U.S. patent application number 16/238044 was filed with the patent office on 2019-07-11 for pulse photodynamic treatment of acne.
This patent application is currently assigned to GALDERMA RESEARCH & DEVELOPMENT. The applicant listed for this patent is GALDERMA RESEARCH & DEVELOPMENT. Invention is credited to Hans Christian WULF.
Application Number | 20190209686 16/238044 |
Document ID | / |
Family ID | 52007045 |
Filed Date | 2019-07-11 |
![](/patent/app/20190209686/US20190209686A1-20190711-D00001.png)
![](/patent/app/20190209686/US20190209686A1-20190711-D00002.png)
![](/patent/app/20190209686/US20190209686A1-20190711-D00003.png)
![](/patent/app/20190209686/US20190209686A1-20190711-D00004.png)
![](/patent/app/20190209686/US20190209686A1-20190711-D00005.png)
![](/patent/app/20190209686/US20190209686A1-20190711-D00006.png)
![](/patent/app/20190209686/US20190209686A1-20190711-D00007.png)
![](/patent/app/20190209686/US20190209686A1-20190711-D00008.png)
![](/patent/app/20190209686/US20190209686A1-20190711-D00009.png)
![](/patent/app/20190209686/US20190209686A1-20190711-D00010.png)
![](/patent/app/20190209686/US20190209686A1-20190711-D00011.png)
View All Diagrams
United States Patent
Application |
20190209686 |
Kind Code |
A1 |
WULF; Hans Christian |
July 11, 2019 |
PULSE PHOTODYNAMIC TREATMENT OF ACNE
Abstract
A pulse photodynamic therapy (or pulse PDT) treatment of acne is
described herein.
Inventors: |
WULF; Hans Christian;
(Espergaerde, DK) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
GALDERMA RESEARCH & DEVELOPMENT |
Biot |
|
FR |
|
|
Assignee: |
GALDERMA RESEARCH &
DEVELOPMENT
Biot
FR
|
Family ID: |
52007045 |
Appl. No.: |
16/238044 |
Filed: |
January 2, 2019 |
Related U.S. Patent Documents
|
|
|
|
|
|
Application
Number |
Filing Date |
Patent Number |
|
|
15107688 |
Jun 23, 2016 |
|
|
|
PCT/EP2014/078931 |
Dec 19, 2014 |
|
|
|
16238044 |
|
|
|
|
Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61K 31/197 20130101;
A61P 17/16 20180101; A61P 17/02 20180101; A61N 2005/0652 20130101;
A61M 37/0015 20130101; A61M 2037/0061 20130101; A61P 35/00
20180101; A61P 17/00 20180101; A61P 17/10 20180101; A61M 37/00
20130101; A61M 2037/0023 20130101; A61N 5/062 20130101; A61N
2005/0657 20130101; A61N 2005/0653 20130101; A61M 2037/0007
20130101; A61P 43/00 20180101; A61N 2005/0663 20130101; A61K 31/22
20130101; A61K 41/0061 20130101 |
International
Class: |
A61K 41/00 20060101
A61K041/00; A61K 31/22 20060101 A61K031/22; A61N 5/06 20060101
A61N005/06; A61K 31/197 20060101 A61K031/197; A61M 37/00 20060101
A61M037/00 |
Foreign Application Data
Date |
Code |
Application Number |
Dec 20, 2013 |
EP |
13306826.2 |
Mar 28, 2014 |
EP |
14162516.0 |
Claims
1. A method of treating acne in an animal, the method comprising
treating the acne by photodynamic therapy (PDT), wherein a
photosensitizer is applied to the skin of the animal after a
pretreatment of the skin.
2. The method according to claim 1, wherein the photosensitizer is
applied for a duration of from 4 minutes to 4 hours.
3. The method according to claim 2, wherein the duration is from 15
minutes to 3 hours.
4. The method according to claim 1, wherein the photosensitizer is
applied for a short period of time.
5. The method according to claim 4, wherein the short period of
time is from 5 minutes to 120 minutes.
6. The method according to claim 4, wherein the short period of
time is from 15 minutes to 60 minutes.
7. The method according to claim 4, wherein the short period of
time is from 20 minutes to 40 minutes.
8. The method according to claim 4, wherein the short period of
time is selected from the group consisting of 25, 26, 27, 28, 29,
30, 31, 32, 33, 34 and 35 minutes.
9. A method of treating acne in an animal, the method comprising
treating the acne by photodynamic therapy (PDT), wherein a
photosensitizer is applied for a short period of time.
10. The method according to claim 9, wherein the short period of
time is from 5 minutes to 120 minutes.
11. The method according to claim 9, wherein the short period of
time is from 15 minutes to 60 minutes.
12. The method according to claim 9, wherein the short period of
time is from 20 minutes to 40 minutes.
13. The method according to claim 9, wherein the short period of
time is selected from the group consisting of 25, 26, 27, 28, 29,
30, 31, 32, 33, 34 and 35 minutes.
14. The method according to claim 1, wherein the method reduces
side effects associated with PDT.
15. The method according to claim 1, wherein the PDT includes a
photoactivation achieved by a natural light source.
16. The method according to claim 15, wherein the PDT includes a
photoactivation for a duration of from 0.5 hour to 3 hours with the
natural light source.
17. The method according to claim 15, wherein the natural light
source is sunlight.
18. The method according to claim 1, wherein the PDT comprises: a)
subjecting the skin of the animal to a pretreatment; b)
administering to the animal a composition comprising the
photosensitizer for a duration of from 5 minutes to 120 minutes;
and c) photoactivating the photosensitizer for a duration of from
0.5 hour to 3 hours with natural light.
19. The method according to claim 18, wherein the pretreatment is
mechanical or chemical pretreatment.
20. The method according to claim 1, wherein the PDT comprises: a)
subjecting the skin of the animal to a pretreatment; b)
administering to the animal a composition comprising the
photosensitizer for a duration of about 30 minutes; c) removing the
photosensitizer; and d) photoactivating the photosensitizer 2.5
hours later for a duration of at least 2 hours with natural
light.
21. The method according to claim 20, wherein the pretreatment is
mechanical or chemical pretreatment.
22. The method according to claim 21, wherein the pretreatment is
sandpaper.
23. The method according to claim 20, wherein the photosensitizer
is administered for a duration selected from the group consisting
of 27, 28, 29, 30, 31 and 32 minutes.
24. The method according to claim 23, wherein the duration is 30
minutes.
25. The method according to claim 1, wherein the photosensitizer is
selected from the group consisting of 5-ALA, 5-ALA derivatives,
5-MAL derivatives, and compounds covered by general formula I:
R.sup.2.sub.2N--CH.sub.2COCH.sub.2--CH.sub.2CO--OR.sup.1 (I)
wherein: R.sup.1 represents a substituted or unsubstituted
straight, branched or cyclic alkyl group; and each R.sup.2
independently represents a hydrogen atom or an optionally
substituted alkyl group; and pharmaceutically acceptable salts
thereof.
