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–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
Citation preview
Phar
mac
eutic
als
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
LTWQEWDREINNYTSLIHSLIEESQNQQEKNEQELL
==
OO==OO
CC1717HH3535-C-NH-CH-C-NH-CH22-CH-CH22-O-CH-O-CH22-CH-CH22-O-CH-O-CH22-C-C
0.01
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n (m
g/m
L)
NGFI peptides have enhanced NGFI peptides have enhanced pharmacokinetic propertiespharmacokinetic properties
ENFENF
Subcutaneous DoseCynomolgus monkey
Normalized to 3 mg/Kg
0.01
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1
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0 1 2 3 4 5 6 7Time (days)
Plas
ma
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ratio
n (m
g/m
L)
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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0 2 4 6 8 10 12 14 16 18Time (days)
Cum
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% R
elea
se
0.001
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0 1 2 3 4 5 6 7Time (days)
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n (µ
g/m
L)Rat PK model: TRI-1144 –
Immediate release formulation
Rat SC injectionNormalized to 3 mg/kg
0.001
0.01
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1
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100
0 1 2 3 4 5 6 7Time (days)
Plas
ma
conc
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n (µ
g/m
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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
0.01
0.1
1
10
100
0 1 2 3 4 5 6 7Time (days)
Plas
ma
conc
entr
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n (µ
g/m
L) Lowburst
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
0.01
0.1
1
10
100
0 1 2 3 4 5 6 7Time (days)
Plas
ma
conc
entr
atio
n (µ
g/m
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
0.001
0.01
0.1
1
10
0 1 2 3 4 5 6 7Time (days)
Plas
ma
Con
cent
ratio
n (µ
g/m
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
LTWQEWDREINNYTSLIHSLIEESQNQQEKNEQELL
==
OO==
OO
CC1717HH3535-C-NH-CH-C-NH-CH22-CH-CH22-O-CH-O-CH22-CH-CH22-O-CH-O-CH22-C-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/kg0.01
0.1
1
10
0 1 2 3 4 5 6 7Time (days)
Plas
ma
Con
cent
ratio
n(m
g/m
L)
0 20 40 60 80 100Time (hours)
0.01
0.1
1
10
100
0 20 40 60 80 100Time (hours)
Plas
ma
Con
cent
ratio
n(μ
g/m
L)NGFI PK: Immediate-release formulationsExtended PK upon moving to primates
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