BR122024025001A2 - USE OF COCRYSTAL OF CARBOXYLIC ACID AND PHOSPHORIC ACID TO PREPARE MEDICATION FOR THE TREATMENT OR PREVENTION OF PORPHYRIA - Google Patents

Abstract

A pharmaceutical preparation for the treatment or prevention of porphyria comprising 1-{2-[(3S,4R)-1-{[(3R,4R)-1-cyclopentyl-3-fluoro-4-(4-methoxyphenyl)pyrrolidin-3-yl]carbonyl}-4-(methoxymethyl)pyrrolidin-3-yl]-5-(trifluoromethyl)phenyl}piperidine-4-carboxylic acid or a pharmaceutically acceptable salt or cocrystal thereof as an active ingredient, wherein the dose of 1-{2-[(3S,4R)-1-{[(3R,4R)-1-cyclopentyl-3-fluoro-4-(4-methoxyphenyl)pyrrolidin-3-yl]carbonyl}-4-(methoxymethyl)pyrrolidin-3-yl]-5-(trifluoromethyl)phenyl}piperidine-4-carboxylic acid or the pharmaceutically acceptable salt or cocrystal of the same is 50 to 500 mg/day.

Description

BACKGROUND OF THE INVENTION Field of invention

[0001] The present invention relates to a pharmaceutical composition for treating or preventing porphyria, comprising a compound with melanocortin receptor (MCR)-combating activity (agonist activity).

Description of Related Art

[0002] Among the light radiated by the sun, rays with wavelengths not exceeding 300 nm are absorbed in the ozone layer in the stratosphere. Thus, the sunlight reaching the ground is composed of ultraviolet light with a wavelength not less than 300 nm, visible light and infrared light. Physiological reactions caused by exposure to sunlight include solar dermatitis (sunburn) and skin changes (wrinkles, sagging and development of pigmented spots) called photoaging that occur due to long-term exposure. On the other hand, there are diseases called photodermatoses, in which pathological changes such as dermatitis occur due to light irradiation even when the light irradiation is at a level to which healthy individuals do not respond. A known example of photodermatosis is porphyria.

[0003] Porphyria is a disease that develops due to the accumulation of porphyrins or their precursors as a result of decreased activity of the heme metabolic enzyme. Porphyria can present with symptoms such as photosensitivity (sunburn, burn-like symptoms) and also gastrointestinal and neurological symptoms. Once porphyria develops, its symptoms usually continue throughout life. Since there is no curative treatment for it, symptomatic treatment, such as protection from light, is performed as the main therapeutic method.

[0004] For example, Patent Document 1 discloses the use of MCR agonist peptides, such as afamelanotide, for the purpose of treating photodermatoses, such as erythropoietic protoporphyria. However, since afamelanotide is not a selective MC1R agonist, there is concern about the occurrence of side effects. Furthermore, since afamelanotide is a peptide, it cannot be administered orally and its half-life is short. Thus, there is a concern that periodic subcutaneous implantation by a medical professional is necessary.

[0005] On the other hand, Patent Document 2 discloses that pyrrolidine compounds such as 1-{2-[(3S,4R)-1-{[(3R,4R)-1-cyclopentyl-3-fluoro-4-(4-methoxyphenyl)pyrrolidin-3-yl]carbonyl}-4-(methoxymethyl)pyrrolidin-3-yl]-5-(trifluoromethyl)phenyl}piperidine-4-carboxylic acid and pharmaceutically acceptable salts, solvates, hydrates, cocrystals and the like thereof have excellent MCR-, especially MC1R-, activating action. Patent Document 2 discloses that the compounds are useful for preventing or treating diseases or symptoms associated with MCR activation, especially MC1R, and that such diseases include protoporphyria. However, the document does not specifically describe their doses.

[0006] Patent Document 3 discloses a cocrystal of 1-{2-[(3S,4R)-1-{[(3R,4R)-1-cyclopentyl-3-fluoro-4-(4-methoxyphenyl)pyrrolidin-3-yl]carbonyl}-4-(methoxymethyl)pyrrolidin-3-yl]-5-(trifluoromethyl)phenyl}piperidine-4-carboxylic acid. However, the document does not specifically describe the dosage of the 1-{2-[(3S,4R)-1-{[(3R,4R)-1-cyclopentyl-3-fluoro-4-(4-methoxyphenyl)pyrrolidin-3-yl]carbonyl}-4-(methoxymethyl)pyrrolidin-3-yl]-5-(trifluoromethyl)phenyl}piperidine-4-carboxylic acid cocrystal for use in the treatment of porphyria.

Prior art documents [Patent Documents]

[0007] [Patent Document 1] WO 2008025094

[0008] [Patent Document 2] WO 2015182723

[0009] [Patent Document 3] WO2020/138481

SUMMARY OF THE INVENTION Problems to be solved by the invention

[0010] Curative treatment methods for porphyria are limited, and the main method to prevent the development of symptoms or to alleviate symptoms has been to avoid exposure of the skin to sunlight. In particular, it is known that patients with visible light-induced photodermatoses tend to avoid going out during the day, so that the quality of life (QOL) of patients can deteriorate notably.

[0011] As described above, an analogue of α-melanocyte stimulating hormone (α-MSH), which is an MCR ligand, has been developed as a therapeutic agent for photodermatoses and the like, such as erythropoietic protoporphyria (Patent Document 1). However, it is not a selective MC1R agonist and cannot be administered orally, since it is a peptide. Furthermore, since it disappears rapidly in the human body, periodic implantation is necessary.

[0012] Therefore, a pharmaceutical composition for the treatment or prevention of porphyria is needed, the pharmaceutical composition of which is safer and less burdensome for patients and which allows effective treatment.

Means to solve problems

[0013] In order to solve the above problems, the present inventors studied intensively. As a result, the present inventors have discovered a dose of 1-{2-[(3S,4R)-1-{[(3R,4R)-1-cyclopentyl-3-fluoro-4-(4-methoxyphenyl)pyrrolidin-3-yl]carbonyl}-4-(methoxymethyl)pyrrolidin-3-yl]-5-(trifluoromethyl)phenyl}piperidine-4-carboxylic acid or a pharmaceutically acceptable salt or cocrystal thereof, which dose is especially effective in a human clinical trial and exerts an excellent therapeutic or prophylactic effect on porphyria, including erythropoietic protoporphyria (EPP) and X-linked porphyria. In particular, a dose at which a significant pharmacological effect can be produced relative to placebo, not only in seasons with long-lasting strong sunlight, such as spring and summer in the Northern Hemisphere, but also in seasons with short-lasting weak sunlight, such as autumn and winter in the Northern Hemisphere North, that is, a dose at which effective treatment or prevention of porphyria is possible throughout the year, could be discovered. The above agent afamelanotide was confirmed to have a therapeutic effect on symptoms occurring after direct sunlight exposure in a clinical trial. In contrast, at the dose in the present invention, 1-{2-[(3S,4R)-1-{[(3R,4R)-1-cyclopentyl-3-fluoro-4-(4-methoxyphenyl)pyrrolidin-3-yl]carbonyl}-4-(methoxymethyl)pyrrolidin-3-yl]-5-(trifluoromethyl)phenyl}piperidine-4-carboxylic acid or a pharmaceutically acceptable salt or cocrystal thereof was confirmed to exert a therapeutic effect not only on symptoms caused by direct sunlight exposure but also symptoms caused by indirect sunlight exposure that may occur even indoors in a building or the like. The present invention was completed based on such findings.

