important symptom to improve in patients with mitochondrial disease. The graph on the left shows the mean change in the KL1333 group and the placebo group; improvement was observed in the KL1333 group, but not in the placebo group. The graph in the center shows the correlation between effect size (change from baseline to day 10) and KL1333 exposure (shown as total AUC(0-τ)(h·ng / mL) or C(min) on day 10). The graph on the right shows the same data, but divides patients who received active treatment into low exposure and high exposure groups. These results indicated that the efficacy of KL1333 was induced in patients treated with high exposure (in all patients, the total AUC(0-τ) of KL1333 exceeded 4500 h·ng / mL or C(min) exceeded 100 ng / mL on day 10). In patients showing low efficacy, the exposure was less than 3000 h·ng / mL or C(min) was less than 65 ng / mL on day 10. The change in NeuroQol fatigue score from baseline was statistically significantly improved in the high-exposure KL1333 group compared to the placebo group (Kruskal-Wallis test).

[0120] Figure 2 shows data obtained from the Daily Fatigue Impact Scale, and Figure 4 shows data obtained from the 30-second stand-up test. The 30-second stand-up test is a functional test strongly associated with patients with primary mitochondrial disease.

[0121] Improvement in tolerability In Parts B and D of this study, the safety and tolerability of KL1333 in healthy volunteers were investigated using repeated dose escalation studies. Part D was further investigated by administering the daily dose in two or three divided doses when tolerability improved. Cohorts B3, D1, and D2 all received a total daily dose of 150 mg for 10 days. Cohort B3 received 150 mg once daily (QD), Cohort D1 received 75 mg twice daily (BID), and Cohort D2 received 50 mg three times daily (TID). Figure 4 plots the time course of loose stool episodes in these three cohorts. The Y-axis shows the severity of loose stools as assessed by the Bristol Stool Characteristics Chart, with Grade 7 being the most severe. Experimental data showed that dividing the daily dose into two daily (BID) or three daily (TID) doses improved the frequency and severity of loose stool episodes.

[0122] Drug exposure The table below shows the total KL1333 exposure levels on day 10 in healthy volunteers in Part D. In all subjects, the drug was administered to achieve a steady-state concentration above 3900 h·ng / mL on day 10, and no subjects had a steady-state concentration below 3000 h·ng / mL on day 10. [Table 1]

[0123] In all cohorts of this study, the safety of KL1333 was confirmed, and no serious adverse events or safety signals were observed. KL1333 was generally well-tolerated in patients and healthy volunteers, with dose-limiting gastrointestinal side effects being the primary tolerability finding, which could be improved by divided daily doses. Similar pharmacokinetic profiles were observed in healthy volunteers and patients.

[0124] Example 2 - Biomarker KL1333 tended to lower the blood lactate / pyruvate ratio in healthy volunteers after 10 days of treatment with KL1333 (Figure 5).

[0125] The lowest blood lactate / pyruvin ratio was observed in subjects whose plasma KL1333 concentration exceeded 100 ng / mL before blood sample collection for analysis (Figure 6).

[0126] In a study of primary mitochondrial disease patients treated daily with KL1333 for 10 days, the lactate / pyruvate ratio in patients on day 10 was lower than in subjects treated with KL1333 on day 1, but this decrease was not observed in subjects treated with placebo (Figure 7).

[0127] One day after treatment with KL1333 in patients with primary mitochondrial disease, niacinamide, a metabolite in the nicotinamide dinucleotide synthesis pathway, increased (Figure 8). The increase in niacinamide was most pronounced in patients with the highest exposure to KL1333.

[0128] One day after treating patients with primary mitochondrial disease with KL1333, the cofactor NAD + The oxidation of hypoxanthine by this agent increased xanthine, a purine metabolic pathway metabolite (Figure 9). The increase in xanthine was most pronounced in patients with the highest exposure to KL1333.

[0129] In conclusion, the blood lactate / pyruvate ratio, niacinamide, and / or xanthine can be used as biomarkers for the therapeutic effect of KL1333 in patients with primary mitochondrial disease. Based on this, it was found that patients who showed the greatest decrease in fatigue scores on the daily fatigue scale on day 10 of KL1333 treatment also had a low serum lactate / pyruvate ratio (Figure 10).

Claims

1. KL1333 for use in the treatment of fatigue.

2. The KL1333 according to claim 1, wherein the fatigue includes fatigue syndrome and disease-related fatigue.

3. The KL1333 according to claim 1 or 2, wherein the fatigue is physical fatigue, mental fatigue, neurological fatigue, or chronic fatigue.

4. The aforementioned fatigue, i) Autoimmune diseases such as celiac disease, systemic lupus erythematosus, multiple sclerosis, Sjögren's syndrome, and spondyloarthritis, ii) Blood disorders such as anemia and hemochromatosis, iii) Cancer (also known as cancer fatigue), iv) Chronic fatigue syndrome (CFS), v) Substance use disorders, including alcohol use disorder, vi) Depression and other mental illnesses, vii) Developmental disorders such as autism spectrum disorder, viii) Eating disorders, ix) Endocrine or metabolic disorders such as diabetes, hypothyroidism, and Addison's disease, x) fibromyalgia, xi) Gulf War Syndrome, xii) heart failure; xiii) HIV, xiv) Idiopathic chronic fatigue (ICF), xv) Congenital metabolic disorders such as fructose malabsorption, xvi) Infectious diseases such as infectious mononucleosis and tuberculosis, xvii) irritable bowel syndrome, xviii) For example, kidney diseases such as acute renal failure and chronic renal failure, xix) Leukemia or lymphoma, xx) Liver failure, or liver disease such as hepatitis, xxi) Lyme disease, xxii) Neurological disorders such as narcolepsy, Parkinson's disease, post-orthostatic tachycardia syndrome, and post-concussion syndrome. xxiii) Physical trauma, and other conditions that cause pain, such as arthritis. xxiv) Sleep deprivation or sleep disorder, xxv) Satsuki disease, xxvi) Stroke, xxvii) thyroid disease, xxviii) Uremia, and xxix) Mitochondrial disease KL1333 as described in any one of the prior claims, relating to a disease selected from the following.

