The recent clinical advance in the HIV prevention field with a successful Phase lib tenofovir (TFV) gel trial coupled to our successful development of a stable tenofovir disoproxil fumarate (TDF) formulation in thermoplastic polyurethane elastomers (TPU) in Project 2 of this U19 supports the expansion of work under this Preclinical and Clinical Development and Regulatory Evaluations Core to move a 30 day TDF intravaginal ring into a pre-Phase 1 trial to evaluate TDF pharmacokinetics and safety. The support will be used to develop GMP manufacturing methods for the product, to produce the clinical supplies and file an exploratory IND. The ability to formulate and stabilize TDF in TPUs is a significant scientific breakthrough as the pharmacokinetics and antiviral activity of the TDF prodrug is much improved over the native TFV;furthermore, the dose required for TDF is two to three orders of magnitude less than TFV, making the formulation and multiday duration delivery of TDF much more feasible than TFV. We have also shown that the other biomedical elastomers (EVA and NuSil Silicone) are too hydrophobic to effectively release the +1 cation TDV. In the expanded core we will use the extensive pharmaceutical manufacturing and development experience at Particle Sciences to (i) develop production scale prototypes;(ii) validate analytical assays to support the clinical supply manufacturing;and (iii) perform pilot scale ring development. These studies will lead to full-scale production of TPU TDF IVRs in accordance with GMP guidelines, completion of the necessary biocompatibility studies on the drug product and the development of an IND to support the clinical evaluation of this product. A cGMP ring stability program with supporting release testing will be conducted in parallel to support the successful completion of the trial. In the early part of year 1 of the supplement, we will also conduct studies in pig-tail macaques at the Center for Disease Control (CDC) in Atlanta with TDF and placebo IVRs to confirm our results in vivo and our ability to achieve appropriate pharmacokinetics in the NHP model.
The Preclinical and Clinical Developmental and Regulatory Evaluations Core will provide all required expertise and capability to lead the product development efforts through the IND-enabling studies and result in the submission of an IND to the FDA for approval to conduct a pre-Phase 1 clinical trial to test the safety of an intravaginal product.
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