[0014] The present invention provides a pharmaceutical product for treating or preventing porphyria, such as erythropoietic protoporphyria or X-linked porphyria, the pharmaceutical product comprising 1-{2-[(3S,4R)-1-{[(3R,4R)-1-cyclopentyl-3-fluoro-4-(4-methoxyphenyl)pyrrolidin-3-yl]carbonyl}-4-(methoxymethyl)pyrrolidin-3-yl]-5-(trifluoromethyl)phenyl}piperidine-4-carboxylic acid or a pharmaceutically acceptable salt or cocrystal thereof as the active ingredient, wherein the dose of 1-{2-[(3S,4R)-1-{[(3R,4R)-1-cyclopentyl-3-fluoro-4-(4-methoxyphenyl)pyrrolidin-3-yl]carbonyl}-4- (methoxymethyl)pyrrolidin-3-yl]-5-(trifluoromethyl)phenyl}piperidine-4-carboxylic acid or the pharmaceutically acceptable salt or cocrystal thereof is 50 to 500 mg/day, preferably 100 to 300 mg/day.

[0015] The present invention provides a method of treating or preventing porphyria, such as erythropoietic protoporphyria or X-linked porphyria, the method comprising the step of administering an effective amount of 1-{2-[(3S,4R)-1-{[(3R,4R)-1-cyclopentyl-3-fluoro-4-(4-methoxyphenyl)pyrrolidin-3-yl]carbonyl}-4-(methoxymethyl)pyrrolidin-3-yl]-5-(trifluoromethyl)phenyl}piperidine-4-carboxylic acid or a pharmaceutically acceptable salt or cocrystal thereof to a subject in need of treatment or prevention, wherein the effective amount is 50 to 500 mg/day, preferably 100 to 300 mg/day.

[0016] The present invention provides 1-{2-[(3S,4R)-1-{[(3R,4R)-1-cyclopentyl-3-fluoro-4-(4-methoxyphenyl)pyrrolidin-3-yl]carbonyl}-4-(methoxymethyl)pyrrolidin-3-yl]-5-(trifluoromethyl)phenyl}piperidine-4-carboxylic acid, or a pharmaceutically acceptable salt or cocrystal thereof, for treating or preventing porphyria, such as erythropoietic protoporphyria or X-linked porphyria, wherein the dose of 1-{2-[(3S,4R)-1-{[(3R,4R)-1-cyclopentyl-3-fluoro-4-(4-methoxyphenyl)pyrrolidin-3-yl]carbonyl}-4- (methoxymethyl)pyrrolidin-3-yl]-5-(trifluoromethyl)phenyl}piperidine-4-carboxylic acid or the pharmaceutically acceptable salt or cocrystal thereof is 50 to 500 mg/day, preferably 100 to 300 mg/day.

[0017] The present invention provides the use of 1-{2-[(3S,4R)-1-{[(3R,4R)-1-cyclopentyl-3-fluoro-4-(4-methoxyphenyl)pyrrolidin-3-yl]carbonyl}-4-(methoxymethyl)pyrrolidin-3-yl]-5-(trifluoromethyl)phenyl}piperidine-4-carboxylic acid or a pharmaceutically acceptable salt or cocrystal thereof, in the manufacture of a pharmaceutical product for treating or preventing porphyria, such as erythropoietic protoporphyria or X-linked porphyria, wherein the dose of 1-{2-[(3S,4R)-1-{[(3R,4R)-1-cyclopentyl-3-fluoro-4-(4-methoxyphenyl)pyrrolidine -3-yl]carbonyl}-4-(methoxymethyl)pyrrolidin-3-yl]-5-(trifluoromethyl)phenyl}piperidine-4-carboxylic acid or the pharmaceutically acceptable salt or cocrystal thereof is 50 to 500 mg/day, preferably 100 to 300 mg/day.

[0018] According to the present invention, the treatment or prevention of porphyria is possible in any indoor or outdoor environment throughout the year. 1-{2-[(3S,4R)-1-{[(3R,4R)-1-Cyclopentyl-3-fluoro-4-(4-methoxyphenyl)pyrrolidin-3-yl]carbonyl}-4-(methoxymethyl)pyrrolidin-3-yl]-5-(trifluoromethyl)phenyl}piperidine-4-carboxylic acid or a pharmaceutically acceptable salt or cocrystal thereof can be administered orally and exhibits excellent kinetics in the human body. Furthermore, being a selective compound for MC1R, it causes fewer side effects and allows safe and effective treatment or prevention of porphyria without imposing a burden on the patient. In particular, in porphyria such as erythropoietic protoporphyria or X-linked porphyria, administration of 1-{2-[(3S,4R)-1-{[(3R,4R)-1-cyclopentyl-3-fluoro-4-(4-methoxyphenyl)pyrrolidin-3-yl]carbonyl}-4-(methoxymethyl)pyrrolidin-3-yl]-5-(trifluoromethyl)phenyl}piperidine-4-carboxylic acid or a pharmaceutically acceptable salt or cocrystal thereof at a particular dose enables excellent therapeutic effects such as prolongation of the time to occurrence of phototoxicity (i.e., time to occurrence of phototoxicity-related symptom or time to prodromal symptoms), reduction of pain events, and improvement of QOL, whether indoors or outdoors year-round.

DETAILED DESCRIPTION OF THE INVENTION The present invention is described below. <Active ingredient>

[0019] The active ingredient of the pharmaceutical product of the present invention, namely 1-{2-[(3S,4R)-1-{[(3R,4R)-1-cyclopentyl-3-fluoro-4-(4-methoxyphenyl)pyrrolidin-3-yl]carbonyl}-4-(methoxymethyl)pyrrolidin-3-yl]-5-(trifluoromethyl)phenyl}piperidine-4-carboxylic acid or a pharmaceutically acceptable salt or cocrystal thereof, is described in Patent Document 2, and can be produced, for example, by the method described in Patent Document 2. A cocrystal of 1-{2-[(3S,4R)-1-{[(3R,4R)-1- cyclopentyl-3-fluoro-4-(4-methoxyphenyl)pyrrolidin-3-yl]carbonyl}-4-(methoxymethyl)pyrrolidin-3-yl]-5-(trifluoromethyl)phenyl}piperidine-4-carboxylic acid and phosphoric acid can be obtained by a conventional method or, for example, the method described in Patent Document 3.

