Treatment of chronic pruritic skin diseases

Abstract

Treatment of chronic pruritic dermatopathy by administration of seradelpal or a salt thereof, or administration of mabodelpal or a salt thereof. The present invention relates to treatment of chronic pruritic dermatopathy by administration of seradelpal or a salt thereof. In various aspects, the present invention includes seradelpal or a salt thereof for use in treating chronic pruritic dermatopathy; use of seradelpal or a salt thereof for treating, or in the manufacture of a medicament for treating, chronic pruritic dermatopathy; and pharmaceutical compositions or medicaments comprising seradelpal or a salt thereof for treating chronic pruritic dermatopathy.

Description

[Technical Field]

[0001] The present invention relates to the treatment of chronic pruritic skin diseases. [Background technology]

[0002] Itching

[0003] Pruritus (itch) is a widespread, frequent, and often distressing symptom (i.e., a self-reported subjective experience) of several conditions, including infections, environmental / allergic exposures, skin disorders, drug reactions, and systemic medical disorders. Although pruritus can be mild and tolerable, it can significantly reduce quality of life, causing severe sleep deprivation and depressed mood, and even inducing suicidal thoughts in the most affected patients.

[0004] Pruritus can be numerically assessed in several ways. Two unidimensional numerical assessment methods are the visual analog scale (VAS), which presents the patient with a line whose left endpoint is labeled "no itch" and whose right endpoint is labeled "worst itch," and the numeric rating scale (NRS), which presents the patient with a ruler-like line, typically labeled 0 to 10 or 0 to 100. In both methods, the patient is asked to mark the location on the line that corresponds to their current level of itch. The term VAS is sometimes used to describe scales in which, in addition to labeled endpoints, the line is marked like a ruler. The 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)). A 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 (degree of intensity), direction (increase or decrease), disability (impact of itch on life), and distribution (body location), and assigns a numerical score to each dimension. In clinical trials, pruritus can be recorded on paper or in an electronic device (electronic diary or similar device).

[0005] Cholestatic disorders associated with pruritus (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), examined IL-31 in a group of treatment-naive patients with PBC and compared them with patients with chronic hepatitis B and healthy volunteers. They found increased serum IL-31 levels in PBC patients (median 20.6 pg / mL) compared with hepatitis B patients (median 11.3 pg / mL) and healthy volunteers (median 11.0 pg / mL). They concluded that "serum IL-31 is elevated in PBC, especially 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 "although the important role of IL-31 in pruritus in skin diseases is well known, we 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 are farnesoid X receptor responsive in NASH," Hepatol. (2022), https: / / doi.org / 10.1002 / hep.32599, tested the farnesoid X receptor (FXR) agonist cilofexor and reported, contradicting Mu et al., that "baseline IL-31 levels in PSC and PBC were positively correlated with the visual analog scale for pruritus and the 5-D itch score." They also reported that cilofexor treatment in NASH increased IL-31 and that IL-31 levels were 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 in human hepatocytes and serum levels of human IL-31." From the prescribing information for obeticholic acid (OCALIVA by Intercept Pharmaceuticals), 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% of patients in the OCALIVA titration group, and 7% of patients in the placebo group.

[0006] Chronic pruritic skin disease and IL-31

[0007] Roh et al., "IL-31 Inhibition as a Therapeutic Approach for the Management of Chronic Pruritic Dermatoses," Drugs, 81, 895-905 (2021), reviewed the literature on the pathogenesis of chronic pruritic dermatoses, the role of IL-31 in itch signaling, and the use of IL-31 antagonism as a therapeutic approach for pruritus. They cited chronic pruritic dermatoses as conditions such as atopic dermatitis; prurigo nodularis; pruritic autoimmune diseases such as bullous pemphigoid and dermatitis herpetiformis, systemic lupus erythematosus, and dermatomyositis; and stasis dermatitis, scabies, mastocytosis, and cutaneous T-cell lymphoma, among other skin diseases. They noted that up to two-thirds of patients experience pruritus, and that the severity of pruritus correlates with serum IL-31 levels. Lotti et al., "Prurigo nodularis and lichen simplex chronicus," Dermatol. Ther., 21(1), 42-46 (2008), describe lichen simplex chronicus as "a skin disorder characterized by lichenification of the skin as a result of primary excessive scratching." Kabashima and Irie, "Interleukin-31 as a Clinical Target for Pruritus Treatment," Front. Med., 8:638325 (2021), list pruritic diseases correlated with IL-31, including atopic dermatitis, prurigo nodularis, psoriasis, cutaneous T-cell lymphoma, bullous pemphigoid, chronic urticaria, dermatitis herpetiformis, allergic contact dermatitis, dermatomyositis, chronic pruritus of unknown cause, and "other dermatological conditions" such as lichen planus, cutaneous amyloidosis, stasis dermatitis, scleroderma, and itching associated with wound healing, but state that there is no detailed data on these conditions.

[0008] Atopic dermatitis (AD, also known as eczema and atopic eczema) is a long-term form of skin inflammation (dermatitis). This dermatitis results in itchy, red, swollen, and cracked skin. The condition can occur at any age but typically begins in childhood and varies in severity over several years. In children under one year of age, many parts of the body can be affected. However, as children grow, the knees and inner elbows are most commonly affected. In adults, the hands and feet are most commonly affected. Scratching the affected area worsens the condition and increases the risk of skin infection in the affected area. Many people with atopic dermatitis develop hay fever or asthma. The cause of AD is unknown, but genetics, immune system dysfunction, environmental exposures, and abnormalities in skin permeability are thought to play a role. If one identical twin is affected, there is an 85% chance that the other twin will also have the condition.

