WO2020053219A1

WO2020053219A1 - Treatment of psoriasis

Info

Publication number: WO2020053219A1
Application number: PCT/EP2019/074123
Authority: WO
Inventors: Maria Cristina DIAZ GALLO; Alexandre Kaoukhov; Maria Teresa SANZ SANTESTEBAN
Original assignee: Almirall SA
Current assignee: Almirall SA
Priority date: 2018-09-13
Filing date: 2019-09-10
Publication date: 2020-03-19
Anticipated expiration: 2021-03-13

Abstract

The present invention relates to a method of treating psoriasis in a human patient, wherein the method comprises orally administering to the human patient a pharmaceutical dose form comprising dimethyl fumarate, and wherein the total amount of dimethyl fumarate administered per day is from 630 to 690 mg.

Description

TREATMENT OF PSORIASIS

FIELD OF THE INVENTION

The present invention relates to new therapies for treating psoriasis, wherein dimethyl fumarate is administered according to an optimised dose regimen.

BACKGROUND OF THE INVENTION

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 (FAE) 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.

In 1994, 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 dosing regimens for Fumaderm® and Skilarence® used in patients are highly complex and variable and range from 30mg per day up to a maximum recommended dose of 720 mg per day. There therefore exists a need for improved dosage regimes for dimethyl fumarate that maximise its efficacy and safety profile for clinical use in treating patients with psoriasis. SUMMARY OF THE INVENTION

It has now surprisingly been found that, for treatment of psoriasis, oral administration of a total daily amount of 630 to 690 mg of dimethyl fumarate per day is optimal. This dosage has been found to provide the best combination of efficacy and safety for clinical use in treating patients with psoriasis.

Accordingly, 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 630 to 690 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 630 to 690 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 630 to 690 mg.

DETAILED DESCRIPTION OF THE INVENTION

The term "treatment" as used herein refers to the treatment of a disease or medical condition in a human patient which includes:

(a) preventing the disease or medical condition from occurring, i.e., prophylactic treatment of a patient;

(b) ameliorating the disease or medical condition, i.e., causing regression of the disease or medical condition in a patient;

(c) suppressing the disease or medical condition, i.e., slowing the development of the

disease or medical condition in a patient; or (d) alleviating the symptoms of the disease or medical condition in a patient.

The term“pharmaceutical dose form”, also known as a“dosage form”, as used herein 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.

The term“solid pharmaceutical dose form” as used herein 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). For instance, 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. For the avoidance of doubt, a capsule comprising a liquid suspension does not constitute a solid pharmaceutical dose form.

The term“active ingredient” as used herein refers to a component in a pharmaceutical dose form which is intended to have a pharmacological effect in the patient to which the

pharmaceutical dose form is to be administered. 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). For instance, 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 fumarate (Dimethyl (E)-butenedioate; CAS RN 624-49-7) is the dimethyl ester of fumaric acid, which has the molecular formula C₆H₈0₄, the molecular mass 144.13 g/mol and the following chemical formula:

According to the German Medicines Codex 2004 (DAC 2004) it is a white crystalline powder having a melting point in the range from 102-105⁵C. 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).

Following administration of dimethyl fumarate to a human patient, the active ingredient is rapidly hydrolysed in-vivo to the metabolite monomethyl fumarate.

Typically, 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. In a preferred embodiment 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 pharmaceutical dose form

The total daily amount of 630 to 690 mg of dimethyl fumarate is administered orally in a suitable pharmaceutical dose form, which may be taken once, twice or three times per day, preferably three times per day. Most preferably, the total daily dose of dimethyl fumarate administered to the patient is 660 mg. Thus, a preferred pharmaceutical dose form comprises 210 mg, 220 mg or 230 mg of dimethyl fumarate. In a preferred embodiment 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.

Preferably, the tablets in the pharmaceutical dose form comprise:

(a) particles of dimethyl fumarate;

(b) lactose;

(c) microcrystalline cellulose; and

(d) croscarmellose sodium.

The particles of dimethyl fumarate may be coated or may not be coated. In a preferred embodiment the particles are not coated.

Descriptions of tablets having a suitable composition for the pharmaceutical dose forms for use in the method of treating psoriasis are provided for example in WO 2015/086467, which is herein incorporated by reference in its entirety.

Method of treatment of psoriasis

The method of treatment of psoriasis comprises administering a total amount of from 630 to 690 mg of dimethyl fumarate per day.

Typically, the plasma concentrations of monomethyl fumarate during the treatment are such that the Cmax is from about 1 ,700 to about 2,800 ng/ml_ and/or the AUC (0-t) is from about 10,100 to about 12,600 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 (PASI); Body Surface Area (BSA); and

Physician Global Assessment (PGA).

