Treatment of uremic pruritus

Abstract

Pruritus (itching) is a widely known, common, and often distressing symptom (i.e., a self-reported subjective experience) of several conditions, including infection, environmental / allergic exposure, skin disorders, drug reactions, and systemic medical disorders. Systemic diseases that cause pruritus include uremia in patients with chronic kidney disease or end-stage renal disease, and the pruritus is called uremic pruritus (UP; also known as chronic kidney disease-associated pruritus, CKD-aP). The present invention relates to the treatment of uremic pruritus by administration of serradelpal or a salt thereof, or by administration of mabodelpal or a salt thereof.

Description

Technical Field

[0001] The present invention relates to the treatment of uremic pruritus.

Background Art

[0002] Pruritus, IL-31, and Uremic Pruritus

[0003] Pruritus (itching) is a widely known, frequent, and often painful symptom (i.e., a self-reported subjective experience) of several conditions such as infection, environmental / allergic exposure, skin disorders, drug reactions, and systemic medical disorders. Pruritus can be mild and tolerable in some cases, but it significantly reduces the quality of life, causes severe sleep deprivation and depression, and in the most affected patients, it can even induce suicidal thoughts.

[0004] Pruritus can be numerically assessed in several ways. Two one-dimensional numerical assessment methods exist: the Visual Analog Scale (VAS), which presents the patient with a line labeled "no itchiness" at the left endpoint and "worst itchiness" at the right endpoint; and the Numerical Rating Scale (NRS), which presents the patient with a line labeled like a ruler, typically ranging from 0 to 10 or 0 to 100. In either method, the patient is asked to mark a location on the line corresponding to their current level of itchiness. The term VAS is sometimes used to describe scales where the line is marked like a ruler, in addition to the endpoints being labeled. The Visual Analog Scale (VAS) has been validated for use in clinical trials to measure pruritus and is recommended by the International Forum for the Study of Itch (Staender et al., "Pruritus Assessment in Clinical Trials: Consensus Recommendations from the International Forum for the Study of Itch (IFSI) Special Interest Group Scoring Itch in Clinical Trials", Acta Derm. Venereol., vol.93, pp.509-514 (2013)). The multidimensional numerical assessment method is the 5-D itch scale (Elman et al., "The 5-D itch scale: a new measure of pruritus", Br.J.Dermatol., vol.162(3), pp.587-593 (2010)). This scale assesses pruritus over the past two weeks in terms of duration (length per day), severity (intensity), direction (increase or decrease), disability (impact of pruritus on daily life), and distribution (body location), and assigns a numerical score to each dimension. In clinical trials, pruritus may be recorded on paper or on an electronic device (electronic diary or similar device).

[0005] Cholestatic disorders associated with pruritus (this pruritus is called cholestatic pruritus) include primary biliary cholangitis (PBC) and primary sclerosing cholangitis (PSC). Mu et al., "Implication of Increased Serum IL-31 for Primary Biliary Cholangitis," Immunol.Invest., 50(6), 662-670 (2021) tested IL-31 in a group of treatment-naive patients with PBC and compared them to patients with chronic hepatitis B and healthy volunteers. They found elevated serum IL-31 levels in PBC patients (median 20.6 pg / mL) compared to hepatitis B patients (median 11.3 pg / mL) and healthy volunteers (median 11.0 pg / mL), concluding that "serum IL-31 is elevated in PBC, particularly AMA-negative PBC, and may be a useful marker for PBC, especially AMA-negative PBC. Furthermore, serum IL-31 is inversely associated with the fibrotic progression of PBC." Mu et al. noted that "while the important role of IL-31 in pruritus in skin diseases is well known, these researchers did not find an association between serum IL-31 levels and pruritus in PBC patients." However, Xu et al., "IL-31 levels correlate with pruritus in patients with cholestatic and metabolic liver diseases and is farnesoid X receptor responsive in NASH", Hepatol. (2022), https: / / doi.org / 10.1002 / hep.32599, tested the farnesoid X receptor (FXR) agonist, cilofexor, and, contrary to Mu et al., reported that "baseline IL-31 levels in PSC and PBC were positively correlated with the visual analog scale and 5-D pruritus score for pruritus," that cilofexor treatment in NASH increased IL-31, and that IL-31 was higher in NASH patients with grade 2-3 pruritus adverse events than in patients with grade 0-1 pruritus adverse events.They also noted that, in a humanized liver mouse model, obeticholic acid increased IL-31 mRNA expression and human IL-31 serum levels in human hepatocytes. Prescription information for obeticholic acid (OCALIVA, Intercept Pharmaceuticals) indicates that in a 12-month double-blind, randomized controlled trial of 216 PBC patients, severe pruritus was reported in 23% of patients in the OCALIVA 10 mg group, 19% in the OCALIVA titration group, and 7% in the placebo group.