[0009] Excessive type 2 inflammation underlies the pathophysiology of atopic dermatitis. Disruption of the epidermal barrier is believed to play an essential role in the pathogenesis of AD, allowing allergens to penetrate the epidermis and reach deeper layers of the skin, ultimately leading to a dysregulated Th2 inflammatory response, which is thought to result in eczematous lesions. Th2 helper T cells are activated, resulting in the release of proinflammatory cytokines, including IL-4, IL-13, and IL-31, which activate the downstream Janus kinase (JAK) pathway and lead to inflammation. AD is also associated with the release of prurigenic substances in the skin, including the Th2 cytokines IL-4, IL-13, IL-31, histamine, and various neuropeptides. Mechanical stimulation from scratching lesions can also result in the release of prurigenic substances that contribute to the itch-scratch cycle, resulting in pruritus or increased itching after scratching the lesion. Chronic scratching of lesions can lead to thickening of the skin or lichen or prurigo nodularis (generalized nodules accompanied by severe itching). Lichen simplex chronicus (LSC) is thick, leathery skin with enhanced skin markings caused by episodic itching and excessive rubbing and scratching. LSC typically results in small bumps, patches, scratches, and scales. People with LSC report itching followed by uncontrollable, excessive scratching of the same body area. The most common sites of LSC are the sides of the neck, scalp, ankles, vulva, pubic area, scrotum, and extensor sides of the forearms. LSC is also associated with atopy, or atopic dermatitis (eczema), and increased histamine levels.For example, for a well-known discussion of AD, see the Wikipedia article "Atopic Dermatitis," https: / / en.wikipedia.org / wiki / Atopic_dermatitis and the references cited therein, and the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS) Health Topics article "Atopic Dermatitis," https: / / www.niams.nih.gov / health-topics / atopic-dermatitis; for a technical discussion of AD, see Staender, "Atopic Dermatitis," N. Engl. J. Med., 384(12), 1136-1143 (2021); for a well-known discussion of these conditions, see the Wikipedia articles "Prurigo nodularis," https: / / en.wikipedia.org / wiki / Prurigo_nodularis, and "Lichen simplex chronicus," https: / / en.wikipedia.org / wiki / Lichen_simplex_chronicus. Rinaldi, "The Itch-Scratch Cycle: A Review of the Mechanisms," Dermatol. Pract. Concept., 9(2), 90-97 (2019) reviews the causes of itch, the scratch response to itch, and some treatments for pruritic conditions.

[0010] Kunimura et al., "The molecular basis for IL-31 production and IL-31-mediated itch transmission: from biology to drug development," Int'l Immunol., 33(12), 731-736 (2021), states, "Atopic dermatitis (AD) is one of the most prevalent chronic inflammatory skin diseases worldwide. It is characterized by recurrent eczematous lesions and intense itching, and many cytokines are involved in the pathogenesis of AD." They report that interleukin-31 (IL-31) is associated with AD, and that serum levels of IL-31 correlate with disease severity in AD patients. They also report that mice treated with intradermal injection of IL-31 and transgenic mice overexpressing IL-31 exhibit excoriation (scratching) behavior and develop severe dermatitis. Kabashima and Irie reported that "in clinical studies, serum IL-31 levels were found to be elevated in patients with atopic dermatitis compared with healthy individuals and to decrease after cyclosporine treatment. Furthermore, IL-31 levels were shown to correlate with disease severity and pruritic symptoms." Kabashima et al., "Trial of Nemolizumab and Topical Agents for Atopic Dermatitis with Pruritus", New Engl.J.Med.,383(2),141-150(2020) reported a phase 3 trial of nemolizumab, a monoclonal antibody that blocks IL-31 receptor A, in AD, and Staender et al., "Trial of Nemolizumab in Moderate-to-Severe Prurigo Nodularis", New Engl.J.Med.,382(8),706-716(2020) reported a trial of nemolizumab in prurigo nodularis.

[0011] Treatment of chronic pruritic skin diseases

[0012] Topical corticosteroids, such as hydrocortisone, have proven effective in managing many cases of AD. Topical calcineurin inhibitors, such as tacrolimus, are also used when topical corticosteroids and moisturizers are ineffective. In 2016, the PDE-4 inhibitor crisaborole (EUCRISA) was approved for the topical treatment of mild to moderate eczema. Other medications used for AD include systemic immunosuppressants such as cyclosporine, methotrexate, interferon gamma-1b, mycophenolate mofetil, and azathioprine. Antidepressants and naltrexone can be used to control pruritus. In 2017, dupilumab (DUPIXENT), an IL-4Rα antagonist monoclonal antibody, was approved to treat moderate to severe eczema, and tralokinumab (ADBRY), an IL-13 antagonist monoclonal antibody, was approved for severe cases in 2021. Another IL-13 antagonist monoclonal antibody, lebrikizumab, is in phase 3 trials. Two orally administered JAK inhibitors, abrocitinib (CIBINQUO) and upadacitinib (RINVOQ), are approved in the United States for the treatment of moderate to severe eczema. Another JAK inhibitor, ruxolitinib (OPZELURA), is approved as a topical treatment for the short-term and discontinuous chronic treatment of mild to moderate eczema (atopic dermatitis) in non-immunocompromised adults and children aged 12 years and older whose disease is not adequately controlled with topical prescription therapies or for whom such therapies are not recommended. And, as mentioned above, the IL-31RA antagonist nemolizumab is under investigation in AD and prurigo nodularis. However, all interleukin antagonist antibodies and JAK inhibitors carry a significant risk of side effects, primarily opportunistic infections.

