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NeoPharm and Collaborators Present IL13-PE38QQR Clinical Data in Brain Cancer


Posted on: 11/17/2003

NeoPharm and Collaborators Present IL13-PE38QQR Clinical Data in Brain Cancer


LAKE FOREST, Ill., Nov. 17 /PRNewswire-FirstCall/ -- NeoPharm, Inc. (Nasdaq: NEOL) today announced that additional Phase I/II worldwide clinical trial data on IL13-PE38QQR, the Company's novel tumor-targeting agent for malignant glioma, from three clinical studies were presented at the 8th Annual Meeting of the Society for Neuro-Oncology (SNO), held in Keystone, CO from November 13-16, 2003. Three abstracts (#RA-5, #TA-15 and #TA-39) were presented as poster discussions and the fourth (#TA-30) was presented as a podium presentation. The overall Phase I/II preliminary data from these three studies and a fourth drug distribution study represent a combined experience from more than 75 patients in various clinical settings, including intra- and peritumoral delivery of IL13-PE38QQR for treatment of malignant glioma. The findings suggest consistent evidence of tumor cytotoxic, cancer cell killing, effects of IL13-PE38QQR against malignant glioma tumor cells and, although not designed to address efficacy, encouraging survival results continue to be observed beyond two years. Copies of NeoPharm's IL13-PE38QQR abstracts have been published in Neuro-Oncology, Volume 5, Issue 4, October 2003, http://neuro-oncology.mc.duke.edu. Copies of the actual posters presented, with updated data, are available on the NeoPharm website www.neophrm.com.

"The findings across the Phase I/II studies appear to be most promising with peritumoral infusion into brain tissue at risk for tumor recurrence and spread," commented James M. Hussey, NeoPharm's President and Chief Executive Officer. "These data provide additional support to our commitment to advance IL13-PE38QQR into a pivotal Phase III clinical trial for the treatment of patients with malignant glioma. We are especially pleased by our advances with convection-enhanced delivery (CED) and believe that CED will play an important role in brain tumor therapy in the future."

NeoPharm is preparing to initiate a pivotal Phase III clinical trial for IL13-PE38QQR (the PRECISE trial) for the treatment of glioblastoma multiforme, a deadly form of brain cancer. The Company currently anticipates that the drug supply for PRECISE will be available by the middle of December 2003, and that the clinical trial will begin in the fourth quarter of 2003 or the first quarter of 2004. IL13-PE38QQR has received orphan drug designation in Europe and the U.S., and fast track drug development program status from the U.S. Food and Drug Administration (FDA). NeoPharm has exclusively licensed IL13-PE38QQR from the National Cancer Institute and the FDA, and is developing the agent under a Cooperative Research and Development Agreement (CRADA) in collaboration with the laboratory of Raj K. Puri, MD, PhD, at FDA Center for Biologics Evaluation and Research (CBER).

Phase I/II IL13-PE38QQR Preliminary Findings

IL13-PE38QQR is currently under investigation in four ongoing Phase I/II clinical trials in patients with recurrent malignant glioma. The first IL13-PE38QQR clinical study is being conducted through the NCI Clinical Trial Evaluation Program (CTEP)-funded New Approaches to Brain Tumor Therapy (NABTT) Consortium. Johns Hopkins University Medical Center is the coordinating site for NABTT. Results from 21 patients enrolled in this trial were presented as a poster discussion at SNO (Abstract #TA-39). These patients were all diagnosed with recurrent supratentorial malignant glioma. IL13-PE38QQR is administered by CED, a novel technique using positive pressure infusion to distribute therapeutic agents within brain tumors and in areas at risk for tumor spread. Two infusions are planned eight weeks apart without planned tumor resection. Patients are dosed with IL13-PE38QQR via two, intra-tumoral catheters at 200 microliters/catheter/hour for 96 hours (total 38.4 mL). The IL13-PE38QQR concentration is being increased in individual cohorts to determine the maximum tolerated dose (MTD). Six patients received IL-13PE38QQR at 0.125 micrograms/mL followed by three patients at each dose level of 0.25, 0.50, 1.0, 2.0 and 4.0 micrograms/mL. Intratumoral infusion of the drug appears to be well tolerated in this population, permitting dose escalation and patient accrual to proceed. Similar adverse events occurred across all cohorts, with most being neurological or related to neurosurgical site. Tumor response, either microscopic or radiologic, has been observed in some patients. Although this trial was not designed to determine efficacy, extended patient survival has also been observed.

