Note: Descriptions are shown in the official language in which they were submitted.
CA 02489851 2004-12-09
COMPOSITION FOR TREATING PSORIASIS
BACKGROUND OF THE INVENTION
a) Field of the invention
The present invention relates in general to the field of the treatment of
psoriasis
and related skin disorders, and more particularly to a non-toxic oral and
topical
formulation that includes a pharmaceutically effective amount of dairy
proteins for the
treatment of psoriasis and related immune system disorders.
b) Description of the prior art
It is not known what causes psoriasis, although there is evidence of a genetic
predisposition and an autoimmune etiology. Onset may be triggered by systemic
infections
such as streptococcus throat, skin injury, vaccinations, and certain oral
medications such
as steroids. Subsequently, the immune system is thought to induce inflammation
and
excessive skin cell reproduction, which can be exacerbated by additional
factors such as
stress and diet.
In normal skin, the time for a cell to move from the basal layer through the
granular layer is 4-S weeks. In psoriatic lesions, the time is decreased 7-10
fold because of
a shortened cell cycle time, an increase in the absolute number of cells
capable of
proliferating, and an increased rate of division. T cell mediated immune
responses appear
to be responsible for the inflammation and hyperproliferation of
keratinocytes. Neutrophils
2 0 are found in psoriatic lesions, associated with increased levels of
plasminogen activator.
Psoriatic fibroblasts have increased levels of enzymes involved in collagen
synthesis,
secondary to expansion of the papillary dermis. Psoriatic plaques comprise HLA-
DR
positive keratinocytes and Langerhans cells, and activated T cells expressing
elevated
levels of IL-2 receptors.
2 5 'The typical lesion of psoriasis is a well-demarcated erythematous plaque,
covered
by thick, silvery scales. Psoriasis can become so extensive as to cause
exfoliative
erythroderma, in which the entire epidermal surface is in a state of
hyperproliferation.
Gluttate psoriasis is a form of the disease following streptococcal
pharyngitis, with widely
distributed characteristic 1-3 cm lesions. Pustular psoriasis is characterized
by numerous
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CA 02489851 2004-12-09
sterile pustules of 2-5 mm in diameter, and may lead to an acute, explosive,
life-
threatening episode of fever, chills, leukocytosis, hypoalbuminemia, and
hypocalcemia,
demanding immediate, vigorous therapy. Previously stable plaque-type psoriasis
can be
acutely exacerbated by viral infections, particularly HIV. Psoriasis is also
associated with
five different forms of psoriatic arthritis, including distal interpharangeal
involvement; an
asymmetric, oligoarticular pattern; a symmetric polyarthritis; arthritis
mutilans; and
sacroiliitis and spondylitis.
The inflammation and hyperproliferation of psoriatic tissue is associated with
a
different histological and antigenic profile. than normal skin. A panel of
anti-carbohydrate
monoclonal antibodies as described in the art, can be used to compare
psoriatic tissue with
the surrounding dermis. The glycosylation pattern in psoriatic epithelium is
changed in
two ways: some carbohydrates are expressed at an earlier stage of cell
maturation. In
addition, certain biosynthetic precursor antigens not expressed in normal skin
were found
in psoriatic skin.
Classical treatments of psoriasis include calcipotriene (a vitamin D3
derivative),
topical coal tar preparations, systemic antimitotic agents such as
methotrexate, and
retinoids, particularly etretinate.
Extensive psoriasis can be treated by photosensitization with oral 8-
methoxypsoralen, followed by ultraviolet A. Corticosteroids are given for
psoriatic
2 0 arthritis and acute attacks of pustular psoriasis. More recently,
cyclosporin A has been
tested in clinical trials at doses of 3-7 mg/kg with promising results, but
associated with
the risk of renal toxicity.
Current biotechnology approaches to psoriasis treatment relate to a direct
pharmaceutical-mediated attack, either on cell proliferation or on the immune
component
2 5 of the disease. Japanese patent application JP 6145069 describes
angiogenesis inhibitors
comprising ganglioside GM3 or a GM3 analog as an active agent. At 100 p,g/mL,
GM3
showed growth of normal human anti-endothelial cells of 4.S×104 on day
5,
compared with 76×104 in controls. U.5. Pat. No. 5,339,977 describes n-
deacetyl-
lysoganglioside derivatives for use as phospholipase A2 inhibitors for the
treatment of
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CA 02489851 2004-12-09
proliferative and autoimmune diseases, including various forms of cancer,
psoriasis, and
rheumatoid arthritis.
An IL-2 fusion toxin has been developed (Seragen, Inc.) that is designed to
selectively destroy activated T cells in psoriatic plaques, leaving normal
cells alone. The
objective is to destroy activated T cells, and thereby clear the psoriasis. A
Phase II study
has been performed in which test doses of S, 10, and 15 ~g/kg were
administered per day.
Comparable improvement was observed in patients with moderate to severe
psoriasis.
However, in order to obtain this response, the compound was administered three
days per
week for four weeks.
Various formulations containing the compound BCX-34 for psoriasis, cutaneous T
cell lymphoma, and HIV infection have been tested (Bioworld Today, Sep. 29,
1997; see
also WO 95/01355; WO 93/21187; WO 90/10631; U.S. Pat. Nos. 5,008,270,
5,008,265,
and 4,985,434). BCX-34 is a small molecule drug that inhibits purine
nucleoside
phosphorylase, a human enzyme believed to be involved in the proliferation of
T cells. An
oral formulation is being tested in an ongoing Phase I/II trial. A topical
formulation
advanced to the Phase III stage for both lymphoma and psoriasis. The Phase III
psoriasis
study showed only a 14% greater improvement in mean lesion scores in the
treated group
compared to placebos, which for these studies was not statistically
significant.
Several drugs have been designed to treat psoriasis by targeting specific
cells,
2 0 specific cytokines, or specific interactions between ligands and
receptors. The main
advantage of these biological agents over cyclosporin and methotrexate is the
absence of
nephrotoxicity and hepatotoxicity, but toxic effects can take years to
develop. Candidates
for biological therapy will be those who cannot comply with the rigours of a
phototherapy
regimen or have received too much PUVA and are at risk of hepatotoxicity and
2 5 nephrotoxicity.
