WO2015067503A1

WO2015067503A1 - Alpha-msh analogues for use in the treatment of psoriasis

Info

Publication number: WO2015067503A1
Application number: PCT/EP2014/073112
Authority: WO
Inventors: Philippe Wolgen
Original assignee: Clinuvel Ag
Priority date: 2013-11-07
Filing date: 2014-10-28
Publication date: 2015-05-14

Abstract

The present invention relates to alpha-MSH analogues, particularly afamelanotide, for use in treatment of psoriasis as well as to combination treatments.

Description

ALPHA-MSH ANALOGUES FOR USE IN THE

TREATMENT OF PSORIASIS

Technical field

The present invention relates to the use of alpha-MSH analogues for treatment of human subjects, to treatment of human subjects with alpha-MSH analogues, and to use of an alpha-MSH analogue for the manufacture of a medicament and to kits comprising drug compositions.

Background to the invention

Psoriasis is a skin disease that often manifests as erythematous papules and plaques covered with silvery scales. Psoriasis is hyper-proliferation of epidermal keratinocytes combined with inflammation of the epidermis and dermis. Multiple factors may contribute including genetics. Common triggers include trauma, infection, and certain drugs. While symptoms are usually minimal, mild to severe itching may occur, cosmetic implications can be major and some people even develop painful arthritis. Diagnosis of psoriasis is generally based on appearance and distribution of lesions.

Despite availability of several different medical treatment approaches, unmet medical need for human subjects suffering from psoriasis remains high. Experimentation to find proof of efficacy and safety of psoriatic treatments is complicated by unavailability of psoriasis in-vitro models and, also, no in-vivo animal models exist. Further complicating research into psoriasis is that it is a complex, multi-faceted disease. Therefore, research requires more than a single in-vitro experiment as indication of efficacy and/or safety. Only in-vivo human can show efficacy. There remains a need for effective and safe treatments of human subjects suffering from psoriasis.

Summary of the invention

According to the invention, we have surprisingly found that alpha-MSH analogues are effective in treatment of psoriasis of human subjects. The invention further relates to a kit of compositions for use in treatment of psoriasis of a human subject, wherein the kit comprises an alpha-MSH analogue in combination with specified other drug therapies. Further, the invention relates to a method of treating psoriasis by administering an alpha-MSH analogue to a human subject suffering from psoriasis. Further, the invention relates to the use of an alpha-MSH analogue for the manufacture of a medicament for the treatment of psoriasis of a human subject. According to the preferred embodiment of the invention, afamelanotide is a particularly preferred alpha-MSH analogue.

Preferably, the invention is directed to psoriasis on the arms, elbows, hand dorsum, legs, knee, foot dorsum, neck, face, scalp and/or hairline of the human subject. The invention is particularly useful for a human subject suffering from psoriasis who has Fitzpatrick skin type I or II.

Preferably, the alpha-MSH analogue (preferably afamelanotide) is present in the blood plasma of the human subject at a level of between at least O.Olng/ml to at most lOng/ml for a period of at least 2 days after administration. Preferably, the alpha-MSH analogue (preferably afamelanotide) is administered subcutaneously. Preferably, the interval between subsequent administrations of the alpha-MSH analogue (preferably afamelanotide ) is between at least 3 weeks, more preferably at least 4 weeks and at most 8 weeks (and for example at most 5 weeks). Preferably, the alpha- MSH analogue (preferably afamelanotide) is used in combination with phototherapy treatment, for instance during a period of from 5 to 7 months. Preferably, the phototherapy treatment is exposure to Narrow Band Ultra Violet B (NB-UVB) irradiation. Preferably, the human subject is exposed to the combined treatment of the alpha-MSH analogue (preferably afamelanotide) and phototherapy during, for instance for a period of from 5 to 7 months. Preferably, the subject is pre-treated and/or post-treated with phototherapy during a period of at least 1 week. Preferably, the subject suffering from psoriasis is exposed for a 1 month period to thrice weekly NB-UVB 311nm irradiation with a level of irradiation of from 150 to 3000mJ/cm2 for a period of less than 5 minutes; wherein the subject is subsequently treated for a 7 months period with a combination of thrice weekly NB-UVB irradiation treatments of 311nm with an irradiation of from 150 to 3000mJ/cm2 for a period of less than 5 minutes and monthly subcutaneously administered afamelanotide, exposing the subject to a level of 0.001 to lOng/ml afamelanotide in the blood plasma for a period of 10 days; and wherein the subject is subsequently exposed for a period of 1 month to thrice weekly NB-UVB 311nm irradiation with a level of irradiation of from 150 to 3000 mJ/cm2 for a period of less than 5 minutes. Preferably, the subject is exposed for a 1 month period to thrice weekly NB-UVB 311nm irradiation with a level of irradiation of from 150 to 3000mJ/cm2 for a period of less than 5 minutes; wherein the subject is subsequently treated with a combination of thrice weekly NB-UVB irradiation treatments of 311nm with an irradiation of from 150 to 3000mJ/cm2 for a period of less than 5 minutes and alpha-MSH analogue that is subcutaneously administered at intervals of 4 to 8 weeks, exposing the subject to a level of 0.001 to lOng/ml alpha-MSH analogue in the blood plasma for a period of up to 10 days; and wherein the subject is subsequently exposed for a period of 1 month to thrice weekly NB-UVB 311nm irradiation with a level of irradiation of from 150 to 3000 mJ/cm2 for a period of less than 5 minutes.

Preferably, the human subject is exposed to a combination of the alpha-MSH analogue

(particularly afamelanotide) with a drug therapy selected from the group consisting of topical drug therapies, systemic immunomodulatory drug therapies, hydroxyurea, psolarens in combination with ultraviolet A (UVA), tumor necrosis factor alpha related compounds, and mixtures thereof.

