CuraGen and TopoTarget announce Southwest Oncology opens new lymphoma trial with PXD101.

CuraGen Corporation (Branford, CT) and TopoTarget A/S (Copenhagen, Denmark) said the Southwest Oncology Group (Ann Arbor, MI), a national clinical trials cooperative group, has just opened a Phase II clinical trial to test the effects of a new investigational agent on aggressive B-cell lymphoma. The agent, PXD101, will be evaluated in patients whose previous treatment regimen did not work or whose cancer returned after treatment. The trial, also known as S0520, is sponsored by the National Cancer Institute (NCI) under a Clinical Trials Agreement signed with CuraGen.

PXD101 is designed to inhibit histone deacetylase (HDAC). Histones are a class of proteins around which DNA is wrapped. The tightness of the wrapping controls the activity of the genes on the DNA. HDAC is an enzyme that changes the way histones bind to the genes. Laboratory studies suggest that drugs such as PXD101 can act on histones to kill cancer cells or prevent them from growing.

The purpose of the trial is to evaluate how B-cell lymphoma cells respond to the new agent, how patients tolerate the treatment and how long patients can live with the treatment without the disease becoming worse. Based on published preliminary data, study leaders are particularly interested in whether PXD101 will enhance expression of immune-mediating molecules on the tumor cells' surface and thereby increase the immune system's ability to target the lymphoma.

Study leaders would like to enroll up to 40 patients with refractory aggressive diffuse large, high-grade Burkitt's or Burkitt's-like or primary mediastinal B-cell lymphoma for the trial. So far, 81 Southwest Oncology Group institutions are participating in the trial.

Patients enrolled in the trial will receive PXD101 intravenously in three-week cycles. The primary goal of this study is to evaluate the response rate for patients receiving treatment with PXD101. In addition, correlative studies will be performed on some of the patients to assess histone acetylation and potential biomarkers.

"HDAC inhibitors are believed to target DNA and lead to reactivating genes that suppress tumors. Since this may slow the growth and survival of tumor cells, we are very interested in investigating PXD101 to assess its potential benefit for patients with B-Cell lymphoma," said Steven H. Bernstein, M.D., the study coordinator.

Dr. Bernstein is Associate Professor of Medicine and Co-director of the Lymphoma Biology Program at the James P. Wilmot Cancer Center at the University of Rochester School of Medicine (Rochester, NY)

B-cell lymphomas are a type of non-Hodgkin's lymphoma (NHL) that account for approximately 85 percent of the approximately 56,000 new cases of NHL diagnosed annually in the United States. B-cell lymphomas are specifically characterized in subtypes by numerous chemical and genetic attributes. These lymphomas are also generally classified into two subsets used to define outcome including indolent, or slow-growing, and aggressive, or rapidly growing. Over the past 30 years, there has been a steady increase in the incidence of NHL, with a greater number of cases diagnosed in men than women, at a median age of older than 50 years. While the exact causes of B-cell lymphomas are unknown, there are several environmental factors and genetic abnormalities that are believed to play a role. Aggressive B-cell lymphomas are typically treated with radiotherapy, chemotherapy regimens, biologics, or a combination of treatments. The overall five-year survival rate for patients with NHL is approximately 60 percent, although response rates and survival vary greatly based on the grade and type of B-cell lymphoma being treated.

PXD101 is a promising small molecule HDAC inhibitor being investigated for its role in the treatment of a wide range of solid and hematologic malignancies either as a single-agent, or in combination with other active anti-cancer agents, including 5-fluorouracil (5-FU), carboplatin, paclitaxel, cis-retinoic acid and Velcade(r) (bortezomib) for Injection. HDAC inhibitors represent a new mechanistic class of anti-cancer therapeutics that target HDAC enzymes and have been shown to: arrest growth of cancer cells (including drug resistant subtypes); induce apoptosis, or programmed cell death; promote differentiation; inhibit angiogenesis; and sensitize cancer cells to overcome drug resistance when used in combination with other anti-cancer agents.

PXD101 is currently being evaluated in multiple clinical trials as a potential treatment for multiple myeloma, T-cell lymphoma, and colorectal and ovarian cancers, either alone or in combination with anti-cancer therapies. In August 2004, CuraGen signed a Clinical Trials Agreement with the NCI under which the NCI will sponsor several clinical trials to investigate PXD101 for the treatment of various cancers, both as a single-agent and in combination chemotherapy regimens. In May 2005, TopoTarget announced the signing of a Cooperative Research and Development Agreement with the NCI to conduct pre-clinical and non-clinical studies on PXD101 in order to better understand its anti-tumor activity and to provide supporting information for clinical trials.

CuraGen is a biopharmaceutical company developing diverse approaches, including novel protein, antibody, and small molecule therapeutics, that aim to offer hope for patients with cancer, inflammatory diseases, and diabetes. CuraGen's strategic alliances have resulted in a deep pipeline of potential therapeutics that is being developed by the company's experienced research and development teams. By leveraging the drug development strengths cultivated over the years, CuraGen expects to make a difference in the lives of patients by bringing forward promising therapeutics that address unmet medical needs. To further capitalize on CuraGen's extensive research and development expertise, CuraGen founded a majority-owned subsidiary, 454 Life Sciences, which has developed and is commercializing advanced technologies for the sequencing of DNA.

TopoTarget is dedicated to developing improved cancer therapies. TopoTarget is founded and run by clinical cancer specialists and combines years of hands-on clinical experience with in-depth understanding of the molecular mechanisms of cancer. Focus lies on key cancer enzyme regulators (mainly HDAC, mTOR, and topoisomerase II inhibitors) and a strong development foundation of proprietary, highly predictive cancer models has been built. TopoTarget has a broad portfolio of small molecule preclinical drug candidates and eight drugs are in clinical development, consisting of both novel anti-cancer therapeutics and new cancer indications for existing drugs. TopoTarget's first product, Savene has been granted marketing approval by EMEA. In addition to organic growth, TopoTarget consistently looks for opportunities to strengthen and expand its activities through acquisitions and in-licensing.

The Southwest Oncology Group is one of the largest cancer clinical trials cooperative research groups in the United States. The Group is a network of more than 5,000 physician-researchers located at nearly 550 institutions. In addition to their regular medical practices, Group investigators work together on clinical trials funded by the National Cancer Institute, part of the National Institutes of Health, to prevent and treat cancer in adults. Among the Group's institutions are 17 of the NCI's 61 designated cancer centers. The Group enrolls nearly 7,200 patients each year and has about 120 clinical trials underway at any given time.

CuraGen Corporation

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www.curagen.com

454 Life Sciences

www.454lifesciences.com

TopoTarget A/S

www.topotarget.com