[0013] Seladelpar Serradelpal (International Nonproprietary 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. Serradelpal, as well as its synthesis, formulation, and uses, are disclosed, for example, in U.S. Pat. No. 7,301,050 (Compound 15 in Table 1, Example M, claim 49), U.S. Pat. No. 7,635,718 (Compound 15 in Table 1, Example M), and U.S. Pat. No. 8,106,095 (Compound 15 in Table 1, Example M, claim 14). The lysine (L-lysine) salt of serradelpal and related compounds are disclosed in U.S. Pat. No. 7,709,682 (Serradelpal l-lysine salt throughout the examples, claimed crystalline forms).

[0014] Serradelpal is an orally active, potent (2 nM) agonist of peroxisome proliferator-activated receptor delta (PPARδ). Serradelpal is specific (>600-fold and >2500-fold more potent than peroxisome proliferator-activated receptor alpha and peroxisome proliferator-activated receptor gamma). PPARδ activation stimulates fatty acid oxidation and utilization, improves plasma lipid and lipoprotein metabolism, glucose utilization, and mitochondrial respiration, and preserves stem cell homeostasis. According to U.S. Patent No. 7,301,050, PPARδ agonists, such as seradelpal, are suggested for treating PPARδ-mediated conditions, including "diabetes, cardiovascular disease, metabolic syndrome X, 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. Serradelpar as the l-lysine dihydrate salt has been studied in mixed dyslipidemia at oral doses equivalent to 50 mg / day and 100 mg / day of seradelpar, which are equivalent to doses of 10 mg / day, 20 mg / day, and 50 mg / day of seradelpar in nonalcoholic steatohepatitis; and doses of 2 mg / day, 5 mg / day, 10 mg / day, 50 mg / day, and 200 mg / day of seradelpar in PBC.

[0015] US Patent Application Publication No. 2019 / 0105291 and PCT Publication No. WO 2019 / 067373 disclose the treatment of cholestatic pruritus with seladelpar and its salts.

[0016] Mavodelpar Mabodelpal (INN) has the chemical name (4-{[(2E)-3-(4-fluorophenyl)-3-{4-[3-(morpholin-4-yl)prop-1-yn-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. Pat. No. 7,943,613 (Example 10, claims 1-5); 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. Pat. No. 11,267,795. According to the Alzheimer's Drug Discovery Foundation's Cognitive Vitality Report on PPARδ agonists from November 2021, Mabodelpal has an EC of 31 nM for PPARδ. 50 On the other hand, EC 50 The agonist activity exceeds 10 μM. In 2017, mabodelpal was described as a functionally selective PPARδ agonist, demonstrating a significant increase in high-density lipoprotein cholesterol and a reduction in low-density lipoprotein cholesterol and triglycerides in animal models and humans. It has also been reported that mabodelpal demonstrated antidiabetic effects in several animal models of type 2 diabetes, and early clinical studies indicated that mabodelpal was well tolerated. Mabodelpal has been granted orphan drug designation by the FDA for primary mitochondrial myopathy. Most recently, mabodelpal was studied in the STRIDE study (NCT04535609), a global, randomized, double-blind, placebo-controlled pivotal Phase 2b trial in adult patients with primary mitochondrial myopathy due to mitochondrial DNA defects. [Prior art documents] [Patent documents]

[0017] [Patent Document 1] U.S. Patent No. 7,301,050 [Patent Document 2] U.S. Patent No. 7,635,718 [Patent Document 3] U.S. Patent No. 8,106,095 [Patent Document 4] U.S. Patent No. 7,709,682 [Patent Document 5] US Patent Application Publication No. 2019 / 0105291 [Patent Document 6] International Publication No. 2019 / 067373 [Patent Document 7] U.S. Patent No. 7,943,613 [Patent Document 8] US Patent Application Publication No. 2023 / 0416210 [Patent Document 9] U.S. Patent No. 1,126,7795 [Non-patent literature]

[0018] [Non-Patent Document 1] Staender et al., "Priritus 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-patent 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)Mu et al.,「Implication of Increased Serum IL-31 for Primary Biliary Cholangitis」,Immunol.Invest.,50(6),662-670(2021)

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[0019] The present invention relates to the treatment of chronic pruritic skin diseases by administering seladelpal or a salt thereof.

[0020] In various aspects, the present invention provides Serradelpal or a salt thereof for use in the treatment of chronic pruritic skin diseases; Use of seladelpal or a salt thereof for treating or in the manufacture of a medicament for treating a chronic pruritic skin disease; and Pharmaceutical composition or drug containing seladelpal or its salt for treating chronic pruritic skin diseases Includes.