Surprisingly, we have found that alpha-MSH analogues, and particularly afamelanotide, provide psoriasis treatment benefits for human subjects as is preferably measured with the PASI or PGA scores. Clinically assessment of treatment results of the present invention is preferably carried out using the Psoriasis Area and Severity Index (PASI; see Frederiksson T, Pettersson U.; "Severe psoriasis - oral therapy with a new retinoid"; Dermatologica, 1978; 157(4):238-44) and/or the Physician Global Assessment (PGA; dynamic but preferably static). Both assessments are well- known in the art. Other measure may also be used, such as the NPF-PS score (see Gottlieb 2003) and the Lattice System Physicians's Global Assessment (see Langley 2004). Preferably, quality of life measures are added as important element in the overall psoriasis treatment outcome.

The invention is preferably directed to treatment of medical indications and preferably relates to therapeutic treatment of human subjects.

Detailed description of the invention

The present invention relates to alpha-MSH analogues for use in psoriasis in human subjects, to treatment of psoriasis in human subjects with alpha-MSH analogues, to use of an alpha-MSH analogue for the manufacture of a medicament for the treatment of psoriasis in human subjects and to kits comprising drugs for use in treatment of human subjects suffering from psoriasis. The preferred alpha-MSH analogue according to the invention is afamelanotide.

We have surprisingly found that alpha-MSH analogue, and especially afamelanotide, treatment of psoriasis of human subjects according to the present invention is particularly beneficial when targeting psoriatic lesions at body locations that are normally exposed to light. Preferably, the invention is directed to human subjects suffering from psoriasis on body parts that are normally subjected to light. Though not wishing to be bound by any theory, Applicant believes that light might be a factor in the pathogenesis of psoriasis on these body locations in these human subjects. However, we have now surprisingly found that the combination of alpha-MSH analogue with specific light (as used in phototherapy treatment), according to the preferred aspect of the invention provides for an effective treatment of psoriasis in these body locations. According to the invention, psoriasis includes psoriatic exacerbations. Accordingly, the present invention relates in particular to treatment of psoriasis on body parts that are -normally- exposed to light, i.e. body parts that are normally not covered by clothing. These body parts may also be defined as UV light exposed body parts. Light exposed body parts are defined according to the present invention to include the arm, elbow, hand dorsum, leg, knee, foot dorsum, neck, face, scalp, and/or hair line. It is noted that psoriasis of the hand palms and foot soles is preferably excluded from this definition. According to a preferred embodiment, the invention provides a treatment for psoriasis on the arm, elbow, hand dorsum, leg, knee, foot dorsum, neck, face, scalp, and/or hair line of a human subject by administration of an alpha-MSH analogue, particularly afamelanotide. Surprisingly, the invention further provides for combination treatment of afamelanotide and phototherapy in the treatment of psoriasis on these light exposed body parts.

Preferably, the invention relates to treatment of plaque psoriasis. Plaque psoriasis typically involves gradual appearance of discrete, erythematous papules or plaques covered with thick, silvery, shiny scales. Lesions may remit and recur spontaneously or with appearance and resolution of triggers and symptoms increase and decrease.

We have found that it is particularly advantageous according to the present invention to treat psoriasis of human subjects with a FitzPatrick skin types I, II, III, and IV, more preferably FitzPatrick skin types I, II, and III, most preferably Fitzpatrick skin types I, and II, and in particular preferred with FitzPatrick skin type I. FitzPatrick skin type is a reference that is commonly known and generally used in the art. The skin type was originally described in Fitzpatrick TB. Soleil et peau. J Med Esthet. 1975 and for instance further described and used in Fitzpatrick T.B., et al, "The validity and practicality of sun-reactive skin types I through VI", Editorial, Arch Dermatol, Vol 124, June 1988, page 869-871. According to the invention, the human subject suffering from psoriasis is preferably exposed to alpha-MSH analogue at a blood plasma level of at least O.Olng/ml, more preferably at least O.lng/ml, most preferably at least lng/ml and preferably at most 20ng/ml, more preferably at most 15ng/ml, most preferably at most lOng/ml and preferably for at least 1 day, more preferably at least 2 days, more preferably at least 5 days and preferably at most 30 days, more preferably at most 20 days, most preferably at most 15 days and particularly preferred for at most 10 days, for instance for 7 days or for 10 days. It will be understood that these alpha-MSH analogue blood plasma levels are achieved after each alpha-MSH analogue administration. As will be understood by a skilled person in the art, after initial alpha-MSH analogue release and absorption by the subject (preferably from the implant) into the blood plasma, the alpha-MSH analogue will be present in the blood plasma of the subject at a level and the time period indicated. Thus, the alpha-MSH analogue is administered in an amount that results in the blood plasma levels indicated. Accordingly, the human subject is subjected to the blood plasma levels indicated.

Thought the human subject suffering from psoriasis may be treated with topical administration, it is preferred according to the present invention to administer the alpha-MSH analogue systemically. Preferably, the alpha-MSH analogue is administered subcutaneously. Preferred systemic administration of the alpha-MSH analogue of the invention is by way of an injection, more preferably by way of a subcutaneously injected implant. Preferred systemic administration is by way of a controlled-release formulation.

According to a preferred treatment of the invention, the alpha-MSH analogue is at least 2 times administered subsequently to a subject suffering from psoriasis, more preferably at least 3 times, most preferably at least 5 times and preferably at most 10 times, more preferably at most 7 times. Preferably, the interval between subsequent administrations is at least 2 weeks, more preferably at least 3 weeks, most preferably at least 4 weeks, and preferably at most 9 weeks, more preferably at most 8 weeks, most preferably at most 7 weeks, in particularly preferred at most 5 weeks. A preferred range for the interval between subsequent administrations is between from 3 to 5 weeks, preferably 1 month. According to the invention, a particularly preferred range for the interval between subsequent administrations of the alpha-MSH analogue is from 4 to 8 weeks. It will be understood that for the purpose of the invention, intervals are separate and subsequent and do not overlap. According to a preferred aspect of the present invention, we have surprisingly found that it is especially advantageous to treat psoriasis of human subjects using a combination treatment of alpha-MSH analogue and phototherapy. Preferably, the human subject is simultaneously exposed to an alpha-MSH analogue and to phototherapy. During exposure to the alpha-MSH analogue, the subject is preferably exposed to phototherapy treatment. This results in exposure to the combination at the same time. In other words, the subject is preferably at least part of the time treated with phototherapy while being exposed to the alpha-MSH analogue, i.e. the subject is at least partially simultaneously exposed to both. Preferably, exposure of the subject to

phototherapy at least partially overlaps with exposure to the alpha-MSH analogue.

