Cytogen Corporation Announces Publication Of Peer Reviewed Preclinical Data Demonstrating Anticancer Activity Of QUADRAMET(R) In Multiple Myeloma

PRINCETON, N.J., Jan. 24 /PRNewswire-FirstCall/ -- Cytogen Corporation announced today the publication of preclinical data from studies involving the use of QUADRAMET(R) (samarium Sm-153 lexidronam) both as a monotherapy and in combination with the novel first-in-class proteasome inhibitor bortezomib (Velcade(R), Millennium Pharmaceuticals, Inc.) for the treatment of multiple myeloma. In results prepublished online as a First Edition Paper in the peer-reviewed journal Blood (http://www.bloodjournal.org/), QUADRAMET demonstrated broad and synergistic activity when administered in combination with bortezomib in a murine myeloma model. This anticancer activity was characterized by significantly prolonged median survival, rapidly reduced clonogenicity of bone-marrow resident 5TGM1 cells, slowed elevation of serum myeloma-associated paraprotein levels, and longer term preservation of bone mineral density.

The publication, "Synergistic activity of the proteasome inhibitor PS-341 with non-myeloablative 153-Sm-EDTMP skeletal targeted radiotherapy in an orthotopic model of multiple myeloma" by Dr. Apollina Goel et al. presents in vitro and in vivo findings from research conducted at the Mayo Clinic.

Research included preclinical studies conducted using a mouse model in which murine myeloma 5TGM1 cells are injected intravenously into syngeneic mice. This in vivo murine model for pre-clinical evaluation of investigational therapies closely mimics human myeloma disease in the following ways: (i) the circulating monoclonal paraprotein reflects tumor burden, (ii) severe bone destruction is detected, and (iii) rapid tumor growth occurs in an immunocompetent host enabling the evaluation of therapeutic effects on survival and growth of the myeloma cells in the normal bone marrow microenvironment.

Using in vitro clonogenic assays as a measure of cellular viability (relative to controls) following treatment of five different myeloma cell lines, researchers sought to determine whether QUADRAMET when used in combination with bortezomib would be more toxic to myeloma cells than either agent alone. According to the results, bortezomib marginally decreased (10%- 30%) the clonogenicity of the various myeloma cell lines, while QUADRAMET alone reduced the colony number by approximately one third to one half. In contrast, there was a significant and synergistic increase in activity following combination treatment with a reduction in colony numbers of more than 80% for all cell lines reported.

The authors also examined the mechanism of synergistic activity between QUADRAMET and bortezomib in 5TGM1 and KAS 6/1 myeloma cell lines following incubation with QUADRAMET with or without bortezomib. In both cell lines, treatment with QUADRAMET resulted in cleavage of procaspase 3 that was much greater in cells co-treated with QUADRAMET and bortezomib, demonstrating that apoptotic pathways participated in cell death. Various pharmacological inhibitors were used to assess the contribution of the mitochondrial and receptor-related apoptotic pathways in QUADRAMET plus bortezomib-mediated lethality. These data suggest that bortezomib enhances QUADRAMET-induced apoptosis, or programmed cell death, in myeloma cells by both caspase 8 and caspase 9 dependent pathways, although the mechanisms underlying the observed in vivo synergy between QUADRAMET and bortezomib have not yet been fully defined.

Apoptosis is the main response of cells to chemotherapeutic agents and results from activation of members of the caspase family of aspartate-specific proteases. Caspases form a proteolytic network within the cell whereby upstream initiator caspases are activated early in the apoptotic process (e.g., caspase 8 and caspase 9) and then activate other downstream caspases (e.g., caspase 3 and caspase 7). The downstream caspases are largely responsible for cleavage of many other cellular proteins, leading to the morphological manifestations of apoptosis.

To determine whether bortezomib could improve the effects of QUADRAMET in multiple myeloma in vivo, the authors used a well-characterized orthotopic, syngeneic murine multiple myeloma model (5TGM1). In this study, median survival of untreated control animals was 21 days following tumor cell infusion. Monotherapy consisting of two doses of bortezomib (0.5 mg/kg) did not significantly prolong the median survival (22 days) over controls. Monotherapy consisting of a single dose of QUADRAMET (22.5 MBq) resulted in significant prolongation of median survival to 28 days (p < 0.0001). Median survival in animals treated with combination therapy comprising two doses of bortezomib (0.5 mg/kg), one day prior to and one day following QUADRAMET (22.5 MBq) showed a dramatically prolonged median survival of 49 days (p < 0.0001).

