WO2020053218A1 - Traitement du psoriasis - Google Patents

Traitement du psoriasis Download PDF

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Publication number
WO2020053218A1
WO2020053218A1 PCT/EP2019/074122 EP2019074122W WO2020053218A1 WO 2020053218 A1 WO2020053218 A1 WO 2020053218A1 EP 2019074122 W EP2019074122 W EP 2019074122W WO 2020053218 A1 WO2020053218 A1 WO 2020053218A1
Authority
WO
WIPO (PCT)
Prior art keywords
dimethyl fumarate
treatment
dose form
pharmaceutical dose
psoriasis
Prior art date
Application number
PCT/EP2019/074122
Other languages
English (en)
Inventor
Maria Cristina DIAZ GALLO
Alexandre Kaoukhov
Maria Teresa SANZ SANTESTEBAN
Original Assignee
Almirall, S.A.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Almirall, S.A. filed Critical Almirall, S.A.
Publication of WO2020053218A1 publication Critical patent/WO2020053218A1/fr

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
    • A61K31/22—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin
    • A61K31/225—Polycarboxylic acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/06—Antipsoriatics

Definitions

  • the present invention relates to new therapies for treating psoriasis, wherein dimethyl fumarate is administered according to an optimised dose regimen.
  • Psoriasis is an incurable inflammatory and autoimmune disease in need of adequate oral treatments that can control the symptoms of the disease.
  • Fumaric acid esters are chemical compounds derived from unsaturated dicarboxylic fumaric acid and have been used in the treatment of psoriasis for years, as originally proposed by the German chemist Walter Schweckendiek.
  • Fumaderm® (Fumapharm AG), a mixture of dimethyl fumarate (DMF) and calcium, magnesium and zinc salts of monoethyl fumarate (MEF), was approved for the treatment of psoriasis in Germany.
  • Fumaderm® is available in two different dosage strengths: low strength tablets (Fumaderm® initial) containing 30 mg dimethyl fumarate and high strength tablets (Fumaderm®) containing 120 mg dimethyl fumarate.
  • Skilarence® (Almirall, SA) has also been approved from the treatment of psoriasis, and is available as tablets containing 30 mg dimethyl fumarate and 120 mg dimethyl fumarate.
  • the core of the Skilarence® tablets contains lactose monohydrate, microcrystalline cellulose, croscarmellose sodium, colloidal anhydrous silica and magnesium stearate.
  • the tablet has a gastro-resistant coating containing methacrylic acid-ethyl acrylate copolymer (1 :1 ), talc, triethyl citrate, titanium dioxide (E171 ), simethicone, indigo carmine (E132) and sodium hydroxide.
  • the present invention provides a method of treating psoriasis in a human patient, wherein the method comprises orally administering to the patient a pharmaceutical dose form comprising dimethyl fumarate, and wherein the total amount of dimethyl fumarate administered per day is 420 to 460 mg.
  • the invention further provides a pharmaceutical dose form comprising dimethyl fumarate for use in a method of treatment of psoriasis, wherein the method comprises orally administering to the patient a pharmaceutical dose form comprising dimethyl fumarate, and wherein the total amount of dimethyl fumarate administered per day is 420 to 460 mg.
  • the invention further provides use of a pharmaceutical dose form comprising dimethyl fumarate in the manufacture of a medicament for use in a method of treating psoriasis, wherein the method comprises orally administering to the patient a pharmaceutical dose form comprising dimethyl fumarate, and wherein the total amount of dimethyl fumarate administered per day is 420 to 460 mg.
  • treatment refers to the treatment of a disease or medical condition in a human patient which includes:
  • a“dosage form” refers to the physical appearance and configuration of a product that is suitable for oral administration to a human patient and that contains a given fixed amount of the active ingredient, i.e. a“dose” of dimethyl fumarate.
  • a pharmaceutical dose form comprising dimethyl fumarate may accordingly be solid, such as a tablet, a capsule or a powder, or liquid, such as a syrup or a solution.
  • a method comprising orally administering a pharmaceutical dose form to a human patient to achieve a total daily amount of dimethyl fumarate administered may accordingly comprise orally administering one or more tablets comprising dimethyl fumarate or one or more capsules comprising dimethyl fumarate per day until the total daily amount of dimethyl fumarate has been administered.
  • solid pharmaceutical dose form refers to a pharmaceutical dose form which consists essentially of solid components. Accordingly, the final composition of such a solid pharmaceutical dose form is substantially free of a liquid component (such as a liquid excipient or liquid diluent).
  • a solid pharmaceutical dose form may be a solid tablet obtained by compressing a pharmaceutical composition comprising dimethyl fumarate and excipients or a capsule having a solid shell and containing a powder or a plurality of solid small tablets (so-called micro-tablets) comprising dimethyl fumarate in the absence of a liquid excipient or liquid diluent.
  • a capsule comprising a liquid suspension does not constitute a solid pharmaceutical dose form.
  • active ingredient refers to a component in a pharmaceutical dose form which is intended to have a pharmacological effect in the patient to which the
  • Dimethyl fumarate is an active ingredient in the pharmaceutical dose form described herein.
  • the term“only active ingredient” as used herein refers to the presence of only the single active ingredient (dimethyl fumarate) in the pharmaceutical dose form.
  • Such a pharmaceutical dose form does not therefore include any other active ingredients (i.e. components which are intended to have a pharmacological effect in the patient).