Preferably, phototherapy treatment uses Ultra Violet (UV) irradiation, more preferably, Ultra Violet B (UVB) irradiation, for instance Broad-Band Ultra Violet B (BB-UVB) irradiation, and most preferably Narrow-Band Ultra Violet B (NB-UVB) irradiation. BB-UVB irradiation preferably has a wavelength of from 280 to 330nm. Preferably, NB-UVB irradiation treatment uses a wavelength of from 308 to 315nm, preferably of from 310 to 312nm, more preferably 311nm. Preferably, at least 40% of the irradiation (in terms of W/cm²) is within these ranges, more preferably at least 60%, most preferably at least 80%. A further NB-UVB option is the use of a 308nm xenon-chloride excimer laser. Preferably, the UV irradiance of the spectrum below 300nm is less than 50% (in W/cm²} of the total irradiance of the UVB irradiation, more preferably less than 20%, most preferably less than 5% of the UVB irradiation. Preferably, side-effects of repetitive UVB treatment are avoided.

Preferably, NB-UVB irradiation is used at a level of at least 150mJ/cm² and preferably at most 3000mJ/cm². Preferably, the irradiation level of the subsequent treatment is based on the erythema occurring in the previous UV treatment. Preferably, the dose is increased by up to 15% or decreased by up to 10%. Depending on any erythema formation of the previous treatment, the dose is preferably increased by 10-15% if no erythema occurred; the dose is kept the same if minimal erythema occurred; or the dose is reduced by 5-10% if mild to moderate erythema occurred. In this last instance, the treating doctor may decide not to give a dose given and in the next treatment either use the last tolerated dose or the scheduled dose.

Preferably, NB-UVB irradiation treatment takes less than 20 minutes, more preferably less than 10 minutes. NB-UVB irradiation is preferably used for less than 6 minutes, for instance maximum 5 minutes and more than 1 minute. Preferably, NB-UVB irradiation treatment involves repetitive exposure and, preferably, the subject is treated with at least 10 NB-UVB treatments per month, more preferably twice to thrice weekly. Preferably, NB-UVB irradiation treatment occurs on non-consecutive days.

Preferably, the subject suffering from psoriasis is exposed to NB-UVB irradiation treatments during a total period of at least 3 months, more preferably at least 4 months, most preferably at least 5 months, in particularly preferred for a period of at least 6 months and preferably up to 24 months, more preferably up to 18 months. A preferred range is from 7 to 9 months.

According to the present invention, the human subject suffering from psoriasis is preferably treated with a combination of alpha-MSH analogue and UV irradiation. The combination treatment period is preferably at least 2 months, more preferably at least 3 months, most preferably at least 4 months and preferably at most 12 months, more preferably at most 9 and most preferably at most 7 months. A preferred range for the combination treatment period is from 5 to 7 months. It is understood that, for the purpose of this invention, the combination treatment period starts at the beginning of the first administration interval of the alpha-MSH analogue and ends at the end of the last administration interval of the alpha-MSH analogue. Preferably, the subject is treated with UV irradiation before exposure to the alpha-MSH analogue (i.e. before the first administration interval of alpha-MSH analogue), preferably for a period of at least 1 week, more preferably at least 2 weeks, and preferably up to 3 months, more preferably up to 2 months, most preferably up to 6 weeks. A preferred period is 1 month. This may be called a pre-combination treatment step.

Preferably, the subject is treated with UV irradiation after the last administration interval of alpha-MSH analogue exposure, preferably for a period of at least 1 week, more preferably at least 2 weeks, and preferably up to 3 months, more preferably up to 2 months, most preferably up to 6 weeks. A preferred period is 1 month. This may be called a post-combination-treatment step. It will be understood that this post-treatment step preferably does not involve administration of the alpha-MSH analogue and only administration of NB-UVB.

A preferred dosing schedule is 1 month NB-UVB pretreatment, 5 to 7 months of combined treatment of afamelanotide and NB-UVB treatment and 1 month of post-treatment with NB-UVB. In one embodiment, a particularly preferred combination treatment regimen using alpha-MSH analogue combined with NB-UVB is as follows:

1. The subject suffering from psoriasis is exposed for a 1 month period to twice to thrice weekly NB-UVB 311nm irradiation with a level of irradiation of from 150 to 3000mJ/cm2 for a period of less than 5 minutes; 2. Subsequently, the subject is treated for a 7 months period with a combination of:

- twice to thrice weekly NB-UVB 311nm irradiation treatments with a level of irradiation of from 150 to 3000mJ/cm2 for a period of less than 5 minutes;

- monthly subcutaneously administered afamelanotide, exposing the subject to a level of 0.001 to lOng/ml afamelanotide in the blood plasma for a period of 10 days; and

3. Then (after expiration of the 7 months), the subject is exposed for a period of 1 month to twice to thrice weekly NB-UVB 311nm irradiation with a level of irradiation of from 150 to 3000 mJ/cm2 for a period of less than 5 minutes. In another preferred embodiment, a particularly preferred combination treatment regimen using alpha-MSH analogue combined with NB-UVB is as follows:

1. The subject suffering from psoriasis is exposed for a 1 month period to thrice weekly NB-UVB 311nm irradiation with a level of irradiation of from 150 to 3000mJ/cm2 for a period of less than 5 minutes;

2. Subsequently, the subject is treated with a combination of thrice weekly NB-UVB irradiation treatments of 311nm with an irradiation of from 150 to 3000mJ/cm2 for a period of less than 5 minutes and alpha-MSH analogue that is subcutaneously administered at intervals of 4 to 8weeks, exposing the subject to a level of 0.001 to lOng/ml alpha-MSH analogue in the blood plasma for a period of up to 10 days; and

3. then (after expiration of the last interval of step 2), the subject is subsequently exposed for a period of 1 month to thrice weekly NB-UVB 311nm irradiation with a level of irradiation of from 150 to 3000 mJ/cm2 for a period of less than 5 minutes.

