WO2015063099A1

WO2015063099A1 - Alpha-msh analogues for use in the treatment of hailey-hailey disease

Info

Publication number: WO2015063099A1
Application number: PCT/EP2014/073139
Authority: WO
Inventors: Philippe Wolgen
Original assignee: CLINUVEL AG
Current assignee: CLINUVEL AG
Priority date: 2013-10-28
Filing date: 2014-10-28
Publication date: 2015-05-07
Anticipated expiration: 2016-04-28

Abstract

The present invention relates to alpha-MSH for use in treatment of Hailey-Hailey disease.

Description

ALPHA-MSH ANALOGUES FOR USE IN

THE TREATMENT OF HAILEY-HAILEY DISEASE

Technical field

The present invention relates to alpha-MSH analogues, particularly afamelanotide, for use in a medical indication and to a medical treatment using alpha-MSH analogues, particularly afamelanotide, and to alpha-MSH analogues, particularly afamelanotide, for the manufacture of a medicament.

Background to the invention

Hailey-Hailey disease is associated with rashes and blisters on the skin and is due to a genetic defect. Available treatments include topical steroids, methotrexate, and thalidomine. Related infections may be treated with antibiotics or antifungals.

Biolcati, G. et al. (2013), "Efficacy of the melanocortin analogue IMIe4-D-Phe7-a-melanocyte- stimulating hormone in the treatment of patients with Hailey-Hailey disease"; Clinical and Experimental Dermatology, proposes afamelanotide for treatment of HHD. Despite the recommended 2 short treatments, there remains a need for further improvement of treatment of Hailey-Hailey disease.

Summary of the invention

Surprisingly, the present invention provides for a simple, effective and safe treatment of Hailey-Hailey disease using a preferred dosing regimen. Accordingly, in one aspect, the present invention is directed to alpha-MSH analogue for use in treating a human subject suffering from Hailey-Hailey disease, wherein the interval between subsequent administrations of the alpha- MSH analogue is at least 5 weeks and at most 8 weeks. Preferably, the interval between subsequent administrations of the alpha-MSH analogue is at least 6 weeks. Preferably, the alpha-MSH analogue is administered systemically. Preferably, the alpha-MSH analogue is administered subcutaneously. Preferably, after each administration 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 at least 2 days. Preferably, the alpha-MSH analogue is administered at least 3 times to the subject. Preferably, the alpha-MSH analogue is administered at most 24 times to the subject. Preferably, the alpha-MSH analogue is a derivative of alpha-MSH which exhibits agonist activity for the melanocortin-l-receptor (MC1R), the receptor to which alpha-MSH binds to initiate the production of melanin within a melanocyte. Preferably, the alpha-MSH analogue is afamelanotide and the interval between subsequent administrations of the afamelanotide is at least 5 weeks and at most 8 weeks. Preferably, the alpha-MSH analogue is administered to the subject in the form of an implant comprising 16mg afamelanotide.

In another aspect, the invention is directed to the use of an alpha-MSH analogue for the manufacture of a medicament for the treatment of Hailey-Hailey disease, wherein the interval between subsequent administrations of the alpha-MSH analogue is at least 5 weeks and at most 8 weeks.

In another aspect, invention is directed to the treatment of a human subject suffering from Hailey-Hailey disease, wherein the interval between subsequent administrations of the alpha- MSH analogue is at least 5 weeks and at most 8 weeks. According to the present invention, we have surprisingly found that, lesion clearance can be improved while treatment side-effects such as tanning, scarring and/or coloring may be limited or avoided. Without wishing to be bound by any theory, Applicant believes that -given the deficiency in keratinocyte adhesion- the direct and indirect effects of the presently claimed administration regimen of the alpha-MSH analogue (particularly afamelanotide) on keratinocytes and melanocyte in the subject's skin provide these benefits, particularly as determined by physicians' assessment and patient reports of clinically significant

improvements of re-epithelialization of epithelium clearance of the skin lesions of Hailey- Hailey disease. We have further found that the particular dosing of the invention surprisingly allows for the reduction of infections, particularly skin infections.

