Pharmaceuticals Next Generation Fusion Inhibitor Candidates TRI-1144 and TRI-999 Have Improved...

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Next Generation Fusion Inhibitor Next Generation Fusion Inhibitor Candidates TRI-1144 and TRI-999 Candidates TRI-1144 and TRI-999

Have Improved Pharmacokinetics and Have Improved Pharmacokinetics and Demonstrate Sustained-ReleaseDemonstrate Sustained-Release

Mary Kay Delmedico, Brian L. Bray, Nick Mary Kay Delmedico, Brian L. Bray, Nick Cammack, Jie Di, David M. Heilman, Peter Cammack, Jie Di, David M. Heilman, Peter Silinski, Dimitrios Stefanidis, Scott D. Silinski, Dimitrios Stefanidis, Scott D. Webb, Stephen A. Wring, Michael Webb, Stephen A. Wring, Michael L. GreenbergL. 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 Next Generation Fusion Inhibitor Goals Goals

– Equal or greater potency against FI-Equal or greater potency against FI-sensitive clinical isolates than ENF.sensitive clinical isolates than ENF.

– 150-200-fold more potent against FI-150-200-fold more potent against FI-resistant isolates than ENF.resistant isolates than ENF.

– Significantly higher genetic barrier to Significantly higher genetic barrier to resistance resistance in vitroin vitro relative to ENF. relative to ENF. ((Davison, Poster #THPE0021)

NGFI Peptides: NGFI Peptides: TRI-1144TRI-1144 & & TRI-TRI-999999

TTWEAWDRAIAEYAARIEALLRALQEQQEKNEAALREL

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CC1717HH3535-C-NH-CH-C-NH-CH22-CH-CH22-O-CH-O-CH22-CH-CH22-O-CH-O-CH22-C-C

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NGFI peptides have enhanced NGFI peptides have enhanced pharmacokinetic propertiespharmacokinetic properties

ENFENF

Subcutaneous DoseCynomolgus monkey

Normalized to 3 mg/Kg

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NGFI peptides have enhanced NGFI peptides have enhanced pharmacokinetic propertiespharmacokinetic properties

TRI-1144TRI-1144

TRI-999TRI-999

Subcutaneous DoseCynomolgus monkey

Normalized to 3 mg/Kg

ENFENF

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 complexMinimal burst & steady release of peptide

37C TRIS buffer pH 7.4

Lowburst

Steady release of peptide into assay solution

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Immediate release formulation

Rat SC injectionNormalized to 3 mg/kg

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Rat SC injectionNormalized to 3 mg/kg

Immediate release formulation

Rat PK model: TRI-1144 – organic salt complexMinimal burst & steady release of peptide

Sustained-release formulation

0.001

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Steady release of peptide into rat

Rat SC injectionNormalized to 3 mg/kg

Immediate release formulation

Rat PK model: TRI-1144 – organic salt complexMinimal burst & steady release of peptide

0.001

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L)Rat PK model: TRI-1144 – organic salt complexModulation of release rate

Rat SC injectionNormalized to 3 mg/kg

Immediate release formulation

Release rate increased

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L)Rat PK Model: TRI-1144 – Gel formulationDelayed 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

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Rabbit PK model: TRI-999 – Gel formulation Delayed release of peptide

Immediate release formulation

Peptide-gel formulation

Rabbit SC injection normalized to 3 mg/kg0.01

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TRI-1144Rat

TRI-999Rabbit

TRI-1144Monkey

TRI-999Monkey

SC injectionsNormalized 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 Summary Next Generation Fusion Inhibitor Next Generation Fusion Inhibitor