[0021] When administered orally for the treatment of primary biliary cholangitis (PBC), seradelpal has been demonstrated to be effective in treating PBC at oral doses of 5 mg / day, 10 mg / day, 50 mg / day, and 200 mg / day and has been found not to exacerbate cholestatic pruritus. Doses of 0.5 mg / day to 25 mg / day are expected to be effective. Studies in PBC at oral doses of 5 mg / day and 10 mg / day have demonstrated seradelpal's efficacy in treating cholestatic pruritus associated with PBC; seradelpal has also been shown to reduce IL-31. Due to this reduction in IL-31, seradelpal is also expected to be useful in treating chronic pruritic skin diseases.

[0022] The present invention also relates to the treatment of chronic pruritic dermatoses by administering mabodelpal or a salt thereof. In various aspects, the present invention also includes mabodelpal or a salt thereof for use in treating chronic pruritic dermatoses; the use of mabodelpal or a salt thereof for treating or in the manufacture of a medicament for treating chronic pruritic dermatoses; and pharmaceutical compositions or medicaments containing mabodelpal or a salt thereof for treating chronic pruritic dermatoses. Because mabodelpal is a selective PPARδ agonist, it is expected to reduce IL-31 and therefore be useful in the treatment of chronic pruritic dermatoses.

[0023] Preferred embodiments of the present invention are characterized by the features of the description and claims 1 to 17 of the present application as filed. DETAILED DESCRIPTION OF THE INVENTION

[0024] definition

[0025] Chronic pruritic dermatopathy is described in the Background Art in the subsections entitled "Chronic Pruritic Dermatopathy and IL-31" and "Treatment of Chronic Pruritic Dermatopathy." Unless the context requires otherwise, references to chronic pruritic dermatosis and to "chronic pruritic dermatoses" are references to any of the conditions described in the subsection "Chronic Pruritic Dermatoses and IL-31" and thus include references to, for example, atopic dermatitis, prurigo nodularis, lichen simplex chronicus, psoriasis, bullous pemphigoid, dermatitis herpetiformis, systemic lupus erythematosus, dermatomyositis, stasis dermatitis, scabies, mastocytosis, cutaneous T-cell lymphoma, chronic urticaria, allergic contact dermatitis, dermatomyositis, chronic pruritus of unknown cause, lichen planus, cutaneous (lichen) amyloidosis, scleroderma, or itch associated with wound healing.

[0026] "Treating" or "treatment" of chronic pruritic skin diseases in humans means: (1) preventing or reducing the risk of developing pruritus, i.e., preventing the development of pruritus associated with chronic pruritic skin diseases in subjects who may be predisposed to conditions in which pruritus is a symptom, but who have not yet experienced or exhibited pruritus (i.e., prevention); (2) inhibiting pruritus, i.e., preventing or reducing the onset of pruritus; and (3) Relieving pruritus, i.e., reducing the number, frequency, duration, or severity of itching Contains one or more of the following: When a chronic pruritic skin disease is caused by an external factor, such as the presence of scabies lice in scabies or lymphoma in cutaneous T-cell lymphoma, it is understood that treatment with seradelpal is a treatment for the pruritus and not a treatment for the external factor.

[0027] A "therapeutically effective amount" of seladelpal or a salt thereof means an amount that, when administered to a human being for treating a chronic pruritic skin disease, is sufficient to cause treatment of pruritus. The therapeutically effective amount for a particular subject will vary depending on the age, health and physical condition of the subject being treated, the pruritus and its severity, the route of administration of seladelpal or a salt thereof, an evaluation of the medical condition, and other relevant factors. It is expected that the therapeutically effective amount will fall in a relatively broad range that can be determined through routine testing.

[0028] Serradelpal is described in the Background Art subsection entitled "Serradelpal."

[0029] Salts (e.g., pharmaceutically acceptable salts) of serradelpal are included in the present invention and are useful in the methods described herein. These salts are preferably formed with pharmaceutically acceptable acids. For an extensive discussion of pharmaceutical salts, their selection, preparation, and use, see, for example, "Handbook of Pharmaceutically Acceptable Salts," Stahl and Wermuth, eds., Verlag Helvetica Chimica Acta, Zuerich, Switzerland. Unless the context requires otherwise, references to serradelpal and to "a compound which is serradelpal or a salt thereof" refer to both serradelpal itself and its salts. An amount of serradelpal salt that is "equivalent" to a specified amount of serradelpal refers to the amount of salt multiplied by the ratio of the formula weight of the salt to the formula weight of serradelpal. For example, when seradelpal L-lysine dihydrate salt is used, the formula weight of seradelpal L-lysine dihydrate salt is about 1.41 times the formula weight of seradelpal, so that an amount of seradelpal L-lysine dihydrate salt of about 14.1 mg / day is equivalent to an amount of seradelpal of 10 mg / day.

[0030] Because Serradelpal contains a carboxyl group, it can form salts when the acidic protons present react with inorganic or organic bases. Typically, Serradelpal is treated with an excess of an alkaline reagent, such as a hydroxide, carbonate, or alkoxide containing the appropriate cation. + , K. + , Ca 2+ , Mg 2+ , and NH4 + are examples of cations present in pharmaceutically acceptable salts. Suitable inorganic bases include calcium hydroxide, potassium hydroxide, sodium carbonate, and sodium hydroxide. Salts can also be prepared using organic bases, such as salts of primary, secondary, and tertiary amines, substituted amines, including naturally occurring substituted amines, and cyclic amines, including isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, 2-dimethylaminoethanol, tromethamine, lysine, arginine, histidine, caffeine, procaine, hydrabamine, choline, betaine, ethylenediamine, glucosamine, N-alkylglucamines, theobromine, purines, piperazine, piperidine, N-ethylpiperidine, and the like. As described in the "Seladelpal" subsection, Seradelpal is currently formulated for oral administration as its L-lysine dihydrate salt.