The second clinical study, presented in two poster discussion sessions (Abstracts #RA-5 [radiographic findings] & #TA-15 [overall findings]), involves several institutions including the University of California San Francisco (UCSF), M.D. Andersen Cancer Center (MDACC), Memorial Sloan- Kettering Cancer Center (MSKCC), and Yale University. Primary objectives of this study include, determination of the dose of IL13-PE38QQR that produce tumor cell death, referred to as the histologically effective concentration (HEC) and the corresponding drug toxicities following IL13-PE38QQR infusion into the tumor and areas adjacent to the tumor. Secondary objectives are the determination of time to tumor progression and patient survival. A total of 29 patients have been treated to date in this study. In Stage 1, patients receive drug intratumorally before (escalating concentrations) and peritumorally after (0.25 micrograms/mL, fixed) tumor resection. On Day 8 of Stage 1, en bloc tumor resection is performed to assess HEC and 2-3 peritumoral catheters are placed adjacent to the resection site in areas where residual tumor cells may be present. In Stage 2, the pre-resection infusion is eliminated and post-resection drug concentrations are escalated. In Stage 1, 15 patients were treated at escalating pre-resection concentrations (0.25, 0.50, 1.0, and 2.0 micrograms/mL). Histopathological (microscopic) analysis revealed early tumor necrosis in most patients receiving concentrations of 0.5 micrograms/mL and higher. Five specimens had necrosis topographically related to the catheter in an ovoid zone extending up to 2.5 cm. All patients were able to complete the post-resection infusion at 0.25 micrograms/mL.

With confirmation of the HEC in Stage I, the pre-resection infusion was omitted and escalation of post-resection peritumoral infusion concentration began at 0.5 micrograms/ml in Stage 2. Stage 2 findings were presented earlier this year during a plenary session of the American Association of Neurological Surgeons (AANS) 71st Annual Scientific Meeting and as a poster presentation at the 15th International Conference on Brain Tumor Research and Therapy. A total of nine patients completed Stage 2 to determine the maximum tolerated infusion concentration (MTIC). All patients tolerated the peritumoral infusion and no dose limiting toxicities were observed for the six patients at 0.5 micrograms/mL. Two of three patients at 1.0 micrograms/mL developed symptomatic radiographic changes near the former catheter insertion location. As a result, 0.5 micrograms/mL was designated the MTIC post- resection. Enrollment of patients in Stage 3, to examine escalation of the infusion duration, has completed. Stage 4, the final part of the study, to assess deferred catheter placement post tumor resection is well underway. While this trial was not designed to determine efficacy, clinical follow-up has revealed prolonged overall patient survival from time of treatment to up to 125+ weeks (median 52 weeks). Furthermore, survival was more prolonged in patients with optimal catheter placement and guidelines have been developed to insure consistent catheter placement. "The data from this study are promising and offer the potential for a therapeutic advance in the treatment of this dismal disease," commented Sandeep Kunwar, MD, Assistant Professor of Neurological Surgery and Principal Investigator, Brain Tumor Research Center, at the University of California, San Francisco.

The third clinical study presented as a podium presentation (Abstract #403) at SNO described preliminary data from a clinical trial being conducted at six participating sites including Tel Aviv Sourasky Medical Center and Chaim Sheba Medical Center in Israel, University Hospital Eppendorf and University Hospital Kiel in Germany, and the Cleveland Clinic and the University of Colorado in the United States. This study is designed to determine the maximum tolerated dose (MTD) in terms of infusion duration and drug concentration of IL13-PE38QQR delivered by CED via one or two intratumoral catheters in patients with recurrent or progressive malignant glioma prior to planned tumor resection. Cohorts of 3-6 patients receive 0.50 micrograms/mL with escalating duration (4-7 days) to determine a MTD based on duration. After determination of maximum duration, drug concentration is escalated from 1.0-4.0 micrograms/mL in cohorts of 3-6 patients to determine a MTD based on concentration. Tumor necrosis at 6-13 days following infusion and proportion of patients surviving at 6 months is also assessed. Twenty- two patients have been enrolled; comprising all four duration periods and three out of four concentration levels. Duration of infusion up to seven days and concentrations of 3.0 micrograms/mL appear to be safe and well tolerated. Evidence of tumor necrosis in some patients has also been observed. Although this trial was not designed to determine efficacy, extended patient survival has also been observed.

A fourth clinical study being conducted at Duke University is assessing drug distribution in patients undergoing treatment with IL13-PE38QQR. This study utilizes a radioactive tracer to confirm drug distribution and parameters for CED of drug.

For additional details regarding IL13-PE38QQR trial design, enrollment criteria and participating centers please refer to www.clinicaltrials.gov (keyword: IL13-PE38QQR).

Background Information

Malignant Glioma: The Disease

Malignant glioma, which includes glioblastoma multiforme and anaplastic astrocytoma tumors, is diagnosed in approximately 17,500 people in the U.S. annually and claims approximately the same number of lives each year. As there are very limited treatment options to prevent tumor progression, most people with glioblastoma multiforme usually live for less than one year after initial diagnosis, and less than six months after the first recurrence.