[0006] Another systemic disease that causes itching is uremia, such as in patients with chronic kidney disease or end-stage renal disease, and the itching is called uremic pruritus (UP; also known as chronic kidney disease-associated pruritus, CKD-aP). According to Westby et al., "A review of the management of uremic pruritus: current perspectives and future directions," Itch, 5:e38 (2020), "Uremic pruritus (UP) is a frequently occurring and distressing symptom experienced by approximately half of patients with end-stage renal disease (ESRD) undergoing dialysis. UP is generally described as itching that occurs daily or almost daily in the absence of findings related to a primary skin condition. UP is associated with several health-related quality of life impairments, including depression, poor sleep quality, and impaired social functioning. Furthermore, UP is independently associated with mortality." Oweis et al., "Elevated interleukin 31 serum levels in hemodialysis patients are associated with uremic pruritus," Cytokine, 138:155369 (2021), https: / / doi.org / 10.1016 / j.cyto.2020.155369, reported that IL-31 levels were significantly higher in the hemodialysis group than in healthy controls (P=0.0001). Krajewski et al., "High Serum IL-31 Concentration Is Associated with Itch Among Renal Transplant Recipients," J.Clin.Med., 11:4309 (2022), https: / / doi.org / 10.3390 / jcm11154309, reported that chronic itching is a frequently observed and troublesome symptom among kidney transplant recipients. They studied the difference in serum IL-31 concentration between recipients with itching and those without, finding that the mean was significantly different (P<0.001), but there was no significant difference between recipients without itching and healthy controls.They describe that their group's research found that the overall incidence of moderate to severe pruritus in hemodialysis patients is 35–44%, that this pruritus can persist after kidney transplantation, and that 50% of pruritus in kidney transplant recipients appears after successful transplantation. Swierczynska et al., "The Serum Level of IL-31 in Patients with Chronic Kidney Disease-Associated Pruritus: What Can We Expect?", Toxins, 14:197 (2022), https: / / doi.org / 10.3390 / toxins14030197 reports that elevated serum IL-31 levels were found in hemodialysis patients with UP compared to both hemodialysis patients without pruritus and healthy controls.

[0007] Treatment of uremic pruritus

[0008] Westby et al. outline the treatment of uremic pruritus. They mention topical treatments such as emollients and ointments, topical calcineurin inhibitors (e.g., tacrolimus), topical anesthetics (e.g., capsaicin and pramoxin hydrochloride), topical anti-irritants (e.g., menthol and camphor), and topical corticosteroids (they state that these have not been shown to be effective in treating pruritus without evidence of underlying inflammation), and conclude that "overall, the use of topical therapies is limited by the systemic nature of UP. It is estimated that about 50% of UP patients have systemic pruritus rather than local symptoms, and therefore topical therapies have inherent limitations such as ease of application, required dosage, and compliance with long-term use." However, they report that endogenous cannabinoids, N-acetylethanolamine and N-palmitoylethanolamine, in topical creams have shown efficacy in UP. They also consider systemic treatments such as gabapentin and pregabalin (they warn of known side effects of drowsiness, dizziness, and somnolence), as well as opioid receptor modulators (referring to nalfurafine, a κ-opioid receptor antagonist, and nalbufine, a mixed μ-opioid receptor partial agonist / antagonist, and a κ-opioid receptor partial agonist). In the United States, difelikefalin (KORSUVA, Cara Pharmaceuticals), a peripherally limited selective κ-opioid receptor agonist, is indicated for the treatment of moderate to severe pruritus associated with chronic kidney disease (CKD-aP) in adults undergoing hemodialysis. Difelikefalin is recommended for administration in dialysis sessions after completion of dialysis and has known side effects of drowsiness, dizziness, and somnolence. For a report on one of the Phase 3 studies, see Fishbane et al., "A Phase 3 Trial of Difelikefalin in Hemodialysis Patients with Pruritus", N.Engl.J.Med., 382(3), 222-232 (2020).

[0009] Seladelpar

[0010] Ceradelpal (International Generic Name - INN) has the chemical name [4-({(2R)-2-ethoxy-3-[4-(trifluoromethyl)phenoxy]propyl}sulfanyl)-2-methylphenoxy]acetic acid [IUPAC name from WHO Recommended INN: List 77], and code number MBX-8025. Ceradelpal, as well as its synthesis, formulation, and use, are disclosed, for example, in U.S. Patent No. 7301050 (Table 1, Example M, Compound 15 of Claim 49), U.S. Patent No. 7635718 (Table 1, Compound 15 of Example M), and U.S. Patent No. 8106095 (Table 1, Example M, Compound 15 of Claim 14). Lysine (l-lysine) salts of Ceradelpal and related compounds are disclosed in U.S. Patent No. 7709682 (Ceradelpal l-lysine salts in all examples, claimed crystalline form).

[0011] Ceradelpal is an orally active, potent (2nM) agonist of peroxisome proliferator-activated receptor δ (PPARδ). Ceradelpal is specific (>600- and >2500-) compared to peroxisome proliferator-activated receptor α and peroxisome proliferator-activated receptor γ. PPARδ activation stimulates fatty acid oxidation and utilization, improving plasma lipid and lipoprotein metabolism, glucose utilization, and mitochondrial respiration, and preserving stem cell homeostasis. According to U.S. Patent No. 7301050, PPARδ agonists, such as Ceradelpal, are suggested to treat PPARδ-mediated conditions including "diabetes mellitus, cardiovascular disease, metabolic X syndrome, hypercholesterolemia, low- and high-density lipoprotein (HDL) cholesterolemia, high- and low-density protein (LDL) cholesterolemia, dyslipidemia, atherosclerosis, and obesity," where dyslipidemia is said to include hypertriglyceridemia and mixed hyperlipidemia. Seradelpal as l-lysine dihydrate has been studied in mixed dyslipidemia at oral doses equivalent to 50 mg / day and 100 mg / day of Seradelpal, which are equivalent to doses of 10 mg / day, 20 mg / day, and 50 mg / day of Seradelpal in non-alcoholic steatohepatitis; and doses of 2 mg / day, 5 mg / day, 10 mg / day, 50 mg / day, and 200 mg / day of Seradelpal in PBC.