According to one aspect, the invention is directed to alpha-MSH analogues. The term "alpha-MSH analogue" as used herein is defined as a derivative of alpha-MSH which exhibits agonist activity for the melanocortin-l-receptor (MC1 ), the receptor to which alpha-MSH binds to initiate the production of melanin within a melanocyte. Such alpha-MSH analogues include derivatives in which (i) one or more amino acid residues are deleted from the native alpha-MSH molecule at the N-terminal end, the C-terminal end, or both; and/or (ii) one or more amino acid residues of the native alpha-MSH molecule are replaced by another natural, non-natural or synthetic amino acid residue; and/or (iii) an intra-molecular interaction forms as a cyclic derivative. Several derivatives of alpha-MSH have been synthesized. In one aspect of the present invention, the alpha-MSH analogues described in US Patents Nos. 4,457,864, 4,485,039, 4,866,038, 4,918,055, 5,049,547, 5,674,839 and 5,714,576 and Australian Patents Nos. 597630 and 618733, which are herein incorporated by reference for their teachings with respect to alpha-MSH analogues and their synthesis thereof, can be used herein. The alpha-MSH analogue may be used as such or in the form of a pharmaceutically acceptable salt thereof.

Preferably, according to the invention, the alpha-MSH analogue is a non-radiation emitting analogue, i.e. the compound is not radioactive that can be damaging to the body. In other words, the alpha-MSH analogue emits low and preferably no radiation including alpha, beta and/or gamma radiation at the level or lower than average background radiation levels.

In one aspect of the invention, the alpha-MSH analogue is selected from the group consisting of: (a) compounds of the formula:

Ac-Ser-Tyr-Ser-M-Gln-His-D-Phe-Arg-Trp-Gly-Lys-Pro-Val-NH₂

wherein M is Met, Nle or Lys; and

(b) compounds of the formula:

W-X-Y-Z- ₂

wherein

i is absent, n-pentadecanoyl, Ac, 4-phenylbutyryl, Ac-Gly-, Ac-Met-Glu, Ac-Nle-Glu-, or Ac-Tyr-Glu-;

W is -His- or-D-His-;

X is -Phe-, -D-Phe-, -Tyr-, -D-Tyr-, or -(pN0₂)D-Phe⁷-;

Y is -Arg- or -D-Arg-;

Z is -Trp- or -D-Trp-; and

R₂ is -NH₂; -Gly-NH₂; or-Gly-Lys-NH₂, as disclosed in Australian Patent No. 597630.

In another aspect, the alpha-MSH analogue may be a linear analogue as disclosed in US 5674,839, and selected from the group consisting of:

Ac-Ser-Tyr-Ser-Nle-Glu-His-D-Phe-Arg-Trp-Lys-Gly-Pro-Val-NH₂,

Ac-Ser-Tyr-Ser-Nle-Asp-His-D-Phe-Arg-Trp-Lys-Gly-Pro-Val-NH₂,

Ac-N le-G lu-H is-D-Phe-Arg-Trp-Lys-Gly-P ro-Va l-N H₂,

Ac-N le-Asp-H is-D-Phe-Arg-Trp-Lys-G ly-Pro-Va l-N H₂,

Ac-Nle-Asp-His-D-Phe-Arg-Trp-Gly-NH₂,

Ac-Nle-Glu-His-D-Phe-Arg-Trp-Lys-NH₂,

Ac-Nle-Asp-His-D-Phe-Arg-Trp-Lys-NH₂, Ac-Nle-Glu-His-D-Phe-Arg-Trp-Orn-NH₂,

Ac-Nle-Asp-His-D-Phe-Arg-Trp-Orn-NH₂,

Ac-Nle-Glu-His-D-Phe-Arg-Trp-Dab-NH₂,

Ac-Nle-Asp-His-D-Phe-Arg-Trp-Dab-NH₂,

Ac-Nle-Glu-His-D-Phe-Arg-Trp-Dpr-NH₂,

Ac-Nie-Glu-His-Phe-Arg-Trp-Lys-NH₂, and

Ac-Nle-Asp-His-Phe-Arg-Trp-Lys-NH₂.

In another aspect, the alpha-MSH analogue may also be a cyclic analogue as disclosed in US Patent No. 5,674,839, selected from the group consisting of:

Ac - NIe - Glu- His- D-Phe -Arg - Trp - Lys - Gly - Pro -Val -NH₂,

Ac - NIe- Glu - His - D-Phe - Arg - Trp - Lys-NH

Ac- NIe - Asp - His - D-Phe - Arg - Trp - Lys-NH₂,

Ac- NIe - Asp - His - D-Phe - Arg - Trp - Orn-NH_2;

Ac- NIe - Asp - His - D-Phe - Arg - Trp - Dab-NH₂,

Ac- NIe - Asp - His - D-Phe - Arg - Trp -Dpr-NH

Ac- Ser - Tyr - Ser- NIe - Asp - His - D-Phe - Arg - Trp - Lys-Gly-Pro-Val-NH₂,

Ac- Ser - Try - Ser -NIe- Asp - His - D-Phe - Arg - Trp - Lys-NH_:

Ac-Tyr - Ser - NIe -Asp- His - D-Phe - Arg - Trp - Lys- H₂, Ac- Ser - NIe - Asp - His - D-Phe - Arg - Trp - Lys-NH

Ac - NIe - Asp - His - D-Phe - Arg - Trp - Lys-Gly-NH_2;

Ac- NIe - Asp - His - D-Phe - Arg - Trp - Lys-Gly-Pro-NH₂, - Nle - Asp - His - D-Phe - Arg - Trp - Lys-Gly-Pro-Val-NH₂, and

Ac - Ser - Nle - Asp - His - D-Phe - Arg - Trp - Lys-Gly-Pro-Val-NH₂. wherein Ala = alanine, Arg = arginine, Dab - 2,4-diaminobutyric acid, Dpr = 2,3- diaminopropionic acid, Glu - glutamic acid, Gly = glycine, His = histidine, Lys = lysine, Met = methionine, Nle = norleucine, Orn = ornithine, Phe = phenylalanine, (pN02)Phe = paranitrophenylalanine, Pig = phenylglycine, Pro = proline, Ser = serine, Trp = tryptophan, TrpFor = N¹ formyl-tryptophan, Tyr = tyrosine, Val = valine.