Another product available in the art consist in a chimeric human tumor
necrosis
factor a monoclonal antibody derived from mouse. It is made of the human
constant and
mouse variable regions of the IgG antibody. This agent is administered by
intravenous
infusion over at least 2 h and neutralizes soluble tumour necrosis factor a
bound to cell
3 0 membranes. Results of several case reports attest to the efficacy of this
agent in treatment
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CA 02489851 2004-12-09
of psoriasis. Drawbacks of the drug include the need for slow intravenous
infusion. A
small but real proportion of patients have infusion reactions, including
potentially serious
reactions such as hypotension, rigors, and allergic reactions. These reactions
can often be
prevented by slowing down the infusion or pre-treating with antihistamines or,
for some
conditions, systemic corticosteroids. Neutralizing antibodies can develop,
making the
treatment less effective. Worse, patient who develop neutralizing antibodies
are more
likely to develop infusion reactions. One of the greatest concerns is the
potential for
infection with this tumor necrosis factor a inhibitor.
Alternatively, recombinant tumour necrosis factor a receptor fusion proteins
were
1 o developed, which consist of two extracellular ligand-binding domains of
the human p75
tumour necrosis factor a receptor fused to the Fc portion of human IgGI. These
fusion
proteins are likely effective for psoriatic arthritis and seems to be safer
than ciclosporin or
methotrexate with no nephrotoxicity or hepatotoxicity. Non-neutralising
antibodies occur
in less than 5% of patients. Antinuclear antibodies and antibodies to double-
stranded DNA
have been reported, but full cases of systemic lupus erythematosus are rare.
Anticardiolipin antibodies also develop but have been attributed to minor
concomitant
infections. Because this agent is a tumour necrosis factor a inhibitor,
concern has been
raised about the potential for immunosuppression leading to infection.
Humanised anti-CDlla monoclonal antibody was also developed for the treatment
2 0 for moderate-to-severe plaque psoriasis and moderate-to-severe rheumatoid
arthritis. It is
normally administered as a subcutaneous (under the skin) injection, and is
designed to
inhibit the binding of immune system T-cells to other cell types and targets
three key
processes in the cascade of events that lead to autoimmune symptoms.
Another family of products is known in the art to prevent T cell activation by
2 5 blocking the LFA-3/CD-2 pathway through binding to the CD2 receptor. It is
an IV/IM
administered product. Since this family of products may cause reduction in
CD4+ and
CD8+ T lymphocyte counts, it may not be appropriate for all individuals.
A fully human fusion protein consisting of a binding site of LFA-3 fused to
the Fc
portion of IgGI CD45Ro+ memory T cells, which have a major role in development
of
3 0 psoriasis, maximally express CD2, a natural ligand of LFA-3 has been
developed. By
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CA 02489851 2004-12-09
binding CD2, it prevents T-cell activation. Moreover, the Fc portion of the
molecule
engages Fc receptors on macrophages and NK cells, which results in apoptosis
of the
CD45R0+ T cells.
Another humanised monoclonal antibody to CD11A was developed, which is a
component of LFA-1 on T cells and ICAM-1 on antigen-presenting cells is an
important
co-stimulatory signal resulting in T-cell activation. ICAM-1 on endothelial
cells also
interacts with LFA-1 on circulating T cells, a necessary step for migration of
T cells into
inflamed skin. It can thus interfere with development of psoriasis by blocking
T-cell
migration into the skin and by preventing T-cell activation. In clinical
trials, some patients
developed flu-like symptoms including headache, chills, fever, nausea,
vomiting, or
myalgias. Symptoms arose on the day of injection or the following 2 days.
These acute
adverse events subsided by the third dose.
Systemic treatment has been used in patients with physically, socially, or
economically disabling psoriasis that has not responded to topical treatment.
The choices
to date have been phototherapy or systemic drug therapy. Generally, systemic
treatment
has employed phototherapy with Ultraviolet B irradiation, photo chemotherapy
which
combines the photosensitizing drug methoxsalen with Ultraviolet A phototherapy
(PUVA), methotrexate, etretinate, systemic corticosteroids, and cyclosporine.
Each of
these systemic treatments has variable efficacy and undesired side effects,
and some of
2 0 them are very toxic and present frequent relapses of the disease.
The number of different and sometimes toxic treatments employed for
amelioration of psoriasis is testimony to the resistant nature of this
disease. Not only is
moderate to severe psoriasis resistant to topical treatments, but because of
its chronic and
recurrent nature, systemic therapy or radiation is often required. The
devastating nature of
2 5 this disease is emphasized by the extent of the side effects that
psoriasis sufferers are
willing to endure to attain a remission to a disease that they know will recur
sooner or
later.
Keratinocyte function is regulated via intracellular signalling pathways
triggered
by growth factors and adhesion molecules. Among them, the EGF family and the
TGF-~i
3 0 family are thought to play central roles; they provide dual mode
regulation of
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CA 02489851 2004-12-09
keratinocytes growth via the proliferation stimulating effect of EGF and the
proliferation
inhibiting effect of TGF-ø. TGF-øs exert a wide range of biological effects on
keratinocytes, such as growth inhibition, production of extracellular matrix,
and synthesis
of plasminogen activator and its inhibitor (PAI 1 ). Among them, growth
inhibition is the
most prominent.
TGF-ø1 and TGF-ø2 are synthesized and secreted in human keratinocytes. It
seems that TGF-ø3 is not a major TGF-ø in human keratinocytes growth. Vitamin
D3 is a
strong inhibitor keratinocyte growth. The involvement of TGF-ø production
induced by
vitamine D3 increased the expression of TGF-ø2 mRNA 4 to 5 fold. In contrast,
TGF-ø1
mRNA and TGF-ø3 mRNA were not increased. Taken together, these data suggest
that
the intrinsic TGF-øs regulate autonomous growth of human keratinocytes, and
have
demonstrate that TGF-ø antagonized the acanthotic and degenerative effect of
TGF-a in
involved psoriatic skin, but TGF-ø alone did not cause granular layers to
appear in the
involved psoriatic epidermis, indicating that TGF-ø alone cannot normalize the
psoriatic
condition of the epidermis.
