Filing Davanat, a polysaccharide carbohydrate polymer, as a functional excipient under Section 505 (b)(2) of the US Food, Drug and Cosmetic Act should shorten the regulatory pathway for the product, which would be co-administered intravenously with the widely used anticancer 5-fluorouracil (5-FU).
Pro-Pharmaceuticals is a US company developing carbohydrate-based compounds for the treatment of cancer as well as liver, microbial, cardiovascular and inflammatory diseases.
It said it plans to submit other combinations of Davanat and anticancers through Section 505 (b)(2), which allows the Food and Drug Administration (FDA) to approve new formulations or variations of an existing drug based on the published literature or a previous finding of that drug's safety and effectiveness.
In March the company sent the FDA "substantial information on chemistry and completed preclinical and clinical data," together with a list of questions on filing Davanat/5-FU as a functional excipient through the Section 505 (b)(2) route.
The agency's response was "in line with our expectations" and "provides us with a clear roadmap in terms of what additional information, primarily manufacturing, they need to allow our NDA submission," said president and CEO David Platt.
The Davanat polymer is made up of mannose and galactose, or galactomannan.
Davanat would extend to chemotherapy applications a drug delivery vehicle already used for oral, topical and vaginal administration of other compounds, Pro-Pharmaceuticals noted.
Galactomannans, which are polysaccharides consisting of a mannose backbone with galactose side-groups, are also often used in food products to viscosify the water phase, the company points out.
Pro-Pharmaceuticals said it planned to file an NDA for Davanat/5-FU "as soon as we complete the additional manufacturing information needed."
The FDA did not ask for any more toxicological or clinical data on the combination, which is currently in two Phase II clinical trials at nine sites as first-line therapy in biliary and colorectal cancers.
A Phase I trial of Davanat/5-FU for end-stage cancer patients with all solid tumours has been successfully completed, as has a Phase II study in end-stage patients with colorectal cancer.
Pro-Pharmaceuticals plans to start a Phase III trial in colorectal cancer once it has reported results from the ongoing Phase II programme.
The company has also been conducting preclinical and clinical studies of Davanat in combination with leucoverin, irinotecan, doxorubicin, oxaliplatin, paclitaxel, cisplatin and bevacizumab (Genentech/Roche's Avastin), anticancers in broad use yet hampered by side-effects ranging from extreme discomfort to severe blood toxicity, gastrointestinal haemorrhage or even death.
Pro-Pharmaceuticals' strategy is to exploit the natural properties of carbohydrates to increase the efficacy and reduce the toxicity of chemotherapeutics, 'rescue' drugs that were shelved due to toxicity or half-life issues, improve the solubility of existing compounds, and develop carbohydrate polymers as new chemical entities.
The company believes Davanat's mechanism of action centres on carbohydrate receptors, know as lectins, that are found on the surfaces of cells.
Theory is that the carbohydrate polymer, which is formulate to attach to lectins on tumour cells, rather than to those on the surrounding healthy tissue, binds to specific lectin receptors - Galectins - that are over-expressed on cancer cells.
Current research indicates that Galectins affect cell development and play important roles in cancer, including tumour cell survival, angiogenesis and tumour metastasis, Pro-Pharmaceuticals says, adding that this form of targeted delivery "may allow for higher doses of chemotherapy administration with no increase in toxicity."
According to the company, Davanat and Davanat/5-FU were well tolerated in Phase I and II clinical trials, without ant drug-related serious adverse events.
Moreover, it notes, "we did not reach dose-limiting toxicity or a maximum tolerated dose."
In an animal model of colorectal cancer, Pro-Pharmaceuticals reports, Davanat with 5-FU or with 5-FU and leucoverin showed increased efficacy and reduced toxicity compared with 5-FU alone or 5-FU/leucoverin.
The Davanat formulation slowed tumour growth and shrank the tumour mass, both actions extending survival time, the company says.
It also reduced weight-loss in the cancer-bearing animals, suggesting that Davanat alleviated the toxicity of 5-FU or the 5-FU/leucoverin regimen.