WO2015063102A1

WO2015063102A1 - Alpha-msh analogues for use in bullous disease

Info

Publication number: WO2015063102A1
Application number: PCT/EP2014/073145
Authority: WO
Inventors: Philippe Wolgen
Original assignee: Clinuvel Ag
Priority date: 2013-10-28
Filing date: 2014-10-28
Publication date: 2015-05-07

Abstract

The present invention relates to alpha-MSH analogues, preferably afamelanotide, for use in treatment of Bullous Disease, leading to clinical efficacy as judged by doctors and patients and limited or no side-effects.

Description

ALPHA-MSH ANALOGUES FOR USE IN BULLOUS DISEASE

Technical field

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

Background to the invention

Bullous Disease is debilitating disorder associated with skin blisters which are also known as bullae. It is an auto-immune disorder in which antibodies circulate through the body and bind to the body's own tissue. Only few treatment options are available for treatment of Bullous Disease including corticosteroids and immunosuppressants. However, these treatments may not be effective, often only treating disease symptoms and/or have considerable side-effects. In view of the limited treatment options and the high unmet medical need of subjects suffering from Bullous Disease, there remains a need for further improvement of treatment of Bullous Disease.

Summary of the invention

Surprisingly, the present invention provides for an effective and safe treatment of Bullous Disease. Accordingly, in one aspect, the present invention is directed to an alpha-MSH analogue, preferably afamelanotide, for use in treating Bullous Disease. Preferably, Bullous Disease is selected from pemphigus vulgaris, pemphigus foliaceus, bullous impetigo, staphylococcal scalded syndrome, linear IgA disease, pemphigoid gestationis, lichen planus pemphigoidis, mucous membrane pemphigoid, epidermolysis bullosa acquisita, dermatitis herpetiformis, cicatricial pemphigoid, bullous systemic lupus erythematosis, bullous pemphigoid, paraneoplastic pemphigus, and fogo selvage. More preferably, Bullous Disease is selected from pemphigus vulgaris, bullous pemphigoid, and epidermolysis bullosa acquisita. In one aspect, the present invention is directed to pemphigus vulgaris. In another aspect, the present invention is directed to bullous pemphigoid. In yet another aspect, the present invention is directed to epidermolysis bullosa acquisita. Preferably, the alpha-MSH analogue is used in a human subject suffering from Bullous Disease. Preferably, the alpha-MSH analogue is administered systemically. Preferably, the alpha-MSH analogue is administered

subcutaneously. Preferably, the alpha-MSH analogue is administered in at least 2 times, wherein the interval between subsequent administrations is between at least 2 weeks and at most 8 weeks. Preferably, the alpha-MSH analogue is administered to the subject in at least 10 times, wherein the interval between subsequent administrations is between at least 5 and at most 6 weeks. Preferably, the alpha-MSH analogue after each administration is present in the blood plasma 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 of the present invention is afamelanotide. Preferably, the alpha-MSH analogue is administered in the form of an implant comprising 16mg

afamelanotide.

In another aspect, the invention relates to a method of treating Bullous Disease using an alpha-MSH analogue.

In a further aspect, the invention relates to the use of an alpha-MSH analogue for the manufacture of a medicament for the treatment of Bullous Disease.

According to the present invention, we have surprisingly found that, bullae can be cleared while potential side-effects of the disease and/or treatment such as tanning, scarring and/or coloring as assessed by doctors and/or patients may be limited or even avoided.

Detailed description of the invention

The present invention is directed to the alpha-MSH analogue, preferably afamelanotide, for use in treatment of Bullous Disease. Further, the invention is directed to a method of treating Bullous Disease using the alpha-MSH analogue, preferably afamelanotide. Further, the invention is directed to use of alpha-MSH analogue for the manufacture of a medicament for the treatment of Bullous Disease.

Bullous Disease is rare disorder associated with skin blisters. The cause of the disorder is related to an auto-immune defect. Treatment options are limited and not leading to optimal results or causing concerns for side-effects. According to the present invention, the alpha-MSH analogue has surprisingly been found effective for treatment of Bullous Disease.

According to the invention, the Bullous Disease treated with the alpha-MSH analogue is preferably selected from pemphigus vulgaris, pemphigus foliaceus, bullous impetigo, staphylococcal scalded syndrome, linear IgA disease, pemphigoid gestationis, lichen planus pemphigoidis, mucous membrane pemphigoid, epidermolysis bullosa acquisita, dermatitis herpetiformis, cicatricial pemphigoid, bullous systemic lupus erythematosis, bullous pemphigoid, paraneoplastic pemphigus, and fogo selvage. More preferably, Bullous Disease is selected from pemphigus vulgaris, bullous pemphigoid, and epidermolysis bullosa acquisita.

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- 1 receptor (MC1R), 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 intramolecular 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.