26. The method according to claim 25, wherein R.sup.1 is a
substituted or unsubstituted straight-chained alkyl group.
27. The method according to claim 1, wherein the photosensitizer is
5-ALA or 5-methyl ALA ester.
28. The method according to claim 1, wherein administering to the
animal of a composition comprising the photosensitizer is carried
out with or without occlusion.
29. The method according to claim 28, wherein the administration of
the photosensitizer is carried out with occlusion.
30. The method according to claim 1, wherein the pretreatment is
selected from the group consisting of mechanical pretreatment and
chemical pretreatment.
31. The method according to claim 30, wherein the mechanical
pretreatment is dermoabrasion or microneedling.
32. The method according to claim 30, wherein the chemical
pretreatment is peeling.
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application is the divisional of U.S. application Ser.
No. 15/107,688, filed Jun. 23, 2016, which is the National Phase of
International Patent Application No. PCT/EP2014/078931, filed Dec.
19, 2014, published on Jun. 25, 2015 as WO 2015/092060 A1, which
claims priority to European Application No. 14162516.0, filed Mar.
28, 2014 and European Application No. 13306826.2, filed Dec. 20,
2013. The contents of these applications are herein incorporated by
reference in their entirety.
FIELD OF THE INVENTION
[0002] The present invention is related to a pulse photodynamic
therapy (or pulse PDT) treatment of acne.
BACKGROUND OF THE INVENTION
[0003] Photodynamic therapy (PDT), is a technique for the treatment
of various abnormalities or disorders of the skin or other
epithelial organs or mucosa, in particular for the treatment of
acne. PDT involves the application of photosensitizing
(photochemotherapeutic) agents to the affected area of the body,
followed by exposure to photoactivating light in order to activate
the photosensitizing agents and convert them into cytotoxic form,
whereby the affected cells are killed (necrosis, apoptosis).
[0004] A range of photosensitizing agents is known, including the
psoralens, the porphyrins (e.g. Photofrin (Registered trademark)),
the chlorins and the phthalocyanins. Amongst the most clinically
useful photosensitizing agents known in the art, however, are
5-aminolevulinic acid and its derivatives, for example esters such
as 5-ALA esters.
[0005] The mechanism of action of PDT relies on intracellular
porphyrins (including PpIX) that are photoactive, fluorescing
compounds and, upon light activation in the presence of oxygen,
singlet oxygen is formed which causes damage to cellular
compartments, in particular the mitochondria.
[0006] Light activation of accumulated porphyrins leads to a
photochemical reaction and thereby phototoxicity to the
light-exposed target cells.
[0007] Although PDT is clinically useful in the treatment of a wide
range of diseases, a major drawback of such treatment is the
concomitant side-effects, particularly at the treatment site. These
often include inflammation such as erythema, swelling, edema,
burning, itching, exfoliation, hyperpigmentation and prolonged
irritation and hypersensitivity after treatment. Such side-effects
are particularly undesirable when the treatment site is the face,
scalp or neck. This is frequently the case when the PDT is for the
treatment of lesions, for example with acne.
[0008] The occurrence of such side effects is recognized in
WO2006/051269 which discloses use of 5-ALA esters in PDT for the
treatment of acne. WO2006/051269 describes a study wherein a cream
comprising 16% wt. methyl ALA ester is applied to the faces of
subjects for 3 hours followed by exposure of the subjects' faces to
non-coherent red light (light dose 37 Jkm-2). The treatment was
then repeated 2 weeks later. Although the results confirmed that
PDT with methyl ALA ester is effective in the treatment of acne,
the subjects also indicated that the treatment caused pain and
induced severe inflammation.
[0009] WO02/13788 discloses a similar study on use of ALA acid in
PDT for the treatment of acne. In this case 20% ALA acid was
applied to the backs of the subjects for 3 hours and then the
subjects were exposed to 150 J/cm2 broad band light. Again the
results confirmed that PDT with ALA is effective for the treatment
of acne, but the subjects also reported a plethora of undesirable
side effects. For example, WO02/13788 reports that erythema,
hyperpigmentation and exfoliation were often seen after PDT
treatment and states that in some cases a subsequent treatment even
had to be postponed. Reports of pain, burning and itching during
and after treatment were also common. WO02/13788 discloses the
above-described treatment regime as a "high dose, high energy"
regime and it is said to provide a permanent improvement to acne.
WO02/13788 additionally discloses a "low dose, low energy" regime
that is said to be designed to provide relief from acne. In this
treatment 0.1 to 10% wt. ALA acid is applied, and after waiting for
the ALA acid to penetrate the skin, is followed by irradiation with
a light dose of 1 to 20 J/cm.sup.2. WO02/13788 suggests that this
regime be used in occasional multiple treatments to alleviate acne
and be repeated as necessary to maintain diminishment thereof.
Although it is recognized that use of such a regime may be pain
free, the implication in WO02/13788 is that the therapeutic effect
of this treatment regime is less than the high dose, high energy
regime it describes and exemplifies.
[0010] A need still therefore exists for alternative PDT methods
that are free from undesirable side effects (e.g. inflammation) but
which have high therapeutic efficacy.
[0011] Inflammation and/or erythema is one of the main problems
associated with PDT treatment. It is generally believed that
inflammation is a necessary element/prerequisite in the cure of
AK/BCC/BD by PDT but is not a so big issue for BCCs and BD as the
lesions are often small and hidden by clothes. On the opposite acne
is located on the face mainly where the need to decrease the
downtime is key.
[0012] A previous, unpublished relation between inflammation and
efficacy of PDT is shown in FIG. 1.
[0013] A need therefore exists for less inflammatory and still
effective methods for treating acne. The present invention
addresses that need.
SUMMARY OF THE INVENTION
[0014] The present invention relates to a PDT treatment of acne,
comprising subjecting the skin of a subject in need thereof to a
pre-treatment such as mechanical ones (like dermoabrasion (e.g.
with sand paper) or microneeding (e.g. with a dermaroller)) or
chemical ones like peeling. The inventors have surprisingly found
that such mechanical pre-treatment is as efficient in cosmetically
or therapeutically treating acne without, or with reduced, adverse
effects observed with a pretreatment implemented with ablative
fractional laser. The PDT then comprises applying onto said skin a
photosensitizer, in particular 5-MAL. In a representative
embodiment, the photosensitizer is applied for a duration comprised
between 4 minutes to 4 hours, in particular between 15 minutes and
3 hours.
[0015] The present inventors have also surprisingly found that
application of a photosensitizer for a shorter time period that is
classically implemented in a PDT, allows the implementation of a
PDT as efficient as in the case where the photosensitizer is used
for a longer period of time, with greatly reduced side effects
usually observed in the prior art PDT protocols.
