EP2259794A1

EP2259794A1 - Method for treatment of photosensitivity and phototoxicity

Info

Publication number: EP2259794A1
Application number: EP09713206A
Authority: EP
Inventors: Philippe Wolgen
Original assignee: Clinuvel Pharmaceuticals Ltd
Current assignee: Clinuvel Pharmaceuticals Ltd
Priority date: 2008-02-22
Filing date: 2009-02-20
Publication date: 2010-12-15
Also published as: WO2009103816A1; AU2009216681A1; CA2716509A1

Abstract

The present invention relates to the use of an alpha-MSH analogue to reduce or ameliorate photosensitivity and/or phototoxicity in a patient due to administration of a photosensitizing agent and the use of an alpha-MSH analogue for the manufacture of a therapeutic or prophylactic preparation for treating photosensitivity and/or phototoxicity in the patient due to administration of a photosensitizing agent.

Description

Method for treatment of photosensitivity and phototoxicity

FIELD OF THE INVENTION The present invention relates to compositions and methods for treating photosensitivity and phototoxicity following the administration of a photosensitizing agent.

BACKGROUND

Alpha melanocyte stimulating hormone (alpha-MSH) is released from UVR exposed keratinocytes in human skin following exposure to ultraviolet radiation. It is understood to act on the melanocortin-1 -receptors (MClR) to, exclusively in melanocytes, induce synthesis of the brownish-black melanin pigment. MClR are expressed on keratinocytes as well as number of other cells including, but not exclusively, immunological cells such as dendritic / Langerhans cells, neutrophils, microglia and monocytes as well as astrocytes, and endothelial cells.

It has previously been disclosed that a super-potent derivative of alpha-MSH, Nle⁴-D-Phe⁷-alpha- MSH (afamelanotide), can induce melanin synthesis in human volunteers. Nle⁴-D-Phe⁷-alpha- MSH contains two amino acid substitutions and is approximately 10 to 1, 000-fold more potent than the native hormone at inducing pigmentation in experimental systems such as the frog skin bioassay or in cultured human keratinocytes.

There is a need for methods for treatment of photosensitivity and phototoxicity occurring after photodynamic treatment of mucosal, intestinal, esophageal, urothelial, interstitial, cardiopulmonary and ophtalmological tissues. Prolonged skin sensitivity and ophtamological sensitivity following PDT is a most common sequelum.

Photodynamic therapy is increasingly being recognised as an attractive treatment modality for superficial cancer (see for example Triesscheijn, M., Baas, P., Schellens, J. H M., and Stewart, F. A. (2006) Photodynamic Therapy in Oncology. The Oncologist 71:1034-1044). The present invention provides the administration of a super-potent derivative of alpha-MSH, Nle⁴-D-Phe⁷-alpha-MSH (afamelanotide; WHO 2008, INN) as a method for prophylactically or therapeutically treating photosensitive and phototoxic reactions following the administration of photosensitizers, for instance such as in systemic or local photodynamic therapy (PDT).

Those skilled in the art will appreciate that the invention described herein is susceptible to variations and modifications other than those specifically described. It is to be understood that the invention includes all such variations and modifications, the invention also includes all of the steps, features, compositions and compounds referred to or indicated in this specification, individually or collectively, and any and all combinations or any two or more of said steps or features

SUMMARY OF THE INVENTION

In a first aspect of the present invention there is provided a method of treating photosensitivity and/or phototoxicity in a patient due to administration of a photosensitizing agent, the method comprising administering to the patient a therapeutically effective amount of an agent which causes an increase in the level of melanin in the skin of the patient, wherein the photosensitizing agent is activated or excited at a wavelength of between 280 nm and 800 nm, and preferably between 390 nm and 800 nm.

In a second aspect of the present invention there is provided the use of an effective amount of an agent which causes an increase in the level of melanin in the skin of a patient for the manufacture of a therapeutic or prophylactic preparation for treating photosensitivity and/or phototoxicity in the patient, wherein the photosensitivity and/or phototoxicity is due to administration of a photosensitizing agent, wherein the photosensitizing agent is activated or excited at a wavelength of between 280 nm and 800 nm, and preferably between 390 nm and 800 nm.

In a third aspect of the present invention there is provided a composition comprising a photosensitizing agent and an agent which causes an increase in the level of melanin in the skin.

DETAILED DESCRIPTION OF THE INVENTION

Before the present methods are disclosed and described, it is to be understood that the aspects described below are not limited to specific methods or uses as such may, of course, vary. It is also to be understood that the terminology used herein is for the purpose of describing particular aspects only and is not intended to be limiting.

In this specification and in the claims that follow, reference will be made to a number of terms that shall be defined to have the following meanings:

Throughout this specification, unless the context requires otherwise, the word "comprise," or variations such as "comprises" or "comprising," will be understood to imply the inclusion of a stated integer or step or group of integers or steps but not the exclusion of any other integer or step or group of integers or steps.

It must be noted that, as used in the specification and the appended claims, the singular forms "a," "an" and "the" include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to "a pharmaceutical carrier" includes mixtures of two or more such carriers, and the like.

"Optional" or "optionally" means that the subsequently described event or circumstance may or may not occur, and that the description includes instances where the event or circumstance occurs and instances where it does not.

Ranges may be expressed herein as from "about" one particular value, and/or to "about" another particular value. When such a range is expressed, another aspect includes from the one particular value and/or to the other particular value. Similarly, when values are expressed as approximations, by use of the antecedent "about," it will be understood that the particular value forms another aspect. It will be further understood that the endpoints of each of the ranges are significant both in relation to the other endpoint, and independently of the other endpoint.

References in the specification and concluding claims to parts by weight, of a particular element or component in a composition or article, denotes the weight relationship between the element or component and any other' elements or components in the composition or article for which a part by weight is expressed. Thus, in a compound containing 2 parts by weight of component X and 5 parts by weight component Y, X and Y are present at a weight ratio of 2:5, and are present in such ratio regardless of whether additional components are contained in the compound.

A weight percent of a component, unless specifically stated to the contrary, is based on the total weight of the formulation or composition in which the component is included.

By "contacting" is meant an instance of exposure by close physical contact of at least one substance to another substance. For example, contacting can include contacting a substance, such as a pharmacologic agent, with a cell, A cell can be contacted with a test compound, for example, an analogue of alpha-MSH, by adding the agent to the culture medium (by continuous infusion, by bolus delivery, or by changing the medium to a medium that contains the agent) or by adding the agent to the extracellular fluid in vivo (by local delivery, systemic delivery, intravenous injection, bolus delivery, or continuous infusion). The duration of contact with a cell or group of cells is determined by the time the test compound is present at physiologically effective levels or at presumed physiologically effective levels in the medium or extracellular fluid bathing the cell.

