Karenitecin^®

Overview

We are developing Karenitecin^® (also known as BNP1350) as an investigational new anti-tumor drug in the camptothecin class of chemotherapy drugs. We are currently conducting an international Phase III clinical trial of Karenitecin^® in advanced ovarian cancer patients.

We believe that Karenitecin has the potential for fewer side-effects, improved efficacy, less susceptibility to drug resistance mechanisms and an improved safety profile compared to the currently marketed camptothecin drugs. Based on prior studies, we believe Karenitecin has a lower incidence of severe diarrhea than that caused by the marketed camptothecin drug irinotecan (Camptosar^®, Pfizer), and a lower incidence and severity of anemia, neutropenia and thrombocytopenia than that caused by the marketed camptothecin drug topotecan (Hycamtin^®, GlaxoSmithKline).

Irinotecan and topotecan, the only FDA-approved camptothecins, are used for the treatment of patients with colorectal, small cell lung, ovarian and cervical cancers. We believe Karenitecin^® may have the following advantages over these drugs:

• Improved effectiveness in the treatment of certain cancers, with a potentially improved safety profile and fewer of the dose-limiting side-effects caused by other camptothecin drugs including:
• lower incidence of severe diarrhea than that caused by irinotecan;
• lower incidence of grade 3 or grade 4 anemia, neutropenia and thrombocytopenia than that caused by topotecan.
• Potential oral administration, due to Karenitecin’s high oral bioavailability (> 40%), making Karenitecin more convenient for patients and physicians.
• Less susceptibility than currently marketed camptothecins to common drug resistance mechanisms found in many types of human cancer cells, including those that are specific to the camptothecin class.

Ongoing Karenitecin Phase III Trial in Advanced Ovarian Cancer.

In early 2008, we commenced a multi-national Phase III clinical trial of Karenitecin in platinum- and taxane-refractory or resistant advanced epithelial ovarian cancer patients. This trial has been designed as a randomized, multi-center open label Phase III trial to prospectively evaluate the safety and efficacy of Karenitecin compared to the currently marketed drug topotecan (also known as Hycamtin^®), with both drugs to be given intravenously daily for 5 consecutive days repeated every 3 weeks. The primary endpoint for the trial is Progression Free Survival, defined as the time period from the date of patient randomization to the date of first radiographic documented progressive disease or date of death due to any cause. We have received written agreement from the U.S. Food and Drug Administration (FDA) on a Special Protocol Assessment (SPA) regarding the clinical trial design and protocol for the trial. The current clinical sites for the Karenitecin Phase III ovarian trial are located in the United States, Russia and Eastern Europe.

We believe the safety and efficacy outcomes from our previously completed Karenitecin Phase II advanced ovarian cancer trial compare favorably with the historically reported results for approved agents. We also believe that there is a large unmet need for 2^nd and 3^rd -line therapies that can prevent progression of recurrent or progressive ovarian cancer with reduced risk of cumulative toxicity in patients who are resistant to platinum/taxane-based chemotherapy.

Camptothecins and Their Limitations.

Camptothecins are a class of highly active chemotherapy drugs that have anti-tumor activity in colorectal, ovarian, cervical and lung cancers. Camptothecins are reported to act by affecting the action of Topoisomerase I, an enzyme found in cells that is involved in the synthesis and replication of DNA. The enzyme is found in significantly higher amounts, and degrades more slowly, in many types of cancer cells as compared to normal cells. There are other potential mechanisms for camptothecins and their antitumor activity which are being studied; thus the understanding of camptothecins’ molecular pharmacology appears to be somewhat limited. The clinical use of camptothecins has been limited, however, due to an incomplete understanding of camptothecins’ mechanisms of action, high levels of toxicity, poor water solubility and inconsistent antitumor activity in different patients.

The use of camptothecins has also been limited in part because of common and serious side effects including diarrhea or depression in the production of white blood cells, platelets or red blood cells by the bone marrow. Nearly all naturally occurring camptothecins are very poorly water-soluble. This property enhances their antitumor activity but makes them difficult, and in many instances impossible, to formulate and administer. As a result, many camptothecins on the market or in development have been made water-soluble so that they can be dissolved in water and more easily administered to patients. We believe increased water solubility can reduce camptothecins’ anti-tumor activity by decreasing the drug’s ability to cross cellular membranes and may also increase their propensity to cause harmful side effects.

Addressing the Clinical Limitations of Camptothecins.

Karenitecins™, a class of camptothecins discovered and developed by BioNumerik, have several potentially useful features, including broad anticancer activity, favorable metabolism and substantially reduced sensitivity to common tumor-mediated drug resistance mechanisms.

Like most other naturally occurring camptothecins, karenitecins are poorly water-soluble. However, we have developed a proprietary process to formulate them that is aimed at avoiding the reduced antitumor activity and increased risk of side effects associated with making camptothecins water-soluble. In preclinical studies, karenitecins appear to have a higher amount of absorption following oral administration, thereby allowing more convenient oral administration. Also, unlike currently marketed camptothecins, karenitecins have not been susceptible to commonly occurring drug-resistance mechanisms in preclinical studies. We have engineered Karenitecins for more favorable drug metabolism aimed at achieving improved antitumor activity and reduced toxicity relative to other camptothecin derivatives by the use of novel silicon-based chemistry.

Additional Ongoing Karenitecin Trials.

In addition to the Karenitecin Phase III ovarian cancer trial, the following clinical trials for Karenitecin are ongoing in the United States:

• a Phase I clinical trial to evaluate the potential safety and effectiveness and the pharmacokinetics and oral bioavailability of intravenously vs. orally administered Karenitecin in adult patients with a variety of solid tumors.

Prior Phase II Karenitecin Clinical Trials.

Four U.S. Phase II clinical trials have been completed for Karenitecin, including trials in patients with advanced ovarian cancer, metastatic melanoma, advanced non-small cell lung cancer, or adult brain tumors. The major dose-limiting side-effects that we observed were neutropenia (reduction in white blood cell counts), anemia, and thrombocytopenia (reductions in the number of platelets in the blood). Based on the Phase II data, we are pursuing the Karenitecin Phase III ovarian cancer trial.

Potential Additional Karenitecin Development Areas.

In addition to treatment for ovarian cancer, we are evaluating the possibility of additional Phase III trials for Karenitecin in the areas of metastatic melanoma, advanced non-small cell lung cancer, small cell lung cancer, colorectal cancer, lymphomas, leukemias and breast cancer.