[0016] Therefore, the invention also relates to a PDT treatment of
acne, comprising administering to a subject in need thereof a
photosensitizer, in particular 5-MAL, for a short duration and then
removing the photosensitizer from the skin surface. This PDT
protocol is alternatively designated pulse-PDT herein.
[0017] Representative photosensitizers include preferably
5-aminolevulinic acid (5-ALA) and derivatives (e.g. an ester) of
5-ALA, more preferably 5-ALA methyl ester (or 5-MAL), or a
pharmaceutically acceptable salt thereof. In the present uses and
methods, photactivation is achieved by natural or artificial light.
In a particular embodiment, the PDT comprises: [0018] (a)
optionally, preparing the area of skin to be treated with the
appropriate pre-treatment, in particular a mechanical pretreatment
such as a curettage, dermoabrasion or micro-needling (or micro
perforation), [0019] (b) administering to said animal a composition
comprising said photosensitizer, in particular for a short
duration; and [0020] (c) photoactivating said photosensitizer.
[0021] In a particular embodiment, the invention implements a
pulse-PDT treatment, comprising administering to a subject in need
thereof a photosensitizer, in particular 5-MAL, for a short
duration and then removing the photosensitizer from the skin
surface. Photoactivation is then carried out as described
throughout the present application. The pulse-PDT treatment of the
invention ensures high intracellular PPIX and low extracellular
PPIX. Excess amounts of PPIX formation during and after the end of
the treatment are thus avoided. In particular, the inventors show
that the pulse-PDT treatment of the invention shows less
inflammation with unchanged efficacy.
[0022] According to an embodiment, the pulse time during which the
photosensitizer is let on the skin is comprised between 5 and 120
minutes. According to a preferred embodiment, the pulse time during
which the photosensitizer is let on the skin is comprised between
15 and 60 minutes, in particular between 20 and 40 minutes. In a
further particular embodiment, the photosensitizer is administered
for about 30 minutes (e.g. for 25, 26, 27, 28, 29, 30, 31, 32, 33,
34 or 35 minutes, more particularly during 30 minutes).
DETAILED DESCRIPTION OF THE INVENTION
[0023] By the term "animal" is meant herein any human or non-human
being. Preferred animals for treatment in accordance with the
invention are humans.
[0024] In a particular embodiment, the subject is a male or female
human subject. In another particular embodiment, the subject is of
the Fitzpatrick I, II, III, IV, V or VI skin type. In a further
embodiment, the subject is of the I, II or III skin type, more
particularly of the II or III skin type.
[0025] Acne vulgaris is a self-limited disease, seen primarily in
adolescents, involving the sebaceous follicles. Most cases of acne
are pleomorphic, presenting with a variety of lesions consisting of
comedones, papules, pustules, nodules, and, as sequels to active
lesions, pitted or hypertrophic scars. Although classically
classified as a sebaceous gland disease, it is actually a process
that involves the pilosebaceous unit.
[0026] Acne is sufficiently common that it often has been termed
physiologic. Mild degrees of acne are often seen at birth, probably
resulting from follicular stimulation by adrenal androgens and mild
cases may continue in the neonatal period. However, it is not until
puberty that acne becomes a common problem. Acne is often an early
manifestation of puberty; in the very young patient the predominant
lesions are comedones. The greatest number of cases is seen during
the middle-to-late teenage period; subsequently, the incidence
decreases. However, particularly in women, acne may persist through
the third decade or even later.
[0027] Although the basic cause of acne is unknown, there is
considerable information on the various factors concerned in its
pathogenesis. Acne is a multifactorial disease, developing in the
sebaceous follicles.
[0028] The primary change is an alteration in the pattern of
keratinization within the follicle. Normally, the keratinous
material in the follicle is loosely organized. The initial changes
in comedones formation are observed in the lower portion of the
follicular infundibulum. The keratinous material becomes more
dense, the lamellar granules are less numerous, keratohyaline
granules are increased, and some of the cells contain amorphous
material, which is probably lipid generated during the process of
keratinization.
[0029] Photosensitizers
[0030] Use of 5-ALA (5-amino-4-oxo-pentanoic acid, otherwise known
as 5-aminolevulinic acid) and derivatives of 5-ALA in PDT is well
known in the scientific and patent literature (see, for example, J.
C. Kennedy et al., J. Clin. Laser Med. Surg. (1996) 14: 289-304,
U.S. Pat. Nos. 5,079,262, 5,211,938, 5,234,940, 5,422,093,
6,034,267, WO91/01727, WO96/28412, WO2005/092838 and
WO2006/051269). 5-ALA and all such derivatives of 5-ALA, as well as
their pharmaceutically acceptable salts, are suitable for the uses
and methods herein described.
[0031] The 5-ALA derivatives useful in accordance with the
invention may be any derivative of 5-ALA capable of forming
protoporphyrin IX (PpIX) or any other photosensitizer (e.g. a PpIX
derivative) in vivo. Typically, such derivatives will be a
precursor of PpIX or of a PpIX derivative (e.g. a PpIX ester) and
which are therefore capable of inducing an accumulation of PpIX at
the site to be treated following administration in vivo. Suitable
precursors of PpIX or PpIX derivatives include 5-ALA prodrugs which
might be able to form 5-ALA in vivo as an intermediate in the
biosynthesis of PpIX or which may be converted (e.g. enzymatically)
to porphyrins without forming 5-ALA as an intermediate. Esters of
5-aminolevulinic acid and N-substituted derivatives thereof are
preferred photosensitizers for use in the invention. Those
compounds in which the 5-amino group is unsubstituted (i.e. the ALA
esters) are particularly preferred. Such compounds are generally
known and described in the literature (see, for example,
WO96/28412, WO02/10120 and WO2005/092838 to PhotoCure ASA). Esters
of 5-aminolevulinic acid with substituted or unsubstituted
alkanols, i.e. alkyl esters are especially preferred
photosensitizers for use in the invention. In particular, 5-MAL and
5-MAL derivatives are particularly preferred. Examples of useful
derivatives include those of general formula I:
R.sup.2.sub.2N--CH.sub.2COCH.sub.2--CH.sub.2CO--OR.sup.1 (I)
[0032] Wherein:
[0033] R.sup.1 represents a substituted or unsubstituted straight,
branched or cyclic alkyl group (e.g. a substituted or unsubstituted
straight-chained alkyl group); and each R.sup.2 independently
represents a hydrogen atom or an optionally substituted alkyl
group, e.g. a group R.sup.1; and pharmaceutically acceptable salts
thereof.
[0034] As used herein, the term "alkyl", unless stated otherwise,
includes any long or short chain, cyclic, straight-chained or
branched aliphatic saturated or unsaturated hydrocarbon group. The
unsaturated alkyl groups may be mono- or polyunsaturated and
include both alkenyl and alkynyl groups. Unless stated otherwise,
such groups may contain up to 40 atoms. However, alkyl groups
containing up to 30, preferably up to 10, particularly preferably
up to 8, especially preferably up to 6, e.g. up to 4 carbon atoms,
for example 1, 2, 3 or 4 carbon atoms, are preferred.