TGF-ø is now recognized as a potent growth inhibitor for human keratinocytes.
TGF-ø2, which was found through the normal human epidermis, was decrease in
the
proriatic epidermis. Since TGF-ø is a strong growth inhibitor for human
keratinocytes this
result indicates the possibility that the decrease of TGF-ø2 is involved in
the pathogenesis
2 0 of psoriasis. Therefore, the decrease in TGF-ø2 in psoriasis epidermis may
induce the
accelerated proliferation of keratinocytes and result in epidermal
hyperplasia. TGF-ø is
also a potent immunosuppressive agent. So the decrease of TGF-ø2 may permit
propagation of an immune/inflammatory reaction in the dermis and epidermis of
involved
psoriasis. It has been supposed that an immune-activation triggers the growth
activation of
2 5 epidermal keratinocytes in psoriasis. In terms of growth regulation of
keratinocytes, an
involvement of two groups of growth factors and cytokines, proliferation-
stimulating
growth factors and proliferation-inhibitory growth factors, has been reported.
EGF family
growth factors (TGF-a, amphiregulin and HB-EGF), KGF and IL-6 are well known
as
proliferation-stimulating growth factors. TGF-ø family growth factors are the
major
3 0 proliferation-inhibitory growth factors. The increase of TGF-a,
amphiregulin and IL-6
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CA 02489851 2004-12-09
was found in psoriasis. Autocrine- or cross-induction of EGF family growth
factors may
play an important role in epidermal hyperplasia.
One important group of growth factors involved in psoriasis mechanisms are the
dermally-derived insulin-like growth factors (IGFs), which support
keratinocyte
proliferation. In particular, IGF-I and IGF-II are ubiquitous peptides each
with potent
mitogenic effects on a broad range of cells. Molecules of the IGF type are
also known as
"progression factors" promoting "competent" cells through DNA synthesis. The
IGFs act
through a common receptor known as the Type I or IGF-I receptor, which is
tyrosine
kinase linked. They are synthesized in mesenchymal tissues, including the
dermis, and act
on adjacent cells of mesodermal, endodermal or ectodermal origin. The
regulation of their
synthesis involves growth hormone (GH) in the liver, but is poorly defined in
most tissues.
Particular proteins, referred to as IGF binding proteins (IGFBPs), appear to
be
involved in autocrine/paracrine regulation of tissue IGF availability. Six
IGFBPs have so
far been identified. The exact effects of the IGFBPs is not clear and observed
effects in
vitro have been inhibitory or stimulatory depending on the experimental method
employed. There is some evidence, however, that certain IGFBPs are involved in
targeting
IGF-I to its cell surface receptor.
Skin, comprising epidermis and underlying dermis, has GH receptors on dermal
fibroblasts. Fibroblasts synthesize IGF-I as well as IGFBPs-3, -4, -5 and -6,
which may be
2 0 involved in targeting IGF-I to adjacent cells as well as to the overlaying
epidermis. The
major epidermal cell type, the keratinocyte, does not synthesize IGF-I, but
possesses IGF-I
receptors and is responsive to IGF-I.
Considering the state of the art described above, there is still a significant
need for
an effective psoriasis treatment that avoids the disadvantages associated with
the currently
2 5 available topical or systemic treatments.
SUMMARY OF THE INVENTION
One aim of the present invention is to provide a composition and uses thereof
for
the prophylaxis or treatment of psoriasis or related disorders, said
composition comprising
between 0.1 to 5 pg of TGF-ail and between 5 to SO p,g of TGF-(32 per gram of
CA 02489851 2004-12-09
composition, and a total protein concentration completed to at least 15%
(w/w), but
preferably to at least 50% , and most preferably 80%, with dairy derived
proteins. TGF-(31
and TGF-(32 can also be dairy derived, and can be found at concentration
between 0.2 to
1.2 pg/g and between 10 to 18 ~g respectively per gram of composition.
The composition may comprises additionally between about 0.1 to 15% of
minerals as defined herein after.
At least 50% of the proteins are hydrosoluble. Preferably, 70%, and most
preferably 80% of the proteins found in the composition are hydrosoluble. The
ratio of
TGF-(31+TGF-(32/IGF-1 is preferably of between about 0.1 to 3.
l0 Someone skilled in the art will recognize that types of psoriasis that can
be
prevented or treated with the method or composition of the present invention
may include
one of nail psoriasis, plaque psoriasis, guttate psoriasis, erythrodermic
psoriasis, pustular
psoriasis, hyperkeratosis, oncholysis, or psoriatic arthritis.
Another aim of the present invention is to provide a method for preventing or
treating psoriasis or related disorders comprising administering to a patient
between 0.1 to
5 ~g of TGF-(31 and between 5 to 50 ~g of TGF-(32 per gram of composition, and
a total
protein concentration completed to at least 80% (w/w) with dairy derived
proteins.
Accordingly, one aspect of the present invention contemplates a method for
ameliorating the effects of a proliferative and/or inflammatory skin disorder
associated
2 0 with psoriasis in a mammal, the method comprising treatment of the
psoriasis and related
diseases with an effective amount of a composition or chemical analogues
thereof capable
of having properties in preventing or treating psoriasis and related diseases.
For the purpose of the present invention the following terms are defined
below.
The term "psoriatic tissue" refers to tissue affected by psoriasis and
affected cells
2 5 contained within the tissue, but not to cells that have migrated to the
site such as
leukocytes. Preferably, the psoriatic tissue is from a human.
The expression "effective amount" as used herein is intended to mean an amount
sufficient to effect a beneficial or desired clinical result. An effective
amount can be
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CA 02489851 2004-12-09
administered in one or more doses. For purposes of this invention, an
effective amount of
growth factors and/or dairy derived proteins, or other composition is an
amount that
induces a treatment or prophylactic response against at least one psoriasis
responsible
factor.
The terms "polypeptide", "peptide" and "protein" are used interchangeably to
refer
to polymers of amino acids of any length, and may be interrupted by non-amino
acids.
The terms "individual" or "subject" treated according to this invention is a
vertebrate, preferably a mammal, more preferably a human. Mammals include, but
are not
limited to, farm animals, sport animals, rodents, primates, and pets.
