Note: Descriptions are shown in the official language in which they were submitted.
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SOLUBLE TUMOR NECROSIS FACTOR RECEPTOR TREATMENT OF
MEDICAL DISORDERS
FIELD OF THE INVENTION
The invention pertains to methods for treating various medical disorders that
are
characterized by abnormal or excessive TNFa levels by administering
compositions
containing a TNFa antagonist, preferably a soluble TNF receptor. The TNFa
inhibitor
may be administered in combination with other biologically active molecules.
BACKGROUND OF THE INVENTION
The pleiotropic cytokine tumor necrosis factor alpha (TNF(x) binds to cells
through membrane receptor molecules, including two molecules having molecular
weights of approximately 55 kDa and 75 kDa (p55 and p75). In addition to
binding
TNFa, the p55 and p75 TNF receptors mediate the binding to cells of
homotrimers of
TNF(3, which is another cytokine associated with inflammation and which shares
structural similarities with TNFa (e.g., see Cosman, Blood Cell Biochem 7:51-
77, 1996).
TNF(3 is also known as lymphotoxin-a (LT(x).
It has been proposed that a systemic or localized excess of TNFa contributes
to
the progression of numerous medical disorders. For example, patients with
chronic heart
failure have elevated levels of serum TNFa, which have been shown to increase
with
disease progression (see, for example, Levine et al., N Eng J Med 323:236-241,
1990). A
variety of other diseases are associated with elevated levels of TNFa (see,
for example,
Feldman et al., Transplantation Proceedings 30:4126-4127, 1998).
Psoriatic arthritis (PsA) is a chronic autoimmune condition that shares some
features with both rheumatoid arthritis (RA) and the inflammatory skin disease
psoriasis
(for review, see Breathnach, In Klippel and Dieppe eds. Rheumatology, 2 d Ed.,
Mosby,
1998, 22.1-22.4). Psoriasis is characterized by epidermal keratinocyte
hyperproliferation,
accompanied by neutrophil and T cell infiltration, and is associated with
elevated levels
of inflammatory cytokines, including TNFa, IL-6 and TGF(3 (see, for example,
Bonifati
et al., Clin Exp Dermatol 19:383-387, 1994). Psoriasis and PsA are different
clinical
entities, and are associated with somewhat different MHC haplotypes (Gladman,
Rheum
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Dis Clin NA. 18:247-256, 1992; Breathnach, 1998). The overall prognosis for
PsA is far
worse than for ordinary psoriasis. Nonetheless, treatments used for the
psoriatic lesions
of PsA generally are similar to those used to treat psoriasis.
Psoriatic skin lesions are present in patients with PsA, although only a
minority of
psoriasis sufferers actually have PsA. Ordinary psoriasis occasionally is
accompanied by
joint pain, but does not involve the extreme pain and often deforming
degeneration of
joints and bone that occurs in PsA patients.
Treatments that sometimes are effective in treating ordinary psoriasis include
topical medications (e.g., steroids, coal tar, anthralin, Dead Sea salts,
various natural oils,
vitamin D3 and its analogs, sunshine, topical retinoids), phototherapy (e.g.,
ultraviolet
light, photochemotherapy (PUVA)), and internal medications (e.g.,
methotrexate,
systemic steroids, oral retinoids, cyclosporine, or a rotating regimen of
these three). In
addition, it has been proposed that psoriasis could be treated with TNF-
derived peptides,
quinolinesulfonamides, pyrrolidinone derivatives, catechol diether compounds,
isoxazoline compounds, matrix metalloproteinase inhibitors or mercapto alkyl
peptidyl
compounds, all of which inhibit either TNFa production or its release from
cultured cells
(see, for example, U.S. 5,691,382, U.S. 5,834,485, U.S. 5,420,154, U.S.
5,563,143,
U.S. 5,869,511 and U.S. 5,872,146), as well as with various combination
therapies
involving TNF antagonists (for example, see U.S. 5,888,511 or U.S. 5,958,413)
Conflicting results have been reported regarding the role of TNFa in
psoriasis.
Some investigators have proposed that overproduction of TNFa contributes to
the
pathology of psoriasis (e.g., Pigatto et al., J Invest Dermatol 94:372-376,
1990; Sagawa et
al., Dermatol 187:81-83, 1993; Ameglio et al., Dermatol 189:359-363, 1994).
One group
reported some improvement after treatment with pentoxifylline, a drug that can
inhibit the
release of TNFa, but which exerts many of its physiological effects by
inhibiting cyclic
AMP phosphodiesterase (Omulecki et al., J Am Acad Dermatol 34:714-715, 1996;
Centola et al., J Androl 16:136-142, 1995; Elferinck et al., Biochem Pharmacol
54:475-
480, 1997). However, other reports have cast doubt on the hypothesis that
overproduction of TNFa exacerbates psoriasis. For example, some investigators
have
reported that treatment with TN-Fa itself actually can mitigate psoriasis
(see, e.g.,
Takematsu et al., Br J Dermatol 124:209-210, 1991; Creaven et al., J Am Acad
Dermatol
24:735-737, 1991).
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In addition to psoriatic lesions, PsA is characterized by distal
interphalangeal joint
(DIP) involvement, enthesopathy, nail lesions, spondylitis and dactylitis. The
histopathogenesis of PsA and the more well-studied rheumatoid arthritis share
certain
features. In both RA and in active PsA, patients exhibit increased levels of
HLA-DR+ T
cells and MHC class II antigens in their synovial membranes and synovial
fluid, as well
as increased expression of the cytokine TNFa. In addition, both diseases are
associated
with prominent synovial vascular changes.
The discovery of rheumatoid factor in the serum of RA patients provided an
important tool for differentiating PsA from RA, but the realization that RA
and PsA are
distinct diseases was based primarily on their many clinical differences
(e.g., Helliwell
and Wright, In Klippel and Dieppe eds. Rheumatology, 2"d Ed., Mosby, 1998,
21.1-21.8).
Studies have shown that levels of TNFa, Il-10, 11-8 as well as TNF receptors
in synovial
fluids were higher in PsA patients than in osteoarthritis patients, though
they were lower
than in RA patients (Partsch et al., J Rheumatol 24:518-523, 1997; Partsch et
al., J
Rheumatol 25:105-110, 1998; Partsch et al., Ann Rheum Dis 57:691-693, 1998).
PsA is
distinguished from RA also by radiographic appearance, a notably higher degree
of
synovial membrane vascularity as well as differences in the levels of various
cytokines in
the synovial fluids (Ritchlin et al., J Rheumatol 25:1544-52, 1998; Veale et
al., Arth
Rheum 36:893-900, 1993). Veale et al. noted differences in synovial membrane
adhesion
molecules and numbers of macrophages when they compared RA and PsA patients,
as
well as observing a minimal degree of hyperplasia and hypertrophy of
synoviocytes in
PsA as compared with RA patients. Because of such differences, coupled with
the
association of PsA but not RA with class I MHC antigens, Ritchlin et al. have
suggested
that PsA must be triggered by different mechanisms than those underlying RA.
Veale et
al. suggested for similar reasons that different cytokines were likely to be
interacting in
the synovium of PsA and RA patients.
Most of the drugs used for treating the arthritic aspects of PsA are similar
to those
used in RA (Salvarini et al., Curr Opin Rheumatol 10:229-305, 1998), for
example the
non-steroidal antiinflammatories (NSAIDs), which may be used alone or in
combination
with the disease-modifying anti-rheumatic drugs, or "DMARDs". DMARDs currently
used include methotrexate, sulfasalazine, gold, azathioprine, cyclosporine,
antimalarials,
steroids and colchicine, as well as many others that are used less frequently.
However,
one group found that long-term administration of methotrexate failed to slow
the
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progression of joint damage in PsA patients (Abu-Shakra et al., J Rheumatol
22:241-45,
1995), and another group reported very little improvement in PsA patients who
had
received methotrexate (Willkens et al., Arthr Rheum 27:376-381, 1984).