To evaluate treatment effects on bone marrow resident myeloma cells, the authors measured (by clonogenetic assay) the viability of tumor cells obtained several days following initiation of treatment for each of the groups described above. For the control and bortezomib monotherapy groups the results were similar (15.1 plus/minus 2.2 and 14.2 plus/minus 2.5 colonies per field, respectively). For animals receiving QUADRAMET monotherapy the clonogenicity was reduced by approximately 60% (6.1 plus/minus 1.3 colonies per field). In animals treated with combination therapy, the clonogenicity of the 5TGM1 cells was reduced by 90% (1.3 plus/minus 0.5 colonies per field). These findings indicate that combination treatment resulted in a significant and rapid synergistic in vivo killing of bone marrow resident myeloma cells in this mouse model system.

Another study was designed to determine whether or not myeloma progression was slower in mice receiving combined treatment with QUADRAMET and bortezomib by monitoring serum IgG2b levels and bone mineral densities. Serum IgG2b levels are an established indicator of 5TGM1 tumor burden in syngeneic mice. On day 14 of this study when the various treatment regimens were initiated, all groups showed a paraprotein level of approximately 4 g/L with no significant difference between control and treatment groups. By day 21, the paraprotein concentrations of both the control and bortezomib monotherapy treated mice had increased to 8 g/L and the animals were moribund. In contrast, day 21 paraprotein levels remained low in mice treated with either QUADRAMET monotherapy or QUADRAMET in combination with bortezomib. The paraprotein concentration in mice receiving QUADRAMET monotherapy increased to 8 g/L by day 28, while mice treated with QUADRAMET in combination with bortezomib did not reach 8 g/L until day 49.

Bone mineral density analyses were performed on days 7 and 20 after tumor cell administration. On day 7 the bone mineral densities of all the treatment groups were similar and comparable to the bone mineral densities of the control group receiving no myeloma cells. On day 20, all of the treatment groups showed a significant decrease in total bone mineral density in femora and lumbar vertebrae with the exception of the QUADRAMET and bortezomib combination group, which showed no loss of bone mineral density and were comparable to the normal non-tumor bearing mice on day 20.

Based on these findings, the study authors conclude that bortezomib is a potent, selective in vivo radiosensitizer that may substantially impact the usefulness of skeletal targeted radiotherapy, such as QUADRAMET, in multiple myeloma.

Cytogen has previously announced the initiation of a Phase I clinical trial to evaluate QUADRAMET administered in combination therapy with bortezomib in patients with relapsed or treatment-refractory multiple myeloma. QUADRAMET is also currently being evaluated in multiple myeloma patients in a Phase I combination trial with zoledronic acid (Zometa(R), Novartis AG).

"Research findings presented in December at the 2005 annual meeting of the American Society of Hematology and now expanded upon in this new publication, further strengthen the growing body of evidence demonstrating that treatment regimens incorporating QUADRAMET have activity in multiple myeloma," said William Goeckeler, Ph.D., senior vice president of operations at Cytogen. "These findings provide a scientific rationale for the investigation of the use of QUADRAMET in treating multiple myeloma and further support the clinical development of QUADRAMET beyond Cytogen's currently advancing programs in solid tumors."

About Multiple Myeloma

Multiple myeloma (also known as myeloma or plasma cell myeloma) is a cancer of the blood in which malignant plasma cells are overproduced in the bone marrow. Multiple myeloma is an incurable malignancy causing more than 10,000 deaths each year in the United States. Standard treatment is with corticosteroids, thalidomide, alkylating agents and stem cell transplantation but median survival remains only four years. Multiple myeloma is highly radiosensitive and is locally radiocurable. Novel systemic radionuclide-based therapies may therefore provide a significant advance in clinical therapy of myeloma.

About QUADRAMET

QUADRAMET is indicated for the relief of pain in patients with confirmed osteoblastic metastatic bone lesions that enhance on radionuclide bone scan. This press release describes clinical applications that differ from that reported in the QUADRAMET package insert.

QUADRAMET is an oncology product that pairs the targeting ability of a small molecule, bone-seeking phosphonate (EDTMP) with the therapeutic potential of radiation (samarium Sm-153). Skeletal invasion by prostate, breast, multiple myeloma, and other cancers often creates an imbalance between the normal process of bone destruction and formation. QUADRAMET selectively targets such sites of imbalance, thereby delivering radioactivity to areas of the skeleton that have been invaded by metastatic tumor.

QUADRAMET has demonstrated a range of characteristics that may be advantageous for the treatment of pain arising from metastatic bone disease, including early onset of pain relief (patients may experience pain relief within the first week with maximal relief generally occurring at three to four weeks after injection), predictable and reversible bone marrow toxicity or myelosuppression, ease of administration, and length of pain relief, lasting an average of four months in responding patients. QUADRAMET is administered as a single intravenous injection, usually on an outpatient basis, and exhibits selective uptake in bone with little or no detectable accumulation in soft tissue.