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-6ln-His-D-Phe-Arg-Trp-Gly-Lys-Pro-Val-NH₂

wherein M is Met, Nle or Lys; and/or

(b) compounds of the formula:

R W-X-Y-Z-Rz

wherein Rt 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

2 is -N H₂; -Gly-NH₂; or-Gly-Lys-N H₂ , 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-N le-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-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-N H₂,

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-NIe-Glu-His-D-Phe-Arg-Trp-Dpr-NH₂,

Ac-Nle-Glu-His-Phe-Arg-Trp-Lys-NH₂ and/or

Ac-Nle-Asp-His-Phe-Arg-Trp-Lys-NH₂.

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

Ac- N le - Asp - His - D-Phe - Arg - Trp - Dab-N H_:

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

- Ser -Tyr - Ser- Nle - Asp - His - D-Phe - Arg - Trp - Lys-Gly-Pro-Val-NH_: Ac- Ser - Try - Ser -Nle- Asp - His - D-Phe - Arg - Trp - Lys-N H₂,

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

Ac- Ser - Nle - 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/or

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]-ct-MSH, Me⁴, D-Phe⁷]-a-MSH_;

D-Ser¹, D-Phe⁷]-a-MSH, D-Tyr², D-Phe⁷]-ct-MSH, D-Ser³, D-Phe⁷]-a-MSH, p-Met⁴, D-Phe⁷]-a-MSH, p-Glu⁵, D-Phe⁷]-a-MSH, p-His⁶, D-Phe⁷]-a-MSH, P-Phe⁷, D-Arg⁸]-a-MSH, P-Phe⁷, D-Trp⁹]-a-MSH, p-Phe⁷ _; D-Lysⁿ]-a-MSH, p-Phe⁷, D-Pro¹²]-a-MSH, p-Phe⁷, D-Val¹³]-a-MSH, p-Ser¹, Nle⁴, D-Phe⁷]-a-MSH, p-Tyr², Nle⁴, 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-Pro¹ ]-a-MSH, ;Nle⁴ _; D-Phe⁷, D-Val¹³]-a-MSH,

[ Cys⁴, Cys¹⁰]-a-MSH,

[ Cys⁴, D-Phe⁷ , Cys¹⁰]-a-MSH,

[ Cys⁴, Cys^u]-a-MSH,

[ Cys⁵ , Cys¹⁰]-a-MSH,

[Cys⁵ , Cys^-a-MSH,

[ Cys⁴, Cys¹⁰]-a-MSH₄.₁₂,

[Nle⁴, D-Phe⁷]-a-MSH₄-io,

[Nle⁴ _; D-Phe⁷]-a-MSH₄-n_;

[ le⁴, D-Tyr⁷]-a-MSH₄-u,

[(pN0₂)D-Phe⁷]-a-MSH₄._n,

[Tyr⁴, D-Phe⁷]-a-MSH₄.₁₀,

[Tyr⁴, D-Phe⁷]- -MSH₄.n,

[Nle⁴]-a-MSH₄-_n,

[Nle⁴, (pN0₂)D-Phe⁷]-a-MSH

[Nle⁴, D-His⁶]-a-MSH₄._n,

[Nle⁴, D-His⁶, D-Phe⁷]-a-MSH₄._u,

[ le⁴, D-Arg⁸]-a-MSH₄. ,

[Nle⁴, D-Trp⁹]-a-MSH₄._u,

[Nle⁴, D-Phe⁷, D-Trp⁹]-a-MSH₄.n,

[Nle⁴, D-Phe⁷]-a-MSH₄.₉, and/or

[Nle⁴, D-Phe⁷, D-Trp⁹]-a-MSH₄.₉. Preferred alpha-MSH analogues thereof are selected from:

[Nle⁴, D-Phe⁷]-a-MSH₄.₁₀,

[Nle⁴, D-Phe⁷]-a-MSH₄-_U,

[Nle⁴, D-Phe⁷, D-Trp⁹]-a-MSH₄._n, and/or

[Nle⁴, D-Phe⁷]-ct-MSH

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 Ci to C₁₇ acyl group, wherein the d to C₁₇ comprises a linear or branched alkyl, cycloalkyi, alkylcycloalkyi, 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 Q to C₁₇ alkyl, aryl, heteroaryl, aikene, alkenyl, or aralkyl chain and more preferably is a Cj 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 N Ie; 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, (Ci-C₁₀)alkyl-halo, (C Ci₀)alkyl, (Ci-C₁₀)alkoxy, (Ci-C₁₀)alkylthio, 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-Qojalkyl-halo, (Q-Ciojalkyl, (C Cio)alkoxy, (Ci-Cio)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 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, cycloalkyi, aryl, alkyl cycloalkyi, 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,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.

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.

According to the present invention, the most preferred alpha-MSH analogue is [Nle⁴, D-Phe⁷]- alpha-MSH. This compound is also called afamelanotide and 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^®.