[0035] The substituted alkyl R.sup.1 and R.sup.2 groups may be mono
or poly-substituted.
[0036] Suitable substituents may be selected from hydroxy, alkoxy,
acyloxy, alkoxycarbonyloxy, amino, aryl, nitro, oxo, fluoro, --SR3,
--NR.sup.3.sub.2 and --PR.sup.3.sub.2 groups, and each alkyl group
may be optionally interrupted by one or more --O--, --NR.sup.3--,
--S-- or --PR.sup.3-- groups, in which R.sup.3 is a hydrogen atom
or a C.sub.1-6 alkyl group).
[0037] Preferred substituted alkyl R.sup.1 groups include those
carrying one or more oxo groups, preferably straight-chained
C.sub.4-12 alkyl (e.g. C.sub.8-10 alkyl) groups substituted by one,
two or three (preferably two or three) oxo groups. Examples of such
groups include 3,6-dioxa-1-octyl and 3,6,9-trioxa-1-decyl
groups.
[0038] Particularly preferred for use in the invention are those
compounds of formula I in which at least one R.sup.2 represents a
hydrogen atom. In especially preferred compounds each R.sup.2
represents a hydrogen atom.
[0039] Compounds of formula I in which R.sup.1 represents an
unsubstituted alkyl group (preferably C.sub.1-8 alkyl, e.g.
C.sub.1-8 alkyl) or an alkyl group (e.g. C.sub.1-2 alkyl,
especially C.sub.1 alkyl) substituted by a substituent as
hereinbefore defined (e.g. by an aryl group such as phenyl or by an
alkoxy group such as methoxy) are also preferred.
[0040] Unsubstituted alkyl groups which may be used in the
invention include both branched and straight-chained hydrocarbon
groups. Compounds of formula I in which R.sup.1 is a C.sub.4-8,
preferably a C.sub.5-8, straight chain alkyl group which is
branched by one or more C.sub.1-6 (e.g. C.sub.1-2 alkyl) groups are
preferred. Representative examples of suitable unsubstituted
branched alkyl groups include 2-methylpentyl, 4-methylpentyl,
1-ethylbutyl and 3,3-dimethyl-1-butyl. 4-methylpentyl is
particularly preferred.
[0041] Compounds of formula I in which R.sup.1 is a C.sub.1-10
straight-chained alkyl group are also preferred. Representative
examples of suitable unsubstituted alkyl groups include methyl,
ethyl, propyl, butyl, pentyl, hexyl and octyl (e.g. n-propyl,
n-butyl, n-pentyl, n-hexyl and n-octyl). Hexyl, especially n-hexyl,
is a particularly preferred group. Methyl is also particularly
preferred.
[0042] Also preferred for use in the invention are those compounds
of formula I in which R.sup.1 represents a C.sub.1-2 alkyl group
(preferably a C.sub.1 alkyl group) optionally substituted by an
aryl group.
[0043] Still further preferred for use in the invention are those
compounds of formula I in which R.sup.1 represents an alkyl group
(e.g. C.sub.1-2 alkyl, especially C.sub.1 alkyl) substituted by an
aryl group (e.g. phenyl). Preferred substituted alkyl R.sup.1
groups which may be present in compounds of formula I include
C.sub.1-8 alkyl, preferably C.sub.1-4 alkyl, particularly
preferably C.sub.1 or C.sub.2 alkyl (e.g. C.sub.1 alkyl)
substituted (preferably terminally substituted) by an optionally
substituted aryl group.
[0044] By an "aryl group" is meant a group which is aromatic.
Preferred aryl groups comprise up to 20 carbon atoms, more
preferably up to 12 carbon atoms, for example, 10 or 6 carbon
atoms.
[0045] Aryl groups which may be present in the compounds of the
invention may be heteroaromatic (e.g. 5-7 membered heteroaromatics)
but are preferably nonheteroaromatic. By "non-heteroaromatic" is
meant an aryl group having an aromatic system comprising electrons
originating solely from carbon atoms. Preferred aryl groups include
phenyl and napthyl, especially phenyl. In preferred compounds for
use in the invention one or two aryl groups may be present,
preferably one.
[0046] Aryl groups which may be present in the compounds of the
invention may optionally be substituted by one or more (e.g. 1 to
5), more preferably one or two, groups (e.g. one group). Preferably
the aryl group is substituted at the meta or para position, most
preferably the para position. Suitable substituent groups may
include haloalkyl (e.g. trifluoromethyl), alkoxy (i.e. --OR groups
wherein R is preferably a C.sub.1-6 alkyl group), halo (e.g. iodo,
bromo, more especially chloro and fluoro), nitro and C.sub.1-6
alkyl (preferably C.sub.1-4 alkyl). Preferred C.sub.1-6 alkyl
groups include methyl, isopropyl and t-butyl, particularly methyl.
Particularly preferred substituent groups include chloro and nitro.
Still more preferably the aryl group is unsubstituted.
[0047] In a further preferred aspect the invention provides the use
of a photosensitiser which is a compound of formula I wherein
R.sup.1 represents an aryl substituted C.sub.1-4 alkyl group
(preferably C.sub.1-2, e.g. C.sub.1), preferably wherein said aryl
group comprises up to 20 carbon atoms (e.g. up to 12 carbon atoms,
especially 6 carbon atoms) and is itself optionally substituted,
and each R.sup.2 is as hereinbefore described.
[0048] Preferred compounds for use in the invention include methyl
ALA ester, ethyl ALA ester, propyl ALA ester, butyl ALA ester,
pentyl ALA ester, hexyl ALA ester, octyl ALA ester, 2-methoxyethyl
ALA ester, 2-methylpentyl ALA ester, 4-methylpentyl ALA ester,
1-ethylbutyl ALA ester, 3,3-dimethyl-1-butyl ALA ester, benzyl ALA
ester, 4-isopropylbenzyl ALA ester, 4-methylbenzyl ALA ester,
2-methylbenzyl ALA ester, 3-methylbenzyl ALA ester,
4-[t-butyl]benzyl ALA ester, 4-[trifluoromethyl]benzyl ALA ester,
4-methoxybenzyl ALA ester, 3,4-[dichloro]benzyl ALA ester,
4-chlorobenzyl ALA ester, 4-fluorobenzyl ALA ester, 2-fluorobenzyl
ALA ester, 3-fluorobenzyl ALA ester, 2,3,4,5,6-pentafluorobenzyl
ALA ester, 3-nitrobenzyl ALA ester, 4-nitrobenzyl ALA ester,
2-phenylethyl ALA ester, 4-phenylbutyl ALA ester,
3-pyridinyl-methyl ALA ester, 4-diphenyl-methyl ALA ester and
benzyl-5-[(1-acetyloxyethoxy)-carbonyl]amino levulinate.