[0012] U.S. Patent Publication No. 2019 / 0105291 and PCT International Publication No. 2019 / 067373 disclose the treatment of cholestatic pruritus with ceradelpal and its salts. Mavodelpar Mabodelpal (INN) has the chemical name (4-{[(2E)-3-(4-fluorophenyl)-3-{4-[3-(morpholin-4-yl)prop-1-in-1-yl]phenyl}prop-2-en-1-yl]oxy}-2-methylphenoxy)acetic acid [IUPAC name from WHO Recommended INN: List 127], and code numbers HPP593 and REN001. Mabodelpal and its salts, as well as their synthesis, formulation and use, are disclosed, for example, in U.S. Patent No. 7,943,613 (Example 10, Claims 1-5); the synthesis is disclosed, for example, in U.S. Patent Application Publication No. 2023 / 0416210. The sodium crystalline salt of Mabodelpal is disclosed, for example, in U.S. Patent No. 1,126,7795. According to Alzheimer's Drug Discovery Foundation's Cognitive Vitality Report on PPARδ agonists since November 2021, Mavodelpal has an EC of 31 nM for PPARδ. 50 It has, on the other hand, EC for PPARα and PPARγ 50 Its concentration is over 10 μM. In 2017, mavodelpal was described as a function-selective PPARδ agonist, showing a significant increase in high-density lipoprotein cholesterol and a decrease in low-density lipoprotein cholesterol and triglycerides in animal models and humans. It has also been reported to have antidiabetic effects in several animal models of type 2 diabetes, and early clinical studies have shown that mavodelpal is well-tolerated. Mavodelpal has been granted orphan drug designation by the FDA for primary mitochondrial myopathy. Most recently, mavodelpal was studied in the STRIDE study (NCT04535609), a global, randomized, double-blind, placebo-controlled, central phase 2b trial in adult patients with primary mitochondrial myopathy due to mitochondrial DNA deficiency. [Prior art documents] [Patent Documents]

[0013] [Patent Document 1] U.S. Patent No. 7301050 [License 2] U.S. Patent No. 7635718 [License 3] U.S. Patent No. 8106095 [License 4] U.S. Patent No. 7709682 [Patent Document 5] U.S. Patent and Trademark Office Publication No. 2019 / 0105291 [License 6] International Publication No. 2019 / 067373 [License 7] U.S. Patent No. 7943613 [License 8] U.S. Patent and Trademark Office Publication No. 2023 / 0416210 [License 9] U.S. Patent No. 11267795 [Non-licensed literature]

[0014] [Non-licensed Document 1] Staender et al., "Pruritus Assessment in Clinical trials: Consensus Recommendations from the International Forum for the Study of Itch (IFSI) Special Interest Group Scoring Itch in Clinical Trials", Acta Derm. Venereol., vol.93, pp.509-514 (2013) [Non-licensed Document 2] Elman et al., "The 5-D itch scale: a new measure of pruritus", Br.J.Dermatol., vol.162(3), pp.587-593(2010) [Non-licensed Document 3] Mu et al.,「Implication of Increased Serum IL-31 for Primary Biliary Cholangitis」,Immunol.Invest.,50(6),662-670(2021)

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Summary of the Invention

[0015] The present invention is for the treatment of uremic pruritus by administration of seladelpar or a salt thereof.

[0016] In various aspects, the present invention seladelpar or a salt thereof for use in the treatment of uremic pruritus; the use of seladelpar or a salt thereof for the treatment of uremic pruritus or in the manufacture of a medicament for the treatment thereof; and a pharmaceutical composition or medicament comprising seladelpar or a salt thereof for the treatment of uremic pruritus is included.

[0017] When orally administered for the treatment of PBC, seladelpar has been demonstrated to be effective for the treatment of PBC at oral dosages of 5 mg / day, 10 mg / day, Fifty mg / day, and 200 mg / day, and has been found not to exacerbate cholestatic pruritus, and is expected to be effective at dosages of 0.5 mg / day to 25 mg / day. In studies on PBC at oral dosages of 5 mg / day and 10 mg / day, seladelpar has been demonstrated to be effective in the treatment of cholestatic pruritus associated with PBC; seladelpar has also been shown to reduce IL-31. Due to this reduction in IL-31, seladelpar is expected to be useful also for the treatment of uremic pruritus.

[0018] The present invention also relates to the treatment of uremic pruritus by administration of mavodelpal or a salt thereof. In various embodiments, the present invention also includes mavodelpal or a salt thereof for use in the treatment of uremic pruritus; the use of mavodelpal or a salt thereof in the manufacture of a drug for treating or for treating uremic pruritus; and pharmaceutical compositions or drugs comprising mavodelpal or a salt thereof for the treatment of uremic pruritus. Since mavodelpal is a selective PPARδ agonist, it is expected to reduce IL-31 and therefore be useful in the treatment of uremic pruritus.

[0019] Preferred embodiments of the present invention are characterized by the features of the specification and claims 1 to 16 of this application. [Modes for carrying out the invention]

[0020] definition

[0021] Uremic pruritus and its treatment are described in the background information subsections titled “Pruritus, IL-31, and Uremic Pruritus” and “Treatment of Uremic Pruritus.”

[0022] "To treat" or "treatment" of uremic pruritus in humans is: (1) To prevent or reduce the risk of developing pruritus; that is, to prevent pruritus in subjects who are susceptible to a condition in which uremic pruritus is a symptom, but who have not yet experienced or shown pruritus (i.e., prevention); (2) Inhibiting itching, that is, preventing or reducing the onset of itching, (3) To reduce itching, that is, to reduce the number, frequency, duration or severity of itching. Includes one or more of the following.