The term "minerals" as used herein is intended to mean salt constituents and
minerals at concentrations normally found in dairy products. For example,
there can be
different concentration of calcium, phosphorus, magnesium, potassium, sodium,
chloride,
sulfur, and citric acid. This also means that trace elements known in the art
as found in
dairy products can be assimilated or inferred therein.
Other terms used in this disclosure are explained where they arise.
BRIEF DESCRIPTION OF THE DRAWINGS
Fig. 1 illustrates knee skin ofpatient no. 4 after 1, 28 and 56 days of
treatment with
the composition XL-828L according to one embodiment of the present invention;
Fig. 2 illustrates knee skin of patient no. 9 after 1, 28 and 56 days of
treatment with
2 0 the composition XL-828L according to one embodiment of the present
invention; and
Fig. 3 illustrates knee skin of patient no. 4 after 1, 56 and 84 days of
treatment with
the composition XL-828L according to one embodiment of the present invention;
DESCRIPTION OF THE PREFERRED EMBODIMENT
The present invention now will be described more fully hereinafter with
reference
2 5 to the accompanying drawings, in which preferred embodiments of the
invention are
shown. This invention, may, however, be embodied in many different forms and
should
not be construed as limited to the embodiments set forth herein; rather, these
embodiments
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CA 02489851 2004-12-09
are provided so that this disclosure will be thorough and complete, and will
fully convey
the scope of the invention to those skilled in the art.
All patents, patent applications, articles and publications mentioned herein,
both
supra and infra, are hereby incorporated herein by reference.
In accordance with the present invention, there is provided composition and
methods for treating psoriasis in an individual, comprising administering a
composition
effective in stimulating a specific immunological response against a
physiological
imbalance aberrantly expressed in psoriatic tissue. These compositions)
comprise a
cocktail of products that shares growth and regeneration characteristics of a
growth factor
that is aberrantly expressed in psoriatic tissue (such as human psoriatic
tissue). Particular
growth factors included in the composition of the present invention, but are
not limited to
transforming growth factors, such as TGF-(31 and TGF-(32, and at least 15% of
dairy
derived proteins. Preferably, the composition of the present invention will
comprised of at
least 40% or 50% of dairy derived proteins, and most preferably more than 80%
of dairy
derived proteins. In one particular embodiment of the present invention, at
least 70%, and
preferably 80%, of the proteins are hydrosoluble. The proteins may be
comprised, for
example but not limited to, of at least 60% (w/w) of (3-lactoglobulin, and/or
between 0.1 to
30% (w/w) of lactoferrin. Milk proteins are naturally presents as follows:
2 0 grams/ litre % of total protein
Total Protein 33 100
Total Caseins 26 79.5
alpha s1 10 30.6
2 5 alpha s2 2.6 8.0
beta 9.3 28.4
kappa 3.3 10.1
Total Whey Proteins 19.3
6.3
alpha lactalbumin 1.2 3.7
3 0 beta lactoglobulin3.2 9.8
BSA 0.4 1.2
Immunoglobulins 0.7 2.1
Proteose neutone 0.8 2.4
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CA 02489851 2004-12-09
Whet/ Proteins
The proteins appearing in the supernatant of milk after precipitation at pH
4.6 are
collectively called whey proteins. These globular proteins are more water
soluble than
caseins and are subject to heat denaturation. Native whey proteins have good
gelling and
whipping properties. Denaturation increases their water holding capacity. The
principle
fractions are 13 -lactoglobulin, alpha-lactalbumin, bovine serum albumin
(BSA), and
immunoglobulins (Ig).
f3 -Lactoglobulins: (MW - 18,000; 162 residues) This group, including eight
genetic variants, comprises approximately half the total whey proteins. 13 -
Lactoglobulin
has two internal disulfide bonds and one free thiol group. The conformation
includes
considerable secondary structure and exists naturally as a noncovalent linked
dimer. At the
isoelectric point (pH 3.5 to 5.2), the dimers are further associated to
octamers but at pH
below 3.4, they are dissociated to monomers.
alpha-Lactalbumins: (MW - 14,000; 123 residues) These proteins contain eight
cysteine groups, all involved in internal disulfide bonds, and four tryptophan
residues.
alpha-Lactalbumin has a highly ordered secondary structure, and a compact,
spherical
ternary structure. Thermal denaturation and pH <4.0 results in the release of
bound
calcium.
Enzymes
2 0 Enzymes are a group of proteins that have the ability to catalyze chemical
reactions
and the speed of such reactions. The action of enzymes is very specific. Milk
contains both
endogenous and exogenous enzymes. Exogenous enzymes mainly consist of heat-
stable
enzymes produced by psychrotrophic bacteria: lipases, and proteinases. There
are many
endogenous enzymes that have been isolated from milk. The most significant
group are
2 5 the hydrolases: lipoprotein lipase; plasmin; and alkaline phosphatase.
Lipoprotein lipase LPL): A lipase enzyme splits fats into glycerol and free
fatty
acids. This enzyme is found mainly in the plasma in association with casein
micelles. The
milk fat is protected from its action by the fat globular matrix (FGM). If the
FGM has
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CA 02489851 2004-12-09
been damaged, or if certain cofactors (blood serum lipoproteins) are present,
the LPL is
able to attack the lipoproteins of the FGM. Lipol r~sis may be caused in this
way.
Plasmin: Plasmin is a proteolytic enzyme; it splits proteins. Plasmin attacks
both 13
-casein and alpha(s2)-casein. It is very heat stable and responsible for the
development of
bitterness in pasteurized milk and UHT processed milk. It may also play a role
in the
ripening and flavour development of certain cheeses, such as Swiss cheese.
Alkaline phosphatase: Phosphatase enzymes are able to split specific phosporic
acid esters into phosphoric acid and the related alcohols. Unlike most milk
enzymes, it has
a pH and temperature optima differing from physiological values; pH of 9.8.
The enzyme
is destroyed by minimum pasteurization temperatures, therefore, a phosphatase
test can be
done to ensure proper pasteurization.
While a detectable immunological or tissue response is likely to be
beneficial,
efficacy can also be deduced by an improvement in symptoms or control of the
psoriatic
condition beyond what would be expected without treatment.
