Register for Two anticancer agents may help reduce platinum-, taxane-associated toxicities
Cancer Drug ToxicityAugust 11, 2003
BioNumerik Pharmaceuticals, Inc., presented new data on two novel agents in clinical trials that have been engineered with the help of physics-based high performance computing to help address common and important unmet needs in cancer therapy.
BioNumerik's Tavocept (also known as BNP7787) is a novel chemoprotective agent designed to prevent the common and often severe toxicities associated with platinum and taxane administration without inhibiting the antitumor activity of these drugs. Karenitecin (BNP1350) is a member of a new class of highly lipophilic camptothecins developed by BioNumerik. Karenitecin is a silicon-containing agent that has been specifically crafted to overcome known problems of commercially available camptothecins such as poor oral bioavailability, severe diarrhea, tumor mediated drug resistance, and chemical instability of the active species of the drug.
BioNumerik presented new data at AACR verifying additional novel mechanisms by which Tavocept appears to exert its chemoprotective effects for taxane and platinum drugs, which are widely used for cancer therapy.
"Chemotherapy induced peripheral nerve damage (such as that associated with taxane or platinum drug administration) is a common and serious clinical problem that in many patients results in a dose reduction, treatment delays or in severe cases, treatment discontinuation," said Frederick H. Hausheer, MD, chairman and CEO of BioNumerik. "Further verification of the mechanism(s) underlying this clinically important toxicity may provide valuable insights and more optimal administration of these agents."
In its research, BioNumerik combined physics-based supercomputer simulations with laboratory experimentation to further verify and characterize Tavocept's mechanisms. Based on this research, BioNumerik has demonstrated that the mechanisms of action underlying the chemoprotective effects of Tavocept relate to its properties as a synthetic substitute or modulator of sulfur containing molecules that are involved in antioxidant and detoxification roles in the body.
The results presented may also be important in supporting the idea that Tavocept could have a better safety profile with reduced drug-drug interactions than a molecule containing a freely reactive sulfur. The Tavocept molecule has been designed to lack a reactive sulfur in order to improve its safety, allow selective inactivation of toxic platinum drug species, and protect against taxane drug nerve damage without tumor protection or any additive toxicity. The new data reported by BioNumerik may also help to explain the toxicities observed with the administration of many first generation protecting agents.
BioNumerik also presented data from separate studies that examined whether various nerve damaging cancer drugs are transported, concentrated, and/or distributed into a key region of the peripheral nervous system called the dorsal root ganglia. Unlike the brain or spinal cord, the dorsal root ganglia are not protected by a pharmacologic barrier. For this reason, the dorsal root ganglia are a likely target for chemotherapy induced nerve damage. BioNumerik has developed a new model system for testing drugs on dorsal root ganglia.
Previously, BioNumerik reported its identification of a primary mechanism of platinum associated nerve damage, which involves damage to tubulin caused by platinum drugs. Tubulin is a protein that is in high concentrations in all cells, including nerve cells. BioNumerik has confirmed that Tavocept appears to protect against tubulin toxicity caused by platinum drugs and taxanes; and that increasing concentrations of Tavocept result in increasing levels of tubulin protection.
In Phase I trials of Tavocept with paclitaxel (175 mg/m2) and cisplatin (75 mg/m2) or single agent cisplatin (75 mg/m2) administered every 21 days, no Grade 3 or Grade 4 nerve damage has been observed in more than 100 patients. For patients treated with the combination of paclitaxel and cisplatin, the incidence of Grade 2 nerve damage was 15% for all Tavocept dose levels (4.1 to 41.0 grams/m2) and 10% at doses of 18.4 grams/m2.
The incidence and severity of nerve damage when Tavocept is administered appears markedly reduced compared with the chemotherapy-induced nerve damage reported in historical studies using a similar treatment regimen, which were 42% for greater than or equal toGrade 2 and 21% for Grades 3 and 4. Phase III clinical studies are currently ongoing to evaluate the efficacy and safety of Tavocept.
In separate presentations, BioNumerik presented data on the binding preferences and intra-cellular distribution of BioNumerik's Karenitecin (BNP1350) and other compounds in the camptothecin class. In its research efforts, BioNumerik combined physics based supercomputer simulations with laboratory experimentation to evaluate these parameters.
Because the mechanisms of action for camptothecins have not been fully determined, the data reported by BioNumerik may be helpful in developing a deeper understanding of the major cellular actions of camptothecins and in explaining and addressing the limitations of existing camptothecin drugs.
BioNumerik has completed phase I clinical studies for Karenitecin. Phase II clinical studies are ongoing or have been recently completed for Karenitecin in advanced non-small cell lung cancer, adult primary brain tumors, melanoma, and advanced ovarian cancer. Karenitecin has demonstrated substantially increased bioavailability (the extent to which the active form of the drug enters systemic circulation in the body) compared to other compounds in the camptothecin class and BioNumerik is planning clinical trials for an oral formulation of Karenitecin. This article was prepared by Health & Medicine Week editors from staff and other reports.
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