Similarly, Clegg
et al. found only a slight improvement over placebo in PsA patients treated
with
sulfasalazine (Clegg et al., Arthritis Rheum 39: 2013-20, 1996). Some studies
have
indicated that the immunosuppressor cyclosporine is effective in treating PsA
(reviewed
in Salvarini et al., 1998), though this drug has severe side effects. In
addition, others have
proposed that psoriatic arthritis could be treated with truncated TNFa
receptors or with a
combination of methotrexate and antibodies against TNFa (WO 98/01555; WO
98/0537).
A recent meta-analysis of a number of PsA treatment studies concluded that PsA
and RA differed not only in their response to treatment with specific drugs,
but in the
relative magnitudes of improvement in the placebo arms of the studies (Jones
et al., Br J
Rheumatol 36:95-99, 1997). As an example, PsA patients responded better to
gold salt
therapy than did RA patients, though the gold did not affect the psoriatic
skin lesions
(Dorwart et al., Arthritis Rheum 21:515-513, 1978).
It has been suggested that the suppression of TNFct might be beneficial in
patients
suffering from various disorders characterized by abnormal or excessive TNFa
expression. However, although progress has been made in devising effective
treatment
for such diseases, improved medicaments and methods of treatment are needed.
SUMMARY OF THE INVENTION
Provided herein are methods for treating a number of medical disorders
characterized by abnormal TNFa expression by repeatedly administering an
antagonist of
TNFa, such as TNFR:Fc, for a period of time sufficient to induce a sustained
improvement in the patient's condition.
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According to one aspect of the present invention,
there is provided a physiologically acceptable composition
for treating ordinary psoriasis in a human patient who is
suffering from ordinary psoriasis, which comprises: (a) a
chimeric protein comprising a soluble TNFa receptor derived
from TNFRp75 and an Fc portion of an antibody, and (b) a
physiologically acceptable carrier, excipient or diluent,
wherein the soluble TNFa receptor can bind to TNFa.
According to another aspect of the present
invention, there is provided use of a chimeric protein in
the manufacture of a medicament for therapeutic treatment of
ordinary psoriasis, wherein the chimeric protein comprises a
soluble TNFu receptor derived from TNFRp75 and an Fc portion
of an antibody, wherein the soluble TNFu receptor can bind
to TNFc.
According to still another aspect of the present
invention, there is provided a physiologically acceptable
composition for treating ordinary psoriasis in a pediatric
human patient who is suffering from ordinary psoriasis,
which comprises: (a) a chimeric protein comprising a soluble
TNFu receptor derived from TNFRp75 and an Fc portion of an
antibody, and (b) a physiologically acceptable carrier,
excipient or diluent, wherein the composition comprises a
maximum of 25 mg of the chimeric protein, and wherein the
soluble TNFa receptor can bind to TNFO.
According to yet another aspect of the present
invention, there is provided a physiologically acceptable
composition for treating ordinary psoriasis in an adult
human patient who is suffering from ordinary psoriasis,
which comprises: (a) a chimeric protein comprising a soluble
TNFa receptor derived from TNFRp75 and an Fc portion of an
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antibody, and (b) a physiologically acceptable carrier,
excipient or diluent, wherein the composition comprises 25
or 50 mg of the chimeric protein, and wherein the soluble
TNFa receptor can bind to TNFu.
DETAILED DESCRIPTION OF THE INVENTION
This invention provides compounds, compositions
and methods for treating a mammalian patient, including a
human patient, who is suffering from a medical disorder that
is characterized by abnormal or elevated expression of TNFa.
For purposes of this disclosure, the terms "illness",
"disease", "medical condition", "abnormal condition" and the
like are used interchangeably with the term "medical
disorder".
The subject methods involve administering to the
patient a soluble TNFa antagonist that is capable of
reducing the effective amount of endogenous biologically
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active TNFa, such as by reducing the amount of TNFa produced, or by preventing
the
binding of TNFa to its cell surface receptor (TNFR). Antagonists capable of
inhibiting
this binding include receptor-binding peptide fragments of TNFa, antibodies
directed
against TNFa, and recombinant proteins comprising all or portions of receptors
for TNFa
or modified variants thereof, including genetically-modified muteins,
multimeric forms
and sustained-release formulations. Other compounds suitable for treating the
diseases
described herein include thalidomide and pentoxifylline.
Preferred embodiments of the invention utilize soluble TNFRs as the TNFa
antagonist. In certain embodiments of the invention, the soluble TNFR
derivative is one
that mimics the 75 kDa TNFR or the 55 kDa TNFR and that binds to TNFa in the
patient's body. The soluble TNFR mimics of the present invention may be
derived from
TNFRs p55 or p75 or fragments thereof. TNFRs other than p55 and p75 also are
useful
for deriving soluble compounds for treating the various medical disorders
described
herein. Soluble TNFR molecules used to construct TNFR mimics include, for
example,
analogs or fragments of native TNFRs having at least 20 amino acids, that lack
the
transmembrane region of the native TNFR, and that are capable of binding TNFa.
Antagonists derived from TNFRs compete for TNFa with the receptors on the cell
surface, thus inhibiting TNFa from binding to cells, thereby preventing it
from
manifesting its biological activities. Binding of soluble TNFRs to TNFa or LTa
can be
assayed using ELISA or any other convenient assay. This invention provides for
the use
of TNFR:Fc in the manufacture of a medicament for the treatment of numerous
diseases.
The soluble TNFR polypeptides or fragments of the invention may be fused with
a second polypeptide to form a chimeric protein. The second polypeptide may
promote
the spontaneous formation by the chimeric protein of a dimer, trimer or higher
order
multimer that is capable of binding a TNFa and/or LTa molecule and preventing
it from
binding to cell-bound receptors. Chimeric proteins used as antagonists include
proteins
that contain portions of both an antibody molecule and a TNFR. A preferred TN-
Fa
antagonist suitable for treating diseases in humans and other mammals is
recombinant
TNFR:Fc, a term which as used herein refers to "etanercept," which is a dimer
of two
molecules of the extracellular portion of the p75 TNFa receptor, each molecule
consisting of a 235 amino acid TNFR-derived polypeptide that is fused to a 232
amino
acid Fc portion of human IgG,. Etanercept is currently sold by Immunex
Corporation
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under the trade name ENBREL. Because the p75 receptor protein that it
incorporates
binds not only to TNFc , but also to the inflammatory cytokine LTa, etanercept
can act as
a competitive inhibitor not only of TNFa, but also of LTa. This is in contrast
to-
antibodies directed against TNF, which cannot inhibit LTa. Also encompassed by
the
invention are treatments using a compound that comprises the extracellular
portion of the
55 kDa TNFR fused to the Fc portion of IgG, as well as compositions and
combinations
containing such a molecule. Encompassed also are chimeric proteins derived
from the
fusion of the Fc portion of IgG to the extracellular regions of TNF receptor
molecules
other than the p55 and p75 TNFRs.
In one preferred embodiment of the invention, sustained-release forms of
soluble
TNFRs are used, including sustained-release forms of TNFR:Fc. Sustained-
release forms
suitable for use in the disclosed methods include, but are not limited to,
TNFRs that are
encapsulated in a slowly-dissolving biocompatible polymer, admixed with such a
polymer, and or encased in a biocompatible semi-permeable implant. In
addition, the
soluble TNFR may be conjugated with polyethylene glycol (pegylated) to prolong
its
serum half-life or to enhance protein delivery. Soluble forms of TNFRs
including
monomers, fusion proteins (also called "chimeric proteins), dimers, trimers or
higher
order multimers, are particularly useful in formulating TNF antagonists.
To treat a medical disorder characterized by abnormal or excess expression of
TNFa, a molecule comprising a TNFa-binding soluble TNFa receptor, preferably
TNFR:Fc, is administered to the patient in an amount and for a time sufficient
to induce a
sustained improvement in at least one indicator that reflects the severity of
the disorder.