The terms "prophylactic treatment", "prevention" or "preventing" mean the administration of an active compound or composition to a subject at risk for an undesirable condition. The condition can include a disease, disorder or reaction, or a predisposition to a disease, disorder or reaction. Prophylactic treatment can range from a reduction in the risk for the condition or of the severity of the condition to the complete prevention of the condition.

The terms "therapeutic treatment" and "treating" mean the administration of an active compound or composition to a subject having an undesirable condition such as a disease, disorder or reaction. Therapeutic treatment can range from reduction in the severity of the condition in the subject to the complete recovery of the subject from the condition.

By "effective amount and time" means a therapeutic amount and time needed to achieve the desired result or results, e.g., preventing or treating photosensitivity and phototoxicity associated with photosensitisation following photodynamic therapy (PDT) in a subject.

By "induce" means initiating a desired response or result that was not present prior to the induction step. The term "induce" also includes the term "potentiate".

By "intermittent" means administering an active compound or composition in a series of discreet doses over a determined period, e.g., a period of sustained release of more than 4 hours, preferably more than 8 hours, more preferably more than 16 hours or 24 hours of an alpha-MSH analogue every two months.

The term "potentiate" means sustaining a desired response at the same level prior to the potentiating step or increasing the desired response over a period of time.

The term "melanogenesis" as referred to herein is defined as the ability of a subject to produce melanin by melanin-producing cells, or melanocytes.

The term "dermal or epithelial tissue" as referred to herein includes in particular the skin of a subject.

Disclosed are compounds, compositions, and components that can be used for, can be used in conjunction with, can be used in preparation for, or are products of the disclosed methods and compositions. These and other materials are disclosed herein, and it is understood that, when combinations, subsets, interactions, groups, etc. of these materials are disclosed that while specific reference of each various individual and collective combinations and permutation of these compounds may not be explicitly disclosed, each is specifically contemplated and described herein This concept applies to all aspects of this disclosure including, but not limited to, steps in methods of making and using the disclosed compositions. Thus, if there are a variety of additional steps that can be performed it is understood that each of these additional steps can be performed with any specific embodiment or combination of embodiments of the disclosed methods, and that each such combination is specifically contemplated and should be considered disclosed.

Described herein are methods for prophylactically or therapeutically treating photosensitivity and phototoxicity associated photosensitisation of skin and eyes following photodynamic therapy (PDT).

According to the invention an alpha-MSH analogue is used to reduce or ameliorate photosensitivity and/or phototoxicity in a patient due to administration of a photosensitizing agent. Also according to the invention an alpha-MSH analogue is used for the manufacture of a therapeutic or prophylactic preparation for treating photosensitivity and/or phototoxicity in the patient due to administration of a photosensitizing agent. The above used reduces or ameliorates photosensitivity and phototoxicity following the treatment with photodynamic therapy (PDT).

The photosensitizer compounds is selected from delta-aminolevulinic acid (ALA-PpIX), benzoporphyrin derivative monoacid A (BCP-MA), mono-aspertyl chlorine 6 (MACE), meta- tetrahydroxyphenylchlorin (mTHPC), a silicon phtalocyanine (Pc4), porphyrin sodium (Photofrin), metallopurin derivaties, fluorine-based derivatives, Temoporfin, Hypocrellins, tetracycline, Thiazide Diurectics, Hypoglycemic agents, Sulfonamides, Phenothiazines, Nalidixic Acid, Quinidine, Quinine, Lomotil, Griseofulvin, Psoralens, Oil of Bergamot, deodorants soaps, and figs, limes, celery, parsnips plants.

Preferably, the alpha-MSH-analogue is Nle⁴-D-Phe⁷-alpha-MSH and/or the alpha-MSH-analogue _ _

reduces the susceptibility of patients with Erythropoeitic Protoporphyria (EPP) to provocation with light. Also preferably the alpha-MSH-analogue exhibits agonist activity for MClR and/or upregulates the melanocortin-1 receptor (MClR).

5 The photosensitizing agent may be activated or excited at a wavelength of between 280 ran and 800 nm, and preferably between 390 nm and 800 nm.

Photosensitivity and phototoxicity may arise due to administration of photosensitizers following PDT in patients undergoing treatment for lesions, ulcerations, aberrations, stricture, stenosis,

10 dystrophy, hypertrophy, dysplasia, metaplasia, anaplasia, cancer precursors, actinic keratosis, carcinoma in situ, Bo wens' disease, basal cell carcinoma, squamous cell carcinoma, bile duct lesions and strictures, other lesions of the urinary tract, gastrointestinal tract, and reproductive system, psoriasis, viral inactivation, macular degeneration, ocular anomalies, glaucoma and various vascular diseases.

15

Furthermore, the present invention provides for a method of treating photosensitivity and/or phototoxicity due to photosensitizing agents, by increasing level of melanin in the skin of the patient.

20 Also the present invention provides for a method of administering an alpha-MSH analogue that increases melanin in the skin before, simultaneously or subsequent to administering of a photosensitizing agent. The alpha-MSH analogue may be administered intermittently.

According to the present invention there is also provided a composition comprising a 2.5 photosensitizing agent and an alpha-MSH-analogue which causes an increase in the level of melanin in the skin.

In a first aspect of the present invention there is provided a method of treating photosensitivity and/or phototoxicity in a patient due to administration of a photosensitizing agent, the method 30 comprising administering to the patient a therapeutically effective amount of an agent which causes an increase in the level of melanin in the skin of the patient, wherein the photosensitizing agent is activated or excited at a wavelength of between 280 nm and 800 nm, and preferably between 390 nm and 800 nm.

35 In a second aspect of the present invention there is provided the use of an effective amount of an agent which causes an increase in the level of melanin in the skin of a patient for the manufacture of a therapeutic or prophylactic preparation for treating photosensitivity and/or phototoxicity in the patient, wherein the photosensitivity and/or phototoxicity is due to administration of a photosensitizing agent, wherein the photosensitizing agent is activated or excited at a wavelength of between 280 ran and 800 nm, and preferably between 390 nm and 800 ran.

In a second aspect of the present invention there is provided the use of an effective amount of an agent which causes an increase in the level of melanin in the skin of a patient for the manufacture of a therapeutic or prophylactic preparation for treating photosensitivity and/or phototoxicity in the patient, wherein the photosensitivity and/or phototoxicity is due to and following the administration of a photosensitizing agent, wherein the photosensitizing agent is activated or excited at a wavelength of between 280 nm and 800 nm, and preferably between 390 nm and 800 nm.

In a preferred embodiment of the present invention the photosensitizing agent is activated or excited at a wavelength of between 280 nm and 800 nm, and preferably between 390 nm and 800 nm.

In another preferred embodiment of the present invention the agent which increases the level of melanin in the skin of the patient upregulates the melanocortin-1 receptor (MClR).

In yet another preferred embodiment of the present invention the agent which increases the level of melanin in the skin of the patient is an alpha-MSH analogue.

In yet another preferred embodiment of the present invention the agent which increases the level of melanin in the skin of the patient is Forskolin and/or an analogue thereof.