  • the pharmaceutical dose form may not comprise any other pharmaceutical compounds.
  • Such a pharmaceutical dose form may, however, comprise excipients and diluents such as lactose, silica, cellulose, croscarmellose sodium and mangnesium stearate.
  • Dimethyl fumarate (Dimethyl (E)-butenedioate; CAS RN 624-49-7) is the dimethyl ester of fumaric acid, which has the molecular formula C 6 H 8 0 4 , the molecular mass 144.13 g/mol and the following chemical formula:
  • German Medicines Codex 2004 it is a white crystalline powder having a melting point in the range from 102-105 5 C.
  • the crystallographic properties of dimethyl fumarate are described Kooijman H et al, Acta Cryst. (2004), E60, o917-o918.
  • Dimethyl fumarate can be obtained by reacting fumaric acid and methanol under the presence of concentrated sulphuric acid as catalyst (Ma Hongfei, Chemical industry Times, 2005, Vol. 19, No. 4, 18-19).
  • the active ingredient is rapidly hydrolysed in-vivo to the metabolite monomethyl fumarate.
  • the dimethyl fumarate is in solid form, for example in the form of particles.
  • the dimethyl fumarate can be sieved and/or milled to control its particle size.
  • the dimethyl fumarate has a particle size distribution d(10) between 5-20 pm, a d(50) between 30-70 pm, and a d(90) between 80-150 pm, measured using the laser diffraction particle size analyzer Mastersizer 2000 (Malvern Instruments).
  • the total daily amount of 420 to 460 mg of dimethyl fumarate is administered orally in a suitable pharmaceutical dose form, which may be taken once or twice per day, preferably twice per day. Most preferably, the total daily dose of dimethyl fumarate administered to the patient is 440 mg.
  • a preferred pharmaceutical dose form comprises 210 mg, 220 mg or 230 mg of dimethyl fumarate.
  • the pharmaceutical dose form comprising the amount of dimethyl fumarate to be administered, i.e. the dose is a capsule containing several small tablets (so- called micro-tablets) comprising dimethyl fumarate.
  • Each of the micro-tablets comprises a fraction of the dose of dimethyl fumarate.
  • Each micro-tablet typically has a diameter of 500 pm to 5 mm, preferably of 1 to 4 mm.
  • the micro-tablets are preferably coated with a gastro- resistant composition to prevent dissolution in the stomach.
  • the tablets in the pharmaceutical dose form comprise:
  • the particles of dimethyl fumarate may be coated or may not be coated. In a preferred embodiment the particles are not coated.
  • the method of treatment of psoriasis comprises administering a total amount of from 420 to 460 mg of dimethyl fumarate per day.
  • the plasma concentrations of monomethyl fumarate during the treatment are such that the Cmax is from about 1 ,200 to about 2,200 ng/ml_ and/or the AUC (0-t) is from about 6,100 to about 8,900 ng.h/mL.
  • the method of the invention is for the treatment of psoriasis.
  • the severity of psoriasis can be readily determined by any skilled physician using the following tools:
  • Psoriasis Area and Severity Index Psoriasis Area and Severity Index (PASI); Body Surface Area (BSA); and
  • PAS I combines the assessment of the severity of lesions and the area affected into a single score in the range 0 (no disease) to 72 (maximal disease). Response to treatment is often reported as a percentage response rate; e.g., PASI 50, PASI 75, PASI 90, PASI 100.
  • PASI 75 represents the percentage (or number) of patients who have achieved a 75% or more reduction in their PASI score from baseline.
  • BSA is the percentage of the body surface area affected by psoriasis, and is typically
  • PGA is measured on a scale of 0 to 5 (0 representing no psoriasis, to 5 represents very severe psoriasis). The erythema, induration and scale of the psoriasis assessed, each on a scale of 0 to 5, and the average is reported as the PGA.
  • the psoriasis is chronic plaque psoriasis.
  • the psoriasis may be moderate to severe psoriasis (which may be as measured by PGA).
  • the psoriasis treated by the invention may be severe psoriasis.
  • the total amount of dimethyl fumarate administered to the human patient per day is 440 mg. More preferably, the human patient is orally administered a pharmaceutical dose form comprising 220 mg of dimethyl fumarate twice daily.
  • the two pharmaceutical dose forms comprising 220 mg of dimethyl fumarate administered each day can be administered at the same time. Alternatively, it may be preferable to administer the two pharmaceutical dose forms comprising 220 mg of dimethyl fumarate at different times of the day. For example, a first pharmaceutical dose form comprising 220 mg of dimethyl fumarate could be administered in the morning and a second pharmaceutical dose form comprising 220 mg of dimethyl fumarate could be administered in the afternoon or evening.
  • Psoriasis is chronic and, at present, incurable. Accordingly, it is desirable to provide a treatment regime that can be taken for long periods of time (ideally without causing unmanageable side effects), to reduce symptoms and/or prevent the recurrence of symptoms when in remission. Such a treatment regime is commonly referred to as a“maintenance treatment”.
  • a“maintenance treatment” is commonly referred to as a“maintenance treatment”.
  • a maintenance treatment is a long-term treatment typically lasting several months (for instance for at least 2 months or for from 2 to 36 months).
  • the method may further comprise a prior period of treatment, wherein the prior period of treatment comprises orally administering to the human patient a total daily amount of from 640 to 680 mg of dimethyl fumarate for a period of from 12 to 20 weeks, preferably for 14 to 18 weeks, most preferably 15 or 16 weeks.