An improvement is considered "sustained" if the patient exhibits the
improvement on at
least two occasions separated by one to four weeks. The degree of improvement
is
determined based on signs or symptoms, and may also employ questionnaires that
are
administered to the patient, such as quality-of-life questionnaires.
Various indicators that reflect the extent of the patient's illness may be
assessed
for determining whether the amount and time of the treatment is sufficient.
The baseline
value for the chosen indicator or indicators is established by examination of
the patient
less prior to administration of the first dose of the etanercept or other TNFa
inhibitor.
Preferably, the baseline examination is done within about 60 days of
administering the
first dose. If the TNFa antagonist is being administered to treat acute
symptoms, such as
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for example to treat a traumatic knee injury, the first dose is administered
as soon as
practically possible after the injury has occurred.
Improvement is induced by repeatedly administering a dose of TNFR:Fc or other
TNFa antagonist until the patient manifests an improvement over baseline for
the chosen
indicator or indicators. In treating chronic conditions, this degree of
improvement is
obtained by repeatedly administering this medicament over a period of at least
a month or
more, e.g., for one, two, or three months or longer, or indefinitely. A period
of one to six
weeks, or even a single dose, often is sufficient for treating acute
conditions.
Although the extent of the patient's illness after treatment may appear
improved
according to one or more indicators, treatment may be continued indefinitely
at the same
level or at a reduced dose or frequency. Once treatment has been reduced or
discontinued, it later may be resumed at the original level if symptoms should
reappear.
Any efficacious route of administration may be used to therapeutically
administer
TNFR:Fc or other TNFa antagonists. If injected, TNFR:Fc can be administered,
for
example, via intra-articular, intravenous, intramuscular, intralesional,
intraperitoneal or
subcutaneous routes by bolus injection or by continuous infusion. Other
suitable means
of administration include sustained release from implants, aerosol inhalation,
eyedrops,
oral preparations, including pills, syrups, lozenges or chewing gum, and
topical
preparations such as lotions, gels, sprays, ointments or other suitable
techniques.
Alternatively, proteinaceous TNF inhibitors, such as a soluble TNFR, may be
administered by implanting cultured cells that express the protein, for
example, by
implanting cells that express TNFR:Fc. In one embodiment, the patient's own
cells are
induced to produce TNFR:Fc by transfection in vivo or ex vivo with a DNA that
encodes
TNFR:Fc. This DNA can be introduced into the patient's cells, for example, by
injecting
naked DNA or liposome-encapsulated DNA that encodes TNFR:Fc, or by other means
of
transfection. When TNFR:Fc is administered in combination with one or more
other
biologically active compounds, these may be administered by the same or by
different
routes, and may be administered simultaneously, separately or sequentially.
TNFR:Fc or other soluble TNFRs preferably are administered in the form of a
physiologically acceptable composition comprising purified recombinant protein
in
conjunction with physiologically acceptable carriers, excipients or diluents.
Such carriers
are nontoxic to recipients at the dosages and concentrations employed.
Ordinarily, the
preparation of such compositions entails combining the TNF antagonist with
buffers,
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antioxidants such as ascorbic acid, low molecular weight polypeptides (such as
those
having fewer than 10 amino acids), proteins, amino acids, carbohydrates such
as glucose,
sucrose or dextrins, chelating agents such as EDTA, glutathione and other
stabilizers and
excipients. Neutral buffered saline or saline mixed with conspecific serum
albumin are
exemplary appropriate diluents. TNFR:Fc preferably is formulated as a
lyophilizate using
appropriate excipient solutions (e.g., sucrose) as diluents. Appropriate
dosages can be
determined in standard dosing trials, and may vary according to the chosen
route of
administration. In accordance with appropriate industry standards,
preservatives may also
be added, such as benzyl alcohol. The amount and frequency of administration
will
depend, of course, on such factors as the nature and severity of the
indication being
treated, the desired response, the age and condition of the patient, and so
forth.
In one embodiment of the invention, TNFR:Fc is administered one time per week
to treat the various medical disorders disclosed herein, in another embodiment
is
administered at least two times per week, and in another embodiment is
administered at
least three times per week. An adult patient is a person who is 18 years of
age or older.
If injected, the effective amount of TNFR:Fc per adult dose ranges from 1-20
mg/m2, and
preferably is about 5-12 mg/m2. Alternatively, a flat dose may be
administered, whose
amount may range from 5-100 mg/dose. If the dose is to be administered more
than one
time per week, an exemplary dose range for a flat dose is about 20-30 mg per
dose. If the
dose is to be given one time per week or less often than one time per week, an
exemplary
dose range is about 25-60 mg per dose. In one embodiment of the invention, the
various
indications described below are treated by administering a preparation
acceptable for
injection containing TNFR:Fc at 25 mg/dose, or alternatively, containing 50 mg
per dose.
The 25 mg or 50 mg dose is administered repeatedly. If a route of
administration other
than injection is used, the dose is appropriately adjusted in accord with
standard medical
practices. In many instances, an improvement in a patient's condition will be
obtained by
injecting a dose of about 25 mg of TNFR:Fc one to three times per week over a
period of
at least three weeks, or a dose of 50 mg of TNFR:Fc one time per week for at
least three
weeks, though treatment for longer periods may be necessary to induce the
desired degree
of improvement. For incurable chronic conditions, the regimen may be continued
indefinitely.
For pediatric patients (age 4-17), a suitable regimen involves the
subcutaneous
injection of 0.4 mg/kg, up to a maximum dose of 25 mg of TNFR:Fc, administered
by
subcutaneous injection one or more times per week.
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The invention further includes the administration of TNFR:Fc concurrently with
one or more other drugs that are administered to the same patient, each drug
being
administered according to a regimen suitable for that medicament. This
encompasses
pre-treatment, simultaneous treatment, sequential treatment and alternating
regimens.
Examples of such drugs include but are not limited to antivirals, antibiotics,
analgesics,
corticosteroids, antagonists of inflammatory cytokines, DMARDs and non-
steroidal anti-
inflammatories. Additionally, TNFR:Fc may be combined with a second TNF
antagonist,
including an antibody against TNF or TNFR, additional TNFR derivatives, or
other
molecules that reduce endogenous TNF levels, such as inhibitors of the TNFa
converting
enzyme (see e.g., U.S. 5,594,106). In further embodiments, TNFR:Fc is
administered in
combination with pentoxifylline or thalidomide.
In one preferred embodiment of the invention, the various medical disorders
disclosed herein as being treatable with inhibitors such as TNFR:Fc are
treated in
combination with another cytokine or cytokine inhibitor. For example, TNFR:Fc
may be
administered in a composition that also contains a compound that inhibits the
interaction
of other inflammatory cytokines with their receptors. The TNFR:Fc and other
cytokine
inhibitor may be administered as separate compositions, and these may be
administered
by the same or different routes. Examples of cytokine inhibitors used in
combination
with TNFR:Fc include those that antagonize, for example, TGF(3, IFNy, 11-6 or
11-8. The
combination of TNFR:Fc and IFNy-lb, for example, is useful in treating
idiopathic
pulmonary fibrosis and cystic fibrosis. Other combinations for treating the
hereindescribed diseases include the use of TNFR:Fc with compounds that
interfere with
the binding of RANK and RANK-ligand, such as soluble forms of RANK-ligand, or
soluble forms of RANK, including RANK:Fc. For example, the combination of
TNFR:Fc and RANK:Fc are useful for preventing bone destruction in various
settings
including but not limited to various rheumatic disorders, osteoporosis,
multiple myeloma
or other malignancies that cause bone degeneration, or anti-tumor therapy
aimed at
preventing metastasis to bone, or bone destruction associated with prosthesis
wear debris
or with periodontitis. TNFa inhibitors such as TNFR:Fc also may be
administered in
combination with GM-CSF, IL-2 and inhibitors of protein kinase A type 1 to
enhance T
cell proliferation in HIV-infected patients who are receiving anti-retroviral
therapy. In
addition, TNFR:Fc may be administered in combination with soluble forms of an
IL-17
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receptor (such as IL-17R:Fc), IL-18 binding protein, or antibodies against
CD30-ligand or
against CD4.