In one embodiment of the present invention, the alpha-MSH analogue is administered in a manner such as to maintain an effective plasma level of the alpha-MSH analogue for a period of at least 24 hours wherein the level is less than 100 ng/ml. Preferably also, the administration of the alpha- MSH analogue to the subject is intermittent administration. In a preferred embodiment of the invention, the subject is a human subject.

The agent which causes an increase in the level of melanin in the skin of the patient may be administered before, simultaneously or subsequent to the administration of the photosensitizing agent.

The photosensitizing agent will typically be administered topically, locally, systemically orally or parentally. In some cases the purpose of the agent is to cause photosensitivity such as in photodynamic therapy, however, in some cases photosensitivity is simply a side effect of administration of the agent.

Photosensitivity and phototoxicity are conditions of the skin and eyes that are associated with photosensitisation the use and or administration of photosensitizing drugs, in particular following photodynamic therapy (PDT). Photosensitizing drugs exhibit photosensitivity due to their chemical structure and composition. Photosensitivity and phototoxicity may arise due to the administration of photosensitizers following PDT in patients undergoing treatment for lesions, ulcerations, aberrations, strictures, stenosis, dystrophy, hyperplasia, hypertrophy, dysplasia, metaplasia, anaplasia, cancer precursors, actinic keratosis, carcinoma in situ, Bowens' disease, basal cell carcinoma, squamous cell carcinoma, epithelioma, endothelioma, urethelioma, small lung cell carcinoma, ovarian carcinoma, bile duct lesions and strictures, other lesions of the urinary tract, gastrointestinal tract, and reproductive system. In addition, photosensitivity and phototoxicity of the skin and or eyes may occur after photodynamic treatment of psoriasis, viral inactivation, macular degeneration, ocular' anomalies, glaucoma and various vascular diseases. These anomalies may be due to some acquired or genetic defect in a subject. As a result of the photodynamic therapy of the aforementioned tracts and anomalies, photosensitivity and phototoxicity of the skin and eyes due to the administration of other photosensitizing agents and pharmacologically active compounds and molecules have been recognized. Further information regarding PDT may be found in Triesscheijn, M., Baas, P., Schellens, J. H M., and Stewart, F. A. (2006) Photodynamic Therapy in Oncology. The Oncologist 71:1034-1044.

' The present invention extends to treatment of all such anomalies by photodynamic therapy using photosensitizers, whether the photosensitivity associated with the condition arises from administration of the photosensitizer to be used in photodynamic therapy or not.

Examples of photosensitizer compounds used in photodynamic therapy (PDT) include delta- _

aminolevulinic acid (ALA-PpIX), benzoporphyrin derivative monoacid A (BPD-MA), mono- aspertyl chlorine 6 (MACE), meta-tetrahydroxyphenylchlorin (mTHPC), a silicon phtalocyanine (Pc4), poiphin sodium (Photofrin), metallopurin derivatives, fluorene-based derivatives, Temoporfin and Hypocrellins.

Examples of other compounds in which photosensitivity is a side-effect and in which it is believed the method of the present invention may be applicable include:-

1. Tetracycline (Declomycin Vibramycin)

2. Thiazide Diurectics (Diuril, Hydrodiuril, Hygroton, Dyazide) 3. Hypoglycemic agents (Antidiabetics)

4. Sulfonamides

5. Phenothiazines (Phenergan, Thorazine, Stelazine, Compazine)

6. Nalidixic Acid

7. Quinidine and Quinine 8. Lomotil

9. Griseofulvin

10. Psoralens

11. Oil of Bergamot (perfumes, cologne)

12. Some deodorants soaps 13. Plants (figs, limes, celery, parsnips).

Accordingly, the methods of the present invention help to reduce or ameliorate phototoxicity and/ or photosensitivity following administration or application of certain photosensitizer compounds to a patient.

The term "alpha-MSH analogue" referred to herein is defined as a derivative of alpha-MSH which exhibits agonist activity for MClR, the receptor to which alpha-MSH binds to initiate the production of melanin within a melanocyte. Such derivatives 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 (Hi) an intramolecular interaction forms as a cyclic derivative.

Several derivatives of a-MSH have been synthesized. In one aspect, 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 certain embodiments of the present invention, the alpha-MSH analogue may be a compound as disclosed in Australian Patent No. 597630, selected from compounds of the formula:

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

wherein M is Met, NIe or Lys; and

(b) compounds of the formula:

R₁-W-X-Y-Z-R₂

wherein

Ri is Ac-GIy-, Ac-Met-Glu, Ac-NIe-GIu-, or Ac-Tyr-Glu-; W is -His- or -D-His-; X is -Phe-, -D-Phe-, -Tyr-, -D-Tyr-, or -(pNO₂)D-Phe⁷-, Y is -Arg- or -D-Arg-; Z is -Trp- or -D-Trp-; and R₂ is -NH₂; -GIy-NH₂; or -GIy-LyS-NH₂.

In another aspect, the alpha-MSH analogue may be selected from cyclic analogues which are disclosed in Australian Patent No. 618733 where an intramolecular interaction (such as a disulfide or other covalent bond) exists (1) between the amino acid residue at position 4 and an amino acid residue at position 10 or 11, and/or (2) between the amino acid residue at position 5 and the amino acid residue at position 10 or 11.

The alpha-MSH analogue may be a linear analogue as disclosed in US Patent No. 5,674,839, selected from the group consisting of:

Ac-Ser-Tyr- Ser-Nle-Glu-His-D-Phe-Arg-Trp-Lys-Gly-Pro-Val-N^ Ac-Ser-Tyr-Ser-Nle-Asp-His-D-Phe-Arg-Trp-Lys-Gly-Pro-Val-NH₂ _ _

Ac-Nle-Glu-His-D-Phe-Arg-Tφ-Lys-Gly-Pro-Val-NH₂ Ac-Nle-Asp-His-D-Phe-Arg-Trp-Lys-Gly-Pro VaI-NH₂ Ac-Nle-Asp-His-D-Phe-Arg-Trp-Gly-NHa 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-NIe- 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 Ac-Nle-Asp-His-Phe-Arg-Trp-Lys-NHb