QUADRAMET Safety Profile

QUADRAMET causes bone marrow suppression. In clinical trials, white blood cell counts and platelet counts decreased to a nadir of approximately 40% to 50% of baseline in 123 (95%) of patients within 3 to 5 weeks after QUADRAMET, and tended to return to pretreatment levels by 8 weeks. Because of the unknown potential for additive effects on bone marrow, QUADRAMET should not be given concurrently with chemotherapy or external beam radiation therapy unless the clinical benefits outweigh the risks. Blood counts should be monitored weekly for at least 8 weeks, or until recovery of adequate bone marrow function. Non- hematologic adverse events that occurred in 5% or more of patients and greater than placebo were plain flare (7%), diarrhea (6%), infection (7%), spinal cord compression (6.5%), arrhythmias (5%), and hematuria (5%). Patients who receive QUADRAMET should be advised that for several hours following administration, radioactivity will be present in excreted urine. To help protect themselves and others in their environment, precautions need to be taken for 12 hours following administration.

A copy of the full prescribing information for QUADRAMET, including warnings, precautions, adverse events and other safety information, may be obtained in the U.S. from Cytogen Corporation by calling toll-free 800-833- 3533 or by visiting the web site at http://www.cytogen.com, which is not part of this press release.

About Bortezomib

Bortezomib, a drug in the proteasome inhibitor class of agents, is cytotoxic to a variety of cancer cell types in vitro. The proteasome pathway plays an essential role in regulating the intracellular concentration of specific proteins, thereby maintaining homeostasis within cells. Disruption of normal homeostatic mechanisms can lead to cell death.

Bortezomib also exhibits potent radiosensitizing capability (through G2/M arrest, NF-kappa B suppression and Fas induction) that may be synergistic with QUADRAMET. For this reason, current and planned trials are exploring the optimal dose and schedule of administration of bortezomib with concurrent QUADRAMET radiotherapy.

ABOUT CYTOGEN CORPORATION

Founded in 1980, Cytogen Corporation of Princeton, NJ, is a biopharmaceutical company that acquires, develops and commercializes innovative molecules targeting the sites and stages of cancer progression. Cytogen's marketed products include QUADRAMET(R) (samarium Sm-153 lexidronam injection) and PROSTASCINT(R) (capromab pendetide) kit for the preparation of Indium In-111 capromab pendetide in the United States. Cytogen also has exclusive United States marketing rights to COMBIDEX(R) (ferumoxtran-10) for all applications, and the exclusive right to market and sell ferumoxytol (previously Code 7228) for oncology applications in the United States. Cytogen's development pipeline consists of therapeutics targeting prostate- specific membrane antigen (PSMA), a protein highly expressed on the surface of prostate cancer cells and the neovasculature of solid tumors. Full prescribing information for the Company's products is available at http://www.cytogen.com or by calling 800-833-3533. For more information, please visit the Company's website at http://www.cytogen.com, which is not part of this press release.

This press release contains certain "forward-looking" statements within the meaning of the Private Securities Litigation Reform Act of 1995 and Section 21E of the Securities Exchange Act of 1934, as amended. All statements, other than statements of historical facts, included in this press release regarding our strategy, future operations, financial position, future revenues, projected costs, prospects, plans and objectives of management are forward-looking statements. Such forward-looking statements involve a number of risks and uncertainties and investors are cautioned not to put any undue reliance on any forward-looking statement. There are a number of important factors that could cause Cytogen's results to differ materially from those indicated by such forward-looking statements. In particular, Cytogen's business is subject to a number of significant risks, which include, but are not limited to: the risk of obtaining additional capital; the risk of obtaining the necessary regulatory approvals; the risk of whether products result from development activities; the risk of shifts in the regulatory environment affecting sales of Cytogen's products such as third-party payor reimbursement issues; the risk associated with Cytogen's dependence on its partners for development of certain projects, as well as other factors expressed from time to time in Cytogen's periodic filings with the Securities and Exchange Commission (the "SEC"). As a result, this press release should be read in conjunction with Cytogen's periodic filings with the SEC. The forward-looking statements contained herein are made only as of the date of this press release, and Cytogen undertakes no obligation to publicly update such forward-looking statements to reflect subsequent events or circumstances.

Cytogen Corporation

CONTACT: Media/Investors contact: Jonathan Fassberg, The Trout Group,+1-212-477-9007 x16, for Cytogen Corporation

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