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ANN ARBOR,
MI - The University of Michigan
Health System today welcomed the approval by the U.S. Food and
Drug Administration of a psoriasis treatment that was first developed
in a U-M Medical School
laboratory.
Alefacept,
a specially designed molecule that blocks a specific immune-system
reaction involved in the painful skin condition, was approved for
marketing today under the name Amevive. Biogen,
Inc. of Cambridge, Mass., will market the drug.
Alefacept traces
its roots to research done at the U-M in the mid-1990s by a team
led by former dermatology faculty member Kevin D. Cooper, M.D. The
University and Biogen share the patent on the engineered molecule
with Cooper, who is now chair of dermatology at Case Western Reserve
University in Cleveland.
Advanced-phase
clinical trials demonstrated alefacept's ability to significantly
ease or clear the painful symptoms of psoriasis - relief that continues
even after treatment stops.
Dermatologist
Charles Ellis, M.D., who has no financial connection to the patent,
was selected to help design and lead the Phase II and III studies
because of his long experience studying and treating the immune
response in psoriasis. Ellis is associate chair of dermatology
at UMHS and chief of dermatology at the VA Ann Arbor Healthcare
System.
The results
of the phase II trial were published in the July 26, 2001 issue
of the New England Journal of Medicine. No patients in the
Phase II or III studies were treated at UMHS. Ellis shared leadership
of the study with Gerald G. Krueger, M.D., a professor of dermatology
at the University of Utah School of Medicine. Biogen, which funded
the study, compensates Ellis and Krueger for consulting on the development
and testing of the alefacept product.
Psoriasis,
which stems from a runaway immune response in the skin, causes skin
itching, redness, flaking, pain, and cracking in about 2 percent
of the population, or 5.5 million people, each year. The availability
of alefacept may improve treatment of the disease, which currently
relies on broad-based anti-inflammation techniques with limited
effectiveness or side effects.
Alefacept directly
affects psoriasis-related inflammation through a specific immune-blocking
action - without undercutting the rest of the immune system and
its ability to fight off infection. It relieves symptoms during
treatment and may spur remission.
The promise
of a new tool against psoriasis, especially one that zeroes in on
the immune response involved in the disease, is exciting, says Ellis.
"This is a unique approach that targets a specific cell that
drives the over-responsive immune system in psoriasis," he
comments.
Only in recent
years have Cooper and others pieced together enough information
about the intricacies of molecular immunology to give the insight
needed to design tailored treatments.
The process
started more than a decade ago when Ellis and colleagues performed
research that led to a paradigm shift: Instead of seeing psoriasis
as the product of abnormal skin cells, they found that the disease
was instead driven by immune system processes gone wild.
This realization
came from Ellis' and others' treatment of psoriasis with cyclosporine,
a broad anti-immune response drug often given to organ transplant
recipients. It also helped explain why standard treatments like
topical creams, ultraviolet light therapy and methotrexate, a cancer
drug, worked - they helped calm the runaway immune system and thus
decreased symptoms.
John Voorhees,
M.D., FRCP, Professor and Chair of the U-M Department of Dermatology,
and recipient of the National Psoriasis Foundation's Lifetime Achievement
Award, was instrumental in the development of the concept of psoriasis
as an autoimmune disorder.
Researchers
have since found out that psoriasis depends on the successful completion
of a particular "handshake" between immune system agents
known as T cells and antigen-presenting, or dendritic, cells. The
process starts when dendritic cells, which are a kind of master
cell for immune response, show a protein called LFA-3 on their surface.
The LFA-3 protein
latches on to a receptor on the T cells called CD2, completing the
handshake and prompting the T cells to set off on a path that leads
to inflammation. As the process repeats, individual T cells can
build up their level of surface CD2 and other proteins, earning
them the name "memory effector cells" and making them
more able to prompt inflammation. As a result, CD2-rich memory effector
T cells are a good target in psoriasis treatment.
Cooper's research
at UMHS, performed in conjunction with Biogen, helped piece together
this specific knowledge and led to the realization that a new molecule
could be designed to interfere with this crucial handshake. After
several years of research, alefacept was developed.
Alefacept's
targeted immunological action comes from its unique molecular design,
a Y shape that combines the heads of two LFA-3 molecules with the
tail of an immunoglobulin molecule that usually signals the immune
system's "attack dogs", called natural killer cells and
macrophages, to come fight off invaders.
Because alefacept
uses the part of LFA-3 that attaches to CD2 on the surface of T
cells, it completes that half of the handshake - and because it
has two LFA-3 fragments close to one another, it only binds with
memory effector T cells that have a high concentration of CD2. But,
with the other half of LFA missing, the handshake with a dendritic
cell is impossible. It's almost as if the T cell is shaking hands
with a fake hand-on-a-stick out of a circus clown's routine.
In the meantime,
the immunoglobulin tail of the alefacept molecule sticks out, and
signals natural killer cells and macrophages to come attack. When
these cells spot the T cell on the other end of the alefacept molecule,
they start a process that causes the T cell to self-destruct - a
kind of cell death called apoptosis.
This highly
specific action, and the lack of serious side effects, is what might
give alefacept an edge over other more standard treatments, Ellis
suspects. Cyclosporine can be toxic to kidneys, methotrexate can
harm the liver, and UV therapy can increase the risk of skin cancer.
Special notes
on this release
Patients interested
in Amevive may call its manufacturer's toll-free number, 866-AMEVIVE.
Patients interested in participating in other psoriasis research
at the U-M Health System may call 734-936-4070.
Written
by: Kara Gavin
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