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-Tφ-Lys-Gly-Pro-Val-NH₂

Ac-Nle-Glu-His-D-Phe-Arg-Trp-Lys-NH₂

I I

Ac-NIe- Asp-His-D-Phe-Arg-Trp-Lys-NH₂

Ac-Nle-Asp-His-D-Phe-Arg-Trp-Orn-NH₂

Ac-NIe- Asρ-His-D-Phe-Arg-Trp-Dab-NH₂ Ac-NIe-ASp-HiS-D-PlIe-AIg-TrP-DPr-NH₂

Ac-SCr-TyT-SCr-NIe-ASp-HiS-D-PlIe-ArE-TrP-LyS-GIy-PrO-VaI-NH₂ I I

Ac-Ser-Try-Ser-Nle-Asp-His-D-Phe-Arg-Trp-Lys-NH₂

Ac-Tyr-Ser-Nle-Asp-His-D-Phe-Arg-Tφ-Lys-NH₂

Ac-Ser-Nle-Asp-His-D-Phe-Arg-Tφ-Lys-NH₂

Ac-Nle-Asp-His-D-Phe-Arg-Trp-Lys-NH₂

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

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

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

Where referred to herein, Ala = alanine, Arg = arginine, Dab = 2,4-diaminobutyric acid, Dpr = 2,3-diaminopropionic acid, GIu = glutamic acid, GIy = glycine, His = histidine, Lys = lysine, Met = methionine, NIe = norleucine, Orn = ornithine, Phe = phenylalanine, (pNC>2)Phe = paranitrophenylalanine, PIg = phenylglycine, Pro = proline, Ser = serine, Trp = tryptophan, TrpFor = N¹- formyl-tryptophan, Tyr = tyrosine, VaI = 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 one aspect, the alpha-MSH analogue can be

[D-Phe⁷]-alpha-MSH,

[Nle⁴, D-Phe⁷]-alpha-MSH,

[D-Ser¹, D-Phe⁷] -alpha-MSH,

[D-Tyr², D-Phe⁷]-alpha-MSK,

[D-Ser³, D-Phe⁷]-alpha-MSH,

[D-Met⁴, D-Phe⁷]-alpha-MSH,

[D-GIu⁵, D-Phe⁷]-alpha-MSH,

[D-His⁶, D-Phe⁷]-alpha-MSH,

[D-Phe⁷, D-Arg⁸]-alpha-MSH,

[D-Phe⁷, D-Trp⁹]-alpha-MSH, _ _

[D-Phe⁷, D-Lys^π]-alpha-MSH, [D-Phe-⁷, D-Pro¹²]-alpha-MSH, [D-Phe⁷, D-Valⁿ]-alpha-MSH,

[D-Sei^ Nle⁴, D-Phe⁷] -alpha-MSH,

[D-Tyr², Nle⁴, D-Phe⁷] -alpha-MSH,

[D-Ser³, NIe⁴, D-Phe⁷] -alpha-MSH,

[NIe⁴, D-GIu⁵, D-Phe⁷] -alpha-MSH, [NIe⁴, D-His⁶, D-Phe⁷] -alpha-MSH,

[NIe⁴, D-Phe⁷, D-Arg⁸] -alpha-MSH,

[NIe⁴, D-Phe⁷ ₅ D-Trp⁹] -alpha-MSH,

[NIe⁴, D-Phe⁷, D-Lys¹¹ ]-alpha-MSH,

[NIe⁴, D -Phe⁷, D-Pro¹²]-alpha-MSH, [NIe⁴, D-Phe⁷, D-VaI 13]-alpha-MSH,

[Cys⁴, Cys^lo]-alpha-MSH

[Cys⁴, D-Phe⁷, Cys¹⁰]-alpha-MSH [Cys⁴, Cysⁿ]-apha-MSH

[Cys⁵, Cys^lo]-alpha-MSH

[Cys⁵, Cysⁿ]-alpha-MSH

[Cys⁴, Cys^lo]-alpha-MSH₄-i3

[Cys⁴, Cys¹⁰]-alpha-MSH4-₁₂

[NIe⁴, D-Phe⁷]-alpha-MSH₄.-io,

[NIe⁴, D-Phe⁷]-alpha-MSH_4-ii, [D-Phe⁷]-alpha-MSH₅-n,

[NIe⁴, D-Tyr⁷]-alpha-MSH₄-π

[(pN0₂)D-Phe⁷]-alpha-MSH_4-π

[Tyr⁴, D-Phe⁷]-alpha-MSH₄.io

[Tyr⁴, D-Phe⁷]-alpha-MSH₄.ii [NIe⁴] -alpha-MSHφn _ _

[NIe⁴, (pN0₂)D-Phe⁷]-alpha-MSH₄-π

[NIe⁴, D-His⁶]-alpha-MSH₄-π

[NIe⁴, D-His⁶, D-Phe⁷]-alpha-MSH4-π

[NIe⁴, D-Arg⁸]-alpha-MSH_4-n

[NIe⁴, D-Trp⁹]-alpha-MSH₄-π

[NIe⁴, D-Phe⁷, D-Trp⁹]-alpha-MSH_4-π

[NIe⁴, D-Phe⁷]-alpha-MSH_4-9, or

[NIe⁴, D-Phe⁷, D-Trp⁹] -alpha-MSH^

In a further aspect, the alpha-MSH analogue is

[Nle⁴, D-Phe⁷]-alpha-MSH4-i₀

[NIe⁴, D-Phe⁷]-alpha-MSH_4-π

[NIe⁴, D-Phe⁷, D-Trp⁹]-alpha-MSH_4-11, or

[NIe⁴, D-Phe⁷]-alpha-MSH_4-9.

In a particularly preferred aspect, the alpha-MSH analogue is [NIe⁴, D-Phe⁷] -alpha-MSH.

The alpha-MSH analogue may be administered in a sustained-release delivery system a disclosed in International Patent Application No. PCT/AU2005/000181 (WO 2006/012667), or topically using a transdermal delivery system as disclosed in International Patent Application No. PCT/AU2005/001552 (WO 2006/037188).

It will be appreciated that the actual preferred amounts of the alpha-MSH analogue in a specified _ _

case will vary according to the specific compounds being utilized, the particular compositions formulated, the mode of application, and the particular situs and subject being treated. Dosages for a given host can be determined using conventional considerations, e.g., by customary comparison of the differential activities of the subject compounds and of a known agent, e.g., by means of an appropriate conventional pharmacological protocol. Physicians and formulators, skilled in the art of determining doses of pharmaceutical compounds, will have no problems determining doses for prophylactically or therapeutically treating photodermatoses by administration of an amount of an alpha-MSH analogue by the methods described herein. In one aspect, the alpha-MSH analogue is administered in an amount which is effective to prophylactically or therapeutically treat photodermatoses, particularly if due to and following the administration of photosensitizing agents.

