Two novel supercomputer-engineered anticancer agents to benefit tumour treatment

Philadelphia 12 April 1999 At the 90th Annual Meeting of the American Association for Cancer Research (AACR), BioNumerik Pharmaceuticals has presented new data on two novel supercomputer-engineered small molecule agents designed to help address common and important unmet needs in cancer therapy. BNP7787 is a new chemo-protecting agent, developed to increase the therapeutic index and protect against the common toxicities of widely used anticancer drugs, such as taxane and platinum based agents. In turn, karenitecin is a novel silicon-containing anticancer compound that has showed potent antitumour activity at concentrations as low as parts per trillion in laboratory testing with human cancer cell lines and in animals bearing human tumours. The agent is in the drug class known as camptothecins and has been designed to avoid problems with oral bio-availability, unfavourable metabolism, toxicity and drug resistance that have been associated with other camptothecins.

Advertisement

At the 90th Annual Meeting of the American Association for Cancer Research (AACR), BioNumerik Pharmaceuticals has presented new data on two novel supercomputer-engineered small molecule agents designed to help address common and important unmet needs in cancer therapy. BNP7787 is a new chemo-protecting agent, developed to increase the therapeutic index and protect against the common toxicities of widely used anticancer drugs, such as taxane and platinum based agents. In turn, karenitecin is a novel silicon-containing anticancer compound that has showed potent antitumour activity at concentrations as low as parts per trillion in laboratory testing with human cancer cell lines and in animals bearing human tumours. The agent is in the drug class known as camptothecins and has been designed to avoid problems with oral bio-availability, unfavourable metabolism, toxicity and drug resistance that have been associated with other camptothecins.

BioNumerik has introduced new data from animal and laboratory studies that confirm the ability of BNP7787 to protect against drug-induced nerve damage or neuro-toxicity, which is associated with administration of taxane and platinum drugs, two widely used classes of anticancer agents. In addition, BioNumerik reported positive laboratory evidence asserting the fact that BNP7787 does not reduce the antitumour effects of taxanes, platinum or other cytotoxic drugs in human cancer cell lines and in implanted human cancers in animals. Taxane and platinum drugs both are important in the treatment of a variety of cancers, like breast, lung, ovarian and many other tumours. However, the administration of these agents, particularly in their combined administration, frequently results in clinically important neuro-toxicity that poses certain risks and possibly limits the amount of the drug that can be given. Currently, there is no commercially available agent that effectively protects against such drug induced neuro-toxicity.

The studies presented at the AACR Conference describe observations from non-clinical research conducted by BioNumerik together with investigators at the University of Milan and Novuspharma, Italy. In these studies, the pre-treatment with BNP7787 by either the oral or intravenous route followed by administration of otherwise toxic doses of either paclitaxel or cisplatin has resulted in complete protection against nerve damage, as measured by the changes in nerve conduction velocity. The administration of identical doses of either paclitaxel or cisplatin without BNP7787 amounted in a significant neuro-toxicity in the treated subjects. Outcomes in the BNP7787 pre-treated cisplatin or paclitaxel populations were statistically significant relative to the subjects who received either paclitaxel or cisplatin without BNP7787.

These laboratory observations are highly supportive to ongoing clinical tests of BNP7787, since no patient in the ongoing US or European Phase I human clinical trials with BNP7787 has showed symptoms of clinically important neuro-toxicity. This includes patients who have received more than 8 cycles of paclitaxel and cisplatin, and more than 9 cycles of single agent cisplatin. It is notable that only one patient out of 35 patients, globally submitted to this BNP7787 pre-treatment with either paclitaxel + cisplatin or cisplatin alone developed Grade 2 neuro-toxicity. The incidence of clinically significance in neuro-toxicity in the former paclitaxel/cisplatin regimen alone is more than 70% at 6 cycles and approximately 100% with 9 cycles of cisplatin. For the moment, BioNumerik is finalizing its strategy for the future advancement of BNP7787 into more advanced clinical trials to support possible approval.

Investigators at BioNumerik have also identified the primary mechanism of platinum associated neuro-toxicity, that involves damage to tubulin caused by platinum drugs. Tubulin is a protein that is in high concentrations in all cells, including nerve cells. The company confirmed that BNP7787 appears to protect against tubulin toxicity caused by platinum and taxanes; and that increasing concentrations of BNP7787 result in increasing levels of tubulin protection. Richard L. Schilsky, M.D., Director of the University of Chicago Cancer Research Center and Principal Investigator for the BNP7787 Phase I trial being conducted at the University of Chicago Medical Center, indicated that BNP7787 is well tolerated and appears to prevent significant neuro-toxicity. No patient in the study has experienced worse than the Grade 2 neuropathy despite high cumulative doses of cisplatin and paclitaxel. It is also encouraging that tumour responses have been observed in this trial.

In a separate study titled "Karenitecins: new pre-clinical developments with BNP1350; a novel, potent highly lipophilic camptothecin", the company presented data comparing the antitumour activity of BioNumerik's compound, karenitecin BNP1350, to the activity of SmithKline Beecham's topotecan. In this research, conducted in mice which were bearing human ovarian tumours, both oral and intravenous karenitecin showed significantly superior antitumour activity relative to topotecan administered by the same route. This work was performed in collaboration with investigators at the Roswell Park Cancer Institute in Buffalo, New York. The company has also determined in laboratory studies that karenitecin has superior antitumour potency in over 20 different types of common human solid tumours relative to topotecan and other existing camptothecin derivatives. No evidence of cumulative toxicity has been observed in the animal studies conducted with karenitecin.

Karenitecin is in Phase I clinical trials at the University of Chicago Medical Center and it represents BioNumerik's third new drug that has been brought from discovery to the clinic with the help of supercomputer simulations. The pre-clinical development time for BioNumerik's three drugs has averaged 18 to 24 months compared to the pharmaceutical industry average of six years. In pre-clinical animal studies, orally administered karenitecin demonstrated excellent antitumour activity against human solid tumours such as prostate, colon, breast, lung, melanoma and ovary, and a superior potency against a variety of human cancers compared to the existing camptothecin derivatives. Karenitecin has equally showed the ability to bypass tumour-mediated drug resistance mechanisms to which many other camptothecins appear to be susceptible. Because it is lipophilic, karenitecin might have enhanced tissue penetration, drug delivery and bio-availability compared to the existing water soluble camptothecins.

BioNumerik Pharmaceuticals, headquartered in San Antonio, is an emerging pharmaceutical company with an innovative, proprietary technology platform for the rapid discovery and clinical development of small molecule based pharmaceuticals for cancer. The company is a leader in a powerful new area called "mechanism based drug discovery" integrating medicine, quantum physics, synthetic chemistry, pharmaceutical sciences, and Silicon Graphics and Cray Research supercomputing. Its approach is considered to be a fourth generation technology relative to drug and automated screening, combinatorial chemistry, and rational drug design. BioNumerik believes its approach has the potential to greatly reduce the time to discover and bring new drugs into clinical development and to minimize risk of failure in clinical development.


Leslie Versweyveld

[Medical IT News][Calendar][Virtual Medical Worlds Community][News on Advanced IT]