[0020] In this specification, the "dose of 1-{2-[(3S,4R)-1-{[(3R,4R)-1-cyclopentyl-3-fluoro-4-(4-methoxyphenyl)pyrrolidin-3-yl]carbonyl}-4-(methoxymethyl)pyrrolidin-3-yl]-5-(trifluoromethyl)phenyl}piperidine-4-carboxylic acid or the pharmaceutically acceptable salt or cocrystal thereof" or the dose or amount of "Compound A" refers to the dose or amount in terms of the amount of 1-{2-[(3S,4R)-1-{[(3R,4R)-1-cyclopentyl-3-fluoro-4-(4-methoxyphenyl)pyrrolidin-3-yl]carbonyl}-4- (methoxymethyl)pyrrolidin-3-yl]-5-(trifluoromethyl)phenyl}piperidine-4-carboxylic acid as the free form.

<Pharmaceutical Application>

[0021] Since 1-{2-[(3S,4R)-1-{[(3R,4R)-1-cyclopentyl-3-fluoro-4-(4-methoxyphenyl)pyrrolidin-3-yl]carbonyl}-4-(methoxymethyl)pyrrolidin-3-yl]-5-(trifluoromethyl)phenyl}piperidine-4-carboxylic acid or a pharmaceutically acceptable salt or cocrystal thereof has excellent MC1R agonist activity, it exerts excellent therapeutic and prophylactic effects in porphyria, such as prolonging the time to occurrence of phototoxicity, reducing pain events, and improving QOL, in any setting throughout the year.

[0022] Furthermore, 1-{2-[(3S,4R)-1-{[(3R,4R)-1-cyclopentyl-3-fluoro-4-(4-methoxyphenyl)pyrrolidin-3-yl]carbonyl}-4-(methoxymethyl)pyrrolidin-3-yl]-5-(trifluoromethyl)phenyl}piperidine-4-carboxylic acid or a pharmaceutically acceptable salt or cocrystal thereof exerts an especially excellent effect in prolonging the time to the occurrence of phototoxicity in a certain group of patients (group of patients whose baseline median erythrocyte protoporphyrin IX level is not less than 1980.50 mcg/dL), thus exerting excellent therapeutic and prophylactic effects on porphyria.

[0023] Furthermore, 1-{2-[(3S,4R)-1-{[(3R,4R)-1-cyclopentyl-3-fluoro-4-(4-methoxyphenyl)pyrrolidin-3-yl]carbonyl}-4-(methoxymethyl)pyrrolidin-3-yl]-5-(trifluoromethyl)phenyl}piperidine-4-carboxylic acid or a pharmaceutically acceptable salt or cocrystal thereof exerts an excellent effect in prolonging the time for the occurrence of phototoxicity in a specific patient group (patient group whose median melanin density is not less than 3.0915) regardless of the dose, and exerts an excellent effect in prolonging the time for the occurrence of phototoxicity in a certain patient group (patient group whose median melanin density is less than 3.0915) at a particular dose (preferably at a daily dose of 300 mg), thus exerting excellent effects therapeutic and prophylactic in porphyria.

[0024] Thus, a pharmaceutical product containing 1-{2-[(3S,4R)-1-{[(3R,4R)-1-cyclopentyl-3-fluoro-4-(4-methoxyphenyl)pyrrolidin-3-yl]carbonyl}-4-(methoxymethyl)pyrrolidin-3-yl]-5-(trifluoromethyl)phenyl}piperidine-4-carboxylic acid or a pharmaceutically acceptable salt or cocrystal thereof as an active ingredient is useful for the treatment or prevention of porphyria.

[0025] Examples of porphyria include erythropoietic protoporphyria, X-linked porphyria, congenital erythropoietic porphyria, variegate porphyria, acute intermittent porphyria, porphyria cutanea tarda, and hereditary coproporphyria.

[0026] Erythropoietic protoporphyria herein includes congenital erythropoietic protoporphyria.

[0027] The time to the occurrence of phototoxicity has the same meaning as the time to the occurrence of the phototoxicity-related symptom, or simply a symptom. It also means the time to the prodromal symptom. Examples of phototoxicity-related symptoms, symptoms or prodromal symptoms include burning, tingling, itching and stinging.

[0028] 1-{2-[(3S,4R)-1-{[(3R,4R)-1-cyclopentyl-3-fluoro-4-(4-methoxyphenyl)pyrrolidin-3-yl]carbonyl}-4-(methoxymethyl)pyrrolidin-3-yl]-5-(trifluoromethyl)phenyl}piperidine-4-carboxylic acid may be subjected to pharmaceutical use either in free form or in the form of a pharmaceutically acceptable salt or cocrystal thereof.

[0029] Herein, 1-{2-[(3S,4R)-1-{[(3R,4R)-1-cyclopentyl-3-fluoro-4-(4-methoxyphenyl)pyrrolidin-3-yl]carbonyl}-4-(methoxymethyl)pyrrolidin-3-yl]-5-(trifluoromethyl)phenyl}piperidine-4-carboxylic acid or the pharmaceutically acceptable salt or cocrystal thereof includes any of the intramolecular salts and adducts and solvates, hydrates, crystalline polymorphs and the like.

[0030] Examples of pharmaceutically acceptable salts, cocrystals, intramolecular salts and adducts include those containing: an inorganic acid, such as hydrochloric acid, sulfuric acid, phosphoric acid or hydrobromic acid; or an organic acid, such as acetic acid, fumaric acid, oxalic acid, citric acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid or maleic acid. Cocrystals with phosphoric acid are especially preferred.

[0031] One of, or two or more of, 1-{2-[(3S,4R)-1-{[(3R,4R)-1-cyclopentyl-3-fluoro-4-(4-methoxyphenyl)pyrrolidin-3-yl]carbonyl}-4-(methoxymethyl)pyrrolidin-3-yl]-5-(trifluoromethyl)phenyl}piperidine-4-carboxylic acid, and pharmaceutically acceptable salts and cocrystals thereof may be administered as is to the patient. Preferably, however, 1-{2-[(3S,4R)-1-{[(3R,4R)-1-cyclopentyl-3-fluoro-4-(4-methoxyphenyl)pyrrolidin-3-yl]carbonyl}-4-(methoxymethyl)pyrrolidin-3-yl]-5-(trifluoromethyl)phenyl}piperidine-4-carboxylic acid or a pharmaceutically acceptable salt or cocrystal thereof may be admixed with a pharmacologically and pharmaceutically acceptable additive(s) to be provided as a formulation in a form well known to those skilled in the art.