  • the prior period of treatment comprises orally administering to the human patient a total daily amount of 660 mg of dimethyl fumarate for a period of from 12 to 20 weeks.
  • the prior period of treatment may comprise orally administering to the human patient three times daily a pharmaceutical dose form comprising 220 mg of dimethyl fumarate for a period of from 12 to 20 weeks.
  • the method for treating psoriasis may accordingly therefore comprise a prior period of treatment during which the patient is administered three times daily a pharmaceutical dose form
  • the prior period of treatment may further comprise an initial treatment period, wherein the initial treatment period comprises orally administering to the human patient a total daily amount of from 420 to 460 mg of dimethyl fumarate during the first week of the prior period of treatment.
  • the total amount of dimethyl fumarate administered to the human patient per day during the initial treatment period is typically 440 mg.
  • the initial treatment period may therefore comprise orally administering to the human patient twice daily a pharmaceutical dose form comprising 220 mg of dimethyl fumarate during the first week of the prior period of treatment.
  • the human patient may be orally administered a first pharmaceutical dose form comprising 220 mg of dimethyl fumarate in the morning and a second pharmaceutical dose form comprising 220 mg of dimethyl fumarate in the afternoon or evening during the initial treatment period.
  • the method for treating psoriasis may therefore comprise (i) an initial period of treatment during which the patient is administered twice daily a pharmaceutical dose form comprising 220 mg of dimethyl fumarate for one week followed by (ii) a prior period of treatment during which the patient is administered three times a day a pharmaceutical dose form comprising 220 mg of dimethyl fumarate for from 12 to 20 weeks followed by (iii) a period of treatment during which the patient is administered twice daily a pharmaceutical dose form comprising 220 mg of dimethyl fumarate.
  • the pharmaceutical dose form is typically a solid pharmaceutical dose form.
  • the pharmaceutical dose form is preferably a tablet or a capsule comprising dimethyl fumarate in solid form.
  • the pharmaceutical dose form may be a capsule comprising a dry powder comprising dimethyl fumarate.
  • a solid pharmaceutical dose form which is a capsule is substantially free of a liquid excipient or liquid diluent.
  • the content of the capsule may consist of micro-tablets comprising dimethyl fumarate.
  • dimethyl fumarate is the only active ingredient present in the pharmaceutical dose form.
  • the pharmaceutical dose form typically does not comprise another derivative of fumaric acid (such as a salt of monomethyl fumarate or monoethyl fumarate).
  • the pharmaceutical dose form typically does not comprise an enzyme modulator selected from tricalcium phosphate and disodium EDTA and does not comprise a permeation enhancer which is sodium lauryl sulfate.
  • the pharmaceutical dose form does not comprise an enzyme modulator and does not comprise a permeation enhancer.
  • the pharmaceutical dose form comprises (i) a capsule and, within the capsule, (ii) micro-tablets as defined herein, it is preferred that neither an enzyme modulator nor a permeation enhancer is present (either as part of the capsule, part of the tablets, or otherwise within the capsule).
  • the pharmaceutical dose form is not a pulsatile-release pharmaceutical composition.
  • the pharmaceutical dose form is administered during a meal or within about one hour after a meal. Preferably, it is administered to the patient during a meal or not later than 30 minutes after a meal. Thus, the patient is typically in a fed state when the pharmaceutical dose form is administered.
  • Lymphocyte subsets such as lymphocytes T-CD4 and T-CD8 (Time Frame: baseline, week 8 and 12).
  • the starting dose will be 440 mg daily and after 7 days, the dose will be increased to 220 mg three times per day (daily 660 mg) or matching placebo.
  • patients receiving placebo will be switched to active treatment with 660 mg per day of DMF, as described above, while patients receiving 660 mg per day of DMF will be randomised to receive 440 mg daily or 660 mg daily, in a blinded manner until the end of the trial.
  • the patients will visit the study center at baseline (Day 1 , Visit 1 ) and at Weeks 1 (Visit 2), 3 (Visit 3), 5 (Visit 4), 8 (Visit 5), 12 (Visit 6) and 16 (Visit 7). After 16 weeks the blind will be opened and the patients will be treated for further 32 weeks until last study visit (V8 at week 24 and V9 at week 48).
  • Safety analysis set All subjects who were randomized and received at least one dose of investigational medicinal product.
  • PPS Per Protocol set
  • FAS Full Analysis Set
  • the two co-primary efficacy variables, percentage of patients achieving a PASI75 at week 16 and percentage of patients achieving PGA of clear (0) or almost clear (1 ) with at least 2 points reduction from baseline at week 16 will be analysed by means of Cochran Mantenl Haenszel test (CMH) stratified by geographical site/geographical region.
  • CMH Cochran Mantenl Haenszel test
  • the p-values for both co-primary tests must be less than 0.05 for the trial to be considered to have met the primary efficacy objective.
  • the Last Observation Carried Forward (LOCF) will be the main approach for handling missing data.
  • the Non-Responder Imputation (NRI) approach and Multiple Imputation (IM) will be used as sensitivity analyses.
  • Safety data (AEs, Vital signs, laboratory parameters and ECG) will be based on SAS population and will be summarised by means of descriptive statistics across treatment groups.