All peptides are written with the acyl-terminal end at the left and the amino terminal end to the right; the prefix "D" before an amino acid designates the D-isomer configuration, and unless specifically designated otherwise, all amino acids are in the L-isomer configuration.

In another aspect, the alpha-MSH analogue is preferably selected from the group consisting of:

[D-Phe⁷]-a-MSH,

[Nle⁴, D-Phe⁷]-a-MSH,

[D-Ser¹, D-Phe⁷]-a-MSH,

[D-Tyr², D-Phe⁷]- -MSH,

[D-Ser³, D-Phe⁷]-a-MSH,

[D-Met⁴, D-Phe⁷]-a-MSH,

[D-Glu⁵, D-Phe⁷]-a-MSH,

[D-His⁶, D-Phe⁷]-a-MSH,

[D-Phe⁷, D-Arg⁸]-a-MSH,

[D-Phe⁷, D-Trp⁹]-a-MSH,

[D-Phe⁷, D-Lysⁿ]-a-MSH,

[D-Phe⁷, D-Pro¹²]-a-MSH,

[D-Phe⁷, D-Val¹³]-a-MSH,

[D-Ser¹, Nle⁴, D-Phe⁷]-a-MSH,

[D-Tyr², Nle⁴, D-Phe⁷]-a-MSH,

[D-Ser³, Nle⁴, D-Phe⁷]-a-MSH,

[Nle⁴, D-Glu⁵, D-Phe⁷]-a-MSH,

[Nle⁴, D-His⁶, D-Phe⁷]-a-MSH,

[Nle⁴, D-Phe⁷, D-Arg⁸]-a-MSH, [Nle⁴, D-Phe⁷, D-Trp⁹]-a-MSH, [Nle⁴, D-Phe⁷, D-Lys^u]-a-MSH, [Nle⁴, D-Phe⁷, D-Pro¹²]-a- SH, 4, D-Phe⁷, D-Val¹³]-a-MSH,

4, D-Phe⁷, Cys¹⁰]-a-MSH,

[ Cys⁵, Cys¹⁰]- -MSH,

[Cys⁵, Cysⁿ]-a-MSH,

[Cys⁴, Cys¹⁰]-a-MSH₄.

; Cys⁴, Cys¹⁰]-a-MSH4.₁₂,

;Nle⁴, D-Phe⁷]-a-MSH₄.₁₀,

;Nle⁴, D-Phe⁷]-a-MSH₄._n,

;Nle⁴, D-Tyr⁷]-a-MSH₄.n,

;(pN0₂)D-Phe⁷]-a-MSH₄.n,

Tyr⁴, D-Phe⁷]- -MSH₄.₁₀,

Tyr⁴, D-Phe⁷]-a-MSH₄. ,

;Nle⁴]-a-MSH₄._n,

[Nle⁴, (pN0₂)D-Phe⁷]-a-MSH₄-H,

[Nle⁴, D-His⁶]-a-MSH₄._n,

[Nle⁴, D-His⁶, D-Phe⁷]-a-MSH₄.n,

[Nle⁴, D-Arg⁸]- -MSH₄._u,

[Nle⁴, D-Trp⁹]-a-MSH₄.ii,

[Nle⁴, D-Phe⁷, D-Trp⁹]-a-MSH₄._11;

[Nle⁴, D-Phe⁷]- -MSH₄.₉, and

[Nle⁴, D-Phe⁷, D-Trp⁹]-a-MSH₄.₉. Preferred a!pha-MSH analogues thereof are selected from the group consisting of:

[Nle⁴, D-Phe⁷]-a-MSH₄-io,

[Nle⁴, D-Phe⁷]-a-MSH₄. ,

[Nle⁴, D-Phe⁷, D-Trp⁹]-a-MSH₄-n, and

[Nle⁴, D-Phe⁷]-a-MSH₄.₉.

In another aspect, the alpha-MSH analogue is a cyclic peptide of formula (I): Z-Xaa^Xaa^Xaa'-Xaa^Xaa^Xaa^Xaa^Y (I)

or a pharmaceutically acceptable salt thereof, wherein:

Z is H or an N-terminal group wherein the N-terminal group is preferably a Q to C₁₇ acyl group, wherein the Q to C₁₇ comprises a linear or branched alkyl, cycloalkyl, alkylcycloalkyl, aryl or alkylaryl, a linear or branched Q to C17 alkyl, aryl, heteroaryl, alkene, alkenyl, or aralkyl chain or an N-acylated linear or branched Qt to C₁₇ alkyl, aryl, heteroaryl, alkene, alkenyl, or aralkyl chain and more preferably is a Ci to C₇ acyl group;

Xaa¹ is optionally present, and if present is from one to three L- or D-isomer amino acid residues, and preferably an amino with a side chain including a linear or branched alkyl, cycloalkyl, cycloheteroalkyi, aryl or heteroaryl, and more preferably is an L- or D-isomer of Nle;

Xaa² and Xaa⁶ are L- or D-isomer amino acids wherein the side chains thereof comprise a cyclic bridge, and, preferably, one of Xaa² and Xaa⁶ is an L- or D-isomer of Asp, hGlu or Glu and the other of Xaa² and Xaa⁶ is an L- or D-isomer of Lys, Orn, Dab or Dap or, in an alternative preferred aspect, Xaa² and Xaa⁶ are each Cys, D-Cys, Pen or D-Pen;