[0032] Examples of the pharmacologically and pharmaceutically acceptable additive(s) include suitable excipients, disintegrants, binders, lubricants, coating agents, colorants, diluents, bases and isotonic agents commonly used in the production of pharmaceutical products. Examples of the excipients include glucose, lactose, D-mannitol, starch and crystalline cellulose. Examples of the disintegrants include carboxymethyl cellulose, starch and calcium carboxymethyl cellulose. Examples of the binders include hydroxypropyl cellulose, hydroxypropylmethyl cellulose, polyvinylpyrrolidone and gelatin. Examples of the lubricants include magnesium stearate and talc. Examples of the coating agents include hydroxypropylmethyl cellulose, sucrose, polyethylene glycol and titanium oxide. Examples of the bases include petrolatum, liquid paraffin, polyethylene glycol, gelatin, kaolin, glycerin, purified water and hard fat. In addition, for formulations suitable for injection or infusion, the following may be used as formulation additives: solvents and solubilizers which may constitute aqueous solutions for injection, or may constitute injectable solutions to be prepared before use, such as distilled water for injection, saline solution, and propylene glycol; isotonic agents such as glucose, sodium chloride, D-mannitol, and glycerin; pH regulators such as inorganic acids, organic acids, inorganic bases, and organic bases; and the like.

[0033] 1-{2-[(3S,4R)-1-{[(3R,4R)-1-cyclopentyl-3-fluoro-4-(4-methoxyphenyl)pyrrolidin-3-yl]carbonyl}-4-(methoxymethyl)pyrrolidin-3-yl]-5-(trifluoromethyl)phenyl}piperidine-4-carboxylic acid or the pharmaceutically acceptable salt or cocrystal thereof, together with the additives described above, can be prepared into a suitable dosage form (such as a powder, an injection solution, a tablet, a capsule or a topical preparation) and can then be administered to a patient (human or animal) using an appropriate administration method according to the dosage form (such as intravenous administration, oral administration, percutaneous administration or topical administration). Among these, oral administration is preferred.

[0034] The dose of the pharmaceutical product comprising 1-{2-[(3S,4R)-1-{[(3R,4R)-1-cyclopentyl-3-fluoro-4-(4-methoxyphenyl)pyrrolidin-3-yl]carbonyl}-4-(methoxymethyl)pyrrolidin-3-yl]-5-(trifluoromethyl)phenyl}piperidine-4-carboxylic acid or a pharmaceutically acceptable salt or cocrystal thereof is an amount at which the pharmaceutical product can be used safely with low toxicity and at which a therapeutic effect or prophylactic effect can be exerted on porphyria indoors or outdoors throughout the year. The dose in terms of the amount of 1-{2-[(3S,4R)-1-{[(3R,4R)-1-cyclopentyl-3-fluoro-4-(4-methoxyphenyl)pyrrolidin-3-yl]carbonyl}-4-(methoxymethyl)pyrrolidin-3-yl]-5-(trifluoromethyl)phenyl}piperidine-4-carboxylic acid or the pharmaceutically acceptable salt or cocrystal thereof is 50 to 500 mg/day, more preferably 80 to 400 mg/day, especially preferably 100 to 300 mg/day. Examples of the dose include 100 mg/day, 150 mg/day, 200 mg/day, 250 mg/day, 300 mg/day and doses in between.

[0035] Oral administration is especially preferred. The dose of the pharmaceutical product comprising 1-{2-[(3S,4R)-1-{[(3R,4R)-1-cyclopentyl-3-fluoro-4-(4-methoxyphenyl)pyrrolidin-3-yl]carbonyl}-4-(methoxymethyl)pyrrolidin-3-yl]-5-(trifluoromethyl)phenyl}piperidine-4-carboxylic acid or a pharmaceutically acceptable salt or cocrystal thereof for oral administration, in terms of the amount of 1-{2-[(3S,4R)-1-{[(3R,4R)-1-cyclopentyl-3-fluoro-4-(4-methoxyphenyl)pyrrolidin-3-yl]carbonyl}-4-(methoxymethyl)pyrrolidin-3-yl]-5-(trifluoromethyl)phenyl}piperidine-4-carboxylic acid or the pharmaceutically acceptable salt or cocrystal thereof is 50 to 500 mg/day, preferably 80 to 400 mg/day, more preferably 100 to 300 mg/day, more specifically, 100 mg/day, 150 mg/day, 200 mg/day, 250 mg/day, 300 mg/day or a dose between these. The pharmaceutical product is administered especially preferably in a dose of 100 mg/day, 200 mg/day or 300 mg/day.

[0036] Even more preferably, a cocrystal of 1-{2-[(3S,4R)-1-{[(3R,4R)-1-cyclopentyl-3-fluoro-4-(4-methoxyphenyl)pyrrolidin-3-yl]carbonyl}-4-(methoxymethyl)pyrrolidin-3-yl]-5-(trifluoromethyl)phenyl}piperidine-4-carboxylic acid and phosphoric acid is administered at a dose of 100 mg/day or 300 mg/day in terms of the amount of 1-{2-[(3S,4R)-1-{[(3R,4R)-1-cyclopentyl-3-fluoro-4-(4-methoxyphenyl)pyrrolidin-3-yl]carbonyl}-4-(methoxymethyl)pyrrolidin-3-yl]-5-(trifluoromethyl)phenyl}piperidine-4-carboxylic acid.

[0037] Otherwise, preferably, a cocrystal of 1-{2-[(3S,4R)-1-{[(3R,4R)-1-cyclopentyl-3-fluoro-4-(4-methoxyphenyl)pyrrolidin-3-yl]carbonyl}-4-(methoxymethyl)pyrrolidin-3-yl]-5-(trifluoromethyl)phenyl}piperidine-4-carboxylic acid and phosphoric acid is administered at a dose of 100 mg/day or 200 mg/day in terms of the amount of 1-{2-[(3S,4R)-1-{[(3R,4R)-1-cyclopentyl-3-fluoro-4-(4-methoxyphenyl)pyrrolidin-3-yl]carbonyl}-4-(methoxymethyl)pyrrolidin-3-yl]-5-(trifluoromethyl)phenyl}piperidine-4-carboxylic acid.