Mechanism of Action of IL13-PE38QQR

Malignant glioma cells, as compared to normal brain cells, express interleukin-13 (IL13) receptors at a high density. IL13 is an immune regulatory cytokine, or protein, secreted by cells. IL13-PE38QQR (a recombinant protein) is designed to detect and bind to IL13 receptors on the surface of malignant glioma cancer cells, and then selectively deliver a potent bacterial cytotoxic agent called PE38, derived from a bacteria called Pseudomonas aeruginosa, to destroy tumor cells while sparing healthy surrounding cells. In contrast, conventional, non-specific chemotherapeutic drugs attack abnormal cancer cells by stopping them from dividing and reproducing, but can also damage normal cells because these agents do not discriminate between cancerous and healthy cells. Furthermore, standard chemotherapy drugs are usually administered systemically, which leads to their distribution throughout the body rather than to one area, such as a tumor in the brain. Common chemotherapy side effects may occur when bone marrow is damaged and cannot produce enough red blood cells (causing weakness and fatigue), white blood cells (lowering the body's resistance to infections) or platelets (preventing blood from clotting properly, which can lead to excessive bleeding).

IL13-PE38QQR, on the other hand, is being developed as a highly specific tumor-targeting agent. It is administered directly to the tumor by positive- pressure CED, through catheters inserted in the tumor or brain surrounding the tumor, before and/or following surgical resection of the tumor. CED is designed to infuse IL13-PE38QQR directly to the tumor site and adjacent brain tissue to prevent recurrence of tumor cell growth. Investigators have sought to identify the optimum "therapeutic window" to provide patients with the safest, most effective dose at sufficient concentration to kill malignant cells while minimizing exposure to healthy brain tissue.

A study describing tumor regression mechanisms by IL-13 receptor-targeted cancer therapy involving apoptotic pathways was published in the 1 January 2003 issue of the International Journal of Cancer, a Publication of the International Union Against Cancer. The authors provide evidence that human glioma tumor cells that express the IL-13 receptor undergo programmed cell death, or apoptosis, following intratumoral administration of IL13-PE38QQR, by two major pathways.



About NeoPharm NeoPharm, Inc., based in Lake Forest, IL, is a publicly traded biopharmaceutical company dedicated to the research, development and commercialization of new and innovative cancer drugs for therapeutic applications. The Company has a broad portfolio of compounds in various stages of development.

Additional information about NeoPharm and recent news releases can be obtained by visiting NeoPharm's Website at: www.neophrm.com . For copies of scientific abstracts related to IL13-PE38QQR from recent medical meetings, contact Ken Johnson, PharmD, NeoPharm, at 847.295.8678.

Forward Looking Statements

This press release contains "forward-looking statements" within the meaning of Section 27A of the Securities Act of 1933 and Section 21E of the Securities Exchange Act of 1934. The Company has tried to identify such forward-looking statements by use of such words as "expects," "intends," "hopes," "anticipates," "believes," "could," "may," "evidences" and "estimates," and other similar expressions, but these words are not the exclusive means of identifying such statements. Such statements include, but are not limited to, any statements relating to the Company's drug development program, including, but not limited to the initiation, progress and outcomes of clinical trials involving IL13-PE38QQR, and any other statements that are not historical facts. Such statements involve risks and uncertainties, including, but not limited to, those risks and uncertainties relating to difficulties or delays in development, testing, regulatory approval, production and marketing of the Company's drug and non-drug compounds, including, but not limited to IL13-PE38QQR, uncertainty regarding the availability of third party lyophilization capacity, uncertainty regarding the outcome of damage claims made by or against the Company, including the outcome of the pending arbitration with Pharmacia, unexpected adverse side effects or inadequate therapeutic efficacy of the Company's drug and non-drug compounds that could slow or prevent products coming to market, uncertainty regarding the Company's ability to market its drug and non-drug products directly or through independent distributors, the uncertainty of patent protection for the Company's intellectual property or trade secrets and other risks detailed from time to time in filings the Company makes with the Securities and Exchange Commission including our annual reports on Form 10-K and our quarterly reports on Forms 10-Q. Such statements are based on management's current expectations, but actual results may differ materially due to various factors, including those risks and uncertainties mentioned or referred to in this press release. Accordingly, you should not rely on these forward-looking statements as a prediction of actual future results.

SOURCE NeoPharm, Inc.

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11/17/2003 /CONTACT: Larry Kenyon, CFO of NeoPharm, Inc., +1-847-295-8678, Investors contact, Janet Dally of MontRidge, LLC, +1-203-894-8038, or Media contact, Kristin Fayer of Outlook Marketing, +1-847-509-3099/ /Web site: http://www.neophrm.com /

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