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  • Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Chemical & Material Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • Medicinal Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • General Chemical & Material Sciences (AREA)
  • Dermatology (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Engineering & Computer Science (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Emergency Medicine (AREA)
  • Epidemiology (AREA)
  • Organic Chemistry (AREA)

Abstract

La présente invention concerne un procédé de traitement du psoriasis chez un patient humain, le procédé comprenant l'administration par voie orale au patient humain d'une forme posologique pharmaceutique comprenant du fumarate de diméthyle, et la quantité totale de fumarate de diméthyle administrée par jour étant de 420 à 460 mg.
PCT/EP2019/074122 2018-09-13 2019-09-10 Traitement du psoriasis WO2020053218A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
EP18382655 2018-09-13
EP18382655.1 2018-09-13

Publications (1)

Publication Number Publication Date
WO2020053218A1 true WO2020053218A1 (fr) 2020-03-19

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Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2015028472A1 (fr) * 2013-08-26 2015-03-05 Forward Pharma A/S Composition pharmaceutique contenant du fumarate de diméthyle pour une administration à une faible dose journalière
WO2015086467A1 (fr) 2013-12-12 2015-06-18 Almirall, S.A. Compositions pharmaceutiques contenant du fumarate de diméthyle
US9511043B2 (en) * 2014-02-28 2016-12-06 Banner Life Sciences Llc Fumarate ester pharmaceutical compositions
WO2017040272A1 (fr) * 2015-08-31 2017-03-09 Banner Life Sciences Llc Formes posologiques d'ester de fumarate
WO2017072699A1 (fr) * 2015-10-28 2017-05-04 Sun Pharmaceutical Industries Limited Compositions pharmaceutiques de fumarate de diméthyle

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2015028472A1 (fr) * 2013-08-26 2015-03-05 Forward Pharma A/S Composition pharmaceutique contenant du fumarate de diméthyle pour une administration à une faible dose journalière
WO2015086467A1 (fr) 2013-12-12 2015-06-18 Almirall, S.A. Compositions pharmaceutiques contenant du fumarate de diméthyle
US9511043B2 (en) * 2014-02-28 2016-12-06 Banner Life Sciences Llc Fumarate ester pharmaceutical compositions
WO2017040272A1 (fr) * 2015-08-31 2017-03-09 Banner Life Sciences Llc Formes posologiques d'ester de fumarate
WO2017072699A1 (fr) * 2015-10-28 2017-05-04 Sun Pharmaceutical Industries Limited Compositions pharmaceutiques de fumarate de diméthyle

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
KOOIJMAN H ET AL., ACTA CRYST., vol. E60, 2004, pages o917 - o918
MA HONGFEI, CHEMICAL INDUSTRY TIMES, vol. 19, no. 4, 2005, pages 18 - 19

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