Detailed description of the invention

The present invention is directed to alpha-MSH analogues, particularly afamelanotide, for use in treatment of Hailey-Hailey disease. Further, the invention is directed to a medical treatment of Hailey-Hailey disease using alpha-MSH analogues, particularly afamelanotide. Further the invention is directed to use of alpha-MSH analogues, particularly afamelanotide, for the manufacture of a medicament for the treatment of Hailey-Hailey disease. Hailey-Hailey disease is rare disorder associated with skin rashes and blisters. The cause of the disorder seems related to a chromosomal defect. Treatment options are limited and not leading to optimal results or causing concerns for side-effects. Preferably, according to the treatment of the invention, the alpha-MSH analogue, particularly afamelanotide, is administered at least 3 times to a subject suffering from Hailey-Hailey disease, more preferably at least 6 times, most preferably at least 10 times and preferably at most 24 times and particularly preferred the alpha-MSH analogue, particularly afamelanotide, is administered 12 times. In one aspect, the interval between subsequent administrations is at least 3 weeks, more preferably more than 4 weeks, most preferably more than 31 days and in particular preferred at least 5 weeks. Preferably, the interval between subsequent administrations is at most 8 weeks, more preferably at most 7 weeks, most preferably at most 6 weeks. A particularly preferred range for the interval between subsequent administrations is between from 5 to 6 weeks. In another aspect, the interval between subsequent

administrations is preferably at least 5 weeks, more preferably at least 6 weeks and preferably at most 10 weeks, more preferably at most 9 weeks and most preferably at most 8 weeks, with a preferred range for the interval being 5 to 8 weeks and a particularly preferred range being 6 to 8 weeks. It will be understood that for the purpose of the invention, the intervals are separate and subsequent and do not overlap.

Preferably, the subject has the alpha-MSH analogue (preferably afamelanotide) blood plasma level -resulting from each administration- 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 up to 10 days, for instance for 7 days or for 10 days. It will be understood that these the alpha-MSH analogue (preferably afamelanotide) blood plasma levels are achieved after each administration. As will be understood by a skilled person in the art, after initial the 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 (preferably afamelanotide) is administered in an amount that results in the blood plasma levels indicated. Accordingly, the human is subjected to the blood plasma levels indicated. According to the invention, the alpha-MSH analogue, particularly afamelanotide, is preferably systemically administered. Preferably, the alpha-MSH analogue, particularly afamelanotide, is administered subcutaneously.

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:

R W-X-Y-Z-R₂ wherein

R_x 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-Nle-Glu-His-D-Phe-Arg-Trp-Lys-Gly-Pro-Val-NH₂,

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

Ac-N!e-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-0rn-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-Nle-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 - Nle - Glu- His- D-Phe -Arg - Trp - Lys - Gly - Pro -Val -NH₂, Ac - Nle- Glu - His - D-Phe - Arg - Trp - Lys-NH₂,

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

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

Ac- Nle - Asp - His - D-Phe - Arg - Trp -Dpr-NH₂,

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

Ac-Tyr - Ser - Nle -Asp- His - D-Phe - Arg - Trp - Lys

Ac- Ser - N le - Asp - His - D-Phe - Arg - Trp - Lys-N H₂,

- Nle - Asp - His - D-Phe - Arg - Trp - Lys-Gly-NH

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

Ac - 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]- -MSH, Nle⁴, D-Phe⁷]-a-MSH, D-Ser¹, D-Phe⁷]-a-MSH_;

D-Tyr², D-Phe⁷]-a-MSH, D-Ser³, D-Phe⁷]-a-MSH, D-Met⁴, D-Phe⁷]-a-MSH, D-Glu⁵, D-Phe⁷]-a-MSH, p-His⁶, D-Phe⁷]-a-MSH, P-Phe⁷, D-Arg⁸]-a-MSH, D-Phe⁷, D-Trp⁹]-a-MSH, D-Phe⁷, D-Lys ]-a-MSH, p-Phe⁷, D-Pro¹²]-a-MSH, p-Phe⁷, D-Val¹³]-a-MSH, p-Ser¹, Nle⁴, D-Phe⁷]-a-MSH, p-Tyr², Nle , D-Phe⁷]-a-MSH, p-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-MSH, ;Nle⁴, D-Phe⁷, D-Val¹³]-a-MSH,

