- Novel class of highly lipophilic camptothecins, known as Karenitecins, demonstrates potent oral antitumor activity, acceptable safety and appear to be insensitive to common tumor-associated drug resistance mechanisms
- BioNumerik's novel chemoprotecting agent BNP7787 appears to completely protect against major toxicities associated with widely used platinum anticancer drugs such as cisplatinum
New Orleans, LA - March 30, 1998 -- BioNumerik Pharmaceuticals, Inc. this week presented new research results on two novel supercomputer-engineered small molecule agents designed to help address significant existing problems in current cancer therapy. These results continue to strengthen the correlation between actual experimental observations and the computational simulations provided by BioNumerik's innovative supercomputer simulations and mechanism based approach to new pharmaceutical discovery and development.
Regarding BioNumerik's BNP7787 and Karenitecins, Martin D. Abeloff, M.D., Director of the Johns Hopkins Oncology Center, stated, "These drugs have the potential to make a significant impact on current cancer therapy. The data reported by BioNumerik is particularly meaningful because the discovery and design of both of these agents was supported by BioNumerik's mechanism based computational studies and supercomputer simulations."
Frederick H. Hausheer, M.D., BioNumerik's Chairman and Chief Executive Officer, presented these findings at the 89th Annual Meeting of the American Association for Cancer Research held March 28 - April 1, 1998.
In a presentation titled "Karenitecins: A Novel Class of Orally Active Highly Lipophilic Topoisomerase I Inhibitors", the results presented by BioNumerik of studies conducted in BALB/c mice indicate that orally administered Karenitecin had excellent antitumor activity against solid tumors (prostate, colon, breast, lung) and had superior antitumor potency compared to existing camptothecin derivatives. These results also demonstrate the ability of BioNumerik's Karenitecins to bypass common drug resistance mechanisms (MDR, MRP & LRP) to which many other camptothecins appear to be susceptible. Because its compounds are lipophilic, BioNumerik believes its Karenitecins will have enhanced tissue penetration, drug delivery and bioavailability compared to water soluble camptothecins.
Camptothecins, described as Topoisomerase I inhibitors, represent some of the most active anticancer drugs in existence. Due to formulation problems, however, the great majority of camptothecins in development or on the market have been made water soluble to allow easier drug dissolution and administration. BioNumerik believes that this approach may limit the utility of these drugs and the Company has developed a new generation of proprietary highly lipophilic (fat loving) camptothecins, known as Karentitecins, that have been designed to overcome problems that exist with camptothecin and the current camptothecin derivatives.
Using its mechanism-based approach, BioNumerik used its Cray supercomputers to construct a detailed computational model involving human Topoisomerase I and DNA in order to understand and more precisely target the key interactions between camptothecin-Topo I/DNA. BioNumerik used this information to guide and complement the discovery and optimization of novel compounds for laboratory synthesis and preclinical testing.
In a presentation titled "BNP7787: Administration In Vivo Results in Increased Therapeutic Index and Toxicity Reduction of Platinum Drugs", BioNumerik also presented data on its proprietary agent BNP7787, a novel water soluble disulfide that was engineered to increase the therapeutic index of cisplatin and carboplatin, two widely used anticancer drugs.
Although platinum chemotherapy is widespread, formulations of cisplatin and carboplatin have a major risk of kidney toxicity (cisplatin), nausea and vomiting, bone marrow suppression, neurotoxicity and other toxicities. BioNumerik has designed BNP7787 to enhance selective inactivation of toxic platinum drug species and to produce a less toxic drug relative to other protecting agents.
BioNumerik presented preclinical animal study data showing that BNP7787 can completely protect against cisplatin-induced renal, emesis and bone marrow toxicities and can increase cisplatin's antitumor activity. It also showed, for example, complete tumor remissions increased from 13% (with a 50% mortality rate due to cisplatin toxicity) in cisplatin only treated subjects to a 63% complete remission rate with no mortality or toxicity in subjects pretreated with BNP7787 prior to the same toxic dose of cisplatin. In addition to demonstrating safety and efficacy in preclinical studies, BioNumerik also confirmed that a single dose of BNP7787 could reduce the number of episodes and duration of vomiting by 75% and 89%, respectively, in a model of cisplatin induced vomiting. Preclinical studies have also shown that a single dose of BNP7787 substantially protects against cisplatin induced suppression of the bone marrow. It also showed BNP7787 is less toxic than table salt, making it non-toxic by pharmaceutical industry standards.
In presenting the data, Dr. Hausheer stated: "These preclinical studies demonstrate that BNP7787 appears to substantially protect against the common major toxicities of platinum chemotherapy and does not interfere with the antitumor activity of cisplatin. There appears to be reproducible evidence of potentiation or enhancement of cisplatin's antitumor effect by BNP7787. We have found that BNP7787 can safely and effectively protect against up to a 500% increase in the dosage of cisplatin, a 100 percent lethal dose under normal circumstances. To our knowledge, no drug has ever been reported to achieve this level of protection at such a high dose of cisplatin."
Dr. Hausheer added, "We have also obtained confirmatory preclinical data indicating that BNP7787 can protect against carboplatin associated toxicity. If we are able to safely administer higher and more effective doses of cisplatin and carboplatin to cancer patients, this may lead to improved patient response rates."
BNP7787 is currently in Phase I clinical trials in the United States at the University of Chicago Medical Center and the Roswell Park Cancer Institute and in Europe at the Free University Hospital in the Netherlands. Patient enrollment in Phase I is also scheduled to commence soon at The Johns Hopkins Oncology Center.
Richard L. Schilsky, M.D., Director of the University of Chicago Cancer Research Center and Principal Investigator for the University of Chicago BNP7787 Phase I trial indicated, "We are extremely pleased to have the opportunity to conduct Phase I trials on this exciting new drug. BNP7787 has great potential to make cisplatin and carboplatin safer and to provide meaningful increases in tumor response rates."
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 Cray 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 less than 6 years, the Company has rapidly advanced two compounds into human clinical trials and a third new compound into late preclinical development.
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