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FASN inhibitor TVB-2640 shows pharmacodynamic effect and evidence of clinical activity in KRAS mutant NSCLC patients in a Phase 1 study

Fatty Acid Synthase (FASN)• Mediates neoplastic lipogenesis• Generates palmitate

o Acylation of signaling proteins such as KRASo Building block for long chain fatty acids, membranes and lipid raftso Converts glucose and other carbon sources into lipids to support

cancer cell signaling• Upregulated in tumor vs normal tissue• Correlates with poor prognosis in certain tumor types including NSCLC

(Visca et al., 2004)• KRAS-mutant cell lines show increased sensitivity to FASN inhibitors

than KRAS-WT cell lines (Ventura et al., 2015, Heuer et al., AACR 2016

Summary• TVB-2640 is a first in class FASN inhibitor • Inhibition of FASN and inhibition of de novo lipogenesis shown • KRAS-MUT NSCLC pts show increased clinical activity, and provide

a niche population with unmet need for clinical development of TVB-2640

• Potential mechanisms include KRAS4a palmitoylation, KRAS reliance on metabolism, maintenance of membrane architecture, and acylation of other signaling proteins

• Additional biomarker analyses are ongoing• Additional opportunities in other RAS mutant populations

• TVB-2640 is an oral, first-in-class, small-molecule reversible inhibitor of FASN with IC50 < 0.05 μM

• Multicenter, open label, phase 1 FIH study• Oral, once daily with 21 day continuous cycles (monotherapy)• TVB-2640 has a half-life of approx. 16 hours• Ongoing expansion phase dose of 100 mg/m2

• To date, 10 evaluable NSCLC patients enrolled on monotherapy

Marie O’Farrell, Tim Heuer, Katharine Grimmer, Richard Crowley, Joanna Waszczuk, Marina Fridlib, Richard Ventura, Claudia Rubio, Julie Lai, Arjun Panda, Doug Buckley, William McCulloch, George Kemble

3-V Biosciences, Menlo Park, USA.

TVB-2640 inhibits FASN in both KRAS-WT and KRAS-MUT NSCLC patients

FFPE sections stained with FASN CST rabbit Ab C20G5 using a validated method. ELISA for FASN performed on human sera using a commercially available ELISA kit (Immtech), log scale.

FASN palmitate

Malonyl-CoA

Acetyl-CoA

Citrate ACLY

ACC

SCD ELOVLs

Lipid signaling eg. diacylglycerol,

Energy production

Energy storage

Protein signaling eg. palmitoylation myristoylation

Structural role in membranes and rafts eg. phosphatidylcholine.

Fatty Acid Synthesis

Potential mechanism of action against KRAS-MUT

KRAS-MUT NSCLC patients have longer duration on study than KRAS-WT

Phase 1 solid tumor study 3V2640-CLIN-002with TVB-2640, a novel FASN inhibitor

• Tumor RNA expression showed high MUC5AC in Pt 042 (KRAS-MUT, prolonged stable disease) versus other patients

• Serum ELISAs showed higher baseline MUC5AC in Pt 042 and other NSCLC KRAS-MUT patients, decreased with TVB-2640 treatment

• MUC5AC has a palmitoylation site conserved with other mucins, which may require FASN-derived palmitate for function

FASN%

Palmitoyla)on+of+KRAS4a/H/N+

SREPB+mediated+transcrip)on+of+FASN+

Signaling%protein%acyla2on%%Membrane%synthesis%Second%messengers%Protein%trafficking%Metabolic%pathway%regula2on%

palmitate%%%%Acetyl>CoA%%Malonyl>CoA%

KRAS%palmitoyl)farnesyl)

Tumor&growth&and&metabolism&

TVB@2640+

• N=10 NSCLC; 3 KRAS-MUT, 5 KRAS-WT, 2 KRAS-unknown• Similar plasma TVB-2640 exposure across groups

• 100% (3/3) KRAS-MUT > 12 weeks on study • 0% (0/5) KRAS-WT > 12 weeks on study

Comprehensive biomarker sampling for first in class agent

MUC5AC is a potential biomarker of response in KRAS-MUT patients

Malonyl-CoA

FASN Palmitate in complex lipids

Acetyl-CoA

Malonyl Carnitine

TVB-2640

(serum)

(serum, sebum)

Sebum was collected using Sebutape® patches on the forehead for 30 minutes, and profiled by GC-MS and MS-flame ionization detection for lipid content at Metabolon. Normal donors were not administered TVB-2640. Similar inhibition of DNL observed across all patients tested (approx. 20).

Serum used for global metabolite profiling by UPLC-MS/MS, performed at Metabolon. All NSCLC monotherapy patients with data available are shown. Similar effect observed in other tumor types.

RNA-Seq (50 milion paired end reads, Illumina Hi-Seq2500) of fresh pre-treatment biopsies or archival tumor from 14 patients including 2 NSCLC (042 and 051). MUC5AC ELISA performed on serum from 8 NSCLC patients.