The present invention also relates to the disclosed TNF inhibitors and
combination
therapies for use in medicine. The use in medicine may involve the treatment
of any of
the medical disorders as described herein. The TNF inhibitors may be in the
form of
compounds, compositions or combination therapies. Where the compounds are used
together with one or more other components, the compound and the one or more
other
components may be administered simultaneously, separately or sequentially
(usually in
pharmaceutical format).
The present invention also relates to the use of TNF inhibitors (as
disclosed), such
as TNFR:Fc, in the manufacture of a medicament for the prevention or
therapeutic
treatment of each medical disorder disclosed herein.
The disclosed TNF inhibitors, compositions and combination therapies described
herein are useful in medicines for treating bacterial, viral or protozoal
infections, and
complications resulting therefrom. One such disease is Mycoplasma pneumonia.
In
addition, provided herein is the use of TNFR:Fc to treat AIDS and related
conditions,
such as AIDS dementia complex, AIDS associated wasting, lipidistrophy due to
antiretroviral therapy; and Kaposi's sarcoma. Furthermore provided herein is
the use of
TNFR:Fc for treating protozoal diseases, including malaria and
schistosomiasis.
Additionally provided is the use of TNFR:Fc to treat erythema nodosum
leprosum;
bacterial or viral meningitis; tuberculosis, including pulmonary tuberculosis;
and
pneumonitis secondary to a bacterial or viral infection. Provided also herein
is the use of
TNFR:Fc to prepare medicaments for treating louse-borne relapsing fevers, such
as that
caused by Borrelia recurrentis. TNFR:Fc can also be used to prepare a
medicament for
treating conditions caused by Herpes viruses, such as herpetic stromal
keratitis, corneal
lesions; and virus-induced corneal disorders. In addition, TNFR:Fc can be used
in
treating human papillomavirus infections. TNFR:Fc is used also to prepare
medicaments
to treat influenza infection.
Cardiovascular disorders are treatable with the disclosed TNF inhibitors,
pharmaceutical compositions or combination therapies, including aortic
aneurisms;
arteritis; vascular occlusion, including cerebral artery occlusion;
complications of
coronary by-pass surgery; ischemia/reperfusion injury; heart disease,
including
atherosclerotic heart disease, myocarditis, including chronic autoimmune
myocarditis and
viral myocarditis; heart failure, including chronic heart failure (CHF),
cachexia of heart
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failure; myocardial infarction; restenosis after heart surgery; silent
myocardial ischemia;
post implantation complications of left ventricular assist devices; Raynaud's
phenomena;
thrombophlebitis; vasculitis, including Kawasaki's vasculitis; giant cell
arteritis,
Wegener's granulomatosis; and Schoenlein-Henoch purpura.
In addition, the subject TNF inhibitors, compositions and combination
therapies
are used to treat chronic pain conditions, such as chronic pelvic pain,
including chronic
prostatitis/pelvic pain syndrome. As a further example, TNFR:Fc and the
compositions
and combination therapies of the invention are used to treat post-herpetic
pain.
Provided also are methods for using TNF inhibitors, compositions or
combination
therapies to treat various disorders of the endocrine system. For example, the
TNF
inhibitors are used to treat juvenile onset diabetes (includes autoimmune and
insulin-
dependent types of diabetes) and also to treat maturity onset diabetes
(includes non-
insulin dependent and obesity-mediated diabetes). In addition, the subject
compounds,
compositions and combination therapies are used to treat secondary conditions
associated
with diabetes, such as diabetic retinopathy, kidney transplant rejection in
diabetic
patients, obesity-mediated insulin resistance, and renal failure, which itself
may be
associated with proteinurea and hypertension. Other endocrine disorders also
are
treatable with these compounds, compositions or combination therapies,
including
polycystic ovarian disease, X-linked adrenoleukodystrophy, hypothyroidism and
thyroiditis, including Hashimoto's thyroiditis (i.e., autoimmune thyroiditis).
Conditions of the gastrointestinal system also are treatable with TNF
inhibitors,
compositions or combination therapies, including coeliac disease. In addition,
the
compounds, compositions and combination therapies of the invention are used to
treat
Crohn's disease; ulcerative colitis; idiopathic gastroparesis; pancreatitis,
including
chronic pancreatitis; and ulcers, including gastric and duodenal ulcers.
Included also are methods for using the subject TNF inhibitors, compositions
or
combination therapies for treating disorders of the genitourinary system, such
as
glomerulonephritis, including autoimmune glomerulonephritis,
glomerulonephritis due to
exposure to toxins or glomerulonephritis secondary to infections with
haemolytic
streptococci or other infectious agents. Also treatable with the compounds,
compositions
and combination therapies of the invention are uremic syndrome and its
clinical
complications (for example, renal failure, anemia, and hypertrophic
cardiomyopathy),
including uremic syndrome associated with exposure to environmental toxins,
drugs or
other causes. Further conditions treatable with the compounds, compositions
and
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combination therapies of the invention are complications of hemodialysis;
prostate
conditions, including benign prostatic hypertrophy, nonbacterial prostatitis
and chronic
prostatitis; and complications of hemodialysis.
Also provided herein are methods for using TNF inhibitors, compositions or
combination therapies to treat various hematologic and oncologic disorders.
For
example, TNFR:Fc is used to treat various forms of cancer, including acute
myelogenous
leukemia, Epstein-Barr virus-positive nasopharyngeal carcinoma, glioma, colon,
stomach,
prostate, renal cell, cervical and ovarian cancers, lung cancer (SCLC and
NSCLC),
including cancer-associated cachexia, fatigue, asthenia, paraneoplastic
syndrome of
cachexia and hypercalcemia. Additional diseases treatable with the subject TNF
inhibitors, compositions or combination therapies are solid tumors, including
sarcoma,
osteosarcoma, and carcinoma, such as adenocarcinoma (for example, breast
cancer) and
squamous cell carcinoma. In addition, the subject compounds, compositions or
combination therapies are useful for treating leukemia, including acute
myelogenous
leukemia, chronic or acute lymphoblastic leukemia and hairy cell leukemia.
Other
malignancies with invasive metastatic potential can be treated with the
subject
compounds, compositions and combination therapies, including multiple myeloma.
In
addition, the disclosed TNF inhibitors, compositions and combination therapies
can be
used to treat anemias and hematologic disorders, including anemia of chronic
disease,
aplastic anemia, including Fanconi's aplastic anemia; idiopathic
thrombocytopenic
purpura (ITP); myelodysplastic syndromes (including refractory anemia,
refractory
anemia with ringed sideroblasts, refractory anemia with excess blasts,
refractory anemia
with excess blasts in transformation); myelofibrosis/myeloid metaplasia; and
sickle cell
vasocclusive crisis.
Various lymphoproliferative disorders also are treatable with the disclosed
TNF
inhibitors, compositions or combination therapies. These include, but are not
limited to
autoimmune lymphoproliferative syndrome (ALPS), chronic lymphoblastic
leukemia,
hairy cell leukemia, chronic lymphatic leukemia, peripheral T-cell lymphoma,
small
lymphocytic lymphoma, mantle cell lymphoma, follicular lymphoma, Burkitt's
lymphoma, Epstein-Barr virus-positive T cell lymphoma, histiocytic lymphoma,
Hodgkin's disease, diffuse aggressive lymphoma, acute lymphatic leukemias, T
gamma
lymphoproliferative disease, cutaneous B cell lymphoma, cutaneous T cell
lymphoma
(i.e., mycosis fungoides) and Sezary syndrome.
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In addition, the subject TNF inhibitors, compositions and combination
therapies
are used to treat hereditary conditions such as Gaucher's disease,
Huntington's disease,
linear IgA disease, and muscular dystrophy.