According to a preferred aspect, the invention is directed to afamelanotide, a specifically preferred alpha-MSH analogue, for use in treatment of Bullous Disease. Afamelanotide is the generic name for [Nle⁴, D-Phe⁷]-alpha MSH, a synthetic analogue of natural alpha MSH.

According to the invention, afamelanotide is preferably systemically administered. Preferably, afamelanotide is administered subcutaneously. Preferably, afamelanotide is administered in the form of an implant comprising 16mg afamelanotide.

Preferably, the alpha-MSH analogue of the invention is administered in a composition, preferably an implant. Preferred alpha-MSH analogue compositions and 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 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 alpha-MSH analogue is afamelanotide. The % by weight of alpha-MSH analogue 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 alpha-MSH to be delivered to the subject. In one aspect, the amount of alpha- MSH analogue encapsulated in the implant can be up to 50% by weight of the implant. In other aspects, the amount of alpha-MSH analogue 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 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-giycolide), 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. 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 comprising afamelanotide is available under the name of Scenesse^® in Italian and Swiss markets.

Preferably, according to the treatment of the invention, the alpha-MSH analogue is administered at least 2 times to a subject suffering from Bullous Disease, more preferably at least 3 times, most preferably at least 6 times and particularly preferably at least 10 times, and preferably at most 24 times. In one aspect, preferably, the interval between subsequent administrations is at least 2 weeks, more preferably more than 3 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 alpha-MSH analogue 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 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. Consequently, human is subjected to the blood plasma levels indicated.

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

Examples

Afamelanotide is subcutaneously administered to subjects suffering from Bullous 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 of bullous disease. Embodiment 2. Compound for use according to embodiment 1, wherein the bullous disease is selected from pemphigus vulgaris, pemphigus foliaceus, bullous impetigo, staphylococcal scalded syndrome, linear IgA disease, pemphigoid gestationis, lichen planus pemphigoidis, mucous membrane pemphigoid, epidermolysis bullosa acquisita, dermatitis herpetiformis, cicatricial pemphigoid, bullous systemic lupus erythematosis, bullous pemphigoid, paraneoplastic pemphigus, and fogo selvage.

Embodiment 3. Compound for use according to embodiments 1-2, wherein the bullous disease is selected from pemphigus vulgaris, bullous pemphigoid, and epidermolysis bullosa acquisita. Embodiment 4. Compound for use according to embodiments 1-3 in a human subject.

Embodiment 5. Compound for use according to embodiments 1-4, wherein afamelanotide is administered systemically. Embodiment 6. Compound for use according to embodiments 1-5, wherein afamelanotide is administered subcutaneously.

Embodiment 7. Compound for use according to embodiments 1-6, wherein afamelanotide is administered in the form of an implant comprising 16mg afamelanotide.

Embodiment 8. Compound for use according to embodiments 1-7, wherein afamelanotide is administered at least 2 times, wherein the interval between subsequent administrations is between at least 2 weeks and at most 8 weeks. Embodiment 9. Compound for use according to embodiments 1-8, wherein afamelanotide is administered to the subject at least 10 times wherein the interval between subsequent administrations is between at least 3 and at most 6 weeks. Embodiment 10. Compound for use according to embodiments 1-9, wherein afamelanotide after each administration is present in the blood plasma at a level of between at least O.Olng/ml to at most lOng/ml for at least 2 days.

Claims

1. Alpha-MSH analogue for use in treating of bullous disease.

2. Compound for use according to claim 1, wherein the bullous disease is selected from pemphigus vulgaris, pemphigus foliaceus, bullous impetigo, staphylococcal scalded syndrome, linear IgA disease, pemphigoid gestationis, lichen planus pemphigoidis, mucous membrane pemphigoid, epidermolysis bullosa acquisita, dermatitis herpetiformis, cicatricial pemphigoid, bullous systemic lupus erythematosis, bullous pemphigoid, paraneoplastic pemphigus, and fogo selvage.

3. Compound for use according to claims 1-2, wherein the bullous disease is selected from pemphigus vulgaris, bullous pemphigoid, and epidermolysis bullosa acquisita.

4. Compound for use according to claims 1-3 in a human subject.

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

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

7. Compound for use according to claims 1-6, wherein the alpha-MSH analogue is administered at least 2 times, wherein the interval between subsequent administrations is between at least 2 weeks and at most 8 weeks.

8. Compound for use according to claims 1-7, wherein the alpha-MSH analogue is administered to the subject at least 10 times wherein the interval between subsequent administrations is between at least 5 and at most 8 weeks.

9. Compound for use according to claims 1-8, wherein the alpha-MSH analogue after each administration is present in the blood plasma at a level of between at least O.Olng/ml to at most lOng/ml for at least 2 days.

10. Compound for use according to claims 1-9, wherein the alpha-MSH analogue is afamelanotide.

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

12. Method of treating Bullous Disease using an alpha-MSH analogue.

13. Use of an alpha-MSH analogue for the manufacture of a medicament for the treatment of Bullous Disease.