[0049] Still further preferred compounds for use in the invention
include methyl ALA ester, ethyl ALA ester, 2-methoxyethyl ALA
ester, benzyl ALA ester, 4-isopropylbenzyl ALA ester,
4-methylbenzyl ALA ester, 2-methylbenzyl ALA ester, 3-methylbenzyl
ALA ester, 4[t-butyl]benzyl ALA ester, 4-[trifluoromethyl]benzyl
ALA ester, 4-methoxybenzyl ALA ester, 3,4[di-chloro]benzyl ALA
ester, 4-chlorobenzyl ALA ester, 4-fluorobenzyl ALA ester,
2-fluorobenzyl ALA ester, 3-fluorobenzyl ALA ester, 4-nitrobenzyl
ALA ester, 2-phenylethyl ALA ester, 4-phenylbutyl ALA ester,
3-pyridinyl-methyl ALA ester, 4-diphenyl-methyl ALA ester and
benzyl-5-[(1-acetyloxyethoxy)-carbonyl]amino levulinate.
[0050] Particularly preferred compounds for use in the invention
include methyl ALA ester, hexyl ALA ester and benzyl ALA ester,
especially methyl ALA ester.
[0051] The compounds for use in the invention may be prepared by
any conventional procedure available in the art (e.g. as described
in WO02/10120 to PhotoCure ASA). For example, esters of 5-ALA may
be prepared by reaction of 5-ALA with the appropriate alcohol in
the presence of acid. Alternatively compounds for use in the
invention may be available commercially (e.g. from Photocure ASA,
Norway).
[0052] Other photosensitizers that can be used in the field of the
present invention can be 1, 1' bis (2 ethyl 1, 3 dioxolan 2 yl)
cryptocyanine, 3 carbethoxypsoralen, 4, 4', 6 trimethylangelicin,
4' aminomethyl 4, 5', 8 trimethylpsoralen, 4' hydroxymethyl 4, 5',
8 trimethylpsoralen, 5 methylangelicin, aminolevulinic acid hexyl
ester, aminolevulinic acid methyl ester, amotosalen, angelicin,
bacteriochlorin, benzoporphyrin derivative, bergapten,
chloroaluminum phthalocyanine, etiopurpurin, fimaporfin, gadolinium
texaphyrin, hematoporphyrin derivative, hypocrellin A, hypocrellin
B, lemuteporfin, lutetium texaphyrin, merocyanine, methoxsalen,
motexafin, musk ambrette, padeliporfin, padoporfin, photofrin,
photofrin I, photofrin II, phthalocyanine, phthalocyanine aluminum,
phthalocyanine derivative, phthalocyanine zinc, psoralen, psoralen
derivative, rostaporfin, talaporfin, temoporfin, tetrakis (3
hydroxyphenyl) chlorin, tetrakis (4 sulfophenyl) porphine,
tetraphenylporphyrin, tetraphenylporphyrin derivative,
tetrasulfophthalocyanine, tetrasulfophthalocyanine aluminum,
tetrasulfophthalocyanine chloroaluminum, trimethylpsoralen,
trioxysalen, verdin derivative, verteporfin.
[0053] Photoactivation
[0054] According to the present invention, photoactivation is
achieved by either an artificial or natural light source. In a
preferred embodiment, photoactivation of the photosensitizer is
achieve by LED or sunlight.
[0055] Penetrations Enhancers or Pre-Treatment
[0056] Skin penetration enhancers as well as skin pre-treatment for
enhancing penetration of drugs and chemicals have been developed to
improve bioavailability. One action among others of these enhancers
or pre-treatment procedures is to decrease the skin barrier
resistance. These enhancing penetration procedures can be
classified as mechanical, physical and chemical pre-treatments.
[0057] The table below is a non-limitative list of such
pre-treatment/penetration enhancers that may be used according to
the invention.
TABLE-US-00001 Mechanical Physical Chemical Skin preparation pad
Ablative (carbon dioxide) and Superficial peelings (sandpaper)
non-ablative lasers (fractional (alfa-hydroxy acids,
Microdermabration non ablative carbon dioxide, trichloracetic acid,
microneedling erbiumdoped Jessner solution) yttrium aluminium
garnet (Er:YAG), IPL) Curettage Retinoids (tretinoin,
tape-stripping adapalene, pan-scrubber tazarotene) exfoliating
scrub Acid azelaic compress rubbing Vitamin D3 derivates
[0058] Light Sources--Artificial
[0059] Electroluminescence (EL) is an optical and electrical
phenomenon in which a material emits light in response to the
passage of an electric current or to a strong electric field. This
is distinct from black body light emission resulting from heat
(incandescence), from a chemical reaction (chemiluminescence),
sound (sonoluminescence), or other mechanical action
(mechanoluminescence).
[0060] Among the electroluminescence sources, LED (Light emitting
diodes) lamps are well known and preferred as artificial light
source in the present invention. A LED lamp (LED light bulb) is a
solid-state lamp that uses light-emitting diodes (LEDs) as the
source of light. The LEDs involved may be conventional
semiconductor light-emitting diodes, organic LEDs (OLED), or
polymer light-emitting diodes (PLED) devices.
[0061] The LED lamps used in the examples hereafter are defined by
some characteristics like wavelength (in nm), power of the LED
(irradiance in mW/cm.sup.2) energy of the LED (in J/cm.sup.2). Such
particular features are provided below.
[0062] Light Sources--Natural
[0063] This aspect of the invention includes photoactivation with
either natural sunlight or any light source which provides
artificial sunlight (i.e. the entire range from UV to IR). Use of
natural sunlight as the light source has the advantage that the
animal being treated is free to leave the clinical environment
where treatment is normally conducted.
[0064] Light Sources--Intensity
[0065] In the uses and methods of the invention, photoactivation
may be achieved using light sources known in the art. Methods for
the irradiation of different areas of the body, e.g. by lamps or
lasers are well known in the art (see for example Van den Bergh,
Chemistry in Britain, May 1986 p. 430-439). The wavelength of light
used for irradiation may be selected to achieve a more efficacious
photosensitizing effect. The most effective light is light in the
wavelength range 300-800 nm, typically within the 400-700 nm
range.
[0066] Irradiation with an artificial light is preferably performed
for 1 to 30 minutes, preferably for 1 to 15 minutes, more
preferably from 5 to 10 minutes, preferably for 5 minutes,
depending on the light dose and fluence rate. A single irradiation
may be used or alternatively a light split dose in which the light
dose is delivered in a number of fractions, e.g. a 1 to 10 minutes
between irradiations, may be used.
[0067] Photoactivation with natural light is preferably done for a
duration between 5 minutes and 4 hours, in particular for a
duration of 2 hours. In a particular embodiment, a sunscreen is
applied to the sun-exposed area including the treatment area in
both groups during natural daylight-PDT, to avoid sunburn.