[0038] In another embodiment, a cocrystal of 1-{2-[(3S,4R)-1-{[(3R,4R)-1-cyclopentyl-3-fluoro-4-(4-methoxyphenyl)pyrrolidin-3-yl]carbonyl}-4-(methoxymethyl)pyrrolidin-3-yl]-5-(trifluoromethyl)phenyl}piperidine-4-carboxylic acid and phosphoric acid is administered at a dose of 100 mg/day in terms of the amount of 1-{2-[(3S,4R)-1-{[(3R,4R)-1-cyclopentyl-3-fluoro-4-(4-methoxyphenyl)pyrrolidin-3-yl]carbonyl}-4-(methoxymethyl)pyrrolidin-3-yl]-5-(trifluoromethyl)phenyl}piperidine-4-carboxylic acid.

[0039] In another embodiment, a cocrystal of 1-{2-[(3S,4R)-1-{[(3R,4R)-1-cyclopentyl-3-fluoro-4-(4-methoxyphenyl)pyrrolidin-3-yl]carbonyl}-4-(methoxymethyl)pyrrolidin-3-yl]-5-(trifluoromethyl)phenyl}piperidine-4-carboxylic acid and phosphoric acid is administered at a dose of 200 mg/day in terms of the amount of 1-{2-[(3S,4R)-1-{[(3R,4R)-1-cyclopentyl-3-fluoro-4-(4-methoxyphenyl)pyrrolidin-3-yl]carbonyl}-4-(methoxymethyl)pyrrolidin-3-yl]-5-(trifluoromethyl)phenyl}piperidine-4-carboxylic acid.

[0040] In another embodiment, a cocrystal of 1-{2-[(3S,4R)-1-{[(3R,4R)-1-cyclopentyl-3-fluoro-4-(4-methoxyphenyl)pyrrolidin-3-yl]carbonyl}-4-(methoxymethyl)pyrrolidin-3-yl]-5-(trifluoromethyl)phenyl}piperidine-4-carboxylic acid and phosphoric acid is administered at a dose of 300 mg/day in terms of the amount of 1-{2-[(3S,4R)-1-{[(3R,4R)-1-cyclopentyl-3-fluoro-4-(4-methoxyphenyl)pyrrolidin-3-yl]carbonyl}-4-(methoxymethyl)pyrrolidin-3-yl]-5-(trifluoromethyl)phenyl}piperidine-4-carboxylic acid.

[0041] As described in the Examples below, it has been demonstrated that, at a daily dose of 100 mg or 300 mg, 1-{2-[(3S,4R)-1-{[(3R,4R)-1-cyclopentyl-3-fluoro-4-(4-methoxyphenyl)pyrrolidin-3-yl]carbonyl}-4-(methoxymethyl)pyrrolidin-3-yl]-5-(trifluoromethyl)phenyl}piperidine-4-carboxylic acid or a pharmaceutically acceptable salt or cocrystal thereof exerts therapeutic effects such as prolongation of the time to occurrence of phototoxicity, reduction of pain events and improvement of QOL relative to placebo in patients with erythropoietic protoporphyria and patients with X-linked porphyria. In particular, in a group of patients whose baseline median erythrocyte protoporphyrin IX level was not less than 1,980.50 mcg/dL, a statistically significant effect in prolonging the time to the occurrence of phototoxicity compared to placebo was found at a daily dose of 100 mg or 300 mg. According to the comparison between a group of patients whose median melanin density was not less than 3.0915 and a group of patients whose median melanin density was less than 3.0915, the first group showed similar levels of prolongation of the time to the occurrence of phototoxicity at daily doses of 100 mg and 300 mg, but in the latter group, the group of patients with a daily dose of 300 mg showed a better prolongation of the time to the occurrence of phototoxicity.

[0042] Also at daily doses of 100 mg and 200 mg, a test confirming a therapeutic effect of 1-{2-[(3S,4R)-1-{[(3R,4R)-1-cyclopentyl-3-fluoro-4-(4-methoxyphenyl)pyrrolidin-3-yl]carbonyl}-4-(methoxymethyl)pyrrolidin-3-yl]-5-(trifluoromethyl)phenyl}piperidine-4-carboxylic acid or a pharmaceutically acceptable salt or cocrystal thereof in patients with erythropoietic protoporphyria and patients with X-linked porphyria.

[0043] Although Patent Document 2 and Patent Document 3 describe erythropoietic protoporphyria as a target disease, these documents do not specifically describe the doses. In the clinical trial shown in the present invention, it was found that administration at a dose including 100 mg/day and 300 mg/day, for example, 50 to 500 mg/day, preferably 80 to 400 mg/day, more preferably 100 to 300 mg/day, allows to exert excellent therapeutic effects on erythropoietic protoporphyria in indoor or outdoor environments throughout the year, whose therapeutic effects include prolonging the time for the occurrence of phototoxicity, reducing pain events and improving QOL. These findings were not described or suggested in the above documents.

[0044] Thus, one mode of the present invention provides a pharmaceutical product to be administered to a patient with porphyria for treating or preventing porphyria, the pharmaceutical product comprising 1-{2-[(3S,4R)-1-{[(3R,4R)-1-cyclopentyl-3-fluoro-4-(4-methoxyphenyl)pyrrolidin-3-yl]carbonyl}-4-(methoxymethyl)pyrrolidin-3-yl]-5-(trifluoromethyl)phenyl}piperidine-4-carboxylic acid or a pharmaceutically acceptable salt or cocrystal thereof as an active ingredient, wherein the dose of the 1-{2-[(3S,4R)-1-{[(3R,4R)-1-cyclopentyl-3-fluoro-4-(4-methoxyphenyl)pyrrolidin-3-yl]carbonyl}-4- (methoxymethyl)pyrrolidin-3-yl]-5-(trifluoromethyl)phenyl}piperidine-4-carboxylic acid or pharmaceutically acceptable salt or cocrystal thereof for the patient with porphyria is 50 to 500 mg/day, preferably 80 to 400 mg/day, more preferably 100 to 300 mg/day, more specifically, 100 mg/day, 150 mg/day, 200 mg/day, 250 mg/day, 300 mg/day, or a dose between these.

[0045] In another mode of the present invention, a pharmaceutical product is administered to a patient with erythropoietic protoporphyria or to a patient with X-linked porphyria for the treatment or prevention of erythropoietic protoporphyria or X-linked porphyria, wherein the pharmaceutical product comprises 1-{2-[(3S,4R)-1-{[(3R,4R)-1-cyclopentyl-3-fluoro-4-(4-methoxyphenyl)pyrrolidin-3-yl]carbonyl}-4-(methoxymethyl)pyrrolidin-3-yl]-5-(trifluoromethyl)phenyl}piperidine-4-carboxylic acid or a pharmaceutically acceptable salt or cocrystal thereof as the active ingredient, wherein the dose of 1-{2-[(3S,4R)-1-{[(3R,4R)-1-cyclopentyl-3-fluoro-4-(4- The dosage of 4-( ...