Xaa³ is L- or D-Pro, optionally substituted with hydroxyl, halogen, sulfonamide, alkyl,— O-alkyl, aryl, alkyl-aryl, alkyl-O-aryl, alkyl-O-alkyl-aryl, or— O-aryl, or Xaa³ is an L- or D-isomer of an amino acid with a side chain including at least one primary amine, secondary amine, alkyl, cycloalkyl, cycloheteroalkyi, aryl, heteroaryl, ether, sulfide, or carboxyl and preferably is an L- or D-isomer of His;

Xaa⁴ is an L- or D-isomer amino acid with a side chain including phenyl, naphthyl or pyridyl, optionally wherein the ring is substituted with one or more substituents independently selected from halo, (Ci-C_M)alkyl-halo, (C Ci₀)alkyl, (Q-CioJalkoxy, (QrQtoJalkylthio, aryl, aryloxy, nitro, nitrile, sulfonamide, amino, monosubstituted amino, disubstituted amino, hydroxy, carboxy, and alkoxy-carbonyl, and is preferably D-Phe, optionally substituted with one or more substituents independently selected from halo, (C C₁₀)alkyl-halo, (d-C₁₀)alkyl, (C Ci₀)alkoxy, (C C₁₀)alkylthio, aryl, aryloxy, nitro, nitrile, sulfonamide, amino, monosubstituted amino, disubstituted amino, hydroxy, carboxy, and alkoxy-carbonyl;

Xaa⁵ is L- or D-Pro or an L- or D-isomer amino acid with a side chain including at least one primary amine, secondary amine, guanidine, urea, alkyl, cycloalkyl, cycloheteroalkyl, aryl, heteroaryl, or ether and preferably is an L- or D-isomer of Arg, Lys, Orn, Dab or Dap;

Xaa⁷ is optionally present, and if present is from one to three L- or D-isomer amino acid residues, and is preferably an amino acid with a side chain including at least one aryl or heteroaryl, optionally substituted with one or more ring substituents, and when one or more substituents are present, are the same or different and independently hydroxyl, halogen, sulfonamide, alkyl, -0- alkyl, aryl, or -O-aryl, and more preferably is an L- or D-isomer of Trp, Nal 1 or Nal 2; and Y is a C-terminal group and in another aspect preferably a hydroxyl, an amide, or an amide substituted with one or two linear or branched Q to C₁₇ alkyl, cycloalkyl, aryl, alkyl cycloalkyl, aralkyl, heteroaryl, aikene, alkenyl, or aralkyl chains. Preferred cyclic alpha-MSH analogues are Ac-Nle-cyclo(Glu-His-D-Phe-Arg-Dab)-Trp-NH₂ and Ac- Nle-cyclo(Glu-His-D-Phe-Arg-Dap)-Trp-NH₂.

According to this aspect and in addition to the above defined amino acids, the amino acids are defined in US2013/0296256 pages 5 and 6 which are incorporated herein by reference. Further, the terms " ,α-disubstituted amino acid", "N-substituted amino acid", "alkane", "aikene", "alkenyl", "alkyl", "alkyne", "aryl", "aralkyl", "aliphatic", "acyl", "acylated", "omega amino aliphatic chain", "heteroaryl", "amide", "imide", "amine", "nitrile", and "halogen" are defined on pages 6 and 7 thereof and are also incorporated herein by reference. According to the present invention, the most preferred alpha-MSH analogue is [Nle⁴, D-Phe⁷]- alpha-MSH. This preferred compound is sometimes referred to as NDP-MSH. It is also generically known as afamelanotide, which is available as an implant formulation under the trademark SCENESSE^®. Alpha-MSH analogues according to the present invention may also be used in the form of a pharmaceutically acceptable salt thereof. Preferred examples of such salts are acetate, trifluoroacetate, sulphate, and chloride salts. The acetate salt is generally most preferred. Preferably, the alpha-MSH analogue is administered in a composition. Preferably, the composition is a slow release formulation, resulting in longer and/or more controlled exposure of the body to the drug. Most preferably, the composition is an implant. In one preferred embodiment, the alpha-MSH analogue is administered in a prolonged release formulation such as described in US2008305152 (equivalent to WO2006/012667), the disclosure of which is included herein by reference.

The composition preferably comprises at least 5mg of the alpha-MSH analogue, more preferably at least lOmg and preferably at most 30mg, more preferably at most 25mg of the alpha-MSH analogue. Particularly preferred amounts are 20mg or 16mg of the alpha-MSH analogue of which 16mg of the alpha-MSH analogue is the most preferred.

Preferably, the composition comprises a controlled release formulation. In one aspect according to the present invention, the implant (or rod) comprises a biodegradable polymer, wherein the alpha-MSH analogue is imbedded within the implant. In one aspect, the alpha-MSH analogue is encapsulated in an implant composed of poly-(lactide-co-glycolide), poly-(lactide), poly-(glycolide) or a mixture thereof. Lactide/glycolide polymers for drug-delivery formulations are typically made by melt polymerization through the ring opening of lactide and glycolide monomers. Some polymers are available with or without carboxylic acid end groups. When the end group of the poly-(lactide-co-glycolide), poly-(lactide), or poly-(glycolide) is not a carboxylic acid, for example, an ester, then the resultant polymer is referred to herein as blocked or capped. The unblocked polymer, conversely, has a terminal carboxylic group. In one aspect, linear lactide/glycolide polymers are used; however star polymers can be used as well. In certain aspects, high molecular weight polymers can be used for medical devices, for example, to meet strength requirements. The lactide portion of the polymer has an asymmetric carbon. Commercially racemic DL-, L-, and D-polymers are available. The L- polymers are more crystalline and resorb slower than DL- polymers. In addition to copolymers comprising glycolide and DL-lactide or L-lactide, copolymers of L-lactide and DL-lactide are available. Additionally, homo-polymers of lactide or glycolide are available. In the case when the biodegradable polymer is poly-(lactide-co-glycolide), poly-(lactide), or poly-(glycolide), the amount of lactide and glycolide in the polymer can vary. In one aspect, the biodegradable polymer contains 0 to 100 mole %, 40 to 100 mole %, 50 to 100 mole %, 60 to 100 mole %, 70 to 100 mole %, or 80 to 100 mole % lactide and from 0 to 100 mole %, 0 to 60 mole %, 10 to 40 mole %, 20 to 40 mole %, or 30 to 40 mole % glycolide, wherein the amount of lactide and glycolide is 100 mole %. In one aspect, the biodegradable polymer can be poly-(lactide), 85:15 poly-(lactide-co-glycolide), 75:25 poly-(lactide-co-glycolide), or 65:35 poly-lactide-co-glycolide) where the ratios are mole ratios.