[0068] Treatment of the Skin According to the Invention
[0069] The methods and uses of the invention may involve
pretreatment of the skin. As the stratum corneum acts as a barrier
that limits the penetration of substances through the skin, the
purpose of a pretreatment (enhancer) is to favor the absorption of
the photosensitizer to the target tissue and thus a higher
efficacy. Enhancers may comprise mechanical, physical or chemical
preparation of the skin e.g. microdermabrasion (particularly with
an adapted skin preparation pad, sandpaper), microneedling,
tape-stripping, pan-scrubber, exfoliating scrub, compress rubbing,
non ablative lasers at a low-energy delivery and chemical
procedures such as superficial peelings (Retinoids tretinoin,
adapalene, tazarotene), Acid azelaic, Vitamin D3 derivates). For
example, the pretreatment may comprise a mechanical pretreatment of
the skin. Representative mechanical treatments include curettage,
dermoabrasion (in particular with an adapted sandpaper or
micro-needling (or micro-perforation) before application of the
photosensitizer. In a particular embodiment, the pretreatment
includes perforation of the skin using an adapted device such as a
micro-needle device, for example a dermaroller.
[0070] The fact that PDT with artificial light sources for
photorejuvenation can be a painful procedure and therefore often
requires specific pain management is a real issue.
[0071] Daylight mediated PDT appears as the ideal procedure
addressing to all signs of epidermal and dermal actinic damage with
lack of discomfort, lack of pain during therapy, possibility to
treat large areas (as demonstrated by several trials showing the
same efficacy level of both procedures, using daylight or an
artificial source for clearing actinic keratosis with significantly
lower pain score, leading to fewer related adverse (Wiegell JEADV
2011).
[0072] The use of an enhancer, such as a skin pretreatment as
described above, in particular a mechanical pretreatment, more
particularly the use of dermabrasion or microneedling, and more
particularly using a sandpaper, associating natural light could
provide better effects in treating acne with lower side
effects.
[0073] The methods and uses of the invention may also be carried
out with or without occlusion, more preferably with occlusion.
[0074] The photosensitizer may be applied for a duration of between
5 minutes to 4 hours, in particular between 15 minutes to 3 hours,
in particular between 30 minutes and 2 hours. In a particular
embodiment, the photosensitizer may be applied as a pulse therapy
for the time periods provided above, for example for a duration of
about 30 minutes. The inventors herein show that such a pulse
therapy has the advantage of being as efficient as therapy with
longer exposures, but with less PPIX produced, thereby preventing
side effects associated with PPIX.
[0075] In a particular embodiment, the treatment comprises: [0076]
(a) optionally, preparing the area of skin to be treated with the
appropriate pre-treatment, for example a curettage, a dermoabration
or microneedling (micro perforation), in particular a perforation
with an adapted micro-needling device such as a dermaroller; [0077]
(b) administering to said animal a composition comprising said
photosensitizer, in particular for a short period of time; [0078]
(c) photoactivating said photosensitizer; and [0079] (d)
optionally, removing the photosensitizer.
[0080] In an embodiment of the invention, the natural daylight
photodynamic therapy (PDT) on an animal comprises: [0081] a)
optionally, preparing the area of skin to be treated with the
appropriate pre-treatment, for example a curettage, a dermoabration
or microneedling (micro perforation), in particular a perforation
with an adapted micro-needling device such as a dermaroller; [0082]
b) administering to said animal a composition comprising said
photosensitizer for a duration between 5 min to 240 minutes; [0083]
c) photoactivating said photosensitizer for a duration between 1 to
15 minutes with artificial light or 0.5 hour to 3 hours with
natural light; and [0084] d) Optionally, removing the
photosensitizer.
[0085] In a more preferred embodiment of the invention the use of a
photosensitizer in natural daylight photodynamic therapy (PDT) on
an animal comprises: [0086] a) optionally, preparing the area of
skin to be treated with the appropriate pre-treatment, for example
a curettage, a dermoabration or microneedling (micro perforation),
in particular a perforation with an adapted micro-needling device
such as a dermaroller; [0087] b) administering to said animal a
composition comprising said photosensitizer for a duration between
15 min to 180 minutes; [0088] c) photoactivating said
photosensitizer for a duration between 0.5 hour to 2 hours with
natural light; and [0089] d) optionally, removing the
photosensitizer.
[0090] In a more preferred embodiment of the invention the
photosensitizer for use in photodynamic therapy (PDT) on an animal
comprises [0091] a) optionally, preparing the area of skin to be
treated with the appropriate pre-treatment, for example a
dermoabration (sand-paper) or microneedling (micro perforation), in
particular a dermoabration with an adapted sand-paper device such
as silicone carbide sand paper; [0092] b) administering to said
animal a composition comprising said photosensitizer for a duration
of 30 minutes; and [0093] xc) photoactivating said for a duration
of at least 2 hours with natural light; and [0094] d) optionally,
removing the photosensitizer.
[0095] Any of the above particular or preferred embodiments may
comprise a step of mechanically pretreating the skin as described
above, before the step of applying the photosensitizer on the
skin.
[0096] According to another aspect, the invention relates to a kit
comprising a device for implementing a pretreatment as provided
above, and a composition comprising a photosensitizer as described
above. This kit is useful for the implementation of the methods and
uses of the present invention. In a particular embodiment, the kit
comprises an adapted sandpaper or an adapted micro-perforation
device such as a dermaroller and a composition comprising ALA or
esters of ALA such as the methyl ALA ester, hexyl ALA ester and
benzyl ALA ester, especially methyl ALA ester. In addition, the kit
according to the invention may comprise a sunscreen. The kit of the
invention may further comprises instructions to follow for
implementing the methods and uses of the invention.
BRIEF DESCRIPTION OF THE DRAWINGS
[0097] FIG. 1 is a graph showing the inflammation vs. response rate
(3 months) of AK on the face.
[0098] FIG. 2 is a graph showing the mean increased redness the day
after PDT.
[0099] FIG. 3 is a graph reporting the visual redness 1 day after
PDT with different treatment protocols.
[0100] FIG. 4 is a graph showing the pain scale after different
treatments.
[0101] FIG. 5 is a graph showing the cure rate after different
treatments.
[0102] FIG. 6 is a graph showing the increase in erythema
percentage one day after treatment with different protocols.
[0103] FIG. 7 is a graph showing erythema scale after treatment
with different protocols.
[0104] FIG. 8 is a graph showing the mean photobleaching in the
standard treatment and a different "pulse" treatment.
[0105] FIG. 9 is a graph showing the inflammation (erythema)/PpIX
formation relationship.
