Next Generation Fusion Inhibitor Candidates TRI1144 and TRI999 Have Improved Pharmacokinetics and De

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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

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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.

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NGFI Peptides TRI-1144 TRI-999
LTWQEWDREINNYTSLIHSLIEESQNQQEKNEQELL
O
O

• 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)

C17H35-C-NH-CH2-CH2-O-CH2-CH2-O-CH2-C
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NGFI peptides have enhanced pharmacokinetic
properties
Subcutaneous Dose Cynomolgus monkey Normalized
to 3 mg/Kg
ENF
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NGFI peptides have enhanced pharmacokinetic
properties
Subcutaneous Dose Cynomolgus monkey Normalized
to 3 mg/Kg
TRI-1144
ENF
TRI-999
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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

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Sustained-Release Formulation Evaluation

• in vitro release assay
• Small animal model
• Non-human primate model

• Evaluate
• Burst
• Release rate
• Bioavailability

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TRI-1144 Sustained release formulation data

• Formulation approaches
• Peptide organic salt complex
• in situ forming gel
• in vitro release data
• Small animal model Rat

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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
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Rat PK model TRI-1144
Immediate release formulation
Rat SC injection Normalized to 3 mg/kg
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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
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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
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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
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Rat PK Model TRI-1144 Gel formulationDelayed
release of peptide
Immediate release formulation
Gel formulation
Rat SC injection normalized to 3 mg/kg
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TRI-999 Sustained release formulation data
LTWQEWDREINNYTSLIHSLIEESQNQQEKNEQELL
O
O


C17H35-C-NH-CH2-CH2-O-CH2-CH2-O-CH2-C

• 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/kg
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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
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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.