5. KL1333 according to any one of the preceding claims, wherein the fatigue is related to mitochondrial disease.

6. The KL1333 according to claim 5, wherein the mitochondrial disease is as defined herein.

7. The KL1333 according to claim 5 or 6, wherein the mitochondrial disease is caused by a deficiency of complex I.

8. KL1333 for use in the treatment of muscle weakness or in improving muscle endurance.

9. The KL1333 according to claim 8, wherein the aforementioned muscle weakness is neuromuscular fatigue.

10. The KL1333 according to claim 8 or 9, wherein the muscle weakness is caused by a disease.

11. The KL1333 according to claim 10, wherein the disease is selected from diabetes, heart disease, stroke, depression, fibromyalgia, chronic fatigue syndrome, polymyositis, inflammatory muscle disease, mitochondrial disease; and neuromuscular diseases such as muscular dystrophy, multiple sclerosis, Graves' disease, myasthenia gravis, and Guillain-Barré syndrome.

12. The KL1333 according to any one of claims 8 to 11, wherein the muscle weakness is related to mitochondrial disease.

13. The KL1333 according to claim 12, wherein the mitochondrial disease is as defined herein.

14. The KL1333 according to claim 12 or 13, wherein the mitochondrial disease is caused by a complex I deficiency.

15. KL1333 according to any one of the preceding claims, wherein KL1333 is administered once daily, twice daily, or three times daily.

16. The KL1333 according to any one of the preceding claims, wherein the treatment is continued for at least two days, for example, at least five days, at least ten days, at least four weeks, or at least two months.

17. KL1333 for use in a drug administration plan for the treatment of one or more of fatigue, muscle weakness, and mitochondrial disease, The aforementioned drug administration plan, i) To obtain a steady-state blood KL1333 concentration in subjects with fatigue, muscle weakness, or mitochondrial disease, administer 25 mg to 150 mg of KL1333, for example, 25 mg to 100 mg of KL1333 daily for 2 to 10 days. ii) Measure the blood KL1333 concentration, expressed as AUC (area under the curve), Cmin, or Ctrough, and determine whether the AUC is less than 3,000 h·ng / mL, the Cmin is 65 ng / mL or less, or the Ctrough is 130 ng / mL or less, and iii) Adjusting the daily dose to obtain a steady-state blood KL1333 concentration corresponding to an AUC (area under the curve) of at least 3,000 h·ng / mL, a Cmin of at least 65 ng / mL, or a Ctrough of at least 130 ng / mL, thereby obtaining, on day 10 after dose adjustment, at least 3,500 h·ng / mL AUC, at least 77 ng / mL Cmin, or at least 163 ng / mL Ctrough; at least 4,000 h·ng / mL AUC, at least 88 ng / mL Cmin, or at least 196 ng / mL Ctrough; at least 4,500 h·ng / mL AUC, at least 100 ng / mL Cmin, or at least 228 ng / mL Ctrough; or obtaining an AUC in the range of 4,000 to 12,000 h·ng / mL, a Cmin in the range of 88 to 275 ng / mL, or a Ctrough in the range of 196 to 333 ng / mL. KL1333, including.

18. The KL1333 according to claim 17, wherein the drug administration plan is carried out by oral administration.

19. The KL1333 according to claim 17 or 18, wherein details are defined in any one of claims 1 to 16.

20. A lactate / pyruvate ratio as a biomarker of the therapeutic effect of KL1333, wherein a decrease in the lactate / pyruvate ratio after the start of treatment indicates that the treatment is effective, and the treatment is as defined in any one of claims 1 to 19.

21. The lactic acid / pyruvic acid ratio according to claim 20, wherein the decrease in the lactic acid / pyruvic acid ratio is at least 10%, for example, at least 20% or at least 25%.

22. Niacinamide as a biomarker for the therapeutic effect of KL1333, wherein the treatment is shown to be effective by an increase in the ratio of niacinamide concentrations after the start of treatment, and the ratio of niacinamide concentrations is (serum concentration on the test day) / (serum concentration at the start of treatment).

23. The niacinamide as a biomarker according to claim 24, wherein the ratio increase in the niacinamide concentration is twofold or more.

24. xanthine as a biomarker for the therapeutic effect of KL1333, wherein the treatment is shown to be effective by an increase in the ratio of xanthine concentrations after the start of treatment, and the ratio of xanthine concentrations is (serum concentration on the test day) / (serum concentration at the start of treatment).

25. Xanthine as a biomarker according to claim 24, wherein the increase in the ratio of xanthine concentration is 10% or more, for example, 15% or more, 20% or more, 25% or more, or 30% or more.

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