[0046] In another embodiment of the present invention, a pharmaceutical product is administered to a patient with erythropoietic protoporphyria or a patient with X-linked porphyria for prolonging the time to occurrence of phototoxicity and/or reducing pain events, wherein the pharmaceutical product comprises 1-{2-[(3S,4R)-1-{[(3R,4R)-1-cyclopentyl-3-fluoro-4-(4-methoxyphenyl)pyrrolidin-3-yl]carbonyl}-4-(methoxymethyl)pyrrolidine-3-yl]-5-(trifluoromethyl)phenyl}piperidine-4-carboxylic acid or a pharmaceutically acceptable salt or cocrystal thereof as the active ingredient, wherein the dose of the 1-{2-[(3S,4R)-1- {[(3R,4R)-1-cyclopentyl-3-fluoro-4-(4-methoxyphenyl)pyrrolidin-3-yl]carbonyl}-4-(methoxymethyl)pyrrolidin-3-yl]-5-(trifluoromethyl)phenyl}piperidine-4-carboxylic acid or pharmaceutically acceptable salt or cocrystal thereof for the patient with erythropoietic protoporphyria or the patient with X-linked porphyria is 50 to 500 mg/day, preferably 80 to 400 mg/day, more preferably 100 to 300 mg/day, more specifically, 100 mg/day, 150 mg/day, 200 mg/day, 250 mg/day, 300 mg/day or a dose between these.

[0047] In another mode of the present invention, a pharmaceutical product is administered to a patient with erythropoietic protoporphyria or to a patient with X-linked porphyria for the treatment or prevention of erythropoietic protoporphyria or X-linked porphyria, wherein a group of patients is the group whose baseline median erythrocyte protoporphyrin IX level is not less than 1980.50 mcg/dL, wherein the pharmaceutical product comprises 1-{2-[(3S,4R)-1-{[(3R,4R)-1-cyclopentyl-3-fluoro-4-(4-methoxyphenyl)pyrrolidin-3-yl]carbonyl}-4-(methoxymethyl)pyrrolidin-3-yl]-5-(trifluoromethyl)phenyl}piperidine-4-carboxylic acid or a pharmaceutically acceptable salt or cocrystal thereof as an active ingredient, wherein the dose of the acid 1-{2-[(3S,4R)-1-{[(3R,4R)-1-cyclopentyl-3-fluoro-4-(4-methoxyphenyl)pyrrolidin-3-yl]carbonyl}-4-(methoxymethyl)pyrrolidin-3-yl]-5-(trifluoromethyl)phenyl}piperidine-4-carboxylic acid or the pharmaceutically acceptable salt or cocrystal thereof for the patient with erythropoietic protoporphyria or the patient with X-linked porphyria is 50 to 500 mg/day, preferably 80 to 400 mg/day, more preferably 100 to 300 mg/day, more specifically, 100 mg/day, 150 mg/day, 200 mg/day, 250 mg/day, 300 mg/day, or a dose therebetween.

[0048] In another mode of the present invention, a pharmaceutical product is administered to a patient with erythropoietic protoporphyria or a patient with X-linked porphyria for treating or preventing erythropoietic protoporphyria or X-linked porphyria, wherein a group of patients is the group whose median melanin density is not less than 3.0915, wherein the pharmaceutical product comprises 1-{2-[(3S,4R)-1-{[(3R,4R)-1-cyclopentyl-3-fluoro-4-(4-methoxyphenyl)pyrrolidin-3-yl]carbonyl}-4-(methoxymethyl)pyrrolidin-3-yl]-5-(trifluoromethyl)phenyl}piperidine-4-carboxylic acid or a pharmaceutically acceptable salt or cocrystal thereof as the active ingredient, wherein the dose of the 1-{2-[(3S,4R)-1- {[(3R,4R)-1-cyclopentyl-3-fluoro-4-(4-methoxyphenyl)pyrrolidin-3-yl]carbonyl}-4-(methoxymethyl)pyrrolidin-3-yl]-5-(trifluoromethyl)phenyl}piperidine-4-carboxylic acid or the pharmaceutically acceptable salt or cocrystal thereof for the patient with erythropoietic protoporphyria or the patient with X-linked porphyria is 50 to 500 mg/day, preferably 80 to 400 mg/day, more preferably 100 to 300 mg/day, more specifically, 100 mg/day, 150 mg/day, 200 mg/day, 250 mg/day, 300 mg/day or a dose between these.

[0049] In another mode of the present invention, a pharmaceutical product is administered to a patient with erythropoietic protoporphyria or a patient with X-linked porphyria for treating or preventing erythropoietic protoporphyria or X-linked porphyria, wherein a group of patients is the group whose median melanin density is less than 3.0915, wherein the pharmaceutical product comprising 1-{2-[(3S,4R)-1-{[(3R,4R)-1-cyclopentyl-3-fluoro-4-(4-methoxyphenyl)pyrrolidin-3-yl]carbonyl}-4-(methoxymethyl)pyrrolidin-3-yl]-5-(trifluoromethyl)phenyl}piperidine-4-carboxylic acid or a pharmaceutically acceptable salt or cocrystal thereof as an active ingredient, wherein the dose of the 1-{2-[(3S,4R)-1-{[(3R,4R)-1-cyclopentyl-3-fluoro-4-(4-methoxyphenyl)pyrrolidin-3-yl]carbonyl}-4-(methoxymethyl)pyrrolidin-3-yl]-5-(trifluoromethyl)phenyl}piperidine-4-carboxylic acid is ... [(3S,4R)-1-{[(3R,4R)-1-cyclopentyl-3-fluoro-4-(4-methoxyphenyl)pyrrolidin-3-yl]carbonyl}-4-(methoxymethyl)pyrrolidin-3-yl]-5-(trifluoromethyl)phenyl}piperidine-4-carboxylic acid or the pharmaceutically acceptable salt or cocrystal thereof for the patient with erythropoietic protoporphyria or the patient with X-linked porphyria is 50 to 500 mg/day, preferably 80 to 400 mg/day, more preferably 100 to 300 mg/day, more preferably 200 to 300 mg/day, more specifically, 100 mg/day, 150 mg/day, 200 mg/day, 250 mg/day, 300 mg/day, or a dose between these, more preferably 150 mg/day, 200 mg/day, 250 mg/day, 300 mg/day, or a dose in between.

EXAMPLES

[0050] The present invention is described below more specifically by showing Examples. However, the scope of the present invention is not limited to the embodiments in the following Examples.