Other conditions treatable by the disclosed TNF inhibitors, compositions and
combination therapies include those resulting from injuries to the head or
spinal cord, and
including subdural hematoma due to trauma to the head.
The disclosed TNFa inhibitors, compositions and combination therapies are
further used to treat conditions of the liver such as hepatitis, including
acute alcoholic
hepatitis, acute drug-induced or viral hepatitis, hepatitis A, B and C,
sclerosing
cholangitis and inflammation of the liver due to unknown causes.
In addition, the disclosed TNF inhibitors, compositions and combination
therapies
are used to treat various disorders that involve hearing loss and that are
associated with
abnormal TNFa expression. One of these is inner ear or cochlear nerve-
associated
hearing loss that is thought to result from an autoimmune process, i.e.,
autoimmune
hearing loss. This condition currently is treated with steroids, methotrexate
and/or
cyclophosphamide. Also treatable with the disclosed TNF inhibitors,
compositions and
combination therapies is cholesteatoma, a middle ear disorder often associated
with
hearing loss.
In addition, the subject invention provides TNF inhibitors, compositions and
combination therapies for the treatment of non-arthritic medical conditions of
the bones
and joints. This encompasses osteoclast disorders that lead to bone loss, such
as but not
limited to osteoporosis, including post-menopausal osteoporosis, periodontitis
resulting in
tooth loosening or loss, and prosthesis loosening after joint replacement
(generally
associated with an inflammatory response to wear debris). This latter
condition also is
called "orthopedic implant osteolysis." Another condition treatable with the
compounds,
compositions and combination therapies of the invention is temporal mandibular
joint
dysfunction (TMJ).
The following pulmonary disorders also can be treated with the disclosed TNF
inhibitors, compositions and combination therapies: adult respiratory distress
syndrome
(ARDS) caused by a variety of conditions, including exposure to toxic
chemicals,
pancreatitis, trauma or other causes. The disclosed compounds, compositions
and
combination therapies of the invention also are useful for treating broncho-
pulmonary
dysplasia (BPD); and chronic fibrotic lung disease of preterm infants. In
addition, the
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compounds, compositions and combination therapies of the invention are used to
treat
occupational lung diseases, including asbestosis, coal worker's
pneumoconiosis, silicosis
or similar conditions associated with long-term exposure to fine particles. In
other
aspects of the invention, the disclosed compounds, compositions and
combination
therapies are used to treat pulmonary fibrosis, including idiopathic pulmonary
fibrosis and
radiation-induced pulmonary fibrosis; pulmonary sarcoidosis; and allergies,
including
allergic rhinitis, contact dermatitis, atopic dermatitis and asthma.
Other embodiments provide methods for using the disclosed TNF inhibitors,
compositions or combination therapies to treat a variety of rheumatic
disorders. These
include adult and juvenile rheumatoid arthritis; scleroderma; systemic lupus
erythematosus; gout; osteoarthritis; polymyalgia rheumatica; seronegative
spondylarthropathies, including ankylosing spondylitis, and Reiter's disease.
The subject
TNF inhibitors, compositions and combination therapies are used also to treat
psoriatic
arthritis and chronic Lyme arthritis. Also treatable with these compounds,
compositions
and combination therapies are Still's disease and uveitis associated with
rheumatoid
arthritis. In addition, the compounds, compositions and combination therapies
of the
invention are used in treating disorders resulting in inflammation of the
voluntary muscle,
including dermatomyositis and polymyositis.
The TNFa inhibitors, compositions and combination therapies of the invention
are
useful for treating primary amyloidosis. In addition, the secondary
amyloidosis that is
characteristic of various conditions also are treatable with TNF inhibitors
such as
TNFR:Fc, and the compositions and combination therapies described herein. Such
conditions include: Alzheimer's disease, secondary reactive amyloidosis;
Down's
syndrome; and dialysis-associated amyloidosis. Also treatable with the
compounds,
compositions and combination therapies of the invention are inherited periodic
fever
syndromes, including familial Mediterranean fever, hyperimmunoglobulin D and
periodic
fever syndrome and TNF-receptor associated periodic syndromes (TRAPS).
Disorders involving the skin or mucous membranes also are treatable using the
disclosed TNF inhibitors, compositions or combination therapies. Such
disorders include
acantholytic diseases, including Darier's disease, keratosis follicularis and
pemphigus
vulgaris. Also treatable with the subject TNF inhibitors, compositions and
combination
therapies are acne; acne rosacea; alopecia areata; aphthous stomatitis;
bullous
pemphigoid; burns; eczema; erythema, including erythema multiforme and
erythema
multiforme bullosum (Stevens-Johnson syndrome); inflammatory skin disease;
lichen
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planus; linear IgA bullous disease (chronic bullous dermatosis of childhood);
loss of skin
elasticity; mucosal surface ulcers; neutrophilic dermatitis (Sweet's
syndrome); pityriasis
rubra pilaris; psoriasis; pyoderma gangrenosum; and toxic epidermal
necrolysis.
Disorders associated with transplantation also are treatable with the
disclosed TNF
inhibitors, compositions or combination therapies, such as graft-versus-host
disease, and
complications resulting from solid organ transplantation, such as heart,
liver, skin, kidney
or other transplants.
Ocular disorders also are treatable with the disclosed TNF inhibitors,
compositions or combination therapies, including rhegmatogenous retinal
detachment,
and inflammatory eye disease, including inflammatory eye disease associated
with
smoking and macular degeneration.
TNF inhibitors such as TNFR:Fc and the disclosed compositions and combination
therapies also are useful for treating disorders that affect the female
reproductive system.
Examples include, but are not limited to, multiple implant
failure/infertility; fetal loss
syndrome or IV embryo loss (spontaneous abortion); preeclamptic pregnancies or
eclampsia; and endometriosis.
In addition, the disclosed TNF inhibitors, compositions and combination
therapies
are useful for treating obesity, including to bring about a decrease in leptin
formation.
Also, the compounds, compositions and combination therapies of the invention
are used
to treat sciatica, symptoms of aging, severe drug reactions (for example, 11-2
toxicity or
bleomycin-induced pneumopathy and fibrosis), or to suppress the inflammatory
response
prior, during or after the transfusion of allogeneic red blood cells in
cardiac or other
surgery, or in treating a traumatic injury to a limb or joint, such as
traumatic knee injury.
Various other medical disorders treatable with the disclosed TNF inhibitors,
compositions
and combination therapies include; multiple sclerosis; Behcet's syndrome;
Sjogren's
syndrome; autoimmune hemolytic anemia; beta thalassemia; amyotrophic lateral
sclerosis
(Lou Gehrig's Disease); Parkinson's disease; and tenosynovitis of unknown
cause, as
well as various autoimmune disorders or diseases associated with hereditary
deficiencies.
The disclosed TNF inhibitors, compositions and combination therapies
furthermore are useful for treating acute polyneuropathy; anorexia nervosa;
Bell's palsy;
chronic fatigue syndrome; transmissible dementia, including Creutzfeld-Jacob
disease;
demyelinating neuropathy; Guillain-Barre syndrome; vertebral disc disease;
Gulf war
syndrome; myasthenia gravis; silent cerebral ischemia; sleep disorders,
including
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narcolepsy and sleep apnea; chronic neuronal degeneration; and stroke,
including cerebral
ischemic diseases.
In addition to human patients, soluble TNFRs are useful in the treatment of
non-
human animals, such as pets (dogs, cats, birds, primates, etc.), domestic farm
animals
(horses cattle, sheep, pigs, birds, etc.), or any animal that suffers from a
TNFc -mediated
inflammatory or arthritic condition. In such instances, an appropriate dose
may be
determined according to the animal's body weight. For example, a dose of 0.2-1
mg/kg
may be used. Alternatively, the dose is determined according to the animal's
surface
area, an exemplary dose ranging from 0.1-20 mg/m2, or more preferably, from 5-
12
mg/m2. For small animals, such as dogs or cats, a suitable dose is 0.4 mg/kg.