[0031] Mabodelpal is described in the Background Art in the subsection entitled "Mabodelpal." Unless the context requires otherwise, references to mabodelpal and to "a compound which is mabodelpal or a salt thereof" are references to both mabodelpal itself and salts thereof. A "therapeutically effective amount" of mabodelpal or a salt thereof has the same meaning as in relation to seradelpal.

[0032] "Comprising" or "containing" and grammatical variations thereof are words of inclusion, not limitation, and are meant to specify the presence of the stated components, groups, steps, etc., but not to exclude the presence or addition of other components, groups, steps, etc. Thus, "comprising" does not mean "consisting of," "consisting essentially of," or "consisting only of." For example, a formulation "comprising" a compound must contain the compound, but may also contain other active ingredients and / or excipients.

[0033] Formulation and Administration

[0034] Seradelpal can be administered by any route appropriate 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; and oral administration. Formulations may optionally be liposomal formulations, emulsions, formulations designed to deliver drugs through mucous membranes, or transdermal formulations. Suitable formulations 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 administered systemically, seradelpal is orally available, so the typical formulation is oral, and the typical dosage form is a tablet or capsule for oral administration. As noted in the "Seradelpal" subsection, seradelpal has been formulated into capsules for clinical trials. When seradelpal is administered topically, typical formulations are 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.

[0035] 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 single administration of a precise dose when systemic administration is intended. In addition to an effective amount of seladelpal, the composition may contain suitable pharmaceutically acceptable excipients, including adjuvants that facilitate processing of the active compound into a pharmaceutically usable formulation. A "pharmaceutically acceptable excipient" refers to an excipient or mixture of excipients that does not interfere with the effectiveness of the biological activity of the active compound(s) and is not toxic or otherwise undesirable to the subject to which it is administered.

[0036] For solid compositions, conventional excipients include, for example, pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, sodium saccharin, talc, cellulose, glucose, sucrose, magnesium carbonate, and the like. Pharmacologically administrable liquid compositions can be prepared, for example, by dissolving, dispersing, etc., an active compound described herein and any pharmaceutical adjuvants in water or an aqueous vehicle (e.g., water, saline, aqueous dextrose, etc.) to form a solution or suspension. If desired, the pharmaceutical composition to be administered may contain minor amounts of nontoxic auxiliary excipients, such as wetting or emulsifying agents, pH buffering agents, and the like, for example, sodium acetate, sorbitan monolaurate, triethanolamine sodium acetate, triethanolamine oleate, and the like.

[0037] For oral administration, the composition generally takes the form of a tablet or capsule; or, especially for pediatric use, may be an aqueous or non-aqueous solution, suspension or syrup. Tablets and capsules are preferred oral dosage forms. 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 liquid suspensions, the active agent can be combined with emulsifying and suspending excipients. If desired, flavoring agents, coloring agents and / or sweetening agents may also be added. Other optional excipients for incorporation into oral preparations include preservatives, suspending agents, thickening agents, etc.

[0038] A suitable (i.e., therapeutically effective) amount of seladelpal or a salt thereof for oral administration, calculated as seladelpal, 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, but not more than 200 mg / day, e.g., not more than 100 mg / day, or not more than 50 mg / day; for example, for an adult subject with chronic pruritic dermatosis, it is expected to be 5 mg / day, 10 mg / day, 25 mg / day, or 50 mg / day, depending on factors such as the degree and severity of the pruritus and liver and kidney function. That is, a suitable amount of seladelpal for oral administration to an adult to treat chronic pruritic dermatosis is expected to be similar to, but possibly higher than, the amount used to treat cholestatic pruritus. These amounts represent average daily doses and are not necessarily amounts given in a single administration. Dosing can be more frequent than once per day (where the amount or daily dose is divided among the number of daily administrations), but is more typically once per day (where the amount is given in a single administration). Optionally, administration can be less frequent than once per day, such as between once per week and every other day, for example, once per week, twice per week (particularly with administrations at least 3 days apart), three times per week (particularly with administrations at least 2 days apart), or every other day. Thus, as an example, a subject may be administered 5 mg twice per week for an amount (daily dose) of 1.4 mg / day. Due to the high oral bioavailability of seladelpal, the amount administered intravenously is expected to be approximately the same as that administered orally.

[0039] For topical administration, compositions typically contain a fluid or semisolid vehicle, which may include, in addition to seradelpal, polymers, thickeners, buffers, neutralizing agents, chelating agents, preservatives, surfactants or emulsifiers, antioxidants, waxes or oils, emollients, sunscreens, and a solvent or mixed solvent system, but are not limited to these. The solvent or mixed solvent system is important for formulation because it is primarily responsible for dissolving seradelpal. An optimal solvent or mixed solvent system can also maintain clinically relevant levels of seradelpal in solution, even when poor solvents are added to the formulation. Topical compositions can be formulated into a wide variety of product types, including lotions, creams, gels, sticks, sprays, ointments, pastes, foams, mousses, and cleansers. These product types may include several types of carrier systems, including particles, nanoparticles, and liposomes. If desired, disintegrating agents such as cross-linked polyvinylpyrrolidone, agar, or alginic acid or a salt thereof, such as sodium alginate, are added. Techniques for formulation and administration may be found in Remington: The Science and Practice of Pharmacy, supra.