The active compounds according to the invention are distinguished by strong
anti-
inflammatory actions.
For prophylaxis, the active compounds are administered in order to decrease
manifestations of the disease in frequency and strength. Treatment in the
manifest stage
leads to its curtailment and to the alleviation of the symptoms.
2 o In all types of psoriasis, the active compounds of the present composition
can be
used prophylactically and for the treatment of the disorders.
Estimates of the prevalence of psoriasis vary from 0,5 to 6%, with rates
varying
between countries and races. Different types of psoriasis can be prevented or
treated with
the composition of the present invention. Plaque-type psoriasis is the most
common form
2 5 of the disease, occurring in more than 80% of cases. Guttatte psoriasis
occurs in about
10% of patients with psoriasis, and erythrodermic and pustular psoriasis each
occur in
fewer than 3% of patients. Nail psoriasis is generally the first sign of
disease in 4% of
patients. Between 5 to 10% of patients with psoriasis have psoriatic
arthritis, a destructive
and occasionally disabling joint disease. The course of psoriatic arthritis
varies, with some
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CA 02489851 2004-12-09
having mild changes and others severe, rapid destruction of joints. Skin
problems such as
dryness or lesions are symptoms associated with psoriasis.
Erythrodermic psoriasis is characterized by generalized inflamed erythema and
widespread scaling, affecting up to 100% of the body surface area. Patients
lose many of
the protective functions of the skin, including the skin's ability to protect
against infection,
control body temperature, and prevent loss of fluids and nutrients through the
cutaneous
surface.
Generalized pustules psoriasis is characterized by development of sterile
pustules
covering large portions of the trunk and extremities. In severe cases,
pustules become
confluent forming large areas of pus. In this case also, many of the skin's
protective
functions are lost, making patients susceptible to infection and loss of
fluids and nutrients.
A further neurosensory phenomenon is to be regarded as itching in the case of
atopic skin, and also itching in the case of psoriasis related disorders.
According to the invention, it is therefore possible to make available active
compounds and preparations containing those active compounds which, in
particular,
prevent neurosensory phenomena or alleviate them or rapidly make them fade,
i.e. are
suitable for prophylaxis andlor treatment.
"Stinging" phenomena can be regarded as disorders to be treated cosmetically
or
orally, or in other cases by other ways of administration. Severe itching,
however, in
2 0 particular in the case of atopy, in particular neurodermatitis and severe
itching of the skin
occurring during psoriasis, can also be regarded as a relatively serious
dermatological
disorder.
'The active compounds according to the invention can in particular also be
used on
skin superficially appearing to be healthy, e.g. in the case of psoriasis and
atopy, i.e. also
2 5 in addition to the diseased skin areas and, in particular, here too in the
case of related
psoriasis disorders.
The active compounds according to the invention can also be incorporated
without
problems into customary oral, pharmaceutical, dermatological, and cosmetic
bases for
preferred oral administrations and the corresponding pharmaceutical, in
particular
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CA 02489851 2004-12-09
dermatological, and cosmetic topical preparations or compositions can thus be
obtained.
The concentration of compounds in the composition of the present invention are
adjusted
depending of the needs. TGF-(31 can be found at concentration of between 0.1
to 5 ~,g per
gram of composition and TGF-(32 can be found at concentration of between 5 to
SO pg per
gram of composition. Preferably, TGF-ail is found at concentration of 0.2 to
1.2 p.g/g, and
TGF-~2 at between 10 to 18 ~g/g of composition. The preparations can be used
daily in a
customary manner.
In another embodiment of the present invention, the composition comprises at
least
70% (w/w) of dairy derived proteins. The total concentration of proteins in
the
l0 composition would normally of at least 80%. Dairy proteins or dairy
products as used
herein may include milk, colostrums, or whey proteins or derived products or
fractions
thereof. The fat fraction of the composition can be generally found at
concentration
between about 0.5 to 10 % (w/w) in the composition. Though not always the
case, the fat
or compounds of this family of products, can be derived from dairy products,
or from any
other source, such as for example, but not limited to, vegetable or animal
sources,
synthetic or natural sources, allowing the composition of the present
invention to have its
properties as defined herein. For example, the physical properties of milk fat
can be
summarized as follows: density at 20°C is 915 kg/m3; refractive index
(589 nm) is 1.462
which decreases with increasing temperature; solubility of water in fat is
0.14% (w/w) at
2 0 20°C and increases with increasing temperature; thermal
conductivity is about 0.17
J/m/s/K at 20°C; specific heat at 40°C is about 2.lkJ/kg/K;
electrical conductivity is <10-
~z/ohm/cm; and dielectric constant is about 3.1.
At room temperature, the lipids are solid, therefore, are correctly referred
to as
"fat" as opposed to "oil" which is liquid at room temperature. The melting
points of
individual triglycerides ranges from -75°C for tributyric glycerol to
72°C for tristearin.
However, the final melting point of milk fat is at 37°C because higher
melting
triglycerides dissolve in the liquid fat. This temperature is significant
because 37°C is the
body temperature of the cow and the milk would need to be liquid at this
temperature. The
melting curves of milk fat are complicated by the diverse lipid composition:
trans
3 0 unsaturation increases melting points; and odd-numbered and branched
chains decrease
melting points.
- 14-
CA 02489851 2004-12-09
The invention also relates to the use of the active compounds according to the
invention for the production of pharmaceutical compositions, in particular
oral,
pharmaceutical and cosmetic compositions for the prophylaxis and treatment of
psoriasis,
allergies and auto-immune disorders and on dry skin and on sensitive skin.
Likewise, the invention also relates to the use of the compositions as oral,
or
topical preparations.
The present invention also addresses the underlying T-cell disorder that
results in
an inflammatory condition due to psoriasis. The present inventors have
recognized that
most, if not all, of the current therapies for psoriasis or similar T-cell
mediated
inflammatory skin conditions are designed to eliminate T-cells and to thereby
ameliorate
inflammation. It is possible that a major problem with the current treatments
is that the
therapy itself is so toxic that it may promote recurrence during healing. The
toxicity of
current treatments unleashes some or all of the cytokines that are associated
with the
promulgation of these chronic and often rebounding skin diseases.