[0023] The “therapeutic effective dose” of ceradelpal or its salts refers to the amount sufficient to produce relief of pruritus when administered to a human for the treatment of uremic pruritus. The therapeutic effective dose for a particular subject will vary depending on the age, health and physical condition of the subject being treated, the nature and severity of the pruritus, the route of administration of ceradelpal or its salts, the assessment of the medical condition, and other relevant factors. The therapeutic effective dose is expected to fall within a relatively wide range, which can be determined through routine trials.

[0024] Seradelpal is described in the subsection titled "Seradelpal" in the background technology section.

[0025] Salts of ceradelpal (e.g., pharmaceutically acceptable salts) are included in the present invention and are useful in the methods described in this application. These salts are preferably formed with pharmaceutically acceptable acids. For example, for a comprehensive discussion of pharmaceutically acceptable salts, their selection, preparation, and use, see "Handbook of Pharmaceutically Acceptable Salts," Stahl and Wermuth, eds., Verlag Helvetica Chimica Acta, Zuerich, Switzerland. Unless otherwise intended by context, references to ceradelpal and "compounds that are ceradelpal or salts thereof" refer to both ceradelpal itself and its salts. An amount of ceradelpal salt that is "equivalent" to a particular amount of ceradelpal refers to an amount of salt obtained by multiplying the particular amount by the ratio of the formula weight of the salt to the formula weight of ceradelpal. For example, when ceradelpal L-lysine dihydrate is used, the formula weight of ceradelpal L-lysine dihydrate is approximately 1.41 times that of ceradelpal. Therefore, approximately 14.1 mg / day of ceradelpal L-lysine dihydrate is equivalent to 10 mg / day of ceradelpal.

[0026] Since ceradelpal contains carboxyl groups, the acidic protons present can react with inorganic or organic bases to form salts. Typically, ceradelpal is treated with an excess of an alkaline reagent such as a hydroxide, carbonate, or alkoxide containing a suitable cation.+ , K + Ca 2+ Mg 2+ , and NH4 + Cations such as these are examples of cations present in pharmaceutically acceptable salts. Therefore, suitable inorganic bases include calcium hydroxide, potassium hydroxide, sodium carbonate, and sodium hydroxide. Salts can also be prepared using organic bases, e.g., salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, and cyclic amines. Such amines include isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, 2-dimethylaminoethanol, tromethamine, lysine, arginine, histidine, caffeine, procaine, hydravamin, choline, betaine, ethylenediamine, glucosamine, N-alkylglucamine, theobromine, purine, piperazine, piperidine, and N-ethylpiperidine. As described in the “Ceradelpal” subsection, Ceradelpal is currently formulated for oral administration as its L-lysine dihydrate salt.

[0027] Mabodelpal is described in the subsection titled "Mabodelpal" in the background information. Unless otherwise intended by context, references to Mabodelpal and to "compounds that are Mabodelpal or its salts" refer to both Mabodelpal itself and its salts. The "therapeutic dose" of Mabodelpal or its salts has the same meaning as that of Seradelpal.

[0028] "Comprising" or "containing," and their grammatical variations, are words of inclusion, not limitation. They indicate the presence of a listed component, group, step, etc., but do not exclude the presence or addition of other components, groups, steps, etc. Therefore, "comprising" does not mean "consisting of," "substantially consisting of," or "consisting of only." For example, a formulation that "contains" a compound must contain that compound, but may also contain other active ingredients and / or excipients.

[0029] Formulation and administration

[0030] Seradelpal may be administered by any route suitable for the subject being treated and the nature of the subject's condition. Routes of administration include injection, including intravenous, intraperitoneal, intramuscular, and subcutaneous injection; transmucosal or transdermal delivery; topical application; nasal spray; suppository administration; and oral administration. The formulation may optionally be a liposomal formulation, emulsion, formulation designed for drug delivery through mucous membranes, or transdermal formulation. Formulations suitable for each of these administration methods can be found, for example, in "Remington: The Science and Practice of Pharmacy," 20th ed., Gennaro, ed., Lippincott Williams & Wilkins, Philadelphia, Pa., USA. When Seradelpal is administered systemically, since it is orally available, the typical formulation is oral, and the typical dosage form is an oral tablet or capsule. As described in the "Seradelpal" subsection, Seradelpal has been formulated in capsules for clinical trials. When Seradelpal is administered topically, typical formulations include topical solutions, suspensions, lotions, ointments, creams, gels, emulsions, foams, and sprays. Mayba et al., "A Guide to Topical Vehicle Formulations," J.Cutan.Med.Surg., 22(2), 207-212 (2018) provides guidance on the types of topical formulations and their advantages and disadvantages, while Chang et al., "Generic Development of Topical Dermatologic Products: Formulation Development, Process Development, and Testing of Topical Dermatologic Products," AAPS J., 15(1), 41-52 (2013) discusses issues related to formulation development, process development, and testing of such products.

[0031] Depending on the intended mode of administration, the pharmaceutical composition may be in the form of a solid, semi-solid, or liquid dosage form, preferably a unit dosage form suitable for a single dose of a precise amount if systemic administration is intended. In addition to an effective amount of ceradelpal, the composition may contain appropriate pharmaceutically acceptable excipients, including adjuvants that facilitate the processing of the active compound into a pharmaceutically usable formulation. "pharmaceutically acceptable excipients" means excipients or mixtures of excipients that do not interfere with the efficacy of the biological activity of the active compound(s) and are not toxic to the subject to be administered or otherwise undesirable.