Any of the alpha-MSH analogues useful herein can be administered to a subject using a variety of administration or delivery techniques known in the art. It is desirable to maintain low concentrations of the alpha-MSH analogue in the plasma of the subject to induce prophylactically or therapeutically treatment of photodermatoses in the subject. Therefore, the mode of administration will depend upon the subject to be treated and the alpha-MSH analogue selected. In various aspects, the alpha-MSH analogues can be administered orally or parenterally. The term "oral" is used herein to encompass administration of the compounds via the digestive tract. The term "parenteral" is used herein to encompass any route of administration, other than oral administration, by which the alpha-MSH analogue is introduced into the systemic circulation which includes, but is not limited to, intravenous, intramuscular, subcutaneous, intraperitoneal, intradermal, ocular¹, inhalable, rectal, vaginal, transdermal, topical, buccal, sublingual, or mucosal administration. The term "mucosal" as used herein encompasses the administration of the compounds by methods that employ the mucosa (mucous membranes) of the human body-such as, but not limited to, buccal, intranasal, gingival, vaginal, sublingual, pulmonary, or rectal tissue. The term "transdermal" as used herein encompasses the administration of the compounds that go into the skin or go through the skin using formulations such as, but not limited to, transdermal formulations, buccal patches, skin patches, or transdermal patches. The term "topical" as used herein encompasses administration by applying conventional topical preparations such as creams, gels, or solutions for localized percutaneous delivery and/or by solution for systemic and/or localized delivery to areas such as, but not limited to the eye, skin, rectum, and vagina.

In one aspect, delivery systems composed of devices or compositions containing an alpha-MSH analogue can be manufactured that allow for the controlled-release, extended-release, modified- — I o — release, sustained-release, pulsatile-release, or programmed-release delivery of the alpha-MSH analogue in order to maintain concentration of the alpha-MSH analogue in the plasma of the subject. Depending on the delivery system or composition of a formulation or route of administration chosen, drugs or active pharmaceutical ingredients can be delivered for hours, weeks, or months following a single administration. Drug-delivery devices include, but are not limited to pumps, needle-free injectors, metered-dose inhalers, and the like. Transdermal compositions with or without penetration enhancers include but are not limited to transdermal patches, microneedles, and transdermal formulations that achieve drug delivery using inotophoresis, sonophoresis, electroporation, thermoporation, perfusion, adsorption and absorption. Other delivery systems include, but are not limited to, biodegradable or nonbiodegradable rods or other shaped implants, fibers, microparticles, microspheres, microcapsules, nanospheres, nanocapsules, porous silicon nanoparticles, in situ gelling formulations, in situ bolus forming compositions, quick dissolving tablets and the like, buccal patches, films, tablets, capsules, osmotic pressure driven formulations, liquid filled capsules, liposomes and other lipid based compositions and the like, pegalation and the like, hydrogel formulations, emulsions, microemulsions, and suspensions.

In one aspect, polymeric delivery systems can be microparticles including, but not limited to microspheres, microcapsules, nanospheres and nanoparticles comprising biodegradable polymeric excipients, non-biodegradable polymeric excipients, or mixtures of polymeric excipients thereof, or the polymeric delivery systems can be, but not limited to rods or other various shaped implants, wafers, fibers, films, in situ forming boluses and the like comprising biodegradable polymeric excipients, non-biodegradable polymeric excipients, or mixtures thereof These systems can be made from a single polymeric excipient or a mixture or blend of two or more polymeric excipients.

A suitable polymeric excipient includes, but is not limited to, a poly(diene) such as poly(butadiene) and the like; a poly(aikene) such as polyethylene, polypropylene, and the like; a poly(acrylic) such as poly(acrylic acid) and the like; a poly(methacrylic) such as poly(methyl methacrylate), a poly(hydroxyethyl methacrylate), and the like, a poly(vinyl ether); a polyvinyl alcohol); a poly(vinyl ketone); a poly(vinyl halide) such as polyvinyl chloride) and the like; a poly(vinyl nitrile), a polyvinyl ester) such as poly(vinyl acetate) and the like; a poly(vinyl pyridine) such as poly(2-vinyl pyridine), poly(5-methyl-2 -vinyl pyridine) and the like; a poly(styrene), a poly(carbonate); a poly(ester); a poly(orthoester) including a copolymer, a pory(esteramide); a poly(anhydride), a poly(urethane); a poly(amide); a cellulose ether such as _ ^_

methyl cellulose, hydroxyethyl cellulose, hydroxypropyl methyl cellulose, and the like; a cellulose ester such as cellulose acetate, cellulose acetate phthalate, cellulose acetate butyrate, and the like; a poly(saccharide), a protein, gelatin, starch, gum, a resin, and the like. These materials may be used alone, as physical mixtures (blends), or as co-polymers. Derivatives of any of the polymers listed above are also contemplated

In one aspect, the polymeric excipient of the delivery system includes a biocompatible, nonbiodegradable polymer such as, for example, a silicone, a polyacrylate; a polymer of ethylene- vinyl acetate; an acyl substituted cellulose acetate; a non-degradable polyurethane; a polystyrene; a polyvinyl chloride; a polyvinyl fluoride; a poly(vinylimidazole), a chlorosulphonate polyolefm; a polyethylene oxide; or a blend or copolymer thereof.

In another aspect, the polymeric excipient includes a biocompatible, biodegradable polymer such as, for example, a poly(lactide); a poly(glycolide); a poly(lactide-co-glycolide); a poly(lactic acid); a poly(glycolic acid), a poly(lactic acid-co-glycolic acid); a poly(caprolactone); a poly(orthoester); a poly(phosphazene), a poly(hydroxybutyrate) or a copolymer containing a poly(hydroxybutarate); a poly(lactide-co-caprolactone); a polycarbonate; a polyesteramide; a polyanhydride; a poly(dioxanone); a poly(alkylene alkylate), a copolymer of polyethylene glycol and a polyorthoester, a biodegradable polyurethane; a poly(amino acid), a polyetherester; a polyacetal; a polycyanoacrylate; a poly(oxyethylene)/poly(oxypropylene) copolymer, or a blend or copolymer thereof.

In one aspect, the delivery system comprises a gel or liquid formulation or an implant or rod, wherein the implant or rod comprises a biodegradable polymer, wherein the alpha-MSH analogue is embedded within the implant or rod. In one aspect, the alpha-MSH analogue is encapsulated in an implant or rod 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. In other aspects, low molecular weight polymers can be used for drug-delivery and _ _

vaccine delivery products where resorption time and not material strength is as important. 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), 8.5:15 poly(lactide-co-glycolide), 75:25 poly(iactide-co-glycolide), or 65:35 ρoly(lactide-co-glycolide) where the ratios axe 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 0.2.5 to 0.4 dL/g as measured in chloroform at a concentration of 0.5 g/dL at 30 ⁰C.

The amount 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 microcapsule, implant, or rod can be up to 50% by weight of the delivery system. In other aspects, the amount of alpha-MSH analogue encapsulated in the microcapsule, implant, or rod can be from 5 to 60%, 10 to 50%, 15 to 40%, or 15 to 30% by weight of the delivery system.

In another aspect, where the alpha-MSH analogue is delivered by another delivery system such as a transdermal formulation, the amount of alpha-MSH analogue in the formulation can be from 0.001 to 10%, or 0.05 to 5% by weight of the formulation.

