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BioTech Sage Report, January 2000
psoriasis.
What are some of the more
promising compounds
generated by biotechnology for
psoriasis?
Medical research scientists con-
tinue to search for genes that contrib-
ute to the inherited and other causes
of psoriasis. Scientists are also work-
ing to improve our understanding of
what happens in the body to trigger
this disease. In addition, much re-
search is focused on developing new
and better treatments. Some of these
experimental treatments, such as
agents directed at the specific types of
T cells involved, work to improve the
disease with less overall suppression
of the immune system. Whereas oth-
ers experimental therapies target cyto-
kines that are found in abundance in
psoriatic lesions. Each of the experi-
mental approaches has positives at-
tribute and will be evaluated below.
In earlier issues of BioTech Sage
Report (BSR), we discuss immuno-
modulatory proteins, which included
cytokines. For psoriasis, a number of
scientific studies have shown that in-
terleukin-8 (IL-8) may have a contrib-
uting role in the development of the
disease. IL-8, an important inflamma-
tory cytokine produced at sites of in-
flammation, attracts and activates
white blood cells that mediate the in-
flammation process. Clinical studies
have demonstrated significantly in-
creased levels of IL-8 in plasma or
other bodily fluids of patients with
certain inflammatory diseases, includ-
ing psoriasis, rheumatoid arthritis,
reperfusion injury and inflammatory
bowel disease. Antibodies to IL-8
have been shown to block immune
cell infiltration and the associated pa-
thology in animal models of several of
these diseases. Using their patented
XenoMouse technology, Abgenix has
generated ABX-IL8, a proprietary
fully human monoclonal antibody
that binds to IL-8 with high affinity.
Abgenix is currently evaluating
ABX-IL8 for possible use in the treat-
ment of psoriasis and rheumatoid ar-
thritis.
IL-8 should prove to be an effec-
tive target for treating psoriasis.
Concentrations of IL-8 are reported to
be elevated by a factor of 150 in pso-
riatic plaques when compared to nor-
mal tissue. Abgenix believes that IL-
8 may promote psoriasis by contribut-
ing to three distinct disease-
associated processes. First, IL-8 is
produced by a type of skin cell called
keratinocytes, and is a potent growth
factor for these skin cells. It may
therefore contribute to the abnormal
keratinocyte proliferation in psoriatic
plaques. Second, IL-8 attracts and
activates immune cells, which con-
tribute to the inflammation of the
psoriatic plaque. Finally, IL-8 pro-
motes angiogenesis, which augments
the blood supply necessary for growth
of the psoriatic plaque.
Abgenix has completed a Phase I
dose-escalating human clinical trial
examining the safety of administering
a single intravenous infusion of five
different doses of ABX-IL8 to pa-
tients with moderate to severe psoria-
sis. From these studies, Abgenix
found that there were no serious or
unexpected drug-related adverse
events. Abgenix is currently awaiting
the results of a multi-center, multi-
dose, dose-escalating study in moder-
ate to severe psoriasis patients. BSR
is extremely optimistic that ABX-IL8
will do well and make it to market, as
the principle behind the therapy is
similar to Immunex and Centocor's
approach to treat rheumatoid arthri-
tis. However, we believe the technol-
ogy is superior, as the antibody is al-
ready humanized and will not induce
an anti-antibody response in patients
or be subjected to the lengthy altera-
tions associated with humanizing it
for therapeutic utility.
An alternative approach is to at-
tack the cell types that are involved in
the autoimmune response. Biogen
has focused their efforts on it's in-
flammation programs for developing
drugs to inhibit specific cellular inter-
actions critical to the inflammation
process. Central to inflammation is
the activation of T-cells. One of the
cellular pathways, which is important
for the activation of T-cells is the
LFA-3/CD2 pathway. Biogen has
developed AMEVIVE (LFA3TIP) a
recombinantly engineered protein de-
signed to modulate immune responses
by binding to the CD2 receptor. Bio-
gen is evaluating AMEVIVE as a
treatment for certain autoimmune dis-
eases, including psoriasis. In 1998,
Biogen completed evaluation of the
results of two Phase 2a safety studies
of AMEVIVE, and commenced a
Phase 2b study of the safety and effi-
cacy of AMEVIVE compared to a pla-
cebo as a systemic therapy in patients
with moderate and severe psoriasis.
Earlier this month (December), Bio-
gen announced the results of this
Phase II study, which involved 229
patients at 22 sites in the U.S. who
were treated with AMEVIVE or pla-
cebo by intravenous bolus injection
weekly for 12 weeks, followed by a
12-week observation period. The pri-
mary study objective was to determine
the relationship of clinical response to
the dose of AMEVIVE when adminis-
tered once a week for a total of up to
12 doses. The results showed that
AMEVIVE was well tolerated with a
favorable safety profile and provided
significant therapeutic effect. No in-
crease in infection rate or evidence of
cytokine-release or capillary-leak syn-
dromes was observed in AMEVIVE-
treated patients. Results indicate that
AMEVIVE cleared psoriasis rapidly
and to a significant degree. In particu-
lar, in patients who received either of
the two higher doses of AMEVIVE