[0051] Compound A, which was used in the Examples, is the following compound:

[0052] cocrystal containing 1-{2-[(3S,4R)-1-{[(3R,4R)-1-cyclopentyl-3-fluoro-4-(4-methoxyphenyl)pyrrolidin-3-yl]carbonyl}-4-(methoxymethyl)pyrrolidin-3-yl]-5-(trifluoromethyl)phenyl}piperidine-4-carboxylic acid and phosphoric acid.

[0053] 1-{2-[(3S,4R)-1-{[(3R,4R)-1-cyclopentyl-3-fluoro-4-(4-methoxyphenyl)pyrrolidin-3-yl]carbonyl}-4-(methoxymethyl)pyrrolidin-3-yl]-5-(trifluoromethyl)phenyl}piperidine-4-carboxylic acid was produced by the method described in Patent Document 2, and the cocrystal with phosphoric acid was produced by the following method.

[0054] More specifically, a solution of potassium carbonate (3.4 kg) in water (77.0 L) and water (19.3 L) was added sequentially to a suspension of 1-{2-[(3S,4R)-1-{[(3R,4R)-1-cyclopentyl-3-fluoro-4-(4-methoxyphenyl)pyrrolidin-3-yl]carbonyl}-4-(methoxymethyl)pyrrolidin-3-yl]-5-(trifluoromethyl)phenyl}piperidine-4-carboxylic acid 1/2 ethane-1,2-disulfonic acid (19.3 kg) in ethyl acetate (86.6 kg) at 20 to 30°C, and the resulting mixture was stirred for 10 minutes. After allowing the mixture to stand, the aqueous layer was removed and the organic layer was washed twice with water (96.3 L). After concentrating the organic layer to 35 L, ethanol (75.9 kg) was added to it, followed by concentrating the resulting mixture to 35 L. The resulting concentrate was diluted with ethanol (30.3 kg), and the insoluble matter was filtered and washed with ethanol (75.6 kg). The filtrate and washings were combined, concentrated to 35 L, and then diluted with ethanol (17.9 kg). After sequential addition of 24% aqueous sodium hydroxide solution (6.1 kg) and water (15.6 kg) at 20 to 30 °C, the resulting mixture was stirred at 20 to 30 °C for 5 h. At 20 to 40 °C, a solution of phosphoric acid (8.5 kg) in water (28.9 L) and water (115.5 L) were added sequentially. At 30 to 40 °C, compound A (0.48 kg) was added as seed crystals. The resulting mixture was stirred for 19.5 h and then cooled to 20 °C. The solid was collected by filtration and then washed with water (96.3 L). The solid was dried at not more than 50 °C and pulverized to obtain compound A (17.5 kg).

[0055] The obtained compound A was identified using IV.

Example 1

[0056] Time to Occurrence of Phototoxicity-Related Symptom in the Clinical Trial of Compound A for Patients with Erythropoietic Protoporphyria and Patients with X-Linked Porphyria

[0057] Compound A was administered to adult male and female patients with erythropoietic protoporphyria or X-linked porphyria for 16 weeks in a randomized, double-blind clinical trial. As the primary endpoint for clinical effect, the time to first symptom due to exposure to light, including indirect sunlight and direct sunlight, during the period from 1 hour after sunrise to 1 hour before sunset was assessed.

[0058] The median baseline erythrocyte protoporphyrin IX level was determined by measuring the level of protoporphyrin IX in the erythrocyte fraction of the blood.

[0059] Median melanin density was determined by spectrophotometric measurement for skin at the following six sites: forehead, left cheek, inner aspect of the right arm, inner aspect of the left forearm, right side of the abdomen, and left side of the hip.

[0060] Table 1 shows the results of the week 16 assessment obtained for 35 cases in which placebo was administered, 33 cases in which 100 mg of Compound A was taken orally once daily, and 34 cases in which 300 mg of Compound A was taken orally once daily. The groups in which 100 mg or 300 mg of Compound A was administered had time periods of 53.8 minutes and 62.5 minutes, respectively, indicating a significant prolongation of the time period relative to the group in which placebo was administered. [Table 1]

[0061] According to the analysis of the above item in the group of patients whose baseline median erythrocyte protoporphyrin IX level was not less than 1,980.50 mcg/dL, when 100 mg of compound A was administered, the least squares mean of the time (in minutes) to the first occurrence of the symptom in a day was 69.3 minutes (P value, 0.020), and when 300 mg of compound A was administered, the least squares mean of the time (in minutes) to the first occurrence of the symptom in a day was 82.6 minutes (P value, 0.003). Thus, both cases showed statistical significance. Also in the group of patients whose baseline median erythrocyte protoporphyrin IX level was less than 1,980.50 mcg/dL, the time to the first occurrence of the symptom in a day tended to be prolonged.

[0062] Furthermore, the analysis of the above item was performed after dividing the subjects into the group of patients whose median melanin density was not less than 3.0915 and the group of patients whose median melanin density was less than 3.0915. As a result, in the former group, when 100 mg of the compound was administered, the least squares mean of the time (in minutes) to the first occurrence of the symptom within a day was 85.0 minutes (P value, <0.001), and when 300 mg of the compound was administered, it was 80.3 minutes (P value, 0.002). In this latter group, when 100 mg of the compound was administered, the least-squares mean time (in minutes) to first symptom occurrence within a day was 23.2 minutes (P value, 0.499), and when 300 mg of the compound was administered, it was 63.7 minutes (P value, 0.051), indicating that the effect prolonging the time to symptom occurrence related to phototoxicity is greater at 300 mg.

Example 2

[0063] Time to occurrence of phototoxicity-related symptom (Primary Clinical Endpoint) in patients with erythropoietic protoporphyria and patients with X-linked porphyria evaluated for the subgroup in which the initial Compound A dosage was performed in Spring or Summer and the subgroup in which the initial Compound A dosage was performed in Fall or Winter

[0064] The testing in Example 2 was conducted in the Northern Hemisphere. Table 2 shows the Week 16 assessment results obtained for a subgroup in which initial dosing of Compound A was performed in the spring or summer (20 cases in which placebo was administered, 18 cases in which 100 mg of Compound A was taken orally once daily, and 18 cases in which 300 mg of Compound A was administered orally once daily) and a subgroup in which initial dosing of Compound A was performed in the fall or winter (15 cases in which placebo was administered, 15 cases in which 100 mg of Compound A was taken orally once daily, and 16 cases in which 300 mg of Compound A was taken orally once daily). In the spring-summer subgroup, the groups in which 100 mg or 300 mg of compound A were administered showed times of 54.4 minutes and 42.2 minutes, respectively, indicating prolongation of time relative to the group in which placebo was administered. In the autumn-winter subgroup, the groups in which 100 mg or 300 mg of compound A were administered showed times of 52.8 minutes and 95.8 minutes, respectively, indicating a significant prolongation of time relative to the group in which placebo was administered. Thus, both groups in which 100 mg or 300 mg of compound A were administered showed prolongation of time, regardless of season. [Table 2]

Example 3

[0065] Number of Pain Events Recorded in the Electronic Diary by Patients During the 16-Week Evaluation Period in the Clinical Trial of Compound A for Patients with Erythropoietic Protoporphyria and Patients with X-Linked Porphyria

[0066] Compound A was administered to adult male and female patients with erythropoietic protoporphyria or X-linked porphyria for 16 weeks in a double-blind randomized clinical trial. As another endpoint for clinical effect, the number of pain events during the 16-week evaluation period was recorded in an electronic diary by the patients themselves.