[0040] Lotions are formulations applied to the skin without friction and are typically liquid or semi-liquid. Lotions typically contain suspending agents to improve dispersion and compounds useful for localizing and maintaining Seradelpal in contact with the skin, such as methylcellulose, sodium carboxymethylcellulose, etc. Creams containing Seradelpal for topical administration are viscous liquid or semi-solid emulsions, either oil-in-water (O / W) or water-in-oil (W / O). Cream bases are water-washable and contain an oil phase, an emulsifier, and an aqueous phase. The oil phase generally contains petrolatum or a fatty alcohol, such as cetyl or stearyl alcohol. The aqueous phase usually exceeds the oil phase in volume, although this is not required, and generally contains a moisturizer. Emulsifiers in cream formulations are generally nonionic, anionic, cationic, or amphoteric surfactants. Gel formulations can also be used. Gels are semisolids, and single-phase gels typically contain an active agent (here, Seradelpal) substantially uniformly distributed throughout a carrier liquid, which is typically aqueous but may also be a solvent or solvent blend. Ointments, which are semisolid preparations, are typically based on petrolatum or other petroleum derivatives. The particular ointment base used provides optimal delivery of Seradelpal and preferably also provides other desired characteristics (e.g., emollient properties). Like other carriers or vehicles, ointment bases should be inert, stable, nonirritating, and nonsensitizing. As explained in "Remington: The Science and Practice of Pharmacy," ointment bases can be divided into four classes: oleaginous bases; emulsifiable bases; emulsion bases; and water-soluble bases. Oleaginous ointment bases include, for example, vegetable oils, fats obtained from animals, and semisolid hydrocarbons obtained from petroleum. Emulsifiable ointment bases, also known as absorbent ointment bases, contain little or 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 glycols of various molecular weights. Useful formulations also include sprays. Sprays generally provide the active agent in an aqueous and / or alcoholic solution that can be misted onto the skin for delivery. Such sprays include those formulated to provide a concentration of the active agent in solution at the administration site after delivery. For example, the spray solution may be composed primarily of alcohol or a similar volatile liquid in which Seradelpal can be dissolved. Upon delivery to the skin, the carrier evaporates, leaving concentrated Seradelpal at the administration site. Topical pharmaceutical compositions may also contain 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 contain 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 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. Emulsifying Wax NF (US National Formulary) is a mixture of cetearyl alcohol and polysorbate (a polyoxyethylene derivative of sorbitan fatty acid esters).Cholesterol and cholesterol derivatives can also be used in topical emulsions and can promote W / O emulsions. Particularly suitable nonionic emulsifiers are those having a hydrophilic-lipophilic balance (HLB) of about 3-6 for W / O emulsions and 8-18 for O / W emulsions. Topical pharmaceutical compositions can also contain a suitable emollient, which is a substance used to prevent or relieve dryness and protect the skin. Useful emollients include cetyl alcohol, isopropyl myristate, stearyl alcohol, etc., and mixtures of these substances. A wide variety of suitable emollients are known to those skilled in the art and can be used herein.

[0041] Topical pharmaceutical compositions also include suitable antioxidants, such as butylated hydroxytoluene, ascorbic acid, sodium ascorbate, calcium ascorbate, ascorbyl palmitate, 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, including pharmaceutically acceptable salts and esters of these compounds. Topical pharmaceutical compositions may also include suitable preservatives, such as benzyl alcohol, methylparaben, propylparaben, chlorobutanol, and the like, and mixtures of these substances; and suitable chelating agents, such as ethylenediaminetetraacetic acid (EDTA), 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 thickener such as polyacrylic acid. The topical pharmaceutical composition may also contain a suitable penetration enhancer to enhance the penetration of Seradelpal through the skin, particularly the stratum corneum. The penetration enhancer may include water, fatty acids and fatty alcohols, alcohols and glycols, terpenes, sulfoxides, laurocapram, pyrrolidone, and surfactants.

[0042] Typically, seradelpal is present in the topical formulation at a concentration of about 0.5% to about 20%, e.g., 1% to 10%, e.g., 1%, 2%, 5%, or 10%. An appropriate (i.e., therapeutically effective) amount of seradelpal or a salt thereof for topical administration can be readily determined by observing changes in pruritus upon administration of a topical seradelpal formulation.

[0043] Typically, a seradelpal pharmaceutical composition, or a kit containing a seradelpal composition, is packaged in a container with a label, or instructions for use, or both, indicating the use of the pharmaceutical composition or kit in the treatment of chronic pruritic skin conditions.

[0044] Those of ordinary skill in the art of treating chronic pruritic dermatology, typically physicians with ordinary skill in dermatology, will be able to ascertain a therapeutically effective amount of seladelpar or a seladelpar salt for a particular degree of pruritus and patient without undue experimentation, relying on their personal knowledge, the skill in the art, and the disclosures of this application, to achieve a therapeutically effective amount for the treatment of chronic pruritic dermatology.

