ZymoGenetics Announces Start of TACI-Ig Clinical Study in Lupus Patients
Tuesday July 27, 6:00 am ET
Phase 1b Study in Autoimmune Disease with Unmet Medical Needs
SEATTLE--(BUSINESS WIRE)--July 27, 2004--ZymoGenetics (Nasdaq:ZGEN - News) announced today the start of a clinical study of TACI-Ig, which is being developed in collaboration with Serono S.A., in patients with an autoimmune disease called systemic lupus erythematosus (SLE). Over 1 million patients have some form of lupus in the U.S.; ninety percent of these patients are women. Approximately 150,000 patients have a severe form of the disease that could be treated with a drug such as TACI-Ig. Standard care for SLE consists of steroid therapy and immunomodulatory drugs, and these treatments may have severe side effects. The Phase 1b dose escalation study is designed to evaluate the safety and pharmacokinetics of TACI-Ig. The study follows the successful completion of a Phase 1 study of TACI-Ig in healthy volunteers. Additionally, ZymoGenetics and Serono are also planning clinical trials to test TACI-Ig in rheumatoid arthritis and are considering other B cell disorders.
TACI-Ig is a soluble fusion protein that links the extracellular portion of the TACI receptor to the Fc portion of human immunoglobulin (Ig). TACI has been shown to bind to BLyS and APRIL, TNF family cytokines that promote B-cell survival and the production of harmful autoantibodies, which cause certain autoimmune diseases such as SLE. TACI has been shown to affect several stages of B cell development and may inhibit the survival of the cells responsible for making antibodies.
"TACI-Ig shows tremendous potential for addressing the unmet medical needs of lupus patients," said Bruce L. A. Carter, Ph.D., president and CEO of ZymoGenetics. "Current therapies for lupus are inadequate. If successfully developed, TACI-Ig could help an enormous number of patients and thus represents a significant market opportunity."
"We're optimistic about the prospects for this protein in helping patients with a variety of B-cell mediated diseases, including B-cell lymphomas," commented Jan K. Ohrstrom, M.D., senior vice president of Development & chief medical officer of ZymoGenetics. He added, "The market potential is significant and initial research indicates that TACI-Ig has great promise. ZymoGenetics' partnership with Serono has been highly efficient and fruitful."
The Phase 1b study in patients with SLE will assess the systemic and local tolerability of TACI-Ig in a single-dose escalation placebo-controlled double-blind study and will then move into a multi-dose Phase 1b study in the same population. The secondary objective is to characterize the pharmacokinetics and pharmacodynamics of TACI-Ig and to monitor the effects on biological markers of disease activity. The Phase 1b study will be conducted in a total of 32 patients, with 24 receiving TACI-Ig and 8 receiving placebo, and will be conducted by Serono at 3 investigational sites in the United States.
Program Update
In a Phase 1 study of healthy volunteers a single dose of TACI-Ig was administered to 24 subjects segregated into four different dose levels. ZymoGenetics and Serono are in the process of completing data analysis. Preliminary findings indicate that TACI-Ig was well tolerated with no serious adverse events observed in any of the subjects. The companies plan to begin an additional clinical study in patients with rheumatoid arthritis in the second half of 2004.
ZymoGenetics and Serono Collaboration
ZymoGenetics and Serono entered into an exclusive co-development and commercialization agreement in 2001 focused on the development of TACI-Ig. The two companies share research and development expenses worldwide, except for in Japan, where Serono covers all expenses. ZymoGenetics retains the option to co-promote products with Serono in North America. If ZymoGenetics exercises that option, the two companies will share commercialization expenses and profits equally. Serono has exclusive rights to market TACI-Ig in the remainder of the world, for which ZymoGenetics is entitled to receive royalty payments. Serono is responsible for manufacturing the product for both clinical trials and commercial sale.
About TACI-Ig
TACI is a cell-surface receptor found on B lymphocytes, the cells in the blood responsible for producing antibodies. TACI has been shown to bind to BLyS and APRIL, two cytokines that stimulate B-cell growth and the production of antibodies. The importance of the BLyS pathway for regulating B-cell function has been demonstrated by scientists from ZymoGenetics by deleting the gene for BLyS in mice, thereby preventing the production of BLyS protein. These mice had almost no mature B cells and had greatly reduced circulating immunoglobulin. ZymoGenetics scientists further showed that mice genetically engineered to over express the gene for BlyS develop symptoms of SLE, including the generation of autoantibodies. Reports from ZymoGenetics and others have also demonstrated an association between elevated levels of circulating BLyS and BLyS/APRIL heterotrimers and autoimmune disease, including SLE and rheumatoid arthritis in humans. Recently, investigators have shown that BlyS plays a role in the survival of antibody producing B-cells and therefore it has been postulated that TACI-Ig will produce a different effect than other drugs being used for the treatment of these diseases.
By using the receptor portion of TACI responsible for binding the growth factors, ZymoGenetics researchers have produced TACI-Ig, an antagonist protein that can "mop up" excess BLyS and APRIL growth factor in the blood. TACI-Ig prevents binding of the growth factors to the B cells, regulating the development of mature B cells and antibody production. In published studies, scientists at ZymoGenetics demonstrated that in TACI transgenic mice, which are mice that have been genetically engineered to over express a soluble form of the TACI receptor, there are very few mature B cells and reduced levels of circulating antibody. Similar results were observed in normal mice treated with soluble TACI-Ig receptor.
Through the ability of soluble receptors to bind to and eliminate the BLyS and APRIL growth factors and consequently avert production of destructive autoantibodies, it may be possible to limit the extent of tissue damage observed in patients with autoimmune disease. ZymoGenetics has reported data showing the effectiveness of TACI-Ig to inhibit the progression of autoimmune disease in mouse models of lupus and rheumatoid arthritis. By inhibiting BLyS and APRIL, two proteins that are involved in the development and activation of B-cells, TACI-Ig may provide a novel mechanism of action to address lupus, rheumatoid arthritis and other autoimmune diseases. |