TNFR:Fc
(preferably constructed from genes derived from the recipient species), or
another soluble
TNFR mimic, is administered by injection or other suitable route one or more
times per
week until the animal's condition is improved, or it may be administered
indefinitely.
Provided herein are methods of treating or preventing psoriatic lesions that
involve administering to a human patient a therapeutically effective amount of
a soluble
TNFR. A preferred soluble TNFR for this purpose is TNFR:Fc. The treatment is
effective against psoriatic lesions that occur in patients who have ordinary
psoriasis or
psoriatic arthritis.
Patients are defined as having ordinary psoriasis if they lack the more
serious
symptoms of psoriatic arthritis (e.g., distal interphalangeal joint DIP
involvement,
enthesopathy, spondylitis and dactylitis), but exhibit one of the following:
1) inflamed
swollen skin lesions covered with silvery white scale (plaque psoriasis or
psoriasis
vulgaris); 2) small red dots appearing on the trunk, arms or legs (guttate
psoriasis); 3)
smooth inflamed lesions without scaling in the flexural surfaces of the skin
(inverse
psoriasis); 4) widespread reddening and exfoliation of fine scales, with or
without itching
and swelling (erythrodermic psoriasis); 5) blister-like lesions (pustular
psoriasis); 6)
elevated inflamed scalp lesions covered by silvery white scales (scalp
psoriasis); 7) pitted
fingernails, with or without yellowish discoloration, crumbling nails, or
inflammation and
detachment of the nail from the nail bed (nail psoriasis).
In treating ordinary psoriasis, TNFR:Fc is administered in an amount and for a
time sufficient to induce an improvement in the patient's condition as
measured according
to any indicator that reflects the severity of the patient's psoriatic
lesions. One or more
such indicators may be assessed for determining whether the amount of TNFR and
duration of treatment is sufficient. In one preferred embodiment of the
invention, the
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TNFR:Fc is administered in an amount and for a time sufficient to induce an
improvement over baseline in either the psoriasis area and severity index
(PASI) or the
Target Lesion Assessment Score. In another embodiment, both indicators are
used.
When PASI score is used as the indicator, treatment is regarded as sufficient
when the
patient exhibits an at least 50% improvement in his or her PASI score, or
alternatively,
when the patient exhibits an at least 75% improvement in PASI score. Using the
Psoriasis Target Lesion Assessment Score to measure sufficiency of treatment
involves
determining for an individual psoriatic lesion whether improvement has
occurred in one
or more of the following, each of which is separately scored: plaque
elevation; amount
and degree of scaling or degree of erythema; and target lesion response to
treatment.
Psoriasis Target Lesion Assessment Score is determined by adding together the
separate
scores for all four of the aforementioned indicia, and determining the extent
of
improvement by comparing the baseline score the score after treatment has been
administered.
A satisfactory degree of improvement in psoriasis patients is obtained by
administering the TNFR:Fc one or more times per week. For example, the TNFR:Fc
may
be administered one time, two times or three or more times per week. Treatment
may be
continued over a period of at least one week, for two weeks, three weeks, four
weeks or
longer. Treatment may be discontinued after the patient improves, then resumed
if
symptoms return, or alternatively, the treatment may be administered
continuously for an
indefinite period. A preferred route of administration is subcutaneous
injection. In one
preferred method for treating adult psoriasis patients, the amount of TNFR:Fc
administered by injection is 5-12 mg/m2, or a flat dose of either 25 mg or 50
mg. In one
preferred embodiment of this method, a dose of 25 mg is injected two times per
week,
and in another preferred embodiment, a dose of 50 mg is injected one time per
week. In a
preferred method of treating pediatric psoriasis patients, the dose
administered by
injection is 0.4 mg/kg, up to a maximum dose of 25 mg.
TNFR:Fc may be used to treat ordinary psoriasis in combination with one, two,
three or more other medications that are effective against psoriasis. These
additional
medications may be administered before, simultaneously with, or sequentially
with the
TNFR:Fc. Drugs suitable for combination therapies of psoriasis include pain
medications
(analgesics), including but not limited to acetaminophen, codeine,
propoxyphene
napsylate, oxycodone hydrochloride, hydrocodone bitartrate and tramadol. In
addition,
the TNFR:Fc or other TNFR mimic may be administered in combination with
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methotrexate, sulfasalazine, gold salts, azathioprine,
cyclosporine, antimalarials, oral steroids (e.g.,
prednisone) or colchicine. Non-steroidal anti-
inflammatories may also be coadministered with the TNFR
mimic, including but not limited to: salicylic acid
(aspirin); ibuprofen; indomethacin; celecoxib; rofecoxib;
ketorolac; nambumetone; piroxicam; naproxen; oxaprozin;
sulindac; ketoprofen; diclofenac; and other COX-1 and COX-2
inhibitors, salicylic acid derivatives, propionic acid
derivatives, acetic acid derivatives, fumaric acid
derivatives, carboxylic acid derivatives, butyric acid
derivatives, oxicams, pyrazoles and pyrazolones, including
newly developed anti-inflammatories.
Moreover, the TNFR:Fc may be used to treat
psoriasis in combination with topical steroids, systemic
steroids, antagonists of inflammatory cytokines, antibodies
against T cell surface proteins, anthralin, coal tar,
vitamin D3 and its analogs (including 1,25-dihydroxy vitamin
D3 and calcipotriene), topical retinoids, oral retinoids
(including but not limited to etretinate, acitretin and
isotretinoin), topical salicylic acid, methotrexate,
cyclosporine, hydroxyurea and sulfasalazine. In addition,
it may be administered in combination with one or more of
the following compounds: minocycline; misoprostol; oral
colagen; penicillamine; 6-mercaptopurine; nitrogen mustard;
gabapentin; bromocriptine; somatostatin; peptide T; anti-CD4
monoclonal antibody; fumaric acid; polyunsaturated ethyl
ester lipids; zinc; and other drugs that may be used to
treat psoriasis.
Psoriasis moreover may be treated by TNFR:Fc
administered in combination with one or more of the
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following topically applied compounds: oils, including fish
oils, nut oils and vegetable oils; aloe vera; jojoba; Dead
Sea salts; capsaicin; milk thistle; witch hazel;
moisturizers; and Epsom salts.
In addition, psoriasis may be treated by TNFR:Fc
in combination with the following therapies: plasmapheresis;
phototherapy with ultraviolet light B; psoralen combined
with ultraviolet light A (PUVA); and sunbathing.
It is understood that the response by individual
patients to the aforementioned medications or combination
therapies may vary, and the most efficacious combination of
drugs for each patient will be determined by his or her
physician.
For practical use, storage, transportation or the
like, the composition may be put in a commercial package
including a container in which the composition is contained.
Such a commercial package usually also includes a written
matter which is associated with the composition and
describes indications of the composition and how it should
be taken.
The following example is provided to illustrate
the advantages of various embodiments of the invention, and
is not intended in any way to limit the scope of the
disclosure.
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EXAMPLE
TNFR:Fc Treatment of Patients with Psoriatic Arthritis
Sixty patients with active psoriatic arthritis (PsA) were enrolled in a Phase
II
double-blind, randomized, placebo controlled study to determine whether the
subcutaneous biweekly administration of etanercept (recombinant TNFR:Fc) was
safe in
this patient population and whether efficacy could be documented for both the
arthritic
and psoriatic aspects of this disease.
In this study, a flat dose of 25 mg of TNFR:Fc was injected subcutaneously two
times a week. After 12 weeks, patients who completed the study were eligible
for
continuation into a 24 week open-label EXTENSION of the study, with
assessments
made at weeks 16, 36 and 30 days post-study. All patients participating in the
study
EXTENSION received etanercept, including those patients who had received
placebo
during the blinded portion of the study.
