Press Release: ZymoGenetics and Serono to Begin TACI-Ig Clinical Studies in B-Cell Malignancies

ZymoGenetics and Serono to Begin TACI-Ig Clinical Studies in B-Cell Malignancies Expansion into additional therapeutic area adds further depth to ZymoGenetics' pipeline SEATTLE--(BUSINESS WIRE)--Oct. 4, 2004-- ZymoGenetics (Nasdaq:ZGEN) announced today that it received clearance from the Food and Drug Administration to initiate studies with TACI-Ig in patients with advanced B-cell malignancies. These include chronic lymphocytic leukemia, multiple myeloma, and B-cell non-Hodgkin's lymphoma. In the U.S., over 320,000 people are estimated to have some form of these B-cell cancers and each year, approximately 55,000 new cases and 20,000 deaths occur from these cancers. Between 80% and 85% of non-Hodgkin's lymphomas are of B-cell origin. TACI-Ig is a soluble receptor that binds to BLyS and APRIL, thus inhibiting these members of the tumor necrosis factor family that appear to enable malignant B cells to survive. "Using TACI-Ig to starve B-cell cancer of BLyS and APRIL represents targeted therapy at its best," said Bruce L. A. Carter, Ph.D., President and CEO of ZymoGenetics. "Current therapies for these types of cancer don't cure patients, and so we see a meaningful market opportunity in B-cell malignancies and hope to help patients with these devastating diseases. With the addition of these studies, we will have four clinical trials underway for TACI-Ig." Phase 1b studies evaluating the safety and pharmacokinetics of multiple doses of TACI-Ig are planned in patients with multiple myeloma, chronic lymphocytic leukemia, and non-Hodgkin's lymphomas. The Centre Hospitalier Universitaire de Montpellier, France (L'Hopital Lapeyronie) will evaluate TACI-Ig in patients with advanced multiple myeloma and Mayo Clinic in Rochester, Minnesota will conduct a trial in patients with other advanced B-cell malignancies. The trials are expected to be open at both sites later this quarter. The studies follow the successful completion of a Phase 1 trial with TACI-Ig in healthy volunteers. ZymoGenetics and Serono are also conducting separate Phase 1b clinical trials to test TACI-Ig in patients with systemic lupus erythematosus and rheumatoid arthritis. TACI-Ig as a Novel Treatment for B-Cell Malignancies An expanding body of literature suggests that TACI-Ig may prove to be an effective treatment for a variety of B-cell cancers. Researchers from multiple labs in the U.S. and in France have shown that malignant B-cells from essentially all patients with B-cell neoplasms examined to date express one or more of the three known receptors for BLyS and APRIL (TACI, BCMA and BAFF-R). Furthermore, these malignant B-cells also often abnormally express BLyS and APRIL proteins themselves, while normal B-cells do not. These findings seem to suggest that malignant B-cells can both produce and consume the BLyS and APRIL growth factors, leading to their autonomous survival in patients. In fact, BLyS and APRIL levels are usually elevated in the serum of patients bearing these B-cell tumors. Studies from Mayo Clinic suggest that lymphoma patients in whom high levels of BLyS are present in blood samples fare worse than those in whom levels are lower. Thus, BLyS and/or APRIL appear to enhance the survival of malignant B-cells. In support of this theory, scientists have shown that the addition of BLyS or APRIL to cultured cells from non-Hodgkin's lymphoma and multiple myeloma patients enables these cancer cells to survive for extended periods of time. Inhibition of BLyS and APRIL using TACI-Ig causes the cultured malignant B-cells to die rapidly. These results suggest that TACI-Ig might represent an important new cancer therapeutic, specifically targeting malignant B-cells. About TACI-Ig TACI is a cell-surface receptor found on B lymphocytes, cells in the blood responsible for producing antibodies. TACI-Ig is a soluble fusion protein that links the extracellular part of the TACI receptor to the Fc portion of human immunoglobulin (Ig). By using the receptor portion of TACI responsible for binding growth factors, ZymoGenetics researchers have produced TACI-Ig, an antagonist protein that binds to BLyS and APRIL, two cytokines that stimulate B-cell growth and the production of antibodies. TACI-Ig thus prevents binding of the growth factors to the B-cells, regulating the development of mature B-cells and antibody production. 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 a greatly reduced serum antibody response after immunization. Reports from ZymoGenetics and others have also demonstrated an association between elevated levels of circulating BLyS and BLyS/APRIL heterotrimers and autoimmune disease, including systemic lupus erythematosus 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. 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 will receive royalty payments. Serono is responsible for manufacturing the product for both clinical trials and commercial sale. Recently, the companies announced an expansion of their relationship in an alliance separate from the TACI-Ig development collaboration. About ZymoGenetics ZymoGenetics is a biopharmaceutical company focused on the discovery, development and commercialization of therapeutic proteins for the prevention or treatment of human diseases. The Company is developing a diverse pipeline of potential proprietary product candidates that are moving into and through clinical development. These span a wide array of clinical opportunities that include bleeding, autoimmune diseases and cancer. The Company is currently conducting clinical trials for rhThrombin for bleeding; rFactor XIII for bleeding disorders; TACI-Ig for autoimmune diseases and B-cell malignancies; and IL-21 for cancer. ZymoGenetics intends to commercialize these product candidates through internal development, collaborations with partners and out-licensing of patents from its extensive patent portfolio. For further information, visit www.zymogenetics.com. This press release contains "forward-looking statements" within the meaning of the Private Securities Litigation Reform Act of 1995. These forward-looking statements are based on the current intent and expectations of the management of ZymoGenetics. These statements are not guarantees of future performance and involve risks and uncertainties that are difficult to predict. ZymoGenetics' actual results and the timing and outcome of events may differ materially from those expressed in or implied by the forward-looking statements because of risks associated with our unproven discovery strategy, preclinical and clinical development, regulatory oversight, intellectual property claims and litigation and other risks detailed in the company's public filings with the Securities and Exchange Commission, including the company's Annual Report on Form 10-K for the year ended December 31, 2003. Except as required by law, ZymoGenetics undertakes no obligation to update any forward-looking or other statements in this press release, whether as a result of new information, future events or otherwise.