PROJECT SUMMARY/ABSTRACT Patient dosing adherence is often compromised by the complex pill regimes and long duration of current TB drug therapies. These challenges are exacerbated in settings for patients in many social and global settings where TB co-therapy with HIV positive patients is stigmatized. Long-acting drug delivery products should therefore play an important role to increase patient adherence and increase drug efficacy. This project will develop a new injectable depot technology that address a general target product profile that includes multiple-month delivery from a single injection, low volume and low viscosity formulations to reduce patient pain, combination drug formulation where required, sustained drug release with designable PK profiles, minimal initial and run-out burst release to increase safety and prevent drug resistance, and for global settings has low cost of goods and lowered cold-chain requirements. This depot technology also has the important translational product attributes of streamlined CMC and cGMP manufacturing that could lead to more rapid clinical development achievement. A new injectable depot product for TB therapy will be developed that is differentiated from current dispersal based formulation approaches by being a fully synthetic depot. The proposal is structured around 2 specific aims in the R61 phase and two further aims in the R33 phase: (1) Prodrug monomers made by synthetic chemistry are directly polymerized in a second synthetic step to create “drugamer” depot therapeutics that have the drugs built into the depot itself. Compared to current dispersion formulation approaches, the drugamers exhibit higher drug loading efficiencies, the ability to co-formulate drugs of different lipophilicities, and linear, individually tailorable PK profiles that minimize first- and last-week burst release. These PK profiles are kinetically controlled by the linker properties that are tied to the individual drugs, along with polymer architectural design. This aim will exploit a unique high throughput polymer library and screening platform at CSIRO Melbourne to identify lead injectable depot designs using bedaquiline and moxifloxicin as initial drug examples. Sophisticated LC-MS/MS PK characterization will assess the sustained PK profile together with PK/PK modeling. (2) Evolve and optimize depot lead candidates through efficacy in an initial TB model that allows higher throughput imaging characterization of activity. This will be followed by an Mtb model assessment and selection to a lead depot candidate; (3) Test and optimize the two lead drug depot candidates in an A/BSL3 Mtb model, by the criteria of PK/PD, efficacy and dose dependence, and dosing duration. The lead depot will also be characterized in accelerated stability studies to test whether they can avoid cold-chain storage. (4) Evaluate iterated up-selected depots in combination depots from mixing optimized bedaquiline and moxifloxacin depots, including dual ...