In order to qualify for enrollment, subjects had to have at least one of the
following forms of PsA: 1) DIP involvement; 2) polyarticular arthritis,
absence of
rheumatoid nodules and presence of psoriasis; 3) arthritis mutilans; 4)
asymmetric
peripheral arthritis; or 5) ankylosing spondylitis-like PsA. Subjects
furthermore had to
exhibit three or more swollen joints and three or more tender or painful
joints at the time
of enrollment, and to have exhibited an inadequate response to NSAID therapy.
Subjects
who were on other medications, including methotrexate, NSAIDs or oral
corticosteroids
were permitted to continue these other treatments at the same dose so long as
the
investigator considered these other treatments to inadequately control the
patient's
disease. Methotrexate was concurrently taken by 47% of the etanercept group,
and 47%
of the placebo group, NSAIDs were concurrently taken by 67% of the etanercept
and
77% of the placebos and oral corticosteroids by 40% of the etanercept and 20%
of the
placebo patients. Pain medications, including acetaminophen, codeine,
propoxyphene
napsylate, oxycodone hydrochloride, hydrocodone bitartrate and tramadol, also
were
permitted during the study, as well as the use of topical tar compounds.
To qualify as having PsA, patients had to have experienced at least one
psoriatic
lesion of the skin or nails. Patients were evaluated at baseline (day 1 of
treatment) as
follows: 1) complete joint assessment; 2) psoriasis assessment; 3) duration of
morning
stiffness; 4) health assessment (quality of life) questionnaire, visual analog
scale
(HAQ/VAS); 5) patient global assessment; 6) erythrocyte sedimentation rate
(ESR,
Westergren); 7) C-reactive protein (CRP); and 8) urinalysis. At weeks 4 and 8,
patients
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were evaluated as follows: 1) complete joint assessment; 2) psoriasis
assessment;
3) duration of morning stiffness; 4) HAQ/VAS; 5) patient global assessment. At
the end
of 12 weeks, subjects were evaluated as follows: 1) complete joint assessment;
2) psoriasis assessment; 3) focused physical exam; 4) duration of morning
stiffness;
5) HAQ/VAS; 6) patient global assessment; 6) hematology profile; 7) chemistry
profile;
8) ESR; 9) CRP; 10) urinalysis; 11) serum tested for antibody to TNFR:Fc. Only
those
patients whose psoriasis was stable and covered >_3% of body area were
evaluated for
psoriasis response during this trial, although patients whose psoriasis was
inactive or
covered less area were permitted to enroll.
A primary endpoint for clinical improvement or worsening of PsA was the
Psoriatic Arthritis Response score, which is a composite score based on the
following
four measures: 1) patient self-assessment; 2) physician assessment; 3) joint
pain or
tenderness; 4) joint swelling. Both self- and physician assessments, i.e.,
overall
assessment of disease status, were measured according to a five point Likert
scale, in
which a patient was considered as "improved" if his or her score decreased by
one
category, or as "worse" if his or her score increased by one category. Joint
pain or
tenderness was measured on a 5-point scale, wherein 1 = none and 5 = severe
(withdrawal
on examination). Joint swelling was evaluated on a 4-point scale in which 1 =
none;
2 = mild (detectable synovial thickening without loss of bony contour); 3 =
moderate
(loss of distinctness of bony contours); and 4 = severe (bulging synovial
proliferation
with cystic characteristics). For this last measure, a decrease in swelling of
>_30% was
scored as an "improvement," and an increase in swelling of >_30% was scored as
a
"worsening." Patients were classified as "improved" under the Psoriatic
Arthritis
Response scoring system if they exhibited an improvement in at least two of
the four
measures described above, provided that one of the improved areas was joint
pain or joint
tenderness, and where there was no worsening in any of the four measures.
In addition, a secondary endpoint used for assessing psoriatic arthritis was a
modified version of the American College of Rheumatology Preliminary
Definition of
Improvement in Rheumatoid Arthritis (modified ACR 20 response) (Felson et al.,
1995).
To qualify as "improved" according to this measure, a patient must have
exhibited _>20%
improvement in both tender joint count (78 joints assessed) and swollen joint
count (76
joints assessed), and also must have shown an improvement in three of the
following five:
1) subject pain assessment; 2) subject global assessment; 3) physician global
assessment;
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4) subject self-assessed disability; 5) acute-phase reactant (Westergreen
erythrocyte
sedimentation rate or C-reactive protein level). The joint count was done by
scoring
several different aspects of tenderness, such as pressure and joint
manipulation on
physical examination, wherein each joint was scored as "tender" or
"nontender."
Similarly, each joint is scored after physical examination as "swollen" or
"not swollen."
The subject's pain assessment was based on a horizontal visual analog scale
(usually 10
cm) or Likert scale. The subject's and physician's global assessments of the
subject's
current disease status was based on an anchored horizontal visual analog scale
(usually 10
cm), or Likert scale response. The subject's self-assessment of disability was
based on
any of the following measures, all of which have been validated in RA trials:
Arthritis
Impact Measurement Scale (AIMS); Health Assessment Questionnaire ; the Quality
(or
Index) of Well Being Scale; the McMaster Health Inventory Questionnaire
(MHIQ); and
the McMaster-Toronto Arthritis patient preference questionnaire (MACTAR).
A primary endpoint used to assess the psoriatic aspects of PsA was the
standard
psoriasis area and severity index (PASI) (Fredriksson and Petersson,
Dermatologica
157:238-244, 1978). For this study, a positive treatment response was defined
as an at
least 50% or an at least 75% improvement in a patient's PASI score. For
assessing area
and severity, the body is divided into four regions: head (10%); trunk (30%);
upper
extremities (20%); and lower extremities (40%). Each quadrant also was scored
for the
severity of erythema (E), infiltration (I) and desquamation (D), using a four
point scale, in
which 0=no symptoms present; l=slight symptoms; 2=moderate symptoms;
3=striking
symptoms; 4=exceptionally striking symptoms. Using a 6-point scale, each
region was
scored also for the percent of total area that was involved in the psoriatic
manifestations
of the disease, wherein 0=no involvement; 1=<10% involvement; 2=10-<30%
involvement; 3=30-<50% involvement; 4=50-<70% involvement; 5=70-<90%
involvement; 6=90-100% involvement. PASI scores were calculated according to
the
formula given below, in which E=severity score for erythrema, I=severity score
for
infiltration, D=severity score for desquamation and A=total area involved. In
this
formula, the letters "h," "t," "u" and "1" represent, respectively, the scores
in each of the
four body regions, i.e., head, trunk, upper extremities and lower extremities.
The PASI
score varies in steps of 0.1 units from 0.0 (no psoriatic lesions at all) to
72.0 (complete
erythroderma of the severest possible degree).
PASI= 0.1(Eh+Ih+Dh)Ah + 0.3(Et+It+Dt)At + 0.2(Eu+Iu+Du)Au + 0.4(El+Il+DI)Al
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A secondary endpoint used for the psoriatic aspect of psoriatic arthritis was
the
Target Lesion Assessment Score. This score was determined for a single target
lesion
that was selected to be monitored throughout the trial. This measurement is a
composite
of four different evaluations: 1) plaque evaluation; 2) scaling; 3) erythrema;
and 4) target
lesion response to treatment. The following scale was used for the plaque
elevation:
0=none (no evidence of plaque above normal skin level); 1=mild (slight but
definite
elevation above normal skin level); 2=moderate (moderate elevation with
rounded or
sloped edges to plaque); 3=severe (hard, marked elevation with sharp edges to
plaque);
4=very severe (very marked elevation with very hard sharp edges to plaque).
For the
scaling assessment: 0=none (no scaling on the lesion); 1=mild (mainly fine
scales, with
some of the lesion at least partially covered); 2=moderate (somewhat coarser
scales, most
of the lesion at least partially covered); 3=severe (coarse, thick scales,
virtually all the
lesion covered, rough surface); 4=very severe (very coarse thick scales, all
the lesions
covered, very rough surface). For the erythema evaluation: 0=none (no
erythema);
1=mild (light red coloration); 2=moderate (red coloration); 3=severe (very red
coloration); 4=very severe (extreme red coloration). For target lesion
response to
treatment score: 0=completely cleared; 1=almost cleared (-90% improvement);
2=marked response (-75% improvement); 3=moderate response (-50% improvement);
4=slight response (-25% improvement); 5=condition unchanged; 6=condition
worsened.