[0045] Mabodelpar can be formulated in a manner similar to that of seradelpar, and, like seradelpar, a person of ordinary skill in the art of treating chronic pruritic dermatology can determine the therapeutically effective amount of mabodelpar or a mabodelpar salt for a particular patient and degree of pruritus without undue experimentation, relying on personal knowledge, the skills in the art, and the disclosure of this application, to achieve a therapeutically effective amount for treating chronic pruritic dermatology. [Example]

[0046] Example

[0047] Example 1: Serradelpal reduces IL-31 production by CD4 T cells under Th2-promoting conditions

[0048] 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 wells of a U-bottom 96-well plate and cultured under Th2-promoting conditions promoted by IL-4 or IL-33. From days 1 to 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 Seradelpal in DMSO or DMSO control. On day 5 of culture, the anti-CD3 / CD28 beads were diluted by adding 150 μL of TCM. From days 5 to 13, cells were cultured in the presence of the same reagents as on days 1 to 4 plus 50 ng / mL IL-2; the cell culture medium was refreshed every 2–3 days by replacing 50% of the medium volume. On days 13 or 14, expanded T cells in individual wells were split into 4–6 wells of a 96-well plate; and 5 ng / mL phorbol myristate acetate and 500 ng / mL ionomycin were added for 3 days to reactivate the T cells. IL-31 concentrations in the culture medium of each well were determined using the V-PLEX Human IL-31 Kit (Meso Scale Diagnostics, LLC; Rockville, MD, USA).

[0049] The results are shown in the table below, where D represents DMSO control, S represents Serradelpal, SEM is standard error of the mean, and numbers are IL-31 concentrations in pg / mL. [Table 1] For both donors and for both promoters, seradelpal statistically significantly reduced IL-31 production by CD4 T cells under Th2-promoting conditions, p<0.0001, using a non-parametric two-tailed Mann-Whitney test.

[0050] Example 2: Serradelpal does not increase IL-31 production in PXB mice

[0051] The PXB mouse (Phoenix Bio, Inc., Higashihiroshima, Japan) is a liver-humanized chimeric mouse generated by transplanting human hepatocytes into albumin enhancer / promoter-urokinase plasminogen activator cDNA transgenic / SCID mice. These mice have livers repopulated with human hepatocytes at a ratio of over 70%, typically 85-90%, as assessed by measuring the ratio of human albumin to mouse albumin in the blood. The transplanted human hepatocytes express various human messenger RNAs (mRNAs) and proteins, similar to normal human livers. These mouse livers consist of human hepatocytes and a small proportion of mouse hepatocytes and mouse hepatic sinusoidal cells (mainly Kupffer cells, endothelial cells, and stellate cells), and human hepatocytes have been shown to cooperate with mouse hepatic sinusoidal cells in carrying out liver functions.

[0052] This study was conducted at Phoenix Bio. Male PXB mice, approximately 25 weeks old, housed in single cages and fed CRF1 mouse chow supplemented with AS primate chow for vitamin C supplementation (both from Oriental Yeast Co., Ltd., Tokyo, Japan), were randomly assigned to groups (10 mice per group) based on body weight and mean blood human albumin concentration. The mice were administered vehicle (0.5% carboxymethylcellulose in sterile water), seladelpal (10 mg / mL in vehicle), or obeticholic acid (an FXR agonist known to induce pruritus in PBC patients, 1 mg / mL in vehicle) by oral gavage at 10 mL / kg body weight once daily for 19 days. Two hours after the final administration, each mouse was anesthetized with isoflurane, and at least 400 μL of blood was collected by cardiac puncture. The mice were then sacrificed by exsanguination. Blood samples were left at room temperature for at least 5 minutes to clot, then centrifuged at 13,200 x 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 and seradelpal groups showed only a slight increase in serum IL-31 concentrations to 0.16 and 0.19 pg / mL, respectively, whereas obeticholic acid caused a dramatic increase to 3.7 pg / mL.

[0053] Example 3: Serradelpal reduces IL-31 in PBC (ENHANCE, NCT03602560)

[0054] Subjects in this phase 3 study were adults, male or female, 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 2 months, use of experimental treatments for PBC, and use of experimental or unapproved immunosuppressants. Subjects were randomized to receive either placebo, 5 mg / day, or 10 mg / day of seradelpal as L-lysine dihydrate salt, orally in capsule form, once daily for 12 weeks (55, 53, and 53 subjects, respectively). Serum IL-31 and its correlation with patient-reported pruritus numerical rating scale (NRS, 0-10) were assessed.

[0055] 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 levels compared with 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). Serradelpal treatment strongly reduced mean IL-31 levels over the course of the study: placebo (4.3-3.9 pg / mL, not significant), seradelpal 5 mg / day (3.8-1.7 pg / mL, p<0.001), and seradelpal 10 mg / day (4.2-1.7 pg / mL, p<0.001). Subjects with a clinically meaningful improvement in the pruritus NRS (reduction of ≥2) demonstrated a greater dose-dependent reduction in IL-31 from baseline compared with subjects without pruritus improvement. Significant correlations were also observed between changes in IL-31 versus pruritus NRS (r=0.54, p<0.0001), alkaline phosphatase (ALP) (r=0.40, p<0.01), and total bile acids (r=0.63, p<0.0001) in the seradelpal 10 mg / day group.