[0032] In the case of solid compositions, conventional excipients include, for example, pharmaceutical-grade mannitol, lactose, starch, magnesium stearate, sodium saccharin, talc, cellulose, glucose, sucrose, and magnesium carbonate. Pharmacologically administerable liquid compositions can be prepared, for example, by dissolving or dispersing the active compounds described herein and any pharmaceutical adjuvants in water or an aqueous excipient (e.g., water, saline, aqueous dextrose) to form a solution or suspension. If desired, the administered pharmaceutical composition may also contain small amounts of non-toxic auxiliary excipients, such as wetting agents or emulsifiers, pH buffers, etc., such as sodium acetate, sorbitan monolaurate, sodium triethanolamine acetate, and triethanolamine oleate.

[0033] For oral administration, the composition generally takes the form of tablets or capsules; or, especially for pediatric use, it may be an aqueous or non-aqueous solution, suspension or syrup. Tablets and capsules are preferred forms of oral administration. Tablets and capsules for oral use generally contain one or more commonly used excipients (e.g., lactose and corn starch). Lubricants such as magnesium stearate are also typically added. When using a liquid suspension, the activator may be combined with emulsifying and suspension excipients. Flavoring agents, coloring agents and / or sweeteners may also be added, if desired. Other optional excipients for incorporation into oral formulations include preservatives, suspending agents, and thickeners.

[0034] An appropriate (i.e., therapeutically effective) dose of ceradelpal or its salt for oral administration is expected to be at least 0.5 mg / day, e.g., at least 1 mg / day, e.g., at least 2 mg / day, or at least 5 mg / day, when calculated as ceradelpal, but not exceeding 200 mg / day, e.g., not exceeding 100 mg / day, or not exceeding 50 mg / day; for example, for adult subjects with uremic pruritus, depending on factors such as the degree and severity of pruritus and liver and kidney function, it may be 5 mg / day, 10 mg / day, 25 mg / day, or 50 mg / day. In other words, an appropriate dose of ceradelpal for oral administration in adults to treat uremic pruritus is expected to be similar to, but possibly higher than, the dose used to treat cholestatic pruritus. These doses represent average daily doses and are not necessarily the amount given in a single dose. The medication may be administered more frequently than once a day (where the dose or daily dose is divided among the number of daily doses), but more typically it is once a day (where the dose is given as a single dose). Optionally, administration may be less frequent than once a day, such as once a week and every other day, for example, once a week, twice a week (especially with at least 3-day intervals), three times a week (especially with at least 2-day intervals), or every other day. Therefore, as an example, a subject may be administered 5 mg twice a week for a dose of 1.4 mg / day (daily dose). Due to the high oral bioavailability of Seradelpal, the intravenous dose is expected to be approximately the same as the oral dose. Similar to diferikephalin, it may be preferable to administer Seradelpal (especially when administered intravenously) after the completion of dialysis sessions in UP patients undergoing hemodialysis. However, since Seradelpal can be administered orally, it can be administered at a frequency independent of the frequency / timing of dialysis.

[0035] For topical administration, compositions typically include, in addition to Ceradelpal, polymers, thickeners, buffers, neutralizers, chelating agents, preservatives, surfactants or emulsifiers, antioxidants, waxes or oils, emollients, sunscreens, and solvents or mixed solvent systems, but may not include, fluid or semi-solid vehicles. The solvent or mixed solvent system is important in the formulation as it is primarily involved in dissolving Ceradelpal. An optimal solvent or mixed solvent system can also maintain clinically relevant levels of Ceradelpal in solution even if a poorly soluble solvent is added to the formulation. Topical compositions can be prepared in a wide variety of product types, such as lotions, creams, gels, sticks, sprays, ointments, pastes, foams, mousses, and cleansers. These product types may include several types of carrier systems, which may include particles, nanoparticles, and liposomes. If desired, disintegrants such as cross-linked polyvinylpyrrolidone, agar, or salts thereof such as alginic acid or sodium alginate may be added. The techniques for formulation and administration can be found in the aforementioned "Remington: The Science and Practice of Pharmacy."