[ Cys⁴ , Cys¹⁰]-a-MSH,

[ Cys⁴, D-Phe⁷, Cys¹⁰]-a-MSH, [ Cys⁴, Cys^u]-a- SH,

[ Cys⁵ , Cys¹⁰]-a-MSH,

[Cys⁵ , Cys^u]-a-MSH,

[Cys⁴ , Cys¹⁰]- -MSH₄._: ; Cys⁴, Cys¹⁰]-a-MSH₄-i2,

;N!e⁴, D-Phe⁷]-a-MSH₄.io,

;Nle⁴ _; D-Phe⁷]-a-MSH₄-ii,

;Nle⁴, D-Tyr⁷]-a-MSH₄-i_1;

[(pN0₂)D-Phe⁷]-a-MSH₄._11;

[Tyr⁴, D-Phe⁷]-a-MSH₄.io,

[Tyr⁴, D-Phe⁷]-a-MSH₄._u,

[Nle⁴]-a-MSH₄._11;

[Nle⁴, (pN0₂)D-Phe⁷]-a-MSH₄.n,

[Nle⁴, D-His⁶]-a-MSH₄.₁₁₍

[Nle⁴, D-His⁶, D-Phe⁷]-a-MSH₄._Ui

[Nle⁴, D-Arg⁸]-a-MSH₄__11;

[Nle⁴, D-Trp⁹]-a-MSH₄._u,

[Nle⁴, D-Phe⁷, D-Trp⁹]-a-MSH₄.

[Nle⁴, D-Phe⁷]-a-MSH₄.₉, and

[Nle⁴, D-Phe⁷, D-Trp⁹]-a-MSH₄.₉.

Preferred alpha-MSH analogues thereof are selected from the group consisting of:

[Nle⁴, D-Phe⁷]-a-MSH₄-₁₀,

[Nle⁴, D-Phe⁷]-a-MSH₄._11;

[Nle⁴, D-Phe⁷, D-Trp⁹]-a-MSH₄.n, and

[Nle⁴, D-Phe⁷]-ct-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 d 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 aralkyi chain or an N-acylated linear or branched C_x to C₁ alkyl, aryl, heteroaryl, alkene, alkenyl, or aralkyi chain and more preferably is a Q 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, cycloalkyi, cycloheteroalkyl, aryl or heteroaryl, and more preferably is an L- or D-isomer of NIe; 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, cycloalkyi, cycloheteroalkyl, 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, (Cx-CjoJalkyl-halo, (Ci-Cio)alkyl, (Q-C_tojalkoxy, (QrCjolalkylthio, 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, (Ci-Cio)alkyl-halo, (Ci-C₁₀)alkyl, (Ci-Cio)alkoxy, (Ci-Ci₀)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, cycloalkyi, 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, -O-alkyl, aryl, or -O-aryl, and more preferably is an L- or D-isomer of Trp, Nal l or al 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, cycloalkyi, aryl, alkyl cycloalkyi, aralkyl, heteroaryl, alkene, 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", "alkene", "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. Afamelanotide as used in the present invention is the generic name for [Nle⁴, D- Phe⁷]-alpha MSH, a synthetic analogue of natural 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, particularly afamelanotide, is administered in the form of composition, more preferably in the form of an implant. Preferred the alpha-MSH analogue, particularly afamelanotide, implants are described in US2008/0305152 (Kleinig et al.) which is incorporated herein by reference. Preferably, according to this invention, the composition comprises at least 5mg the alpha-MSH analogue (preferably afamelanotide), more preferably at least lOmg and preferably at most 30mg, more preferably at most 25mg. Particularly preferred amounts are 20mg or 16mg the alpha-MSH analogue (preferably afamelanotide) with 16mg afamelanotide being most preferred amount. The % by weight of the alpha-MSH analogue (preferably afamelanotide) that is encapsulated or incorporated in the biodegradable polymer will vary depending upon the selection of the biodegradable polymer, the encapsulation or incorporation technique, and the amount of the alpha-MSH analogue (preferably afamelanotide) to be delivered to the subject. In one aspect, the amount of the alpha-MSH analogue (preferably afamelanotide) encapsulated in the implant can be up to 50% by weight of the implant. In other aspects, the amount of the alpha-MSH analogue (preferably afamelanotide) encapsulated in the implant is preferably 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.