[0056] Example 4: Serradelpal reduces itching in atopic dermatitis through oral treatment

[0057] Adult subjects with pruritic atopic dermatitis are orally treated with seladelpal at doses of 5 mg / day, 10 mg / day, 25 mg / day, and 50 mg / day. Subjects are permitted to take other regular medications. Subjects are evaluated for safety and pharmacodynamic assessments before and at intervals during the study, for example, every 4 weeks during the study and 4 weeks after the last dose of seladelpal therapy. At each visit, subjects are evaluated for their disease symptoms and biomarkers, and for pruritus. Subjects also maintain a health diary, which is reviewed at each visit. Subjects demonstrate improvement in atopic dermatitis-associated pruritus.

[0058] Example 5: Serradelpal reduces itching in atopic dermatitis with topical treatment

[0059] Adult subjects with pruritic atopic dermatitis are topically treated with an ointment containing 1%, 2%, 5%, or 10% seradelpal. Subjects are allowed to take other regular medications. Subjects are evaluated for safety and pharmacodynamic assessments before and at intervals during the study, for example, every 4 weeks during the study and 4 weeks after the last dose of seradelpal therapy. At each visit, subjects are evaluated for their disease symptoms and biomarkers and for pruritus. Subjects also maintain a health diary, which is reviewed at each visit. Subjects demonstrate improvement in atopic dermatitis-associated pruritus.

[0060] Example 6: Mabodelpal reduces itching in atopic dermatitis through oral treatment

[0061] Adult subjects with pruritic atopic dermatitis are treated orally with mabodelpal at doses of 5 mg / day, 10 mg / day, 25 mg / day, 50 mg / day, and 100 mg / day. Subjects are permitted to take other regular medications. Subjects are evaluated for safety and pharmacodynamic assessments before and at intervals during the study, for example, every 4 weeks during the study and 4 weeks after the last dose of mabodelpal therapy. At each visit, subjects are evaluated for their disease symptoms and biomarkers, and for atopic dermatitis-associated pruritus. Subjects also maintain a health diary, which is reviewed at each visit. Subjects demonstrate improvement in atopic dermatitis-associated pruritus.

[0062] Example 7: Mabodelpal reduces itching in atopic dermatitis through topical treatment

[0063] Adult subjects with pruritic atopic dermatitis are topically treated with an ointment containing 1%, 2%, 5%, or 10% mabodelpal. Subjects are permitted to take other regular medications. Subjects are evaluated for safety and pharmacodynamic assessments before and at intervals during the study, for example, every 4 weeks during the study and 4 weeks after the last dose of mabodelpal therapy. At each visit, subjects are evaluated for their disease symptoms and biomarkers and for pruritus. Subjects also maintain a health diary, which is reviewed at each visit. Subjects demonstrate improvement in atopic dermatitis-associated pruritus.

Claims

1. A method of treating a chronic pruritic skin disease in a subject by administering to the subject a therapeutically effective amount of a compound that is seladelpal or a salt thereof.

2. 2. The method of claim 1, wherein said compound is seladelpal L-lysine salt.

3. 3. The method of claim 2, wherein the compound is seladelpal L-lysine dihydrate salt.

4. The method according to any one of claims 1 to 3, wherein the administration is oral administration.

5. The method according to any one of claims 1 to 4, wherein the amount of said compound corresponds to 0.5 mg / day to 200 mg / day of seladelpal.

6. The method of claim 5, wherein the amount of the compound corresponds to at least 1 mg / day, such as at least 2 mg / day, such as at least 5 mg / day of seladelpar.

7. 7. The method of claim 5 or 6, wherein the amount of the compound corresponds to 100 mg / day or less, such as 50 mg / day or less of seladelpar.

8. 8. The method of claim 7, wherein the amount of the compound is equivalent to 5 mg / day, 10 mg / day, 25 mg / day, or 50 mg / day of seladelpar.

9. The method of any one of claims 1 to 3, wherein the administration is topical.

10. The method of any one of claims 1 to 9, wherein the administration is once per day.

11. 10. The method of any one of claims 1 to 9, wherein the administration is more than once a day, such as twice a day, three times a day, or four times a day.

12. 10. The method of any one of claims 1 to 9, wherein the administration is once a week to every other day, such as once a week, twice a week, three times a week, or every other day.

13. The method according to any one of claims 1 to 12, wherein the chronic pruritic skin disease is atopic dermatitis, prurigo nodularis, lichen simplex chronicus, psoriasis, bullous pemphigoid, dermatitis herpetiformis, systemic lupus erythematosus, dermatomyositis, stasis dermatitis, scabies, mastocytosis, cutaneous T-cell lymphoma, chronic urticaria, allergic contact dermatitis, dermatomyositis, chronic pruritus of unknown cause, lichen planus, cutaneous (lichen) amyloidosis, scleroderma, or itch associated with wound healing.

14. A method for treating a chronic pruritic skin disease in a subject by administering to the subject a therapeutically effective amount of a compound that is mabodelpal or a salt thereof.

15. 15. The method of claim 14, wherein the compound is mabodelpal sodium salt.

16. 16. The method of claim 14 or 15, wherein the administration is oral administration.

17. 16. The method of claim 14 or 15, wherein the administration is topical.

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