[0036] Lotions are formulations applied to the skin without friction and are typically liquid or semi-liquid formulations. Lotions typically contain suspending agents for better dispersion, as well as compounds useful for localizing and retaining Ceradelpal in contact with the skin, such as methylcellulose and sodium carboxymethylcellulose. Creams containing Ceradelpal for topical administration are either oil-in-water (O / W) or water-in-oil (W / O) viscous liquids or semi-solid emulsions. The cream base is washable and contains an oil phase, an emulsifier, and an aqueous phase. The oil phase generally contains petrolatum or fatty alcohols, such as cetyl or stearyl alcohol. The aqueous phase is not essential but usually exceeds the volume of the oil phase and generally contains a humectant. Emulsifiers in cream formulations are generally nonionic, anionic, cationic, or amphoteric surfactants. Gel formulations can also be used. The gel is semi-solid, and a single-phase gel typically contains an activator (here, ceradelpal) substantially uniformly distributed throughout the carrier liquid, which is typically aqueous but may be a solvent or solvent blend. Ointments, which are semi-solid preparations, are typically based on petrolatum or other petroleum derivatives. The specific ointment base used provides optimal delivery of ceradelpal and, preferably, further provides other desired characteristics (e.g., emollient properties). Like other carriers or vehicles, the ointment base should be inert, stable, non-irritating, and non-sensitizing. As described in "Remington: The Science and Practice of Pharmacy," ointment bases can be classified into four classes: oily bases; emulsifiable bases; emulsion bases; and water-soluble bases. Examples of oily ointment bases include vegetable oils, fats derived from animals, and semi-solid hydrocarbons derived from petroleum. Emulsifiable ointment bases, also known as absorbable ointment bases, contain little to no water and include, for example, hydroxystearin sulfate, anhydrous lanolin, and hydrophilic petrolatum. Emulsion ointment bases are typically either W / O emulsions or O / W emulsions and include, for example, cetyl alcohol, glyceryl monostearate, lanolin, and stearic acid.Preferred water-soluble ointment bases are prepared from polyethylene glycol of various molecular weights. Useful formulations also include sprays. Sprays generally provide an activator in an aqueous and / or alcoholic solution that can be sprayed onto the skin in a mist for delivery. Such sprays include those formulated to provide a concentration of the activator solution at the administration site after delivery; for example, the spray solution may consist mainly of an alcohol or similar volatile liquid in which Ceradelpal can be dissolved. Upon delivery to the skin, the carrier evaporates, leaving concentrated Ceradelpal at the administration site. Topical pharmaceutical compositions may also include a suitable solid-phase or gel-phase carrier. Examples of such carriers include, but are not limited to, metal salts such as calcium carbonate and calcium phosphate, various sugars, starches, cellulose derivatives, gelatin, and polymers such as polyethylene glycol. Topical pharmaceutical compositions may also include a suitable emulsifier, i.e., an agent that enhances or promotes O / W or W / O emulsion mixing and suspension. The emulsifier may consist of a single emulsifier, or it may be a nonionic, anionic, cationic, or amphoteric surfactant, or a blend of two or more such surfactants. Useful emulsifiers include high molecular weight alcohols such as cetearyl alcohol, cetyl alcohol, and stearyl alcohol. Other examples include glyceryl monostearate, ethylene glycol distearate, sorbitan tristearate, propylene glycol monostearate, sorbitan monooleate, sorbitan monostearate, diethylene glycol monolaurate, sorbitan monopalmitate, sucrose dioleate, sucrose stearate, polyoxyethylene lauryl ether, polyoxyethylene(2) stearyl ether, polyoxyethylene(21) stearyl ether, polyoxyethylene monostearate, polyoxyethylene sorbitan monostearate, polyoxyethylene sorbitan monooleate, polyoxyethylene sorbitan monolaurate, and sodium oleate. Emulsified wax NF (National Medical Code of the United States) is a mixture of cetearyl alcohol and polysorbate (a polyoxyethylene derivative of sorbitan fatty acid ester).Cholesterol and cholesterol derivatives may also be used in topical emulsions and may enhance W / O emulsions. Particularly suitable nonionic emulsifiers have a hydrophilic-lipophilic balance (HLB) of about 3-6 for W / O emulsions and 8-18 for O / W emulsions. Topical pharmaceutical compositions may also include suitable emollients, which are substances used for the prevention or reduction of dryness and for the protection of the skin. Useful emollients include cetyl alcohol, isopropyl myristate, stearyl alcohol, and mixtures thereof, and a wide variety of suitable emollients are known to those skilled in the art and can be used here.

[0037] The topical pharmaceutical composition also includes suitable antioxidants, such as butylated hydroxytoluene, ascorbic acid, sodium ascorbate, calcium ascorbate, palmitate ascorbate, butylated hydroxyanisole, 2,4,5-trihydroxybutyrophenone, 4-hydroxymethyl-2,6-di-tert-butylphenol, erythorbic acid, guaiac gum, propyl gallate, thiodipropionic acid, dilauryl thiodipropionate, tert-butylhydroquinone, and tocopherols such as vitamin E, and includes pharmaceutically acceptable salts and esters of these compounds. The topical pharmaceutical composition may also include suitable preservatives such as benzyl alcohol, methylparaben, propylparaben, chlorobutanol, and mixtures thereof; and suitable chelating agents such as ethylenediaminetetraacetic acid (EDTA) and ethylene glycol-bis(beta-aminoethyl ether)-N,N,N',N'-tetraacetic acid (EGTA). The topical pharmaceutical composition may also contain a suitable neutralizing agent used to control the pH of the composition within a pharmaceutically acceptable range; and a thickening agent such as polyacrylic acid. The topical pharmaceutical composition may also contain a suitable penetration enhancer to enhance the penetration of ceradelpal through the skin, particularly the stratum corneum. Examples of penetration enhancers include water, fatty acids and fatty alcohols, alcohols and glycols, terpenes, sulfoxides, laurocaprum, pyrrolidone, and surfactants.

[0038] Typically, ceradelpal is present in topical formulations at concentrations of approximately 0.5% to 20%, e.g., 1% to 10%, e.g., 1%, 2%, 5%, or 10%. The appropriate (i.e., therapeutically effective) dose of ceradelpal or its salt for topical administration can be easily determined by observing changes in pruritus upon administration of the topical ceradelpal formulation.

[0039] Typically, a medicinal composition of Ceradelpal, or a kit containing a Ceradelpal composition, is packaged in a container with a label or instructions for use indicating the use of the medicinal composition or kit in the treatment of uremic pruritus, or both.

[0040] A person skilled in the art in the treatment of uremic pruritus is typically a physician skilled in the art of nephrology, or a physician skilled in the art of dermatology who is familiar with the problems of kidney disease, and without conducting excessive experiments, can determine the therapeutic effective dose of ceradelpar or ceradelpar salt for a particular patient and the degree of pruritus by relying on their personal knowledge, the art in the relevant field, and the disclosures of this application, and thereby achieve a therapeutic effective dose for the treatment of uremic pruritus.