In one aspect, when the biodegradable polymer is poly-(lactide-co-glycolide), poly-(lactide), or poly-(glycolide), the polymer has an intrinsic viscosity of from 0.15 to 1.5 dL/g, 0.25 to 1.5 dL/g, 0.25 to 1.0 dL/g, 0.25 to 0.8 dL/g, 0.25 to 0.6 dL/g, or 0.25 to 0.4 dL/g as measured in chloroform at a concentration of 0.5 g/dL at 30°C.

The implant preferably comprises alpha-MSH analogue in an amount of from 5% to 60%, more preferably from 10% to 50%, most preferably from 15% to 40%, and in particularly preferred from 15% to 30% by weight of the implant. Preferred implants are described in US2008/0305152 incorporated herein by reference. A preferred implant comprising afamelanotide is available under the name of SCENESSE^® in Italian and Swiss markets.

Other pharmaceutically-acceptable components can be encapsulated or incorporated in the composition or in the implant in combination with the alpha-MSH analogue. For example, the pharmaceutically-acceptable component can include a fatty acid, a sugar, a salt, a water-soluble polymer such as polyethylene glycol, a protein, polysacharride, or carboxmethyl cellulose, a surfactant, a plasticizer, a high- or low- molecular- weight porosigen such as polymer or a salt or sugar, or a hydrophobic low- molecular-weight compound such as cholesterol or a wax. In a preferred embodiment of the invention, alpha-MSH analogue for psoriasis treatment of human subjects is combined with one or more other drug therapies. Preferably, other drug therapies are selected from:

1. topical drug therapies, preferably using emollients (preferably petrolatum and/or mineral oil), corticosteroids (preferably fluocinolone and/or clobetasol propionate), vitamin D analogues (preferably calcipotriol), tazarotene, tar, and/or anthralin;

2. systemic immunomodulatory drug therapies, preferably selected from methotrexate, cyclosporine, fumaric acid esters, azathioprine, leflunomide, mycophenolate mofetil, sulfasalazine, tacrolimus, 6-thioguanine, and/or retinoids (preferably acitretin);

3. hydroxyurea;

4. psolarens, preferably in combination with ultraviolet A (UVA); this combination is often called PUVA; preferred psoralens are tricyclic furocoumarins, and more preferably 8-methoxypsoralen, 5-methoxypsoralen and trimethylpsoralen; and/or

5. tumor necrosis factor alpha related compounds, preferably selected from TNF inhibitor monoclonal antibodies and/or fusion protein. Preferably, TNF inhibitor monoclonal antibodies are selected from infliximab (a mouse-human chimeric anti-TNF-a monoclonal antibody sold under the tradename Remicade), adalimumab (a human monoclonal anti-TNF-α antibody sold under the tradename Humira), certolizumab pegol (a PEGylated Fab fragment of humanized monoclonal TNF-a antibody sold under the tradename Cimzia), and/or golimumab (a human monoclonal anti- TNF-a antibody sold under the tradename Simponi). A preferred fusion protein is etanercept (a soluble p75 TNF-a receptor fusion protein sold under the tradename Enbrel); and

6. mixture thereof.

The invention further relates to a kit of compositions for use in treatment of psoriasis of a human subject, wherein the kit comprises afamelanotide and a medication selected from topical drug therapies, systemic immunomodulatory drug therapies, hydroxyurea, psolarens, tumor necrosis factor alpha related compounds, and mixtures thereof.

In a further embodiment, the invention relates to treating psoriasis by administering

afamelanotide to a human subject suffering from psoriasis. In a further embodiment, the invention relates to use of afamelanotide for the manufacture of a medicament for the treatment of psoriasis of a human subject.

The invention is illustrated by the following non-binding examples. Examples

Afamelanotide is subcutaneously administered to subjects suffering from psoriasis and/or psoriatric exacerbations on the arms, elbows, hand dorsum, legs, knee, foot dorsum, neck, face, scalp and/or hairline in the form of 16mg implants and with an administration intervals of from 4 to 8 weeks. Other psoriasis subjects are included in the placebo group. The subjects had

Fitzpatrick skin type I or II.

Afamelanotide was released from each implant over the course of up to 10 days, with plasma levels of between O.OOOlng/ml and lOng/ml during this period.

Subjects were also exposed to NB-UVB 311nm phototherapy treatment, two to three times a week with an initial dosage of NB-UVB of 130 to 400mJ/cm2 (or at 50% of MED) dependent on skin type, and with subsequent dosage increases by 16-65mJ/cm2 or <105% of MED. NB-UVB treatment started 1 month before first administration of the implant, continued during administration of the afamelanotide implants, and continued until 1 month after the end of the last interval of implant administration. Symptoms improved and positive results were obtained as measured with the Psoriasis Area and Severity Index (PASI) and/or the physician global assessment (PGA).

In a further aspect, preferred embodiments of the invention include:

Embodiment 1. Afamelanotide for use in treatment of psoriasis of a human subject. Embodiment 2. Compound for use according to embodiment 1, wherein the human subject suffers from psoriatic on the arms, elbows, hand dorsum, legs, knee, foot dorsum, neck, face, scalp and/or hairline.

Embodiment 3. Compound for use according to embodiments 1-2, wherein the human subject has Fitzpatrick skin type I or II.

Embodiment 4. Compound for use according to embodiments 1-3, wherein afamelanotide is present in the blood plasma of the subject at a level of between at least O.Olng/ml to at most lOng/ml for a period of at least 2 days after administration.

