Pharmacological inhibition of FASN prevents high fat diet ... · Greg Duke, Richard Crowley, Marie...
Transcript of Pharmacological inhibition of FASN prevents high fat diet ... · Greg Duke, Richard Crowley, Marie...
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TVB-2640 – clinical experience Oral, potent, FASN inhibitor
Pharmacological inhibition of FASN prevents high fat diet induced liver damage in mice and significantly reduces de novo lipogenesis in humans Greg Duke, Richard Crowley, Marie O’ Farrell, William McCulloch, Douglas Buckley, and George Kemble
3-V Biosciences, Inc., Menlo Park, CA
Standard design for Oncology – Accelerated titration - rapidly identify MTD • Identified target-related AE’s (alopecia, hand
foot syndrome, ocular) • Manageable and reversible AEs • Decreased AEs at lower doses
(reduced severity & frequency) • Evidence of anti-tumor activity ♯Ph1b Study – DNL Metabolic syndrome
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TVB$26
40)(n
g/ml))
Time)(hr))
240"mg/m2"120"mg/m2"60"mg/m2"
Malonyl-CoA
FASN Palmitate in complex lipids
Acetyl-CoA
Malonyl Carnitine
TVB-2640
Sebutape: A non-invasive biopsy
Human CD4+ Naïve T cells under 4 days of Th17 differentiation conditions
FASN (fatty acid synthase) Critical lipogenesis & inflammatory target in NASH
N=7 N=8
TVB-3664* prevents steatosis in mice fed a high fat (Western) diet
! !
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PHA*M" Lipoteichoic"Acid"
IL#1%beta%(pg/ml)%
Vehicle" TVB*3166"
(10µM)
FASN Inhibition Reduced IL-1β in ex vivo Stimulated Human PBMC
FASN Inhibition Reduced Serum IL-1β in HFD Mice (14d)
High Fat Diet
Day 1 Day 57
A. Veh (d1-d57) B. TVB-3664 (d1-d57) C. TVB-3664 (d29-d57)
Normal Diet
A.HFD/ Veh
IL-1β response inhibited by 3-V FASN inhibitors
*TVB-3664 is a TVB-2640 analog with better murine PK and potency
Human – Serum PK
C1D1 C1D8/1517.5
20.0
22.5
25.0
27.5
30.0
TG
16:0
(m
ol%
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p < 0.0001
BloodLive
rSkin
Muscle
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Tissue
[14C
]-TVB
-264
0 ug
equ
iv/g
tiss
ue
Tissue Distribution of PO [14C]-TVB-2640in Male SD Rats (1h)
• Plasma levels increase with dose
• Mean half-life ~15 hours • Steady state by day 8 • Exceeds preclinical efficacy • >10X liver distribution vs skin
Rat – Liver Enhanced Tissue Distribution
Excellent pharmacokinetics
Phase 1 – Cancer patients treated with TVB-2640 (n>62) PK, PD and AE profiles point to promising opportunity for NASH
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Severity"Score""
A B
Wilcoxon Rank-Sum p<0.0005 p<0.03*
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predose 1 hour predose 1 hour predose 1 hour
Group 1 Group 2 Group 3
IL-1
b (p
g/m
L)
IL-1β 1 day of Dosing
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predose 1 hour predose 1 hour predose 1 hour
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L)
IL-1β 14 days of Dosing
Vehicle TVB-3664
TVB-3664* and TVB-2640 direct human T-cell differentiation away from pro-inflammatory TH17 and toward anti-inflammatory Treg
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IL-1
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FoxP3
DMSO
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30.0
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DMSO
IL-1
7
FoxP3
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69.4
TVB-2640 100nM
IL-1
7
FoxP3
26.1
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TVB-2640 100nM
IL-1
7
FoxP3
20.4
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73.2
TH17 Treg
TH17 Treg
IL-1
7
FoxP3
DMSO
69
31.0
0.05
DMSO
IL-1
7
FoxP3
1.1
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TVB-3664 50nM
IL-1
7
FoxP3
24.2
1.7
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TVB-3664 50nM
IL-1
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FoxP3
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TH17
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or 1
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onor
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60#80%100%120%240%
% (A
E >=
2)
Alopecia
Skin
Ocular
TVB-2640 (Daily, oral)
Above MTD Oncology (MTD)
NASH
Dose (mg/m2) 240 120 100 60-80 <60
N 4 6 42 10 TBD♯
Inhibits FASN Yes Yes Yes Yes ?
Predose vs Day8 2.15 Fold Change
Predose vs ~Day30 10.1 Fold Change
3-V FASN inhibitors – preclinical studies Prevent diet induced steatosis & inflammation
Conclusions
3-V’s FASN Inhibitors: • Reduce high fat diet liver damage in mice
• 38% reduction in liver steatosis • Inhibited IL-1β production in serum • Treated established disease with short therapy
• Ex vivo stimulated human PBMC • Inhibited IL-1β production • Inhibited differentiation to Th17 – replaced with Treg
TVB-2640: oral, potent, first-in-class FASN inhibitor
• Demonstrated inhibition of FASN & lipogenesis in humans • Excellent PK – liver enhanced distribution • Potential to significantly reduce dose for NAFLD/NASH
Next step: Phase 1b – Identify dose for hepatic DNL in metabolic syndrome
• Evaluate low doses of TVB-2640 to inhibit hepatic lipogenesis (collaboration with E. Parks at University of Missouri)
© 2016 MAYO IL-1β
IL-17A Others
Apoptosis
NAFLD Hepatocyte
Normal Hepatocyte
TGF-β1
Collagen TGF-β1 Fibrosis
Inflammation
FASN/ DNL
TVB-2640
TVB-2640
TVB-2640
Th17
TVB-2640
Stellate Cell
MΦ
C
B. HFD/ TVB-3664
Apoptotic Bodies
TVB-2640 TVB-2640 – Serum metabolomics – inhibition of FASN in humans
IL-1β
(pg/
mL)
IL-1β
(pg/
mL)
p=0.0001 p=0.0004
Predose Day8 Predose Day8
TVB-2640 inhibits lipogenesis in human skin (sebum)
• TVB-2640 dose for cancer patients inhibits lipogenesis in skin by >90%
• Expecting much lower doses needed to inhibit liver fat synthesis in NASH patients based on tissue distribution of TVB-2640
Sapenic acid (16:1n-10) TG
N=49
Malonyl Carnitine Tripalmitin