Thanks to the clinical site teams, the patients and their families. Also to Metabolon, Mosaic, Personalis, Trovagene and BioAgilityx for sample analysis. Poster available at www.3vbio.com

Acknowledgements

FASN expression in human NSCLC

TVB-2640 inhibits de novo lipogenesis

TVB-2640 plasma PK parameters calculated from day 1 of administration. All NSCLC monotherapypatients with PK data available are shown. Pts 094 and 121 pending.Un-monitored clinical data

Novel Non-Invasive Sebum Lipidomics

E. Dean1, G. Falchook2, M. Patel3, A. Brenner4, J. Infante5, HT. Arkenau6, E. Borazanci7,J. Lopez8, K. Moore9, P. Schmid10, AE. Frankel111The Christie NHS Foundation Trust, Manchester, UK, 2Sarah Cannon Research Institute at HealthONE, Denver, CO, 3Sarah Cannon Research Institute/Florida Cancer Specialists, FL, 4Cancer Therapy & Research Center, San Antonio, TX, 5Sarah Cannon Research Institute/Tennessee Oncology, 6Sarah Cannon Research Institute, London, 7Honor Health Research Institute/Translational Genomics Research Institute, AZ, 8The Royal Marsden/Institute of Cancer Research, Sutton, UK, 9Sarah Cannon Research Institute Univ. of Oklahoma, OK, 10Barts Cancer Institute, London, UK, 11Univ. of Texas Southwestern Medical Center, Dallas, TX

Phase 1 Investigators: 3V2640-CLIN-002

042$054$024$

003$105$043$045$051$

094$121$

Pt$ 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45

2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2

2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2

2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2

2 2 2 2 2

2 2 2 2 2

2 2 2 2

2 2 2

2 2 2

2 2 2 2 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0

2 2 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0

KRAS$MUT$KRAS$MUT$KRAS$MUT$

KRAS$WT$KRAS$WT$KRAS$WT$KRAS$WT$KRAS$WT$

TBD$TBD$

Serum Metabolomics

0"

3"

6"

9"

12"

15"

Pre$PD$ Post$PD$ Pre$SD$ Post$SD$

Malon

ylcarni1ne

$(Serum

)$

0"

0.2"

0.4"

0.6"

0.8"

1"

1.2"


Tripalma0

n$(Serum

)$$

Progressive)disease)2)KRAS1WT,)1)KRAS1UK)

Stable)disease)3)KRAS1MUT)

Pt)051)

Pt)045)Pt)043)

Pt)042)

Pt)024)

Pt)054)



Pt)045)

Pt)051)Pt)043)

Pt)042)

Pt)024)

Pt)054)

0.01

0.1

1

10

1 2 8 22 1 2 8 22 1 2 8 22 1 2 8 22 1 2 8 22 1 2 8 22

Fold

chn

age

vers

us C

1D1

pred

ose

Time (days)

Wax esters Triacylglycerols Free fatty acids Diacylglycerols Squalenes

Pt#042#KRAS+MUT#

Normal##donor#X#

Pt#054#KRAS+MUT#

Pt#043#KRAS+WT#

Pt#051#KRAS+WT#

Normal##donor#Y#

0 8 22 43 64 85 127 169 211 0 8 22 64 1270

250

500

750

0

50

100

150

200

Time (days)

nmol

es p

er s

ebut

ape

Sapenic Acid TG Sat + Monounsat TG

nmoles per sebutape

Pt#042,#KRAS,MUT# Pt#054,#KRAS,MUT#

4 20 28 39 48 58 59 72 37 38 73 82 42 510123

100

200

300

Patient number

Tum

or M

UC

5AC

leve

ls(m

RN

A, R

PK

M)

0"

20"

40"

60"

80"

100"


MUC5

AC$(n

g/ml)$



Pt)094)

Pt)043,)041)

Pt)042)

Pt)024)

Pt)054)Pt)045,)051)

Tumor&Genotype&

Tumor&&RNA0Seq&

Tumor&IHC&

Serum&Proteomics&

Serum&Metabolomics&

Sebum&Lipidomics&

FASN Tumor IHCSurvival FASN Serum ELISA

NSC

LC

0

50

100

150

200

250

FASN

IHC

(H s

core

in tu

mor

cel

ls)

50# 100# 150# 200#Months'

FASN*nega/ve#

FASN*posi/ve###########(p=0.1)#

Survival'Fun

c1on

'

0.2#

0.4#

0.6#

0.8#

1.0#

(Visca#et#al.,#2004)#

Nor

mal

mal

e

Nor

mal

fem

ale

NS

CLC

Sec

rete

d FA

SN

(ng/

ml)

!!!!!!!!Low

!!!!!!!!!Mod

erate!!!!!!!!!H

igh!!!

Weeks on study for monotherapy NSCLC patients

!Pt!

!KRAS!

Dose!!(mg,!mg/m2)!

Cmax!!(ng/ml)!

AUC0:24!(hr*ng/ml)!

024$ MUT$Q61H$ 100,$$80$ 3320$ 41360$042$ MUT$G13C$ 250,$130$ 3460$ $40900$

054$ MUT$(nd)$ 150,$100$ 3990$ 42490$

Average$ 3950$ 41583$

!Pt!

!KRAS!

Dose!!(mg,!mg/m2)!

Cmax!!(ng/ml)!

AUC0:24!(hr*ng/ml)!

003$ WT$$ 450,$240$ 4650$ 72740$

043$ WT$ 250,$130$ 7410$ $101200$

045$ WT$ 150,$100$ 2800$ 43960$

051$ WT$ 200,$100$ 3320$ 45440$

Average$ 4545$ 65835$

fasn inhibitor tvb -2640 shows pharmacodynamic …€¦ · fasn inhibitor tvb -2640 shows...

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