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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

1"

10"

100"

1000"

10000"

100000"

0" 4" 8" 12" 16" 20" 24"

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

! !

0"

50"

100"

150"

200"

250"

300"

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%

)

p < 0.0001

BloodLive

rSkin

Muscle

0

50

100

150

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

1"

2"

3"

4"

5"

1.5$ 2$ 2.5$ 3$ 3.5$ 4$ 4.5$

Severity"Score""

A B

Wilcoxon Rank-Sum p<0.0005 p<0.03*

0

10

20

30

40

50

60

70

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

0

10

20

30

40

50

60

70

predose 1 hour predose 1 hour predose 1 hour

Group 1 Group 2 Group 3

IL-1

b (p

g/m

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

!

IL-1

7

FoxP3

DMSO

69

30.0

0.06

DMSO

IL-1

7

FoxP3

0.04

30.2

69.4

TVB-2640 100nM

IL-1

7

FoxP3

26.1

10.3

63.6

TVB-2640 100nM

IL-1

7

FoxP3

20.4

6.4

73.2

TH17 Treg

TH17 Treg

IL-1

7

FoxP3

DMSO

69

31.0

0.05

DMSO

IL-1

7

FoxP3

1.1

37.2

62

TVB-3664 50nM

IL-1

7

FoxP3

24.2

1.7

74

TVB-3664 50nM

IL-1

7

FoxP3

30.2

1.6

68

TH17

Treg

Treg

TH17

Don

or 1

D

onor

2

0

25

50

75

100

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