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NeoPharm Announces New Clinical Trial Data for IL13-PE38QQR in Brain Cancer

Posted on: 04/30/2003

NeoPharm Announces New Clinical Trial Data for IL13-PE38QQR in Brain Cancer

Preliminary Data From Ongoing Trial Presented at the American Association Of Neurological Surgeons (AANS) 71st Annual Scientific Meeting

LAKE FOREST, Ill., April 30 /PRNewswire-FirstCall/ -- NeoPharm, Inc. (Nasdaq: NEOL) today announced that additional Phase I/II clinical trial data on IL13-PE38QQR, the Company's novel tumor-targeting agent for malignant glioma, were presented at the American Association of Neurological Surgeons (AANS) 71st Annual Scientific Meeting in San Diego. On Tuesday, April 29, 2003, Sandeep Kunwar, MD, Assistant Professor, Department of Neurological Surgery, University of California San Francisco, presented information concerning 24 patients from one of several ongoing IL13-PE38QQR Phase I/II clinical trials. The preliminary data presented provide evidence of the cytotoxic (cell killing) effects of IL13-PE38QQR against malignant glioma tumor cells at a concentration range of 0.5-2.0 micrograms/mL when infused directly into the tumor prior to surgical resection. In addition, the results also provide evidence of the clinical effect of IL13-PE38QQR when it is administered after tumor resection (removal) to areas of the brain at risk for tumor recurrence. Although not an efficacy study, prolonged survival has been observed to beyond one year.

An abstract of the presentation -- "Intratumoral and Peritumoral Convection-Enhanced Delivery (CED) of IL13-PE38QQR, a Recombinant Tumor- Targeted Cytotoxin, in Recurrent Malignant Glioma - Phase I Trial" -- appeared in the March 2003 issue of The Journal of Neurosurgery (the official journal of AANS), Volume 98, Issue 3, page 697. Founded in 1931, AANS and its 6,500 members worldwide, is a scientific and educational association dedicated to advancing the specialty of neurological surgery in order to provide the highest quality of neurosurgical care to the public. Information on the AANS meeting also is available at: .

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) with the FDA's Center for Biologics Evaluation and Research (CBER) in the laboratory of Raj K. Puri, MD, PhD.

Clinical Trial Design and Preliminary Findings

The scientific findings presented at the AANS Annual Meeting involved research conducted at several institutions including M.D. Andersen Cancer Center (MDACC), Memorial Sloan Kettering Cancer Center (MSKCC), the University of California San Francisco (UCSF), Yale University, CBER/FDA research collaborators, and NeoPharm, the trial sponsor. This particular clinical trial was designed in three stages to assess the safety, tolerability and biologic effect of IL13-PE38QQR as a complement to surgical resection of recurrent malignant glioma -- a deadly, invasive and rapidly growing type of brain tumor: Stage 1 (15 patients) and Stage 2 (9 patients) were recently completed; Stage 3 is ongoing.

The primary objective of Stage 1 was to determine the histologically effective concentration (HEC) of IL13-PE38QQR in order to provide direct evidence of the drug's ability to destroy malignant glioma tumor cells. Patients underwent an initial tumor biopsy on Day 1, followed by the placement of one intratumoral catheter and continuous convection-enhanced delivery (CED) of IL13-PE38QQR over 48 hours on Days 2-4. The tumor was then surgically resected (en bloc, or completely in one piece, if possible) on Day 8. Tumor tissue was microscopically evaluated for necrosis (cell death) in relation to catheter placement. At the end of the resection procedure, two or three catheters were placed into the peritumoral (brain adjacent to the tumor resection) cavity. Post-resection IL13-PE38QQR was administered by CED for 96 hours on Days 10-14 in an effort to prevent tumor recurrence. Pre-operative CED was well-tolerated. Secondary trial objectives included measurement of survival without tumor progression and overall survival.

In Stage 1, pre-resection IL13-PE38QQR concentrations were escalated from 0.25 to 2.0 micrograms/mL. Histopathological (microscopic) analysis revealed necrosis in patients receiving concentrations of 0.5 - 2.0 micrograms/mL. Five specimens had necrosis topographically related to the catheter in an ovoid zone extending 0.3-2.0 cm from the tip. All 15 patients were able to complete the post-resection infusion at 0.25 micrograms/mL. The most frequently observed adverse events were headache (48%), sensory symptoms (29%), motor symptoms (24%), aphasia (19%), incoordination (19%), seizure (19%), fatigue (14%), confusion (14%) and hemiparesis (14%).

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. A total of nine patients were enrolled 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. Enrollment of patients in Stage 3, to examine escalation of the infusion duration, is ongoing.