Embodiment 5. Compound for use according to embodiments 1-4, wherein afamelanotide is administered subcutaneously.

Embodiment 6. Compound for use according to embodiments 1-5, wherein the interval between subsequent administrations of afamelanotide is between at least 3 weeks and at most 5 weeks.

Embodiment 7. Compound for use according to embodiments 1-6, wherein afamelanotide is used in combination with phototherapy treatment. Embodiment 8. Compound for use according to embodiment 7, wherein the phototherapy treatment is Narrow Band Ultra Violet B (NB-UVB) irradiation.

Embodiment 9. Compound for use according to embodiments 7-8, wherein the subject is exposed to the combined treatment of afamelanotide and phototherapy during a period of from 5 to 7 months.

Embodiment 10. Compound for use according to embodiments 7-9, wherein the subject is pre- treated and/or post-treated with phototherapy during a period of at least 1 week. Embodiment 11. Compound for use according to embodiments 1-10, wherein the subject suffering from psoriasis is exposed for a 1 month period to thrice weekly NB-UVB 311nm irradiation with a level of irradiation of from 150 to 3000mJ/cm2 for a period of less than 5 minutes, wherein the subject is subsequently treated for a 7 months period with a combination of thrice weekly NB-UVB irradiation treatments of 311nm with an irradiation of from 150 to 3000mJ/cm2 for a period of less than 5 minutes and monthly subcutaneously administered afamelanotide, exposing the subject to a level of 0.001 to lOng/ml afamelanotide in the blood plasma for a period of 10 days; and wherein the subject is subsequently exposed for a period of 1 month to thrice weekly NB-UVB 311nm irradiation with a level of irradiation of from 150 to 3000 mJ/cm2 for a period of less than 5 minutes.

Embodiment 12. Compound for use according to embodiments 1-11, wherein the subject is further exposed to a medication selected from the group consisting of topical drug therapies, systemic immunomodulatory drug therapies, hydroxyurea, psolarens in combination with ultraviolet A (UVA), tumor necrosis factor alpha related compounds, and mixtures thereof.

Embodiment 13. Kit of compositions for use in treatment of psoriasis of a human subject, wherein the kit comprises afamelanotide and a medication selected from topical drug therapies, systemic immunosuppressants or immunomodulatory drug therapies, hydroxyurea, psolarens, tumor necrosis factor alpha related compounds, and mixtures thereof.

Embodiment 14. Method of treating psoriasis by administering afamelanotide to a human subject suffering from psoriasis. Embodiment 15. Use of afamelanotide for the manufacture of a medicament for the treatment of psoriasis of a human subject.

Claims

1. Alpha-MSH analogue for use in treatment of a human subject with psoriasis on the arms, elbows, hand dorsum, legs, knee, foot dorsum, neck, face, scalp and/or hairline.

2. Compound for use according to claim 1, wherein the human subject has Fitzpatrick skin type I or II.

3. Compound for use according to claims 1-2, wherein the alpha-MSH analogue is a derivative of alpha-MSH which exhibits agonist activity for the melanocortin-l-receptor (MC1 ), the receptor to which alpha-MSH binds to initiate the production of melanin within a melanocyte.

4. Compound for use according to claims 1-3, wherein the alpha-MSH analogue is afamelanotide.

5. Compound for use according to claims 1-4, wherein the alpha-MSH analogue is administered subcutaneously.

6. Compound for use according to claims 1-5, wherein the alpha-MSH analogue is present in the blood plasma of the subject at a level of between at least O.Olng/ml to at most lOng/ml for a period of at least 2 days after administration.

7. Compound for use according to claims 1-6, wherein the interval between subsequent administrations of the alpha-MSH analogue is between at least 4 weeks and at most 8 weeks.

8. Compound for use according to claims 1-7, wherein the alpha-MSH analogue is used in combination with phototherapy treatment.

9. Compound for use according to claim 8, wherein the phototherapy treatment is Narrow Band Ultra Violet B (NB-UVB) irradiation.

10. Compound for use according to claims 7-9, wherein the subject is pre-treated and/or post- treated with phototherapy during a period of at least 1 week.

11. Compound for use according to claims 1-10, wherein the subject is exposed for a 1 month period to thrice weekly NB-UVB 311nm irradiation with a level of irradiation of from 150 to 3000mJ/cm2 for a period of less than 5 minutes, wherein the subject is subsequently treated with a combination of thrice weekly NB-UVB irradiation treatments of 311nm with an irradiation of from 150 to 3000mJ/cm2 for a period of less than 5 minutes and alpha-MSH analogue that is subcutaneously administered at intervals of 4 to 8weeks, exposing the subject to a level of 0.001 to lOng/ml alpha-MSH analogue in the blood plasma for a period of up to 10 days; and wherein the subject is subsequently exposed for a period of 1 month to thrice weekly NB-UVB 311nm irradiation with a level of irradiation of from 150 to 3000 mJ/cm2 for a period of less than 5 minutes.

12. Compound for use according to claims 1-11, wherein the subject is further exposed to a medication selected from the group consisting of topical drug therapies, systemic

immunomodulatory drug therapies, hydroxyurea, psolarens in combination with ultraviolet A (UVA), tumor necrosis factor alpha related compounds, and mixtures thereof.

13. Kit of compositions for use in treatment of psoriasis of a human subject with psoriasis on the arms, elbows, hand dorsum, legs, knee, foot dorsum, neck, face, scalp and/or hairline, wherein the kit comprises an alpha-MSH analogue and a medication selected from topical drug therapies, systemic immunosuppressants or immunomodulatory drug therapies, hydroxyurea, psolarens, tumor necrosis factor alpha related compounds, and mixtures thereof.

14. Method of treating psoriasis by administering an alpha-MSH analogue to a human subject suffering from psoriasis on the arms, elbows, hand dorsum, legs, knee, foot dorsum, neck, face, scalp and/or hairline.

15. Use of an alpha-MSH analogue for the manufacture of a medicament for the treatment of a subject with psoriasis on the arms, elbows, hand dorsum, legs, knee, foot dorsum, neck, face, scalp and/or hairline.