The patient's Target Lesion Assessment Score was determined by summing the
plaque,
scaling, erythema and target lesion response scores for the monitored lesion.
If the
monitored lesion worsened, the percentage change from baseline was recorded as
a
negative number.
Treatment and placebo groups were compared in accord with the measurements
described above, as well as for demographic and background characteristics;
premature
discontinuation rate; pain medication requirements; toxicities; serious
adverse events;
side effects reported by patients; number of weeks on drug until subjects met
criteria for
improvement, and response according to PsA subtype. Results were analyzed
using
standard statistical methods.
Dosing regimen
Recombinant human TNFR:Fc (etanercept) from Immunex Corporation was used
in this study. The gene fragments encoding the etanercept polypeptides were
expressed in
a Chinese hamster ovary (CHO) expression vector.
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TNFR:Fc was supplied as a sterile lyophilized powder containing 10 mg or 25 mg
TNFR:Fc; 40 mg mannitol, USP; 10 mg sucrose, NF; and 1.2 mg tromethamine
(TRIS),
USP per vial. Patients received either a dose of 25 mg of etanercept or a
placebo. Vials
of etanercept or identically-appearing placebo were reconstituted by aseptic
injection of
1.0 mL Bacteriostatic Water for Injection, USP, (containing 0.9% benzyl
alcohol), and
was not filtered during preparation or prior to administration. If storage was
required, the
reconstituted solutions were stored at 2-8 C (36-46 F) in the original vial or
in a plastic
syringe for a period of no longer than 28 days. Dose was not changed during
the study.
Study drug was given twice weekly at approximately the same time of day.
Results
Study drug was well tolerated in all patients, and adverse events were
consistent
with this population and were equally distributed among both treatment groups.
As
illustrated in Tables 1-4, etanercept induced a significant improvement as
compared with
the placebo group in Psoriatic Arthritis Response (Table 1), ACR20 (Table 2),
ACR50
(Table 3), PASI score, 50% improvement (Table 4), PASI score, 75% improvement
(Table 5) and improvement in Target Lesion Assessment Score (Table 6). The
fractions
shown in Tables 1-5 represent numbers of patients. For example, the first
entry in Table
1, which is "4/30," indicates that 4 of 30 patients in the placebo group
scored as
"improved" according to the Psoriatic Arthritis Response measurements. The
tables
include P-values for the differences between the two study groups, the groups
being
labeled as "PLACEBO" and "TNFR:Fc." All of the tables include data calculated
after
the first four weeks of the open label EXTENSION portion of the study
("EXTENSION"), during which all of the patients in both study groups received
etanercept.
Table 1 shows the number of patients in each treatment group who scored as
"improved" according to the Psoriatic Arthritis Response scoring system
described above.
By four weeks, there was a highly significant difference between etanercept
and placebo
groups. Moreover, after being switched to etanercept during the EXTENSION,
those
patients who had received placebo during the blinded portion of the study were
seen to
exhibit an improvement over baseline (Table 1, Placebo, EXTENSION). These
results
indicate that etanercept acts rapidly to alleviate many aspects of psoriatic
arthritis.
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Table 1. Psoriatic Arthritis Response
Placebo TNFR:Fc P-value
4 weeks 4/30 (13%) 23/30 (77%) 0.000
8 weeks 7/30 (23%) 25/30 (83%) 0.000
12 weeks 6/30 (20%) 26/30 (87%) 0.000
EXTENSION 17/23 (74%) 21/25 (84%) 0.356
Tables 2 and 3, respectively, illustrate the study results for the ACR20 and
ACR50 endpoints. For either measure, a significant difference between
etanercept and
placebo groups was observed at all three time points during the blinded
portion of the
study. Given the differences between test and placebo groups after only four
weeks of
treatment (P=0.000 for ACR20 and P=0.011 for ACR50), these data suggest that
notable
improvement in ACR scores occurred within the etanercept group very soon after
treatment was initiated, possibly after a single dose of etanercept. During
the 4 week
EXTENSION period, during which all of the patients received etanercept, a
striking
improvement in both ACR20 and ACR50 was seen in those patients who had
received
placebo during the first 12 weeks (Tables 2 and 3).
Table 2. ACR20 Response
Placebo TNFR:Fc P-value
4 weeks 1/30 ( 3%) 18/30 (60%) 0.000
8 weeks 3/30 (10%) 19/30 (63%) 0.000
12 weeks 4/30 (13%) 22/30 (73%) 0.000
EXTENSION 11/23 (48%) 18/25 (72%) 0.093
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Table 3. ACR50 Response
Placebo TNFR:Fc P-value
4 weeks 0/30 ( 0%) 6/30 (20%) 0.011
8 weeks 1/30 (3%) 11/30 (37%) 0.001
12 weeks 1/30 (3%) 15/30 (50%) 0.000
EXTENSION 7/23 (30%) 11/25 (44%) 0.316
The results of the psoriasis evaluations are presented in Tables 4-6. Tables 4
and
5, respectively, present the numbers and percentages of patients in each group
who
exhibited a 50% or 75% improvement in PASI score, while Table 6 presents
Target
Lesion Assessment scores, these latter being denoted as percent improvement
over
baseline. The data in Tables 4-6 clearly indicate that etanercept induced an
improvement
in psoriasis for a large percentage of the patients who received it. When
single lesions
were evaluated (Table 6), the improvement in psoriasis was even more apparent
than
when PASI scores were used (Tables 4 and 5). It is notable also that, for
either PASI
scores (Tables 4 and 5) or Psoriasis Target Lesion Assessment Score (Table 6),
the scores
of the placebo group improved after these patients were switched to etanercept
during the
EXTENSION.
Though not shown in Table 6, Target Lesion Assessment Scores for patients who
were concurrently receiving methotrexate (14 of the 30 patients in the
etanercept group,
and 14 patients in the placebo group) were compared with the scores of those
patients
who did not take methotrexate. Little difference in this index was noted
between the
patients who received methotrexate and those who did not receive it.
Table 4. PASI Score - 50% Improvement
Placebo TNFR:Fc P-value
4 weeks 0/19 ( 0%) 4/19 (21%) 0.037
8 weeks 1/19 (5%) 7/19 (37%) 0.019
12 weeks 4/19 (21%) 8/19 (42%) 0.165
EXTENSION 6/16 (38%) 6/15 (40%) 0.856
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Table 5. PASI Response Rate 75% Improvement
Placebo TNFR:Fc P-value
4 weeks 0/19 ( 0%) 1/19 (5%) 0.264
8 weeks 0/19 (0%) 2/19 (11%) 0.153
12 weeks 0/19 ( 0%) 4/19 (21%) 0.037
EXTENSION 1/16 (6%) 4/15 (27%) 0.113
Table 6. Psoriasis Target Lesion Assessment
(Percent Improvement or Worsening Compared with Baseline)
Placebo TNFR:Fc P-value
4 weeks Mean (SD) 2.7 (27.6) 21.2 (35.2) 0.120
Median 0.0 14.3
MIN--MAX -50.0 -50.0 -33.3 -100.0
N 19 19
8 weeks Mean (SD) -7.5 (25.3) 28.5 (34.1) 0.003
Median 0.0 29.2
MIN--MAX -50.0 -20.0 -33.3 -100.0
N 17 18
12 weeks Mean (SD) 9.5 (23.2) 45.7 (31.6) 0.001
Median 0.0 50.0
MIN--MAX -25.0 -50.0 -16.7 -100.0
N 16 19
EXTENSION Mean (SD) 28.9 (41.2) 47.1 (35.8) 0.263
Median 36.7 50.0
MIN--MAX -100.0 -66.7 -33.3 -100.0
N 16 15
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