[0041] Mabodelpal can be formulated in a similar manner to seradelpal, and, like seradelpal, a person skilled in the art of treating uremic pruritus can determine the therapeutic effective dose of mabodelpal or mabodelpal salt for a particular patient and degree of pruritus, and achieve a therapeutic effective dose for the treatment of uremic pruritus, without conducting excessive experiments, relying on personal knowledge, the art in the art, and the disclosures of this application. [Examples]

[0042] Examples

[0043] Example 1: Ceradelpal reduces IL-31 production by CD4 T cells under Th2-promoting conditions.

[0044] CD4 T cells were enriched from peripheral blood mononuclear cells collected from two normal healthy donors using the EasySep® Human CD4+ T Cell Isolation Kit (STEMCELL Technologies). 100,000 CD4 T cells were seeded into the wells of a U-bottom 96-well plate and cultured under Th2-promoting conditions stimulated by IL-4 or IL-33. From day 1 to day 4, cells were cultured in the presence of 200 μL of T cell culture medium (TCM), 2.5 μL of anti-CD3 / CD28 beads, 1 μg / mL of anti-IL-12 / IL-23 antibody, 50 ng / mL of human recombinant IL-4 or 50 ng / mL of human recombinant IL-33, and either 10 μM of Seradelpal or DMSO control in DMSO. On day 5 of culture, the anti-CD3 / CD28 beads were diluted by adding 150 μL of TCM. From day 5 to day 13, cells were cultured in the same reagents as on days 1 to 4 plus 50 ng / mL of IL-2; the cell culture medium was replaced every 2-3 days by changing 50% of the medium volume. On day 13 or 14, the proliferated T cells in individual wells were divided into 4-6 wells of a 96-well plate; and the T cells were reactivated by adding 5 ng / mL of phorbol myristate acetate and 500 ng / mL of ionomycin for 3 days. The IL-31 concentration in the culture medium of each well was determined using the V-PLEX Human IL-31 Kit (Meso Scale Diagnostics, LLC; Rockville, MD, USA).

[0045] The results are shown in the table below. Here, D represents the DMSO control, S represents the Seradelpal, SEM is the standard error of the mean, and the values ​​are IL-31 concentrations in pg / mL. [Table 1] Nonparametric two-sided Mann-Whitney U tests were used for both donors and both promoting factors, and the results showed that Serradelpal statistically significantly reduced IL-31 production by CD4 T cells under Th2-promoting conditions (p<0.0001).

[0046] Example 2: Seradelpal does not increase IL-31 production in PXB mice.

[0047] PXB mice (PhoenixBio Co., Ltd., Higashihiroshima, Japan) are chimeric mice with a humanized liver, created by transplanting human hepatocytes into albumin enhancer / promoter-urokinase-type plasminogen activator complementary DNA transgenic / SCID mice. These mice have a liver regrouped by human hepatocytes, evaluated by measuring the ratio of human albumin to mouse albumin in the blood, at a ratio exceeding 70%, typically 85-90%. The transplanted human hepatocytes express various human messenger RNAs (mRNAs) and proteins, similar to those found in a normal human liver. Such mouse livers consist of human hepatocytes and a small proportion of mouse hepatocytes and mouse sinusoidal cells (primarily Kupffer cells, endothelial cells, and stellate cells), and human hepatocytes have been shown to cooperate with mouse sinusoidal cells in performing liver functions.

[0048] This study was conducted at PhoenixBio. Approximately 25-week-old male PXB mice, housed in single animal cages and fed CRF1 mouse solid feed (both from Oriental Yeast Co., Ltd., Tokyo, Japan) supplemented with AS primate solid feed for vitamin C supplementation, were randomly divided into groups (10 mice / group) based on mean body weight and serum human albumin concentration. These mice were administered by forced oral administration once daily for 19 days at a dose of 10 mL / kg body weight, either vehicle (0.5% carboxymethylcellulose in sterile water), ceradelpal (10 mg / mL in vehicle), or obeticholic acid (FXR agonist, known to cause pruritus in PBC patients, 1 mg / mL in vehicle). Two hours after the last dose, each mouse was anesthetized with isoflurane, at least 400 μL of blood was collected by cardiac puncture, and the mice were sacrificed by hemorrhage. Blood samples were allowed to coagulate at room temperature for at least 5 minutes, then centrifuged at 13200 × g for 3 minutes at 4°C to obtain serum, which was analyzed for human IL-31. Compared to day 0 (0.13 pg / mL), both the vehicle group and the seradelpal group showed only slight increases in serum IL-31 concentration to 0.16 and 0.19 pg / mL, respectively, while obeticholic acid caused a dramatic increase to 3.7 pg / mL.

[0049] Example 3: Ceradelpal reduces IL-31 in PBC (ENHANCE, NCT03602560)

[0050] The study population in this Phase 3 study consisted of adult males or females diagnosed with PBC. Exclusion criteria included AST or ALT ≥ 3 × ULN, total bilirubin (TBIL) ≥ 2 × ULN, a history of autoimmune hepatitis or chronic viral hepatitis, PSC, current use of fibrates or simvastatin, use of colchicine, methotrexate, azathioprine, or systemic steroids in the past two months, use of experimental treatments for PBC, and use of experimental or unapproved immunosuppressants. Participants were randomized to receive either placebo, 5 mg / day, or 10 mg / day of seradelpal as L-lysine dihydrate, orally once daily in capsule form for 12 weeks, with 55, 53, and 53 participants in three groups, respectively. Serum IL-31 and its correlation with patient-reported pruritus rating scale (NRS, 0-10) were evaluated.