The synergistic effects of the two TGF-(3 factors and dairy derived proteins
results
in a non-toxic, highly effective treatment for psoriasis that is without the
side effects
observed with virtually all other therapies for moderate to severe psoriasis
(mild psoriasis
may be successfully treated with proper moisturizing). As illustrated by the
following
studies, the most common over-the-counter treatment for psoriasis, namely coal
tar, may
2 0 be made more effective by the use of the present composition.
The active compounds according to the invention can be mixed with customary
pharmaceutically tolerable diluents or vehicles and, if appropriate, with
other auxiliaries
and administered, for example, orally or parenterally. They can preferably be
administered
orally in the form of granules, capsules, pills, tablets, film-coated tablets,
sugar-coated
2 5 tablets, syrups, emulsions, suspensions, dispersions, aerosols and
solutions and also
liquids, or else also as suppositories, vaginal suppositories or parenterally,
e.g. in the form
of solutions, emulsions or suspensions. Preparations to be administered orally
can contain
one or more additives such as sweeteners, aromatizing agents, colorants and
preservatives.
Tablets can contain the active compound mixed with customary pharmaceutically
3 0 tolerable auxiliaries, for example inert diluents such as calcium
carbonate, sodium
-15-
CA 02489851 2004-12-09
carbonate, lactose and talc, granulating agents and agents which promote the
disintegration
of the tablets on oral administration, such as starch or alginic acid, binding
agents such as
starch or gelatin, lubricants such as magnesium stearate, stearic acid and
talc.
Suitable excipients are, for example, lactose, gelatin, maize starch, stearic
acid,
ethanol, propylene glycol, ethers of tetrahydrofurfuryl alcohol and water.
The formulations are prepared, for example, by extending the active compounds
with solvents and/or excipients, if appropriate using emulsifiers and/or
dispersants, it
being possible, for example, in the case of the use of water as a diluent
optionally to use
organic solvents as auxiliary solvents.
l0 Administration is carned out in a customary manner, preferably orally or
parenterally, in particular perlingually, sublingually, or intravenously. In
the case of oral
administration, apart from the excipients mentioned, tablets, of course, can
also contain
additives, such as sodium citrate, calcium carbonate and dicalcium phosphate
together
with various additives, such as starch, preferably potato starch, gelatin and
the like.
Furthermore, lubricants such as magnesium stearate, sodium lauryl sulphate and
talc can
additionally be used for tableting. In the case of aqueous suspensions and/or
elixirs, which
are intended for oral administration, the active compounds can be mixed, apart
from with
the above-mentioned auxiliaries, with various flavors enhancers or colorants.
In the case of parenteral administration, solutions of the active compounds
using
2 0 suitable liquid excipients can be employed.
Capsules can contain the active compound as a single constituent or mixed with
a
solid diluent such as calcium carbonate, calcium phosphate or kaolin. The
injectable
preparations are also formulated in a manner known per se.
Ointments and topical formulations are particularly of interest also when
2 5 considering the use of the composition of the present invention for
treating psoriasis.
The preferred compositions according to the invention can be formulated as
liquid,
pasty or solid preparations, for example as aqueous or alcoholic solutions,
aqueous
suspensions, emulsions, for example W/O or O/W emulsions, ointments, gels,
lotions,
creams, oils, powders or sticks. Depending on the desired formulation, the
active
- 16-
CA 02489851 2004-12-09
compounds can be incorporated into pharmaceutical and cosmetic bases for
topical
application, which as further components contain, for example, oil components,
fat and
waxes, emulsifiers, anionic, cationic, ampholytic, zwitterionic and/or non-
ionic
surfactants, lower mono- and polyhydric alcohols, water, preservatives, buffer
substances,
thickeners, fragrances, colorants and opacifiers. Preferably, the emulsions,
e.g. W/O
emulsions, or ointments are used.
Furthermore, it is preferred according to the invention to add antioxidants to
the
active compounds and to the pharmaceutical and topical preparations. The use
of natural
or naturally identical compounds such as, for example, tocopherols is
particularly
preferred here. The antioxidants mentioned are contained in the compositions
according to
the invention, for example, in amounts from 0.01-5% by weight, in particular
from 0.5-2%
by weight, based on the total composition.
'The present invention will be more readily understood by refernng to the
following
examples which are given to illustrate the invention rather than to limit its
scope.
EXAMPLE I
Clinical efficiency of oral treatment.
Materials and Methods
Protocol design
The study was carried out in de "Centre de Recherche Dermatologique du Quebec
2 0 Metropolitain". The study protocol was approved by an external ethic
committee (Ethics
Clinical Research inc., Montreal). All patients were submitted to a washout
period of 28
days for the systemic therapies and 14 days for the topic therapies (including
phototherapy) before the beginning of the study. Only tar or salicylic acid
based shampoos
for the scalp, mild topic corticosteroids for genital and facial areas, and an
hydrating
2 5 cream provided by the clinic were permitted during the washout and the
treatment periods.
During the initial 56-day treatment period, patients received one pouch (5g)
of XP-
828L twice a day. For the remaining of the study, the product provided by the
sponsor was
concentrated by a factor 2X in terms of growth factors. Therefore only 2.5g of
XP-828L
were put in the pouches in order to administer the equivalent amount of growth
factors on
- 17-
CA 02489851 2004-12-09
a daily basis, i.e. 60 ~g of active ingredient. All patients participating at
the extension
study received the new lot and were informed of the introduction of the new
product in the
protocol.
All patients provided written informed consent. Eligible patients were at
least 18
years of age and diagnosed as having active plaque psoriasis with at least 2 %
of total
body surface area affected.
Assessments
Patients were evaluated at screening, baseline and at days 28, 56, 84 and 112
of
treatment. The assessments performed at each visit are summarized on Table 1.
Psoriasis
The score for the psoriasis area-and-severity index (PASI) was the primary
outcome measured by the physician. The PASI combines assessments of psoriasis
induced
erythema, scaling and skin thickness, each weighted according to the size of
the affected
area. The composite score ranges from 0 to 72.
