DESIGN AND PRECLINICAL DEVELOPMENT OF DENDRIMER BASED TOPICAL MICROBICIDES FOR HIV AND STI PREVENTION

摘要

Dendrimers are a new class of macromolecule characterized by highly branched, three-dimensional architectures that are assembled in a precise, step-wise manner. This controlled synthesis allows the assembly of highly defined structures that radiate out in generations from a central initiator core. The result of this iterative growth process is a single macromolecular entity that contrasts with the polydisperse nature of alternative macromolecular structures such as traditional polymers. In developingdendrimers as pharmaceuticals, Starpharma has had a focus on the prevention of HIV and sexually transmitted infections (STIs) through the development of microbicide candidates. Early examples of Starpharma's dendrimers had activity against HIV and herpes simplex virus-2. Lead optimization resulted in a series of optimized dendrimer based microbicides being identified from which SPL7013 emerged as a development candidate. Following a range of preclinical studies, Starpharma submitted an InvestigationalNew Drug application (IND) for SPL7013 gel (VivaGel~(TM) to the United States Food and Drug Administration (FDA), the first such submission for a dendrimer based drug. This presentation will discuss the discovery of dendrimer based microbicide candidates, the lead optimization phase and the preclinical development path that led to the IND filing and the commencement of clininal trials of VivaGel~(TM).