[0051] Baseline IL-31 levels were positively correlated with pruritus NRS (r=0.54, P<0.0001). Subjects with NRS ≥ 4 had significantly higher baseline median [interquartile range] IL-31 compared to subjects with pruritus NRS < 4 (7.6 pg / mL [1.2, 14.5] vs. 1.2 pg / mL [0.3, 2.8], p<0.0001). At baseline, IL-31 also correlated with serum total bile acids (r=0.54, p<0.0001) and alkaline phosphatase (ALP) (r=0.44, p<0.0001). Theradelpal treatment significantly reduced mean IL-31 levels during the study: placebo (4.3–3.9 pg / mL, not significant), theradelpal 5 mg / day (3.8–1.7 pg / mL, p<0.001), and theradelpal 10 mg / day (4.2–1.7 pg / mL, p<0.001). Subjects with clinically meaningful improvement in pruritus NRS (≥2 reduction) showed a greater dose-dependent reduction in IL-31 from baseline compared to subjects without pruritus improvement. Significant correlations were also observed between changes in IL-31 and pruritus NRS (r=0.54, p<0.0001), ALP (r=0.40, p<0.01), and total bile acids (r=0.63, p<0.0001) in the theradelpal 10 mg / day group.

[0052] Example 4: Seradelpal reduces pruritus in uremic pruritus with oral treatment.

[0053] Adult subjects with end-stage renal disease receiving routine hemodialysis will be treated orally with Ceradelpal at doses of 5 mg / day, 10 mg / day, 25 mg / day, and 50 mg / day. Subjects will be permitted to take other usual medications. Subjects will be evaluated for safety and pharmacodynamic evaluations before and during the study, for example, every four weeks during the study and four weeks after the last dose of Ceradelpal therapy. At each visit, subjects will be evaluated for their disease symptoms and biomarkers, and for uremic pruritus. Subjects will also keep a health diary, which will be reviewed at each visit. Subjects will demonstrate improvement in uremic pruritus.

[0054] Example 5: Seradelpal reduces uremic pruritus with topical treatment.

[0055] Adult subjects with end-stage renal disease receiving routine hemodialysis will be treated topically with an ointment containing 1%, 2%, 5%, or 10% Ceradelpal. Subjects will be permitted to take other usual medications. Subjects will be evaluated for safety and pharmacodynamic evaluations before and during the study, for example, every four weeks during the study and four weeks after the last dose of Ceradelpal therapy. At each visit, subjects will be evaluated for their disease symptoms and biomarkers, and for pruritus. Subjects will also keep a health diary, which will be reviewed at each visit. Subjects will demonstrate improvement in uremic pruritus.

[0056] Example 6: Mabodelpal reduces uremic pruritus with oral treatment.

[0057] Adult subjects with end-stage renal disease receiving routine hemodialysis will be treated orally with mavodelpal at doses of 5 mg / day, 10 mg / day, 25 mg / day, 50 mg / day, and 100 mg / day. Subjects will be permitted to take other medications as usual. Subjects will be evaluated for safety and pharmacodynamic evaluations before and during the study, for example, every four weeks during the study and four weeks after the last dose of mavodelpal therapy. At each visit, subjects will be evaluated for their disease symptoms and biomarkers, and for uremic pruritus. Subjects will also keep a health diary, which will be reviewed at each visit. Subjects will demonstrate improvement in uremic pruritus.

[0058] Example 7: Mabodelpal reduces uremic pruritus with topical treatment.

[0059] Adult subjects with end-stage renal disease undergoing routine hemodialysis will be treated topically with an ointment containing 1%, 2%, 5%, or 10% mavodelpal. Subjects will be permitted to continue their usual other medications. Subjects will be evaluated for safety and pharmacodynamic assessments before and during the study, for example, every four weeks during the study and four weeks after the last dose of mavodelpal therapy. At each visit, subjects will be evaluated for their disease symptoms and biomarkers, and for pruritus. Subjects will also keep a health diary, which will be reviewed at each visit. Subjects will demonstrate improvement in uremic pruritus.

Claims

1. Compounds selected from ceradelpar and its salts for use in the treatment of uremic pruritus.

2. The compound for use according to claim 1, wherein the compound is ceradelpar L-lysine salt.

3. The compound for use according to claim 2, wherein the compound is ceradelpal L-lysine dihydrate salt.

4. The compound for use according to any one of claims 1 to 3, wherein the compound is administered orally.

5. The compound for use according to any one of claims 1 to 4, wherein the amount of the compound corresponds to 0.5 mg / day to 200 mg / day of Seradelpal.

6. The compound for use according to claim 5, wherein the amount of the compound corresponds to at least 1 mg / day, for example, at least 2 mg / day, for example, at least 5 mg / day of Seradelpal.

7. The compound for use according to claim 5 or 6, wherein the amount of the compound corresponds to 100 mg / day or less, for example, 50 mg / day or less of Ceradelpal.

8. The compound for use according to claim 7, wherein the amount of the compound corresponds to 5 mg / day, 10 mg / day, 25 mg / day, or 50 mg / day of Seradelpal.

9. The compound for use according to any one of claims 1 to 3, wherein the compound is administered locally.

10. The compound for use according to any one of claims 1 to 9, wherein the compound is administered once daily.

11. The compound for use according to any one of claims 1 to 9, wherein the compound is administered more frequently than once a day, such as twice a day, three times a day, or four times a day.

12. The compound for use according to any one of claims 1 to 9, wherein the compound is administered once a week to every other day, for example, once a week, twice a week, three times a week, or every other day.

13. A compound selected from mabodelpal and its salts for use in the treatment of uremic pruritus.

14. The compound for use according to claim 13, wherein the compound is mabodelpar sodium salt.

15. The compound for use according to claim 13 or 14, wherein the compound is administered orally.

16. The compound for use according to claim 13 or 14, wherein the compound is administered topically.

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