At each visit, the physician performed the Physician's Global Assessment
(PGA),
which is a general evaluation of the patient's psoriasis. The PGA uses a 5-
point scale: very
severe (S); severe (4); moderate (3); mild (2); almost clear (1) and absence
of disease (0)
(Table 1 ).
Patients also evaluated their psoriasis using the Patient's Global Assessment
2 0 (Patient GA, 10-point scale) and the Pruritus Assessment (4-point scale).
The percentage of Body Surface Area (BSA) affected by psoriasis was also
evaluated.
Pictures of a specific area were taken at each visit.
Evaluation of side effects
2 5 Side effects were evaluated in all patients. Safety measurements included
the
monitoring of adverse events throughout the study. In addition, vital signs
(heart rate,
blood pressure), eye examination, urinalysis, and blood chemistry (creatinine,
albumin,
-18-
CA 02489851 2004-12-09
total bilirubin, alanine transaminase ALT, aspartate transaminase AST) were
assessed.
Haematology analysis (complete blood count) was also performed. Safety
measurements
were performed at screening, at baseline and at days 28 and 56 of treatment.
Other antipsoriasis treatments
None were authorized at the exception of tar- or salicylic acid-based shampoos
or
of weak corticosteroids for application on facial lesions or genital organs.
A hydrating cream was provided to each participant for the duration of the
trial.
The participant were allowed to use the cream whenever needed, except during
the 24h-
period before each visit.
Medication for treatments of conditions other than psoriasis
All other medication shall remain constant during the trial. If for any reason
these
treatments should change, the modifications were recorded in the medical
dossier of the
patients.
CLINICAL RESULTS
A total of 11 patients, 7 males and 4 females, met the inclusion criteria and
were
enrolled in the study. All 11 patients completed the initial 56 days study.
The age of
patients ranged from 27 to 69 years old. The PASI score at baseline ranged
from 5.2 to
17.4 and the BSA with psoriasis at baseline ranged from 2 to 20 %. Seven (7)
out of the
11 patients were available and agreed to participate to the additional 8 weeks-
extension
2 o study.
Chars eg s in psoriasis symptoms
PASI scores
After one month of treatment, XP-828L improved the score of psoriasis area-and
severity index in 6 out of 11 subjects (55 %). At the end of the 56 days
study, 7 of the 11
subjects (64 %) had an improvement of their PASI score ranging from 9.5 to
81.3 %. One
patient achieved PASI 75 (at least 75 % improvement in PASI relative to
baseline) at day
56 of treatment. PASI 75 is the currently recognized benchmark of end points
used in
- 19-
CA 02489851 2004-12-09
psoriasis clinical trials. One patient experienced an increase in its PASI
score of 13.6 %.
For the other 3 patients, the PASI score remained unchanged. (Table 2).
Table 1
Summary of the assessments at each patient's visit.
Day
of
the
visit
(screening)(baseline)
-30 1 7 28 56 84 112
Written informedx
consent
Review of criteriax x x x x x x
Examination x
of skin
Blood pressure x x x x x x x
Pregnancy test x x x x x x x
Blood sample x x x x x x x
(hematology
&
biochemistry)
Examen du fond x x
de 1'oeil
Prosiasis evaluation
%BSA x x x x x
PASI x x x x x
PGA x x x x x
Patient GA x x x x x
Prurit x x x x x
Photographs x x x x x
Report of adverse x x x x x
effects
-20-
CA 02489851 2004-12-09
Table 2
PASI scores and changes in PASI score (%) of subjects with psoriasis treated
for 56
days (11 patients) or 112 days (7 patients) with 5 g twice daily of XP-828L.
PASI Changes
score in PASI
score
Day 56 Day 84 Day 112
PatientDay D Da6yg~ Di relative relative relative
b 1 g ~ to to to
baseline baseline baseline
% %
1 9 9 9 8.4 8.4 0 -6.7 -6.7
2 7.2 6.4 4.8 - - -33.3 - -
3 14.214.2 14.214.214.1 0 0 -0.7
4 10.27.8 7.8 2.9 2.2 -23.5 -71.6 -78.4
6 8.4 7.6 7.6 7.6 S.6 -9.5 -9.5 -33.3
7' 7.6 8.5 8.8 - - +15.8 - -
8 5.2 4.9 3.7 3.9 3.7 -28.8 -25.0 -28.8
9 17.410.3 7.4 6.6 6.6 -57.5 -62.1 -62.1
10' 10.810.4 8.9 - - -17.6
12' 5.9 4.3 1.1 - - -81.3 - -
13 11.411.4 11.411.41i.4 0 0 0
Mean -21.4+28.3-25.0129.9-30130.8
n 11 7 7
Patient
2
was
excluded
from
extension
study
(at
day
72)
because
of
a
dental
surgery
Patients
5
and
11
were
excluded
at
the
beginning
of
the
study
'
Patients
have
refused
to
participate
to
the
extension
study
At day 84 in the extension study, 5 patients out of 7 had an improvement of
the
PASI score relative to baseline ranging from 6.7 to 71.6 %. 3 patients of 7
had smaller
PASI scores at day 84 compared to day 56 of treatment. At the end of the
extension study,
at 112 days of treatment, PASI score improvement ranged from 6.7 to 78.4 %.
Another
patient reached PASI 75 after 112 days of treatment. 2 patients out of 7 had a
further
significant reduction of their PASI score at day 112 compared to day 84 of
treatment.
Body surface area
The body surface area affected by psoriasis didn't change significantly during
the
trial (Table 3).
-21 -
CA 02489851 2004-12-09
Table 3
Changes in body surface area (BSA, %) during the trial.
