Alefacept, a specially designed molecule that blocks a specific immune-system reaction involved in the painful skin condition psoriasis, 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.From the University of Michigan Health System:U-M Health System welcomes FDA approval of psoriasis treatment developed and studied at UMHS
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.
UMHS also played a major role in the advanced-phase clinical trials that 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.
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.