Other pharmaceutically-acceptable components can be encapsulated or incorporated in the delivery system in combination with the alpha-MSH analogue. For example, the pharmaceutically- 2. _L — 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, polysaccharide, or carboxmethyil 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 delivery system comprises an implant or rod, wherein the alpha-MSH analogue is [NIe⁴, D-Phe⁷]-alpha-MSH in the amount from 15% to 45% by weight of the implant or rod, wherein the rod or implant comprises poly(lactide) or poly(lactide-co-glycolide) such as, for example, 85:15 poly^actide-co-glycolide).

Any of the delivery systems described herein can be administered using techniques known in the art. In one aspect, the delivery system can be administered subcutaneously to the subject. In this aspect, the duration of administration can vary depending upon the amount of alpha-MSH analogue that is encapsulated and the biodegradable polymer selected. In one aspect, the delivery system is administered subcutaneously to the subject and releases the alpha-MSH analogue for a period of at least 2, 4, 6, 8, 10 or 12 days. In one aspect, the delivery system releases the alpha- MSH analogue in the subject for¹ up to three months. In various other aspects, the delivery system releases the alpha-MSH analogue in the subject for 10 days, 15 days, 20 days, 25 days, or 30 days.

In one aspect, any of the alpha-MSH analogues can be combined with at least one pharmaceutically-acceptable carrier to produce a pharmaceutical composition. The pharmaceutical compositions can be prepared using techniques known in the art. In one aspect, the composition is prepared by admixing the alpha-MSH analogue with a pharmaceutically- acceptable carrier. The term "admixing" is defined as mixing the two components together so that there is no chemical reaction or physical interaction. The term "admixing" also includes the chemical reaction or physical interaction between the alpha-MSH analogue and the pharmaceutically-acceptable carrier.

Pharmaceutically-acceptable earners are known to those skilled in the art. These most typically would be standard carriers for administration to humans, including solutions such as sterile water, saline, and buffered solutions at physiological pH.

Molecules intended for pharmaceutical delivery may be formulated in a pharmaceutical composition. Pharmaceutical compositions may include carriers, thickeners, diluents, buffers, preservatives, surface active agents and the like in addition to the molecule of choice, _ _

Pharmaceutical compositions may also include one or more active ingredients such as antimicrobial agents, anti-inflammatory agents, anesthetics, and the like.

Preparations for administration include sterile aqueous or non-aqueous solutions, suspensions, and emulsions. Examples of non-aqueous carriers include water, alcoholic/aqueous solutions, emulsions or suspensions, including saline and buffered media. Parenteral vehicles, if needed for collateral use of the disclosed compositions and methods, include sodium chloride solution, Ringer's dextrose, dextrose and sodium chloride, lactated Ringer's, or fixed oils, intravenous vehicles, if needed for collateral use of the disclosed compositions and methods, include fluid and nutrient replenishers, electrolyte replenishers (such as those based on Ringer's dextrose), and the like. Preservatives and other additives may also be present such as, for example, antimicrobials, anti-oxidants, chelating agents, and inert gases and the like.

Formulations for topical administration may include ointments, lotions, creams, gels, drops, ointments, suppositories, sprays, liquids and powders Conventional pharmaceutical carriers, aqueous, powder or oily bases, thickeners and the like may be necessary or desirable. The alpha- MSH analogue can be admixed under sterile conditions with a physiologically acceptable carrier and any preservatives, buffers, propellants, or absorption enhancers as may be required or desired Reference is made to documents cited herein, e.g., U.S. Patent No 5,990,091, WO 98/00166, and WO 99/60164, for the preparation of compositions for topical applications, e g., viscous compositions that can be creams or ointments, as well as compositions for nasal and mucosal administration.

In the case when the composition is administered mucosally, ocularly, intranasally, or by inhalation, the formulation can be in the form of a drop, a spray, an aerosol, or a sustained release format. The spray and the aerosol can be achieved through use of the appropriate dispenser. The sustained release format can be an ocular' insert, credible microparticulates, swelling mucoadhesive particulates, pH sensitive microparticulates, nanoparticles/latex systems, ion- exchange resins and other polymeric gels and implants (Ocusert, Alza Corp., California; Joshi, A., S. Ping and K J. Himmelstein, Patent Application WO 91/19481).

These systems maintain prolonged drug contact with the absorptive surface preventing washout and nonproductive drug loss.

The invention is further described with reference to the following non-limiting Examples which _ _

illustrate various embodiments of the invention.

EXAMPLE 1

Following photodynamic therapy, consisting of the administration of a photosensitizer, and subsequent treatment by a light source with a wavelength between 200 nm and 900 nm, a patient may suffer from photosensitivity and or phototoxicity of skin and or eyes pre- and post- treatment, These patients will need to avoid outdoors, incandescent and/or fluorescent light sources indoors.

Patients who are suffering from photosensitivity and or phototoxicity of skin and or eyes have been shown to react to UV-exposure as expressed by various immediate or delayed dermal and ocular reactions. Factors such as the variance in patients, intensity of the UV-light varying by time of day, seasonal influence, a family history of photodermatoses and photosensitivity are important factors in the onset of disease. The first step in evaluating a photosensitive patient is based on the dose and time of photosensitizer administered.

Photosensitivity and phototoxicity of skin and or eyes, is an acquired symptom or side effect following the administration of a photosensitizer used in photodynamic therapy. It is most often the accumulation of (proto)porphyrin in the skin and eyes that, is is responsible for cutaneous and ocular photosensitivity and phototoxicity leading to (i) pain, (ii) swelling, (iii) discrete scarring and (iv) formation of ulcers or lesions, In the presence of light at 380 nm and above, (protoporphyrin or porphyrin are being excited (brought in state of excitation) and generates reactive oxygen species resulting in the typical phototoxic reactions.

During these photosensitive and phototoxic reactions, pain and light sensitivity are most severe and cause unbearable and unsustainable pain and suffering to patients following exposure to UV, natural, incandescent and/or fluorescent light. The symptoms may last for several hours, days and often weeks, and may be accompanied by swelling and redness (erythema) on sun, UV and or light exposed areas.

Available treatment modalities and therapeutic agents for patients with photosensitivity and phototoxicity are very limited. Avoidance of sun and UV light, either from direct exposure or indirectly through window glass, and the use of protective clothing is essential to prevent phototoxic reactions. Therapy with an alpha-MSH analogue such as CUV 1647 (afamelanotide), as provided by the present invention reduces the symptoms of photosensitivity and phototoxicity during and following photodynamic therapy.

An open-label study was carried out in 5 EPP patients with a severe history of photodermatoses exacerbated on the surfaces of their bodies, with a primary objective of determining whether CUV 1647 (afamelanotide) implants can reduce the susceptibility of patients with EPP to provocation with a standardized light source (time to appearance of provoked symptoms). The study was conducted in accordance with the Declaration of Helsinki and its revisions, ICH guidelines for Good Clinical Practice (GCP) governing the conduct of studies, and all applicable local regulations.