BSA (%)
Day 1 Day 28 Day 56 Day 84 Day 112
Patient 6 6 6 6 6
1
Patient 6 6 6 6* -
2
Patient 11.5 I 1.5 11.5 13.5 13.5
3
Patient 8 8 8 5 5
4
Patient 6 6 6 6 6
6
Patient 6.5 7 7.5 - -
7
Patient 2 1.75 1.75 1.75 1.75
8
Patient 11.5 11.5 11.5 11.5 11.5
9
Patient 6 6 5.8 - -
Patient 3.75 3.75 1.5 - -
12
Patient 20 20 20 20 20
13
Meanstd 7.94.9 7.954.9 7.85.2 8.75.9 9.1f6.2
5
* Patient 2 was excluded from extension study (at day 72) because of a dental
surgery
Psoriasis global assessment
The PGA decreased for 2 patients (patient 4 and patient 9) after one month of
treatment, and for 2 patients (patient 8 and patient 12) after 2 months of
treatment by one
10 point. Two patients considered that their psoriasis improved significantly
with XP-828L,
showed by the important decrease of the Patient GA (from 10 to 5 for patient 4
and from 6
to 4 for patient 13 at 28 days of treatment). (Table 4 and Table 5).
In the extension study, the PGA and the Patient GA further decreased for
patient 4
at day 112. The patient 4 continued to consider that his psoriasis was very
improved
(Patient GA from 10 at baseline to 3 at day 112).
-22-
CA 02489851 2004-12-09
Table 4
Changes in physician's global assessment of psoriasis (PGA) during the trial.
PGA
Day 1 Day 28 Day 56 Day 84 Day 112
Patient 3 3 3 3 3
1
Patient 3 3 3 3* -
2
Patient 3 3 3 3 3
3
Patient 3 2 2 2 1
4
Patient 3 3 3 3 3
6
Patient 3 3 3 - -
7
Patient 3 3 2 3 3
8
Patient 4 3 3 - -
9
Patient 3 3 3 - -
Patient 2 2 1 - -
12
Patient 3 3 3 3 ?
13
T ranem ~ was excmded nom extension study (at day lZ) because of a dental
surgery
Table 5
5 Changes in patient's global assessment of psoriasis (Patient GA) during the
trial.
Patient
GA
Day 1 Day 28 Day 56 Day 84 Day 112
Patient 7 5 6 7 5
1
Patient 7 6 7 6* -
2
Patient 6 6 6 8 8
3
Patient 10 5 5 5 3
4
Patient 6 6 6 6 6
6
Patient 9 10 10 - -
7
Patient 3 3 3 3 3
8
Patient 5 8 5 7 7
9
Patient 8 8 10 - -
10
Patient 2 3 2 - -
12
Patient 6 4 4 5
13 I
rauc~u ~ was excmaea from extension stuay fat nay i~) because of a dental
surgery
Pruritus
10 The pruritus scale did not change significantly during the trial. Tree
patients
experienced a reduction of their pruritus Table 6).
-23-
CA 02489851 2004-12-09
Table 6
Changes in pruritus reported by the patients during the trial.
Pruritus
Day 1 Day 28 Day 56 Day 84 Day 112
Patient 1 1 1 1 1
1
Patient 1 1 1 1 * -
2
Patient 1 1 1 1 1
3
Patient 2 2 1 1 1
4
Patient 2 1 1 1 1
6
Patient I 2 3 - -
7
Patient 3 2 3 3 3
8
Patient 1 1 0 1 1
9
Patient 2 3 2 - -
Patient 1 1 1 - -
12
Patient 1 1 1 0 0
13
* Patient 2 was excluded tcom extension study (at day ~1) because or a aemai
surgery
Changes in hematolo;?v & biochemical measurements
5 XP-828L was well tolerated. No clinically significant laboratory
abnormalities or
pattern of changes in vital signs were observed during the XP-828L treatment.
Table 7 reports the data for creatinine, ALT and AST. It can be noticed that
two
ALT values for patient 3 were out of range at days 28 (ALT=63) and 56
(ALT=62). These
fluctuations were not considered significant since all other values for
patient 3 were within
10 ranges.
Also, two patients (patients 12 and 13) experienced not clinically significant
temporary fluctuations in creatinine values during the trial. Appendix 3
reports all these
fluctuations in creatinine which occurred only once for patient 13 but on
three times for
patient 12. In each case, a new blood test 2-4 days later showed creatinine
values back to
normal.
Adverse events
No clinically significant adverse events were reported during the treatment.
-24-
CA 02489851 2004-12-09
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CA 02489851 2004-12-09
Efficacy of XP-828L
In this open label study on patients with mild-to-moderate chronic plaque
psoriasis,
XP-828L treatment for 56 days showed to improve psoriasis. Scores for the
psoriasis area-
and severity index started to decrease after one month of treatment which can
be
considered a remarkable achievement for a nutraceutical product. Two patients
have
reached PASI 75, one after 56 days of treatment and one after 112 days of
treatment.
The extent of PASI scores reduction was generally lower during the extension
period. As shown in Table 2, the average decrease in PASI scores was 21.5% at
day 56
and -25.0 at day 112. The other parameters (PGA, patient's global assessment,
pruritus)
l0 remained stable during the extension study. This suggests that the efficacy
of XP-828L
has reached its maximum after day 56. It also shows that the improvements of
XP-828L
on psoriasis are preserved during the extension period.
No patient experienced a complete elimination of the psoriasis symptoms,
suggesting perhaps that a higher dose would lead to more important effects in
terms of
PASI scores reduction.
Safety of XP-828L
Since there were no clinical significant side effects or adverse events with
the use
of XP-828L for 112 days, it is suggested that XP-828L may represent a safe way
to treat
psoriasis. Only one patient experienced fluctuations of his creatinine values
but no
2 o fluctuation pattern was found and no other abnormalities were observed.
The main findings of this open label study are:
XP-828L showed to have the potential of improving psoriasis on patients with
mild-to-moderate chronic plaque psoriasis. Scores for the psoriasis area-and
severity index
already started to decrease after one month of treatment.
2 5 No clinically significant adverse events or laboratory abnormalities were
observed
during the XP-828L treatment. This results suggest that XP-828L is safe.
-26-
CA 02489851 2004-12-09
Overall, the tolerability of XP-828L was good. Patients reported that they
liked the
product and found its use very convenient.
While the invention has been described in connection with specific embodiments
thereof, it will be understood that it is capable of further modifications and
this application
is intended to cover any variations, uses, or adaptations of the invention
following, in
general, the principles of the invention and including such departures from
the present
disclosure as come within known or customary practice within the art to which
the
invention pertains and as may be applied to the essential features
hereinbefore set forth,
and as follows in the scope of the appended claims.
-27-
