SBIR-STTR Award

The long-term goal of this research is to develop drugs that are safe and effective against drug-resistant malaria. Malaria is one of the most common infectious diseases in the world. It affects approximately 300 million people and leads to more than 2 million death a year. The increasing prevalence of multiple drug resistant strains of Plasmodium falciparum in most malaria endemic areas has significantly reduced the efficacy of current antimalarial drugs for both treatment and prophylaxis and there is a clear need for new medicinal agents based on novel mode of action. Febrifugine is an alkaloid isolated from roots of Dichroa febrifuga Lour and showed powerful antimalarial activity against P. falciparum. Strong liver toxicity has precluded its clinical use against malaria. In this Phase I study, a focused library of thirty novel febrifugine analogues will be synthesized. They are expected to retain the potent antimalarial activity and desirable ADME (adsorption, distribution, metabolism, and excretion) properties. Lower liver toxicity will be achieved by reducing the tendency to form chemically reactive and toxic intermediates and metabolites. For efficacy evaluation, synthesized compounds will be tested in vitro against two P. falciparum malaria parasite clones: W2 (susceptible to mefloquine but resistant to chloroquine, sulfadoxine, pyrimethamine, and quinine) and D6 (resistant to mefloquine but susceptible to chloroquine, sulfadoxine, pyrimethamine and quinine). For toxicological studies, these compounds will be tested in human adult liver epithelial cells and mouse mammary tumor cells. The specific aim would be the discovery of some less toxic yet still potent compounds whose selectivity (defined as toxicity/anti-malarial activity) equals or greater than 1000. In Phase II study, compounds with desirable selectivity will be synthesized in a large scale and pre-clinical trials will begin by testing these compounds in rodent and primate models to obtain efficacy, ADME and toxicity data. An investigational new drug (IND) application will then be filed with FDA

The long-term goal of this project is to develop a new drug (new chemical entity [NCE]) that is inexpensive, orally active, non-toxic and can provide cure for P. falciparum malaria. SBIR Phase I research and additional work at Radix Pharmaceuticals have demonstrated that some novel febrifugine analogues are potent inhibitors of both sensitive and multi-drug resistant human malaria strains in vitro at low nanomolar concentrations. These compounds possess new mode of action by impairing haemazoin formation required for maturation of the parasite at the trophozoite stage. Synthesized compounds demonstrated low toxicity in human adult liver epithelial cells and freshly isolated rat hepatocytes. No in vitro cardiotoxicity or genotoxicity was observed. A scalable synthetic route to make radioactive [3H] compounds for PK studies has been established. FDA suggestions have been obtained regarding the necessary ongoing pre-clinical studies to warrant investigational new drug (IND) submission. Based on successful completion of the feasibility study, the overall goal of this Phase II project is to establish detailed pre-clinical profiles for the candidates. Under Phase II support, we will perform the scale up synthesis of these compounds and begin pre-clinical studies in animal models to obtain toxicity, pharmacokinetics, and efficacy data. The following interactive studies will be performed to obtain rodent pre-clinical profiles efficiently and effectively: (i) The six compounds identified in Phase I research will be synthesized in a larger scale (2-3 kg per compound) for efficacy and toxicity studies as well as in radioactive [3H] form (100 mg per compound) for pharmacokinetic studies. (ii) Test compounds will be tested in rodent models to obtain acute and sub-acute toxicity, fetotoxicity, anorectic toxicity, and neurotoxicity information. (iii) Test compounds will be administered intraperitoneally, subcutaneously, or orally to rats and mice and pharmacokinetic parameters will be calculated. (iv) Antimalarial efficacy data will be obtained in immunocompromised BXN mice infected with human malaria strains and male Swiss albino mice infected with rodent malaria strain P. berghei. These pre-clinical studies would clearly validate the candidate's potential as an ideal new drug for the treatment of acute malaria. On completion of the Phase II studies, one or two compounds that are orally active and possess good bioavailability and therapeutic index will be selected for further development. The successful completion of rodent pre-clinical studies will enable Radix Pharmaceuticals to raise additional funding and attract a commercial partner to push the drug candidate to the market. Phase III follow up work would include pre-clinical data (PK, toxicity, and efficacy) in Rhesus monkey (having data from two species that were produced under the same laboratory conditions is required by FDA), followed by GMP manufacturing and GLP evaluation. Investigational new drug (IND) application will then be filed with FDA. Radix Pharmaceuticals has strategic alliance with commercial partners for Phase III development