Overview
Karenitecin®, also known as BNP1350, is a member of a novel class of camptothecins that we have named karenitecins™. Camptothecins are chemotherapy drugs that have anti-tumor activity in colorectal, ovarian and lung cancers, but their use has been limited in part because of common and serious side effects including diarrhea or depression in the production of white blood cells or red blood cells by the bone marrow. BioNumerik has designed karenitecin with a view to address many of the clinical limitations common to camptothecins that are used clinically. Karenitecin, a novel camptothecin based silicon-containing molecule, is currently in Phase III clinical development.
 | Camptothecins |
Camptothecins are a class of highly active anticancer drugs. Several camptothecins are currently marketed by pharmaceutical companies in the U.S. and several more are undergoing development. Camptothecins are reported to act by inhibiting 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. The clinical use of camptothecins has been limited due to an incomplete understanding of camptothecins’ mechanism of action, high levels of toxicity, poor water solubility and inconsistent antitumor activity in different patients. Nearly all naturally occurring camptothecins are 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. We believe increased water solubility reduces 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.
| Karenitecins™ |
Karenitecins™ 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 camptothecins, karenitecins™ are poorly water-soluble, but we have developed a 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. Unlike currently marketed camptothecins, karenitecins™ have not been susceptible to commonly occurring drug-resistance mechanisms in preclinical studies. Karenitecins™ have been engineered for more favorable drug metabolism to achieve improved antitumor activity and reduced toxicity relative to other camptothecin derivatives.
BioNumerik has pursued the discovery and development of karenitecins™ with a view to:
- increase antitumor efficacy;
- enhance oral bioavailability;
- achieve more consistent pharmacokinetic behavior;
- attempt to reduce common and serious toxicities, such as severe diarrhea;
- reduce susceptibility to unfavorable metabolism which leads to inactivation and/or toxicity;
- reduce susceptibility to common tumor-mediated drug resistance mechanisms.
Karenitecin® Clinical Trial Summary
Phase I Trials A single-center, non-randomized open-label Phase I study of intravenous karenitecin® was conducted in adult patients with advanced and incurable types of cancer. This study enrolled a total of 51 patients. The primary objectives for this Phase I trial were to determine the maximum tolerated dose (MTD) and a clinically recommended dose and administration schedule of karenitecin® for use in future clinical studies and to characterize the pharmacokinetics of karenitecin®.
A multi-center, non-randomized, open-label Phase I study of intravenous karenitecin® was conducted in pediatric patients with solid tumors. This study enrolled a total of 19 patients. The primary objectives for this Phase I trial were to determine the maximum tolerated dose (MTD) at which reversible side effects occur and to characterize the pharmacokinetic behavior of karenitecin® in pediatric patients. The endpoints of the study included identifying any clinically important side-effects and to determine a recommended Phase II dose for use in pediatric patients.
The major dose-limiting adverse events observed in the Phase I trials included major reduction of the white blood cells (cells that fight infection) and severe reduction of platelets (cellular components in the blood that help it to clot). These adverse events were reversible and were expected based upon pre-clinical toxicity studies in animals.
An additional Phase I clinical trial of karenitecin® has been completed with primary adult brain tumors. The purpose of this Phase I study was to characterize potentially important metabolism and biotransformation of karenitecin® that may be observed in patients with primary brain tumors who receive anticonvulsant therapy that induces p450 metabolism in the liver. Such unfavorable metabolism has been observed in patients who receive other commercially available camptothecins.
We have initiated Phase I testing of an oral formulation of karenitecin® in cancer patients with solid tumors. The objectives of the Phase I trial are to determine the safety and maximum tolerated dose (MTD) and recommended Phase II dose of oral karenitecin®, and to characterize the oral bioavailability and pharmacokinetic behavior of orally administered karenitecin® in patients with cancer.
Phase II Trials Five U.S. Phase II clinical trials (including the Phase I/II trial discussed above) have been completed for Karenitecin®, including trials in patients with , metastatic melanoma, advanced ovarian cancer, advanced non-small cell lung cancer, or adult brain tumors.
Based on the Phase II data, we are pursuing Phase III clinical development of Karenitecin®.
We also believe that the outpatient administration of intravenous or oral Karenitecin® may offer some potential therapeutic and convenience advantages for patients in comparison to currently marketed camptothecins.
Phase III Trials We have commenced a global Phase III clinical trial of karenitecin® in advanced ovarian cancer patients. The Phase III trial has been designed as a global, randomized, multi-center open label trial to prospectively evaluate the safety and efficacy of karenitecin compared to the chemotherapy drug topotecan (also known as Hycamtin®). Either karenitecin or topotecan will be given intravenously daily for 5 consecutive days repeated every 3 weeks to advanced ovarian cancer patients who have previously been treated with platinum and taxane chemotherapy drugs but have become resistant to the platinum/taxane therapy. 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. We believe the safety and efficacy outcomes from the previously completed karenitecin Phase II advanced ovarian cancer trial compare favorably with the historically reported results of approved agents. We also believe that there is a large unmet need for 2nd and 3rd -line therapies that can prevent progression of recurrent or progressive ovarian cancer with reduced risk of cumulative toxicity in patients who have become resistant to platinum/taxane-based chemotherapy. Based on the Phase II outcomes and our pre-clinical data, we are pursuing karenitecin Phase III testing in advanced ovarian cancer patients who have become resistant to platinum/taxane chemotherapy.