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 (preferably afamelanotide) is imbedded within the implant. In one aspect, the alpha-MSH analogue, particularly afamelanotide, 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, homopolymers 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 polylactide-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.

Other pharmaceutically-acceptable components can be encapsulated or incorporated in the composition in combination with the alpha-MSH analogue (preferably afamelanotide). For example, the pharmaceutically-acceptable component can include, but is not limited to, 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 another aspect, the implant comprises [Nle⁴, D- Phe⁷]- alpha-MSH in the amount from 15% to 45% by weight of the implant, wherein the implant comprises poly(lactide) or poly(lactide-co-glycolide) such as, for example, 85:15 poly(lactide-co-glycolide). Preferred implants are described in US2008/0305152. A preferred implant is available under the name of Scenesse^® in Italian and Swiss markets.

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

Afamelanotide is subcutaneously administered to subjects suffering from Hailey Hailey disease in the form of 16mg implants and with subsequent administration intervals of from 6 to 8 weeks. Afamelanotide was systemically released from each implant for at least 2 days, with plasma levels of between O.OOOlng/ml and lOng/ml during this period.

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

Embodiment 1. Afamelanotide for use in treating a human subject suffering from Haiiey-Hailey disease, wherein afamelanotide is administered at least 3 times to the subject, wherein after each administration 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 at least 2 days, and wherein the interval between subsequent administrations of afamelanotide is between at least 3 weeks and at most 6 weeks.

Embodiment 2. Compound for use according to embodiment 1, wherein afamelanotide is administered systemically.

Embodiment 3. Compound for use according to embodiments 1-2, wherein afamelanotide is subcutaneously administered.

Embodiment 4. Compound for use according to embodiments 1-3, wherein afamelanotide is administered to the subject in the form of an implant comprising 16mg afamelanotide.

Embodiment 5. Compound for use according to embodiments 1-4, wherein afamelanotide is administered at least 10 times to the subject with an interval between subsequent administrations of between at least 5 weeks and at most 6 weeks.

Claims

1. Alpha-MSH analogue for use in treating a human subject suffering from Hailey-Hailey disease, wherein the interval between subsequent administrations of the alpha-MSH analogue is at least 5 weeks and at most 8 weeks.

2. Compound for use according to claim 1, wherein the interval between subsequent administrations of the alpha-MSH analogue is at least 6 weeks.

3. Compound for use according to claims 1-2, wherein the alpha-MSH analogue is administered systemically.

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

5. Compound for use according to claims 1-4, wherein after each administration 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 at least 2 days.

6. Compound for use according to claims 1-5, wherein the alpha-MSH analogue is administered at least 3 times to the subject.

7. Compound for use according to claims 1-6, wherein the alpha-MSH analogue is administered at most 24 times to the subject.

8. Compound for use according to claims 1-7, wherein the alpha-MSH analogue is a derivative of alpha-MSH which exhibits agonist activity for the melanocortin-l-receptor (MC1R), the receptor to which alpha-MSH binds to initiate the production of melanin within a melanocyte.

9. Compound for use according to claims 1-8, wherein the alpha-MSH analogue is afamelanotide and wherein the interval between subsequent administrations of the afamelanotide is at least 5 weeks and at most 8 weeks.

10. Compound for use according to claims 1-9, wherein the alpha-MSH analogue is administered to the subject in the form of an implant comprising 16mg afamelanotide.

11. Use of an alpha-MSH analogue for the manufacture of a medicament for the treatment of Hailey-Hailey disease, wherein the interval between subsequent administrations of the alpha- MSH analogue is at least 5 weeks and at most 8 weeks.

12. Treatment of a human subject suffering from Hailey-Hailey disease, wherein the interval between subsequent administrations of the alpha-MSH analogue is at least 5 weeks and at most 8 weeks.