While the trial was not designed to determine efficacy, clinical and radiographic follow-up revealed survival without tumor progression of 3 to 90+ weeks. In addition, overall survival from time of treatment ranged from 12 to 90+ weeks (median 45 weeks).

"While numerous questions as to how best to optimize drug delivery remain to be addressed in this and subsequent trials, we have observed that the selective molecular targeting of IL13-PE38QQR when coupled with CED is among the more hopeful therapies we have investigated in controlling the infiltrative tumor burden," commented Sandeep Kunwar, MD, Assistant Professor, Department of Neurosurgical Surgery, University of California San Francisco, who presented the abstract at the AANS Annual Meeting. "Although this is a small group of patients, the degree of response in a Phase I study is encouraging." In recognition of his research efforts, AANS selected Dr. Kunwar to receive the Ronald L. Bittner Award for Brain Tumor Research, as the top young investigator at this year's Annual Meeting, as selected by the AANS Scientific Program Committee.

"These data support our commitment to transform progress into promise for patients with malignant glioma," commented James M. Hussey, NeoPharm's President and Chief Executive Officer. "We are working diligently to advance IL13-PE38QQR into pivotal Phase II/III clinical trials later this year. The sooner we can move IL13-PE38QQR through the testing and approval process, the sooner we can try to improve the outlook of people around the world combating this devastating disease."

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. Most people with glioblastoma multiforme usually live for less than one year after diagnosis, as there are very limited treatment options to prevent tumor progression after its first recurrence.

The Mechanism 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. It then selectively delivers 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 are not selective solely for cancer cells and cannot discriminate between cancer and healthy cells. They are also almost always administered systemically. This means that the systemic medicines are distributed throughout the body rather than being delivered 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 through positive-pressure CED, which uses catheters inserted in the tumor or brain surrounding the tumor before and/or following surgical resection of the tumor. CED is employed 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 mechanism of action study involving IL13-PE38QQR was published in the October 2002 issue of Molecular Cancer Therapeutics, a journal of the American Association for Cancer Research ( ). In a series of laboratory experiments designed to help define the molecular mechanisms for the therapeutic properties of IL13-PE38QQR, the authors identified that human glioma tumor cells that express the IL-13 receptor undergo programmed cell death, or apoptosis, following intratumoral administration of IL13-PE38QQR, leading to regression of established tumors. IL13-PE38QQR appears to be tumor-selective and induces apoptosis, which persists after the drug is no longer detectable.

IL13-PE38QQR Clinical Development Program

IL13-PE38QQR is currently under investigation in three ongoing Phase I/II clinical trials. 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. Recent human clinical data from this study were presented in 2002 at the Seventh Annual Meeting of the World Federation of Neuro-Oncology/Society for Neuro-Oncology (SNO). These data indicated that IL13-PE38QQR might have potential as a safe and effective treatment for malignant glioma. Additional findings have recently been accepted for presentation at the American Society for Clinical Oncology (ASCO) Annual meeting in Chicago (May 31-June 2, 2003).

The second clinical study, which is the subject of this press release and the most recent results of which are described above, was initially presented in 2001 at the World Federation of Neuro-Oncology Society/SNO meeting, with additional data announced in 2002 at the CNS Section on Tumors Fifth Biennial Satellite Symposium, held in conjunction with the AANS 70th Annual Scientific Meeting in Chicago and the Fifth Congress of the European Association of Neuro-Oncology (EANO) in Florence.

Finally, enrollment is ongoing in the first global Phase I/II clinical trial of IL13-PE38QQR; the third NeoPharm sponsored clinical study to date in patients with recurrent or progressive malignant glioma. The trial is being conducted at six participating sites including University Hospital Eppendorf and University Hospital Kiel in Germany, Chaim Sheba Medical Center and Dana Hospital Tel Aviv in Israel, and the Cleveland Clinic and the University of Colorado in the United States. This trial's first cohort of three patients was enrolled in the first month of the study and the enrollment for the fifth cohort of patients has recently been completed. Study findings have recently been accepted for presentation at the American Society for Clinical Oncology (ASCO) Annual meeting in Chicago (May 31-June 2, 2003).

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

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

Additional information about NeoPharm and recent ne

ws releases can be obtained by visiting NeoPharm's Website at: . For copies of scientific abstracts related to IL13-PE38QQR from recent medical meetings, contact Lauren Greis, 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 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 candidates, 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 candidates that could slow or prevent products coming to market, 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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/CONTACT: Larry Kenyon, CFO of NeoPharm, Inc., +1-847-295-8678, or Investors, Janet Dally of MontRidge, LLC, +1-203-894-8038, or Media, Kristin Fayer of Outlook Marketing, +1-847-509-3099/ /Web site: / (NEOL)

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