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Optimized potency FI-naïve viruses FI-resistant viruses

Next Generation Fusion Inhibitor Candidates TRI-1144 and TRI-999 Have Improved Pharmacokinetics and Demonstrate Sustained-Release.

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Optimized potency FI-naïve viruses FI-resistant viruses

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  1. Next Generation Fusion Inhibitor Candidates TRI-1144 and TRI-999 Have Improved Pharmacokinetics and Demonstrate Sustained-Release Mary Kay Delmedico, Brian L. Bray, Nick Cammack, Jie Di, David M. Heilman, Peter Silinski, Dimitrios Stefanidis, Scott D. Webb, Stephen A. Wring, Michael L. Greenberg

  2. Next Generation Fusion Inhibitor Goals • Optimized potency • FI-naïve viruses • FI-resistant viruses • High genetic barrier to generation of resistance • Optimized pharmacokinetics • Sustained release formulation to deliver once / week subcutaneous administration.

  3. TTWEAWDRAIAEYAARIEALLRALQEQQEKNEAALREL NGFI Peptides: TRI-1144 & TRI-999 • Equal or greater potency against FI-sensitive clinical isolates than ENF. • 150-200-fold more potent against FI-resistant isolates than ENF. • Significantly higher genetic barrier to resistance in vitro relative to ENF. (Davison, Poster #THPE0021) LTWQEWDREINNYTSLIHSLIEESQNQQEKNEQELL O O = = C17H35-C-NH-CH2-CH2-O-CH2-CH2-O-CH2-C

  4. NGFI peptides have enhanced pharmacokinetic properties Subcutaneous Dose Cynomolgus monkey Normalized to 3 mg/Kg ENF

  5. NGFI peptides have enhanced pharmacokinetic properties Subcutaneous Dose Cynomolgus monkey Normalized to 3 mg/Kg TRI-1144 ENF TRI-999

  6. Desirable Characteristics of a Sustained-Release Formulation • “Burst” – drug immediately released from formulation Minimize drug burst • Slow release of drug into circulation • High bioavailability • “Load” – Ratio of drug : formulation ingredients Maximize drug load

  7. Sustained-Release Formulation Evaluation in vitro release assay Small animal model Non-human primate model • Evaluate: • Burst • Release rate • Bioavailability

  8. TTWEAWDRAIAEYAARIEALLRALQEQQEKNEAALREL TRI-1144: Sustained release formulation data • Formulation approaches • Peptide – organic salt complex • in situ forming gel • in vitro release data • Small animal model : Rat

  9. in vitro release: TRI-1144 – organic salt complexMinimal burst & steady release of peptide Steady release of peptide into assay solution Low burst 37C TRIS buffer pH 7.4

  10. Rat PK model: TRI-1144 – Immediate release formulation Rat SC injection Normalized to 3 mg/kg

  11. Rat PK model: TRI-1144 – organic salt complexMinimal burst & steady release of peptide Immediate release formulation Sustained-release formulation Rat SC injection Normalized to 3 mg/kg

  12. Rat PK model: TRI-1144 – organic salt complexMinimal burst & steady release of peptide Immediate release formulation Steady release of peptide into rat Low burst Rat SC injection Normalized to 3 mg/kg

  13. Rat PK model: TRI-1144 – organic salt complexModulation of release rate Immediate release formulation Release rate increased Rat SC injection Normalized to 3 mg/kg

  14. Rat PK Model: TRI-1144 – Gel formulationDelayed release of peptide Immediate release formulation Gel formulation Rat SC injection normalized to 3 mg/kg

  15. TRI-999: Sustained release formulation data LTWQEWDREINNYTSLIHSLIEESQNQQEKNEQELL O • Formulation approaches • in situ forming gel • Small animal model : Rabbit O = = C17H35-C-NH-CH2-CH2-O-CH2-CH2-O-CH2-C

  16. Rabbit PK model: TRI-999 – Gel formulation Delayed release of peptide Immediate release formulation Peptide-gel formulation Rabbit SC injection normalized to 3 mg/kg

  17. NGFI PK: Immediate-release formulationsExtended PK upon moving to primates SC injections Normalized to 3 mg/kg TRI-1144 Monkey TRI-999 Monkey TRI-1144 Rat TRI-999 Rabbit

  18. Summary Next Generation Fusion Inhibitor • Several formulation approaches demonstrate sustained release in vitro and in small animal models. • Formulations being evaluated in monkeys. • Results will guide optimization of release rates and bioavailability.

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