Subjects were recruited from a database of EPP patients. According to the main criteria for entry into the study, eligible subjects are adult male or female patients (aged 18-70 years) with a diagnosis of EPP (confirmed by elevated free protoporphyrin in peripheral erythrocytes and/or ferrochelatase mutation) of sufficient severity that they have requested treatment to alleviate symptoms. Written informed consent was obtained from each patient prior to the performance of any study-specific procedure.

To determine eligibility for entry into the study, patients underwent a screening evaluation at -7 days prior to the first dose of study drug. Approximately 10 eligible patients per center (2 centers) are enrolled and receive afamelanotide (20 mg/implant contained in a poly(D,L-lactide implant core, giving sustained release of study drag over 10 days) on Days 0, 30, 60, 120, 180, 240 and 300.

At the screening visit (Day -7) and again on Days 0, 30, 90, 150, 240, 300 and 360, patients are phototested and a "time taken to develop provoked symptoms" determined on the dorsal surface of one hand. Melanin density (measured spectrophotometrically) is determined at all clinic visits while the number and severity of phototoxic reactions and the use of rescue medication is recorded in patients diaries. Quality of life is measured at Baseline and again on Days 180 and 360. Participants visit the clinic on Days 0, 30, 60, 90, 120, 150, 180, 240, 400 and 360 for assessments of adverse events and for safety bloods. In addition, home visits are scheduled for 24 hours after administration of each implant to collect safety and drug level bloods, and to obtain specimens for urinalysis. An interim efficacy analysis is undertaken after all participants have completed all Day 180 (Part I) requirements and the results of this analysis reviewed by a Data and Safety Monitoring Board or independent Data Review Committee.

The criteria for evaluation of the study are efficacy analyses and safety analyses:

Efficacy Analyses:

The primary efficacy endpoint of this study is the time taken for the development of symptoms provoked during phototesting. The primary efficacy analysis will compare the "time to appearance of provoked symptoms" before (Day -7) and after CUV 1647 treatment (Days 0, 30, 90, 150, 240, 300 and 360) and in each patient by an appropriate statistical method. H₀: there is no difference in "time taken to develop provoked symptoms" before and after treatment.

Secondary efficacy endpoints include:

• the number and severity of photo toxic reactions (to be compared with documented historical data) and the use of rescue medication,

• the level of melanin density in the skin as measured by a spectrophotometer (analysis will compare changes in melanin density from Baseline to the post-treatment assessment at Days 0, 30, 60, 120, 180, 240, 300 and 360),

• quality of life (assessed at Baseline and Days 180 and 360).

Safety Analyses:

The number of participants with treatment-emergent adverse events will be summarized by MedDRA preferred term and body system for each treatment group. Treatment-emergent events will be further summarized by intensity, seriousness, outcome and relationship to study drug.

Participants who prematurely terminate treatment due to adverse events related to study medication will be summarized. Clinical laboratory data will be summarized for each treatment group. Results:

The results measured in 5 patients at Days 0, 30, 60 and 90 are indicated in Table 1. These data demonstrate that the time take to develop provoked symptoms following exposure to UV light (i e. "response time") increases significantly for each patient following administration of CUV 1647.. The exception is Patient 5 where the response time decreases from 655 s to 418 s between Day 30 and Day 60.

Table 1: Measurements of response time, melanin density and PPIX concentration (μmol/L) at Days 0, 30, 60 and 90 following administration of afamelanotide

(S3 n/a = not available

_ _

EXAMPLE 2

Photosensitivity and phototoxicity of skin and or eyes, is an acquired symptom or side effect following the administration of a photosensitizer used in photodynamic therapy. It is most often the accumulation of (proto)porphyrin in the skin and eyes that, is responsible for cutaneous and ocular photosensitivity and phototoxicity leading to (i) pain, (ii) swelling, (iii) discrete scarring and (iv) formation of ulcers or lesions, In the presence of light at 380 nm and above, (proto)porphyrin or porphyrin are being excited (brought in state of excitation) and generates reactive oxygen species resulting in the typical phototoxic reactions.

During these photosensitive and phototoxic reactions, pain and light sensitivity are most severe and cause intolerable and unsustainable pain and suffering to patients following exposure to UV, natural, incandescent and/or fluorescent light. The symptoms may last for several hours, days and often weeks, and may be accompanied by swelling and redness (erythema) on sun, UV and or light exposed areas.

Available treatment modalities and therapeutic agents for patients with photosensitivity and phototoxicity are very limited. Avoidance of sun and UV light, either from direct exposure or indirectly through window glass, compliance to light-avoiding measures and the use of protective clothing is essential to prevent phototoxic reactions.

Therapy with an alpha-MSH analogue such as afamelanotide, as provided by the present invention reduces the symptoms of photosensitivity and phototoxicity during and following photodynamic therapy.

An open-label study was carried out in 8 PDT patients with a history of either Barretts' esophagus (dysplasia of the esophageal epithelium) and cholangio carcinoma (palliative treatment of cancer of the bile duct). Post-operative phototoxicity prevailed in all 4 placebo treated patients, while absent phototoxicity or reduced photosensitivity was reported by the 4 actively treated patients in spring and summer. Main symptoms in the placebo group were photodermatoses exacerbated on the surfaces of their exposed arms, legs and face. The primary objective of this study was to determine under conditions of use of a single-dose the efficacy and safety of afamelanotide 16 mg as a subcutaneous formulation to reduce the susceptibility of patients following PDT treatment with a systemically administered photosensitizer. Endpoints were erythema and pain of the skin upon controlled provocation to light and UV, as tested through specially fabricated gloves. The study was conducted in accordance with the Declaration of Helsinki and its revisions, ICH guidelines for Good Clinical Practice (GCP) governing the conduct of studies, and all applicable local regulations.

Subjects were recruited from a database of the French Cancer Registry, diagnosed with recurrent Barretts' esophagus and cholangio carcinoma. According to the main criteria for entry into the study, eligible subjects are adult male or female patients (aged 18-70 years) with a positive diagnosis of aforementioned disease states. Written informed consent was obtained from each patient prior to the performance of any study-specific procedure.

To determine eligibility for entry into the study, patients underwent a screening evaluation at -7 days prior to the first dose of study drug. In total, 8 eligible patients in one center were enrolled and received a single dose of afamelanotide (16 mg/implant contained in a poly(D,L-lactide implant core, giving sustained release of study drug over 10 days) on Day -7.

At the screening visit (Day -14) patients underwent physical examination. Quality of life was measured at Baseline and again on Days 180 and 360. Participants visited the clinic on Days -14, -7, 0, 30, 60, and 90 for assessments of adverse events and for safety bloods. In addition, telephone calls were made 24 hours after administration of each implant to collect safety and drug data from the patient, and at Day 1, 30 and 90 specimens for urinalysis were obtained.

Efficacy analysis was undertaken after all participants have completed all Day 90 (Part I) requirements and the results of this analysis reviewed by a Data and Safety Monitoring Board or independent Data Review Committee. The criteria for evaluation of the study are efficacy analyses and safety analyses.