[0106] FIG. 10 is a graph showing the values of fluorescence by IMP
and pre-treatment at 405 nm
[0107] FIG. 11 is a graph showing the values of fluorescence by IMP
and pre-treatment at 632 nm
[0108] FIG. 12 is a graph showing TEWL detailed by occlusion and
pre-treatment
EXAMPLES
Example 1--Comparison of Mechanical Penetration Enhancers on
Photosensitizer Skin Penetration
[0109] The effect on the product skin penetration of different
mechanical penetration enhancement techniques (occlusion,
microneedles, ablative fractional laser) has been evaluated.
[0110] 10 healthy volunteers have been treated according to the
following protocol: [0111] pretreatment with either micro-needles
(Dermaroller) or ablative fractional laser (CO.sub.2 laser fraxel
repair (SOLTA)), or no pretreatment; [0112] application of Metvix;
[0113] 3 hours of incubation with or without occlusion. [0114]
Penetration was quantified during incubation using measurement of
photo fluorescence of PpIX at 30 minutes, 1 hour, 2 hours, and 3
hours after product application.
[0115] Both Dermaroller and laser similarly increased Metvix
penetration in surface and deeper skin as measured by blue (405 nm)
(see FIG. 10) and red (632 nm) (see FIG. 11) photo fluorescence as
compared to no pretreatment without occlusion and no pretreatment
with occlusion.
[0116] No difference was observed with or with occlusion before 3
hours.
[0117] In addition, laser pretreatment was found to be more painful
and more irritant than Dermaroller, and laser pretreatment has more
impact in lowering skin barrier function as observed by measuring
transepidermal water loss. (see FIG. 12)
[0118] Therefore, the inventors have surprisingly shown that
mechanical pretreatment with a device such as micro-needle device
is as efficient as a laser pretreatment to increase product skin
penetration but with less adverse events and is therefore more
adapted to the PDT treatment of acne.
Example 2--PDT Procedure Change to Minimize Inflammation in PDT
[0119] According to the just mentioned theory it would be
preferable to keep PPIX and cellular enzymes away from the
extracellular compartment, thereby avoiding inflammation.
[0120] The purpose of this project is therefore to keep the PPIX
formation within the mitochondria and avoid excess amounts of PPIX
to be formed. Simultaneously PPIX should be allowed to be formed
for such a long time that most unnormal cells will be affected.
[0121] So the purpose of PDT is to kill unnormal cells, preferably
by apoptosis. The ideal situation would be to keep PPIX inside the
cell and to destroy the mitochondria only, thereby inhibiting the
ATP formation necessary for cell functions. That should result in
cell death by apoptosis.
[0122] One possible way to achieve this would be to give a short
5-MAL pulse treatment to get a high concentration of 5-MAL in the
cells initially and then diminish further access to 5-MAL by
removing 5-MAL from the skin surface.
[0123] This could be done by only exposing the skin to 5-MAL for a
short time, after which all 5-MAL is removed from the skin surface.
If the right "pulse time" can be found it might ensure high
cellular PPIX and low extracellular PPIX. Excess amounts of PPIX
formation during and after the end of the treatment would thus be
avoided.
[0124] The result shows less inflammation with unchanged efficacy
and thus mitochondria destruction seems to be the most important
factor in PDT.
[0125] To estimate the preferable Metvix "pulse time" a separate
investigation was performed (Method B) on 24 healthy volunteers.
The pulse time was 20 min., 40 min., 60 min., and the conventional
180 min, after which excess amounts of Metvix was removed from the
skin.
[0126] The formation of PPIX after 3 hours is seen in FIG. 8, and
the relation to inflammation is seen in FIG. 9. It is seen that
PPIX concentration speeds up between 20-40 min. of "pulse
exposure", and so we have chosen 30 min. as the minimum "pulse
exposure" time in the following (Method A) investigation of
efficacy and inflammation by this method change. The results are
illustrated in Column 3 in FIGS. 4, 5, 6, and 7. The procedure
change clearly diminishes inflammation (erythema), without
affecting the cure rate (FIG. 5). Pain level is not changed. PPIX
concentration is clearly lower than for the conventional 3-hour
exposure to Metvix (FIG. 8).
[0127] Methods
[0128] Healthy Volunteers
[0129] Twenty-four healthy male volunteers of Scandinavian ancestry
were included in the study (mean age 30 years, range 20-51). A
treatment area was selected on the inside of both forearms of the
volunteer. Each treatment area was divided into four minor
treatment fields of the size 2.times.5 cm with at least 3 cm
between each field using a prefabricated flexible template. In
order to imitate skin lesions all fields were tape stripped 10
times with occlusive dressing before treatment (Tegaderm.TM. Roll,
3M, Glostrup, Denmark).
[0130] On the left forearm vehicle Unguentum M was applied to the
treatment field.
[0131] On the right forearm excess amounts of 5-MAL 16%
(Metvix.RTM., Photocure, Oslo, Norway) were applied to all four
fields of treatment. All fields were covered with
light-impermeable, occlusive dressing. After 20 minutes the
dressing was removed from the first field and the excess cream
gently wiped off. The field was covered again with a thin piece of
gauze and light impermeable dressing. After additional 20 and 40
min same procedure was followed with the second and third field.
180 min after application of 5-MAL and vehicle was removed from all
five fields, and the excess cream was gently wiped of the last
field. All fields were illuminated with red light. Illumination was
performed with red LED light 630 nm peak (Aktilite.TM. 128;
Photocure ASA, Oslo Norway) using a total light dose of 37
J/cm.sup.2 given over 9 min. During and after illumination pain was
recorded. The volunteers were equipped with a special diary for
recording pain in the days after treatment. Four follow-up visits
were performed at day 1, 2, 3 and 8 after treatment.
[0132] PpIX Fluorescence
[0133] 5-MAL-induced PpIX fluorescence was depicted non-invasively
using a fluorescence camera (Medeikonos AB, Gothenburg, Sweden).
The amount of PpIX fluorescence was calculated from the photographs
by the program MatLab.RTM. (MatLab.RTM., MathWorks, Natic, US). The
amount of fluorescence was measured before tape stripping and cream
application (baseline) and before and after illumination.
[0134] The photo bleaching is then the difference in PpIX
fluorescence (AU) calculated from the pre and post illumination
images.
[0135] Erythema and Pigmentation
[0136] As an indicator of inflammation erythema was measured. The
erythema was assessed by an expert evaluator and measured
objectively.
[0137] The objective measurements of erythema and pigmentation were
performed using a skin reflectance meter (Optimize Scientific 558,
Chromo-Light, Espergaerde, Denmark).
[0138] Erythema % and pigmentation % were measured before
treatment, immediately before illumination, immediately after
illumination, and at the four follow-up visits.
[0139] Pain Score
[0140] The volunteers scored their pain every minute during
illumination, and recorded their pain in the diary every hour after
illumination on the treatment day, twice per day the next three
days and once a day on the following five days. Since PDT was
performed at different times of the day the number of evaluations
differed from 3 to 11 the first day. Pain was assessed using a
numerical scale ranging from 0 to 10, where 0 is no pain and 10 is
worst imaginable pain. To make it easier for the patients to
identify the different treated fields, the dairy was supplied with
numbered drawings of the fields.