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, for example, 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 determined visually based on the area of a hand representing 1% of body surface area.

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.

Typically, the psoriasis is chronic plaque psoriasis. The psoriasis may be moderate to severe psoriasis (which may be as measured by PGA). For instance, the psoriasis treated by the invention may be severe psoriasis.

Preferably, the total amount of dimethyl fumarate administered to the human patient per day is 660 mg. More preferably, the human patient is orally administered a pharmaceutical dose form comprising 220 mg of dimethyl fumarate three times a day.

The three 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 three 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, a second pharmaceutical dose form comprising 220 mg of dimethyl fumarate could be administered in the afternoon and a third pharmaceutical dose form comprising 220 mg of dimethyl fumarate could be administered in the 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”. Typically, orally administering a total amount per day of 630 to 690 mg of dimethyl fumarate according to the present invention is a maintenance treatment. The 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).

Typically, the maintenance treatment described above will be preceded by one week of initial treatment (also called titration treatment). Accordingly, the method may further comprise an initial treatment period prior to the maintenance treatment, 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 treatment. Typically, the total amount of dimethyl fumarate administered to the human patient per day during the initial treatment period is 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 treatment. For example, 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 during the initial treatment period.

The method for treating psoriasis may therefore comprise 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 a period of treatment during which the patient is administered three times a day 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. For instance, 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.

Typically, dimethyl fumarate is the only active ingredient present in the pharmaceutical dose form. For instance, 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. Typically, the pharmaceutical dose form does not comprise an enzyme modulator and does not comprise a permeation enhancer. Thus, when 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). In some embodiments, the pharmaceutical dose form is not a pulsatile-release pharmaceutical composition.

Typically, 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.

The invention will be described in more detail with reference to the following Examples.

EXAMPLE

A multi-center, randomized, double-blind, placebo controlled, phase 3 study to investigate the efficacy and safety of DMF vs. placebo in patients with moderate to severe chronic plaque psoriasis

OBJECTIVES

Primary objective:

• To assess the efficacy of DMF in the treatment of moderate to severe chronic plaque psoriasis based on the proportion of patients achieving PASI 75 (a 75% reduction in the Psoriasis Area and Severity Index, PASI) and on the proportion of patients achieving a score of“clear” or’’almost clear” in the Physician’s Global Assessment (PGA) after 16 or 24 weeks of treatment.

Secondary objectives:

• To assess if the treatment with DMF is able to improve the quality of life in patients with chronic plaque psoriasis based on the change from baseline in DLQI.

• To assess the safety of DMF in the treatment of chronic plaque psoriasis.

END-POINTS

Primary end-points:

• Percentage of patients who achieved at least a 75% Improvement (Response) in the Psoriasis Area Severity Index (PASI-75) at week 16 or 24 from baseline.

• Percentage of patients who achieved a Physician Global Assessment (PGA 5- point scale) Score of clear (0) or almost clear (1 ) with at least 2 points reduction at week 16 or 24 from baseline. Secondary end-points:

• Proportion of patients who achieved a 75% Improvement (Response) in the PASI Score (PASI-75) at weeks 3, 8, 24 and 48 from baseline.

• Proportion of patients who achieved a 50% improvement (Response) in the PASI Score (PASI-50) at weeks 3, 8,16, 24 and 48 from baseline.

• Proportion of patients who achieved a 90% improvement (Response) in the PASI Score (PASI-90) at weeks 3, 8,16, 24 and 48 from baseline.

• Proportion of patients who achieved a PGA Score (6-point scale) of clear (0) or almost clear (1 ) with at least 2 points reduction at weeks 3, 8, 24 and 48 from baseline.

• Change from baseline in the PASI Score at weeks 3, 8, 16, 24 and 48.

• Change from baseline in the Dermatology Life Quality Index (DLQI) Total Score at weeks 3, 8, 16, 24 and 48.

• The safety and tolerability of DMF vs. placebo at weeks 3, 8, 16, 24 and 48.

• Lymphocyte subsets (such as lymphocytes T-CD4 and T-CD8) (Time Frame: baseline, week 8 and 12).

• Change from baseline in the clinical signs of nail psoriasis by means of total

NAPSI at weeks 3, 8, 16, 24 and 48.

• Proportion of patients who achieved a ScPGA Score (Scalp PGA) of clear (0) or almost clear (1 ) with at least 2 points reduction at weeks 3, 8, 16, 24 and 48 from baseline.

