Pharmaceuticals 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

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. Next Generation Fusion Inhibitor Goals

–Equal or greater potency against FI-sensitive clinical isolates than ENF. – fold more potent against FI-resistant isolates than ENF. –Significantly higher genetic barrier to resistance in vitro relative to ENF. ( –Significantly higher genetic barrier to resistance in vitro relative to ENF. (Davison, Poster #THPE0021) NGFI Peptides: TRI-1144 & TRI-999 TTWEAWDRAIAEYAARIEALLRALQEQQEKNEAALREL LTWQEWDREINNYTSLIHSLIEESQNQQEKNEQELL = O = O C 17 H 35 -C-NH-CH 2 -CH 2 -O-CH 2 -CH 2 -O-CH 2 -C

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

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

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

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

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

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

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

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

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

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

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

TRI-999: Sustained release formulation data Formulation approaches –in situ forming gel Small animal model : Rabbit LTWQEWDREINNYTSLIHSLIEESQNQQEKNEQELL = O = O C 17 H 35 -C-NH-CH 2 -CH 2 -O-CH 2 -CH 2 -O-CH 2 -C

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

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

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. Summary Next Generation Fusion Inhibitor