The worldwide incidence of new HIV infecti ons remains at a desperately high level. Although more effective treatments continue to be developed, they remain costly and are not readily available in those regions of the world most severely effected by the epidemic. For physiological reasons, women are disproportionately at risk for transmission of HIV infection. There has been great focus in recent years on the development of effective means of preventing new infections. Unfortunately, successful development of a vaccine has yet to be achieved. Although barrier methods can be effective, their use is not controlled by the women at risk. Great attention is now being devoted to the development of women controlled microbicide products that can be applied for the prevention of HIV transmission and other sexually transmitted diseases. All of the most clinically advanced first generation microbicide products involve the formulation of a single active drug compound in a gel or cream dosage form for vaginal use. However, the long term success of microbicides will depend on the availability of such formulations with combinations of active agents that have independent mechanisms of action, and are broad spectrum in terms of target pathogens. This will protect women from other STD that could function as cofactors in HIV infection, and will also reduce or prevent the emergence of resistant virus. Thus, Biosyn proposed a Phase I SBIR program for the development of a combination microbicide containing the broad spectrum surface active agent C31G with the highly potent HIV NNRTI, UC-781. This combination formulation would prevent the emergence of resistance and provide broad spectrum protection. During the Phase I SBIR effort, we demonstrated that these drugs do not interfere with the intrinsic activities of each other. Moreover, it was possible to develop early stage analytical methods that could readily be applied to combinations containing both actives. Finally, a set of candidate gel formulations were developed, which will serve as the basis for additional formulation development and optimization in the Phase II SBIR effort. The combination development proposed here benefits from the fact that Biosyn has independent development programs for UC-781 and C31G. Thus, GMP manufacture of API, acute and chronic toxicology studies, as well as clinical data are all available at no additional cost to the combination program. Therefore, Biosyn is proposing the continued development of a U C-781/C31G combination microbicide in a Phase II SBIR. The overall objective is to develop a combination formulation that can serve as the basis for an INDsubmission to the FDA. This will be achieved by means of expanded study of the physical and chemical nature of this combination, and using this characterization to design and optimize an appropriate formulation. There will be specific investigation of the potential use of C31G as both an active agent and a delivery agent in the combination formulation, which potentially enhances the activity of the product.