[0067] Table 3 shows the evaluation results obtained for 23 cases in which placebo was administered, 24 cases in which 100 mg of Compound A was taken orally once daily, and 24 cases in which 300 mg of Compound A was taken orally once daily. The incidence rates of pain during the evaluation period in the placebo administration group, the 100 mg Compound A administration group, and the 300 mg Compound A administration group were 7.5, 3.3, and 3.5, respectively. Thus, the 100 mg Compound A administration group and the 300 mg Compound A administration group showed significantly reduced pain events by 60% and 50%, respectively, compared to the placebo administration group (Table 3). [Table 3]

Example 4

[0068] Assessment of Health-Related QoL of Patients in a Clinical Trial of Compound A for Patients with Erythropoietic Protoporphyria and Patients with X-Linked Porphyria

[0069] Compound A was administered to adult male and female patients with erythropoietic protoporphyria or X-linked porphyria for 16 weeks in a double-blind randomized clinical trial. As a secondary endpoint for clinical effect, the PGIC (Patient Global Impression of Change) score, which is a health-related QOL, of each patient at week 16 was recorded by the patients themselves. More specifically, each patient was given a questionnaire to score the degree of improvement in general physical and mental health conditions on a 7-point scale. In this case, a PGIC score of 1 indicates that no change occurred or that an exacerbation occurred, and a score of 7 indicates that a notable improvement was achieved.

[0070] Table 4 shows the evaluation results obtained for 30 cases in which placebo was administered, 25 cases in which 100 mg of Compound A was taken orally once daily, and 24 cases in which 300 mg of Compound A was taken orally once daily. The PGIC scores at week 16 in the placebo administration group, the 100 mg Compound A administration group, and the 300 mg Compound A administration group were 2.9, 6.4, and 6.6, respectively. Thus, the 100 mg Compound A administration group and the 300 mg Compound A administration group showed significant increases in PGIC score relative to the placebo administration group, indicating their improvement in global impression (Table 4). [Table 4]

Example 5 Phase III Trial Using Compound A as Test Substance

[0071] Subjects: Male and female patients with erythropoietic protoporphyria or X-linked porphyria, whose ages range from 12 years to 75 years.

[0072] Trial Outline: Double-Blind Randomized Clinical Trial

[0073] In 53 cases, placebo is administered. In 53 cases, 100 mg of compound A is taken orally once a day. In 53 cases, 200 mg of compound A is taken orally once a day.

[0074] Test items

[0075] (1) Time to occurrence of a symptom related to phototoxicity in a clinical trial of compound A for patients with erythropoietic protoporphyria and patients with X-linked porphyria

[0076] In a double-blind randomized clinical trial, compound A is administered to subjects for 26 weeks and, depending on the conditions, further administration is carried out for 26 weeks or up to 58 weeks. As the primary endpoint for clinical effect, the time to the first occurrence of a symptom due to light exposure in a day is assessed at week 26.

[0077] (2) The number of pain events recorded in an electronic diary by patients during a 26-week evaluation period in a clinical trial of compound A for patients with erythropoietic protoporphyria and patients with X-linked porphyria

[0078] In a double-blind randomized clinical trial, compound A is administered to subjects for 26 weeks and, depending on the conditions, further administration is performed for 26 weeks or up to 58 weeks. As a further endpoint for clinical effect, the number of pain events during the 26-week evaluation period is recorded in an electronic diary by the patients themselves.

[0079] (3) Assessment of health-related quality of life of patients in a clinical trial of compound A for patients with erythropoietic protoporphyria and patients with X-linked porphyria

[0080] In a double-blind randomized clinical trial, compound A is administered to subjects for 26 weeks, and depending on the conditions, additional administration is performed for 26 weeks or up to 58 weeks. As a secondary endpoint for the clinical effect, the PGIC (Patient Global Impression of Change) score, which is a health-related QOL, of each patient at week 26 is recorded by the patients themselves. More specifically, each patient is given a questionnaire to score the degree of improvement in general physical and mental health conditions on a 7-point scale. In this case, the lowest score of the PGIC score, 1 point, indicates “Much Improved” and the highest score, 7 points, indicates “Much Worse”.

Claims (4)

1. Use of 1-{2-[(3S,4R)-1-{[(3R,4R)-1-cyclopentyl-3-fluoro-4-(4-methoxyphenyl)pyrrolidine-3-yl]carbonyl}-4-(methoxymethyl)pyrlidin-3-yl]-5-(trifluoromethyl)phenyl}piperidine-4-carboxylic acid or a pharmaceutically acceptable salt or cocrystal thereof as an active ingredient in the manufacture of a medicament for the treatment or prevention of porphyria. 2. Use according to claim 1, characterized in that the porphyria is erythropoietic protoporphyria, X-linked porphyria, congenital erythropoietic porphyria, variegate porphyria, acute intermittent porphyria, porphyria cutanea tarda or hereditary coproporphyria. 3. Use according to claim 2, characterized in that the porphyria is erythropoietic protoporphyria or X-linked porphyria. 4. Use according to any one of claims 1 to 3, characterized in that the 1-{2-[(3S,4R)-1-{[(3R,4R)-1-cyclopentyl-3-fluoro-4-(4-methoxyphenyl)pyrrolidin-3-yl]carbonyl}-4-(methoxymethyl)pyrrolidin-3-yl]-5-(trifluoromethyl)phenyl}piperidine-4-carboxylic acid or the pharmaceutically acceptable salt or cocrystal thereof is a cocrystal of 1-{2-[(3S,4R)-1-{[(3R,4R)-1-cyclopentyl-3-fluoro-4-(4-methoxyphenyl)pyrrolidin-3-yl]carbonyl}-4-(methoxymethyl)pyrrolidin-3-yl]-5-(trifluoromethyl)phenyl}piperidine-4-carboxylic acid and phosphoric.