• Proportion of patients who achieved a PPPGA Score (Palmo-plantar PGA) of clear (0) or almost clear (1 ) with at least 2 points reduction at weeks 3, 8, 16, 24 and 48 from baseline.

• Change from baseline in itching at weeks 3, 8, 16, 24 and 48 according to 5-D itch scale.

TRIAL DESIGN

This is a Phase 3, multi-center, randomized, double-blind, placebo-controlled, pivotal study to evaluate the efficacy and safety of a daily dose of DMF of 660 mg vs placebo (1 :1 ). METHODOLOGY

Patients meeting the main inclusion criteria will enter the study and will be randomly allocated to the treatment or to the placebo group.

In order to achieve an optimum efficacy and tolerability profile, 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.

During the subsequent 14 weeks (Week 2 until Week 16) the patients will receive 660 mg DMF per day or matching placebo.

At week 16, 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).

STATISTICAL METHODS

There will be three different analysis populations in this trial, and will be defined as following:

• Safety analysis set (SAS): All subjects who were randomized and received at least one dose of investigational medicinal product.

• Full analysis set (FAS): All randomized subjects, whether or not they received at least one dose of DMF/placebo or at least one measurement of the primary variable PAS I and PGA at Week 0.

• Per Protocol set (PPS): All subjects from FAS with no relevant protocol deviations. • All efficacy analyses will be performed on Full Analysis Set (FAS) population. Analysis of the two co-primary variables will also be carried out on the Per Protocol population to assess the robustness of the findings from the FAS population. In all statistical tests, the significance level will be set at 0.05 two-sided.

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. 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.

All secondary efficacy variables related to the binary endpoints (responder/non-responder) will be analysed by means of the same methodology as the two co-primary variables described above. All continuous secondary variables defined as either change from

baseline or absolute values, will be analysed by using ANCOVA models. Time-to-event secondary variables will be analysed by means of Kaplan-Meier survival curves and

estimators.

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.

CONCLUSION

Administration of 220 mg of dimethyl fumarate in solid form three times a day is found to provide optimal performance in treating psoriasis, and in particular provide the best balance of efficacy and safety in treating psoriasis.

Claims

1. A method of treating psoriasis in a human patient, wherein the method comprises orally administering to the human patient a pharmaceutical dose form comprising dimethyl fumarate, and wherein the total amount of dimethyl fumarate administered per day is from 630 to 690 mg.

2. A method according to claim 1 , wherein the plasma concentrations of monomethyl

fumarate during the treatment are such that the Cmax is from about 1 ,700 to about 2,800 ng/mL and/or the AUC (0-t) is from about 10,100 to about 12,600 ng.h/mL.

3. A method according to claim 1 or 2, wherein the psoriasis is chronic plaque psoriasis.

4. A method according to claim 1 or 2, wherein the psoriasis is moderate to severe

psoriasis.

5. A method according to claim 1 or 2, wherein the psoriasis is severe psoriasis.

6. A method according to any one of the preceding claims, wherein the total amount of dimethyl fumarate administered to the human patient per day is 660 mg.

7. A method according to claim 6, wherein the human patient is orally administered a

pharmaceutical dose form comprising 220 mg of dimethyl fumarate three times a day.

8. A method according to any one of the preceding claims, wherein the method is a

maintenance treatment.

9. A method according to claim 8, wherein the method further comprises an initial treatment period prior to the maintenance treatment, 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 treatment.

10. A method according to claim 9, wherein the total amount of dimethyl fumarate

administered to the human patient per day during the initial treatment period is 440 mg.

1 1 . A method according to claim 10, wherein the initial treatment period comprises orally administering to the human patient twice daily a pharmaceutical dose form comprising 220 mg of dimethyl fumarate during the first week of treatment.

12. A method according to any one of the preceding claims, wherein the pharmaceutical dose form is a solid pharmaceutical dose form.

13. A method according to any one of the preceding claims, wherein dimethyl fumarate is the only active ingredient present in the pharmaceutical dose form.

14. A method according to any one of the preceding claims, wherein the pharmaceutical dose form is administered during a meal or within about one hour after a meal.

15. A pharmaceutical dose form comprising dimethyl fumarate for use in a method of

treatment of psoriasis, wherein the method is as defined in any one of the preceding claims.

16. A pharmaceutical dose form for use according to claim 15, wherein the pharmaceutical dose form comprises 220 mg of dimethyl fumarate and the method comprises orally administering to the human patient the pharmaceutical dose form comprising 220 mg of dimethyl fumarate three times a day.

17. Use of a pharmaceutical dose form comprising dimethyl fumarate in the manufacture of a medicament for use in a method of treatment of psoriasis, wherein the method is as defined in any one of claims 1 to 14.