[0141] Randomizing
[0142] The study was designed as an open randomised trial. A
statistical adviser made the randomisation. Since the sequence of
treatment duration was predefined, randomization was only
determining which of the four treatment fields should be the
first.
[0143] Statistics
[0144] The sample size was calculated on the bases of data from the
literature. We set the minimal clinical relevant difference to 8.8%
(50% of the earlier found 17.6%) and choose a power of 0.80 and a
significance level of 0.05, 22 volunteers should be included.
[0145] To identify differences in pain score, erythema % and
pigmentation % between the treatment fields we used Wilcoxon Signed
Ranked Test, since all results were paired.
[0146] For all calculations a p-value <0.05 was considered
statistical significant. All analyses were performed with PASW
Statistics 19.0 for Windows (SPSS Inc, Chicago, Ill., USA).
Example 3--Evaluation of Efficacy of 5-Mal in Daylight (DL)-PDT in
Subjects with Moderate to Severe Acne
[0147] 1. Study Objectives and Clinical Hypothesis
[0148] Study Objectives:
[0149] The primary objective of this study is to evaluate the
efficacy of 5-MAL cream combined with DL PDT compared to its
vehicle in patients with moderate to severe facial acne vulgaris
using a randomized, controlled and investigator-blinded study
design.
[0150] The secondary objective of this study is to assess the local
tolerance of CD06809-41 cream.
[0151] Clinical Hypothesis:
[0152] The hypothesis of the study is that 5-MAL is more
efficacious than its vehicle in moderate to severe acne when
combined with DL-PDT. In this study, 5-MAL combined with DL-PDT is
expected to reduce the total number of inflammatory lesions, which
are major symptoms of moderate to severe acne, and also to be
associated with less pain.
[0153] 2. Study Design
[0154] This is an exploratory, single-center, randomized,
placebo-controlled, investigator-blinded, intra-individual (left
versus right comparison) study, involving approximately 16 subjects
with moderate to severe acne, meeting specific inclusion/exclusion
criteria.
[0155] This study consists of: [0156] An up to 4-week screening
period (within 3 to 30 days prior to Baseline) except for women of
childbearing potential for whom a minimum of 2 weeks between the
screening visit and the Day 1 visit (Baseline) is required; [0157]
A treatment session with DL-PDT during which each subject will
receive 5-MAL on one side of the face versus vehicle on the other
side, on pre-treated skin using Homecare Dermaroller (expected hole
depth about 0.2 mm). [0158] A 3-month follow-up period (endpoint)
and an optional second session with DL-PDT during which the side of
the face treated by 5-MAL cream will receive placebo and
vice-versa. [0159] A 1 week follow-up period.
[0160] The second treatment session is not mandatory: it will only
be performed on subjects who request it, and according to
Investigator's judgment.
[0161] 3. Results
[0162] As revealed in the tables below the acne lesions
(inflammatory and non-inflammatory) in the DL-PDT treated area with
Metvix (5-MAL, otherwise referred to as Metvixia) showed better
results comparing to the placebo, with a progressive regression
observed to 3 months concerning the non-inflammatory lesions. The
reduction from baseline was about 59% regarding the inflammatory
lesions after one month of treatment and 56% of the
non-inflammatory lesions at the 3-month follow-up. The total lesion
reduction was around 50%.
TABLE-US-00002 TABLE 9_2_4_1_2 Percent reduction from Baseline in
Inflammatory lesion at each evaluation visit METVIXIA PLACEBO
METVIXIA - PLACEBO p* Week 4/ITT n 15 15 15 Mean +/- sd 54.1 +/-
25.4 35.2 +/- 34.2 18.9 +/- 36.2 Median 58.8 35.3 20.3 0.063 (Min,
Max) (-13.3, 76.5) (-50.0, 90.5) (-31.7, 114.7) Week 8/ITT n 14 14
14 Mean +/- sd 51.8 +/- 30.1 32.4 +/- 32.5 19.4 +/- 32.8 Median
55.9 37.1 24.6 0.068 (Min, Max) (-26.7, 88.2) (-33.3, 81.0) (-43.3,
80.4) Week 12/ITT n 7 7 7 Mean +/- sd 35.3 +/- 30.9 22.7 +/- 37.5
12.6 +/- 47.0 Median 33.3 28.6 26.5 0.678 (Min, Max) (-3.3, 76.5)
(-36.7, 69.2) (-60.9, 51.5) *p-value by two-sided Wilcoxon rank
signed test
TABLE-US-00003 TABLE 9_2_4_1_6 Percent reduction from Baseline in
Non inflammatory lesion at each evaluation visit METVIXIA PLACEBO
METVIXIA - PLACEBO p* Week 4 TT n 15 15 15 Mean +/- sd 37.4 +/-
27.2 30.1 +/- 32.0 7.3 +/- 34.5 Median 38.6 26.7 13.3 0.661 (Min,
Max) (-25.0, 87.5) (-40.0, 81.8) (-45.0, 94.5) Week 8 TT n 14 14 14
Mean +/- sd 34.6 +/- 35.0 17.9 +/- 33.1 16.7 +/- 30.4 Median 32.1
19.4 19.4 0.078 (Min, Max) (-45.0, 84.6) (-60.9, 61.6) (-36.0,
64.8) Week 1 TT n 7 7 7 Mean +/- sd 39.7 +/- 37.6 26.4 +/- 40.8
13.4 +/- 9.5 Median 56.3 38.5 11.8 0.031 (Min, Max) (-18.2, 64.6)
(-30.0, 84.6) (0.0, 30.0) *p-value by two-sided Wilcoxon rank
signed test indicates data missing or illegible when filed
TABLE-US-00004 TABLE 9_2_4_1_8 Percent reduction from Baseline in
Total lesion at each evaluation visit METVIXIA PLACEBO METVIXIA -
PLACEBO p* Week 4 TT n 15 15 15 Mean +/- sd 47.3 +/- 19.8 34.2 +/-
22.4 13.1 +/- 25.1 Median 52.0 34.5 6.0 0.073 (Min, Max) (0.0,
72.7) (-9.5, 78.8) (-26.1, 66.0) Week 8 TT n 14 14 14 Mean +/- sd
43.6 +/- 26.9 25.0 +/-28.5 18.6 +/-27.0 Median 48.0 23.4 20.6 0.030
(Min, Max) (0.0, 87.5) (-24.3, 67.9) (-15.7, 66.6) Week 12 TT n 7 7
7 Mean +/- sd 38.3 +/- 27.9 25.7 +/- 38.2 12.8 +/-24.9 Median 60.0
32.7 17.3 0.219 (Min, Max) (2.9, 71.9) (-24.3, 78.6) (-28.6, 37.7)
*p-value by two sided Wilcoxon rank signed test indicates data
missing or illegible when filed
* * * * *