An example of efficacy is described below: Following photodynamic therapy (PDT), consisting of the administration of a photosensitizer, -

and subsequent treatment by a light source with a wavelength between 200 nm and 900 nm, and preferably between 390 nm and 800 nm, a male middle-aged patient of Caucasian skintype, and who professionally had recently been made redundant, was suffering from Barrett's esophagus exhibited photosensitivity and or phototoxicity of skin and eyes immediately after the administration of a porphyrin-related photosensitizing drug used in the art of systemically administered PDT. This patient was forced to stay indoors, obliged to shield from the effects of UV and visible light during 90 days post-therapy. His inability to comply with the strict light- avoiding measures resulted in a second degree burn to his left arm following moderate sun exposure 42 days post-PDT treatment. His skin remained photosensitive for the duration of 4 years.

A second treatment of PDT followed 4 years later, indicated due to recurrent dysplasia of the distal esophagus. The same patient participated in a clinical trial where he was administered a single dose of subcutaneous controlled-formulation containing afamelanotide 16 mg two days prior to the administration of the photosensitizing drug used in PDT. His phototoxicity was reduced to 7 days post-treatment: the patient was able to resume his outdoors activities from day 8 onwards without contracting any skin burn or erythema.

Efficacy Analyses:

The primary efficacy endpoint of this study is defined as the time taken for the development of symptoms provoked during phototesting under conditions of use. The primary efficacy analysis will compare the "time to appearance of provoked symptoms" before (Day 0) and after afamelanotide treatment (Days 0, 30, 60, 90.) and the two groups of patients, using an appropriate statistical method.

Ho: there is no difference in "time taken to develop provoked symptoms" before and after treatment.

Secondary efficacy endpoints included:

• the level of melanin density in the skin as measured by a spectrophotometer (analysis compared changes in melanin density from Baseline to the post-treatment assessment at Days -14, 0, 30, 90) quality of life (assessed at Baseline and Days 180 and 360).

Safety Analyses:

The number of participants with treatment-emergent adverse events are being summarized by MedDRA preferred term and body system for each treatment group. Treatment-emergent events will be further summarized by intensity, seriousness, outcome and relationship to study drug.

Participants who prematurely terminate treatment due to adverse events related to study medication will be summarized. Clinical laboratory data will be summarized for each treatment group.

Results:

The results measured in 8 patients at Days 0, 30, 60 and 90 indicate that afamelanotide prolonges the time PDT patients are able to spend outside without the risk of skin erythema and burning.

The symptoms exacerbated by UV and light exposure have been demonstrated to improve in the 4 patients who were administered afamelanotide. These data demonstrate that the time take to develop provoked symptoms following exposure to UV light (i e "response time") increased significantly for each patient following administration of afamelanotid.

Throughout this specification the word "comprise", or variations such as "comprises" or "comprising", will be understood to imply the inclusion of a stated element, integer or step, or group of elements, integers or steps, but not the exclusion of any other element, integer or step, or group of elements, integers or steps.

All publications mentioned in this specification are herein incorporated by reference. Any discussion of documents, acts, materials, devices, articles or the like which has been included in the present specification is solely for the purpose of providing a context for the present invention. It is not to be taken as an admission that any or all of these matters form part of the prior art base or were common general knowledge in the field relevant to the present invention as it existed in Australia or elsewhere before the priority date of each claim of this application.

It will be appreciated by persons skilled in the art that numerous variations and/or modifications maybe made to the invention as shown in the specific embodiments without departing from the spirit or scope of the invention as broadly described. The present embodiments are, therefore, to be considered in all respects as illustrative and not restrictive.

Claims

1. Use of an alpha-MSH analogue to reduce or ameliorate photosensitivity and/or phototoxicity in a patient due to administration of a photosensitizing agent.

2. Use of an alpha-MSH analogue for the manufacture of a therapeutic or prophylactic preparation for treating photosensitivity and/or phototoxicity in the patient due to administration of a photosensitizing agent.

3. The use according to claims 1-2 to reduce or ameliorate photosensitivity and phototoxicity following the treatment with photodynamic therapy (PDT).

4. The use according to claims 1-3 to increase or activate the process of melanogenesis of the skin.

5. The use according to claims 1-4 wherein the photosensitizer compounds is selected from delta- aminolevulinic acid (ALA-PpIX), benzoporphyrin derivative monoacid A (BCP-MA), mono- aspertyl chlorine 6 (MACE), meta-tetrahydroxyphenylchlorin (mTHPC), a silicon phtalocyanine (Pc4), porphyrin sodium (Photofrin), metallopurin derivaties, fluorine-based derivatives, Temoporfin, Hypocrellins, tetracycline, Thiazide Diurectics, Hypoglycemic agents, Sulfonamides, Phenothiazines, Nalidixic Acid, Quinidine, Quinine, Lomotil, Griseofulvin, Psoralens, Oil of Bergamot, deodorants soaps, and figs, limes, celery, parsnips plants.

6. The use according to claims 1-5 wherein the alpha-MSH-analogue is Nle⁴-D-Phe⁷ -alpha-MSH and/or wherein the alpha-MSH-analogue reduces the susceptibility of patients with Erythropoeitic Protoporphyria (EPP) to provocation with light.

7. The use according to claims 1-6 wherein the alpha-MSH-analogue exhibits agonist activity for MC 1 R and/or upregulates the melanocortin- 1 receptor (MC 1 R).

8. The use according to claims 1-7 wherein the photosensitizing agent is activated or excited at a wavelength of between 280 nm and 800 nm, and preferably between 390 ran and 800 ran.

9. The use according to claims 3-8 wherein the photosensitivity and phototoxicity may arise due to administration of photosensitizers following PDT in patients undergoing treatment for lesions, ulcerations, aberrations, stricture, stenosis, dystrophy, hypertrophy, dysplasia, metaplasia, anaplasia, cancer precursors, actinic keratosis, carcinoma in situ, Bowens' disease, basal cell carcinoma, squamous cell carcinoma, bile duct lesions and strictures, other lesions of the urinary tract, gastrointestinal tract, and reproductive system, psoriasis, viral inactivation, macular degeneration, ocular anomalies, glaucoma and various vascular diseases.

10. The use according to claims 1-9 wherein the alpha-MSH analogue is administered in a manner such as to maintain an effective plasma level of the alpha-MSH analogue for a period of at least 24 hours wherein the level is less than 100 ng/ml.

11. Method of treating photosensitivity and/or phototoxicity due to photosensitizing agents, by increasing level of melanin in the skin of the patient.

12. Method of administering an alpha-MSH analogue that increases melanin in the skin before, simultaneously or subsequent to administering of a photosensitizing agent.

13. Method according to claim 12, wherein the alpha-MSH analogue is administered intermittently.

14. Composition comprising a photosensitizing agent and an alpha-MSH-analogue which causes an increase in the level of melanin in the skin.