BioNumerik's novel chemoprotecting agent BNP7787 appears to protect against taxane and platinum associated neurotoxicity
Novel class of highly lipophilic camptothecins, known as Karenitecins, demonstrates oral antitumor activity and high potency
Philadelphia, PA; April 12, 1999 -- BioNumerik Pharmaceuticals, Inc. this week is presenting new data on two novel supercomputer-engineered small molecule agents designed to help address common and important unmet needs in cancer therapy. BioNumerik's BNP7787 is a novel chemoprotecting agent designed to increase the therapeutic index and protect against the common toxicities of widely used anticancer drugs, including taxane and platinum based agents.
BioNumerik's karenitecin is a novel silicon-containing anticancer compound that has demonstrated potent antitumor activity at concentrations as low as parts per trillion in laboratory testing with human cancer cell lines and in animals bearing human tumors. Karenitecin is in the drug class known as camptothecins and has been designed to avoid problems with oral bioavailability, unfavorable metabolism, toxicity and drug resistance that have been associated with other camptothecins.
BNP7787 Studies
BioNumerik is presenting new data from animal and laboratory studies that further confirm the ability of BNP7787 to protect against drug-induced nerve damage (or neurotoxicity) that is associated with administration of taxane and platinum drugs, two widely used classes of anticancer compounds. In addition, BioNumerik is reporting additional confirmatory laboratory evidence that BNP7787 does not reduce the antitumor effects of taxanes, platinum or other cytotoxic drugs in human cancer cell lines or in implanted tumors in animals.
Taxane and platinum drugs are administered in the treatment of a variety of common cancers including breast, lung, ovarian and many other tumors. Some of the most widely used taxane and platinum agents are the drugs paclitaxel (Taxol), docetaxel (Taxotere), carboplatin (Paraplatin) and cisplatin (Platinol AQ). However, the administration of these agents (particularly their administration in combination) frequently results in clinically important neurotoxicity that poses certain risks and can limit the amount of the drug that can be given. Currently, there is no commercially available agent that effectively protects against such drug induced neurotoxicity.
The studies presented at AACR describe observations from nonclinical studies conducted by BioNumerik in collaboration with investigators at the University of Milan and Novuspharma, Italy. In these studies, pretreatment with BNP7787 by either the oral or intravenous route followed by administration of otherwise toxic doses of either paclitaxel or cisplatin resulted in complete protection against nerve damage (as measured by changes in nerve conduction velocity). The administration of identical doses of either paclitaxel or cisplatin without BNP7787 resulted in significant neurotoxicity in the treated subjects. The outcomes in the BNP7787 pretreated cisplatin or paclitaxel populations were statistically significant relative to the subjects that received either paclitaxel or cisplatin without BNP7787.
These laboratory observations are strongly supportive of ongoing clinical testing of BNP7787, since no patient in BioNumerik's currently ongoing U.S. or European Phase I human clinical trials with BNP7787 has experienced clinically important neurotoxicity. This includes patients who have received more than 7 cycles of paclitaxel and cisplatin, and more than 9 cycles of single agent cisplatin. The reported incidence of clinically important neurotoxicity in the former paclitaxel/cisplatin regimen is more than 70% at 6 cycles and approximately 100% with 9 cycles of cisplatin. BioNumerik is finalizing its strategy for the future advancement of BNP7787 into Phase III clinical trials.
Investigators at BioNumerik have also identified the primary mechanism of platinum associated neurotoxicity, which involves damage to tubulin caused by platinum drugs. Tubulin is a protein which is in high concentrations in all cells, including nerve cells. BioNumerik has 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: "BNP7787 is well tolerated and appears to prevent significant neurotoxicity. No patient in our study has had worse than grade 2 neuropathy despite high cumulative doses of cisplatin and paclitaxel. It is also encouraging that tumor responses have been observed in this trial."
Karenitecin Data
In a separate presentation titled "Karenitecins: New Preclinical Developments with BNP1350; A Novel, Potent Highly Lipophilic Camptothecin," BioNumerik is presenting data comparing the antitumor activity of BioNumerik's compound, karenitecin BNP1350, to the activity of SmithKline Beecham's topotecan (Hycamptin). In these studies, conducted in mice bearing human ovarian tumors, both oral and intravenous karenitecin demonstrated significantly superior antitumor activity relative to topotecan administered by the same route. This work was conducted in collaboration with investigators at the Roswell Park Cancer Institute in Buffalo, New York.
BioNumerik has also determined in laboratory studies that karenitecin has superior antitumor potency in over 20 different types of common human solid tumors relative to topotecan and other existing camptothecin derivatives. In addition, 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 assistance of supercomputer simulations. The preclinical development time for BioNumerik's three drugs has averaged 18 to 24 months compared to the pharmaceutical industry average of 6 years. In preclinical animal studies, orally administered karenitecin demonstrated excellent antitumor activity against common human solid tumors (including prostate, colon, breast, lung, melanoma and ovary) and superior potency against a variety of common human cancers compared to existing camptothecin derivatives. Karenitecin has also demonstrated the ability to bypass common, tumor-mediated drug resistance mechanisms to which many other camptothecins appear to be susceptible. Because it is lipophilic (fat loving), BioNumerik believes karenitecin will have enhanced tissue penetration, drug delivery and bioavailability compared to existing water soluble camptothecins.
"Unlike Topotecan, BNP1350 was not cross resistant in tumors expressing multidrug resistance markers such as p-glycoprotein or multidrug resistance protein. Among the topoisomerase I inhibitors tested to date, BNP1350 exhibited more in vitro potency against a variety of human tumor cell lines," said Youcef M. Rustum, Ph.D., Senior Vice President for Scientific Affairs at Roswell Park Cancer Institute and a co-investigator on the work presented.
BioNumerik Pharmaceuticals, headquartered in San Antonio, Texas, 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. BioNumerik is a leader in a powerful new area called "mechanism based drug discovery" which integrates medicine, quantum physics, synthetic chemistry, pharmaceutical sciences and Silicon Graphics and Cray Research supercomputing. BioNumerik views its approach as a fourth generation technology relative to drug screening, automated screening and 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 reduce the risk of failure in clinical development.
In addition to the studies described above, several additional investigators presented data at AACR regarding work conducted in collaboration with BioNumerik. Summary abstracts of this work are available at www.noonanrusso.com.