SCYNEXIS Proprietary and Confidential Information

SCYX-6759, an Orally Bioavailable Oxaborole 6-carboxamide, Achieves Therapeutically

Relevant Exposure in Brain and CSF Leading to 100% Cures in a Mouse Model of CNS-stage

Human African TrypanosomiasisStephen Wring, Bakela Nare, Cyrus Bacchi, Beth Beaudet, Tana

Bowling, Daitao Chen, Robert Don, Yvonne Freund, Eric Gaukel, Kurt Jarnagin, Matthew Jenks, Luke Mercer, Andy Noe, Matthew Orr,

Robin Parham, Jacob Plattner, Cindy Rewerts, Jessica Sligar, Nigel Yarlett, and Robert Jacobs.

steve.wring@scynexis.com

Scynexis Inc., Research Triangle Park, Durham, NC27709

SCYNEXIS Proprietary and Confidential Information

Oxaborole Lead Optimization Path for HAT

O

B

OH

NH

OF F

F

AN3520

O

F

F FF

NH

O

B

OH

4'

2'

SCYX-6759

● Oxaborole-6-carboxamides♦ SCYX-6759♦ Potent in vitro activity against T.b.b., T.b.g. and T.b.r♦ Excellent in vitro ADMET profile

■ Metabolically stable (liver S9 half-life >350mins)■ Permeable in MDCK-MDR1 transport assay (~350nm/s)■ Non P-gp substrate (AQ <0.1)■ Modest protein binding (fu ~2%)■ Non-genotoxic in AMES

♦ Enhanced PK and brain disposition in animals

O

B

OH

S

Cl

O

AN2920

● AN2920 ♦ Discovered by Anacor, and recognized as lead

optimization candidate for HAT treatment by DNDi

● Lead Optimization ♦ Enhance PK♦ Improve CNS disposition

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SCYX-6759 Improves Plasma Exposure Following IP Administration to Mice

●SCY-6759 improves exposure (AUC).●Longer apparent elimination half-life after IV dose

AN3520 SCYX-6759

Route IV IV

Dose (mg/kg

2 2*

AUC0-inf (µg.hr/mL)

18.1 33.4

CL 0.111 0.059

Half-life (hr) 2.9 11.4

Vdss (L/kg) 0.474 0.972

* Normalized from 3.3mg/kg dose to 2mg/kg0.001

0.010

0.100

1.000

10.000

100.000

0 5 10 15 20 25

Time Post Dose (hr)

Co

nce

ntr

atio

n (

µg/m

L)

SCYX-6759 IP 50 mg/kg

AN3520 IP 50 mg/kg

AN2920 IP 50 mg/kg

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Efficacy: Stage 1 Murine HAT Model

●SCYX-6759 100% effective after 4 days of b.i.d. oral treatment in murine stage 1 model

Infection with 250,000 T. b. brucei EATRO 110 parasites progressed 24h before treatment

0102030405060708090

100

5 10 20

AN2920

AN3520

SCYX-6759

Oral Dose (mg/kg)

Eff

icac

y (%

)

Dose (mg/kg) Route Cured/Total

AN2920 5 PO 0/3

10 PO 0/3

20 PO 0/3

20 IP 3/3

AN3520 5 PO 3/3

10 PO 2/3

20 PO 3/3

SCYX-6759 5 PO 3/3

10 PO 3/3

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SCYX-6759 Distribution in Sanctuary Tissues

●SCYX-6759 crosses the blood-brain, and blood-testicular barriers in mice.

0.001

0.010

0.100

1.000

10.000

0 5 10 15 20 25Time Post Dose (hr)

Co

nc

en

tra

tio

n (

µg

/mL

)

Plasma 2 mg/kg IVBrain 2 mg/kg IVTestes 2 mg/kg IV

SCYNEXIS Proprietary and Confidential Information

0.01

0.1

1

10

100

0 5 10 15 20

Time (hours)

Co

nc

en

tra

ion

µg

/mL

Plasma

Brain

CSF

SCYX-6759: Disposition in Rat Plasma and CNS Compartments

●Therapeutic levels sustained in CNS for 10 hr after a single 50 mg/kg oral dose.

●Likely requires 50 mg/kg bid for CNS efficacy

In vitro MIC

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Exposure Improved in Primates

● Consistent with QD oral drug for Stage 1 HAT in mice and non-human primates.

Dose 12 mg/kg

Route Oral

AUC0-inf 86 µg*hr/mL

Bioavailability 83%

Half-life 9 hr

Primate PK parameters

0.01

0.10

1.00

10.00

100.00

0 10 20 30 40 50Time Post Dose (hr)

Co

nc

en

tra

tio

n (

µg

/mL

)

SCYX-6759 Mouse PO 12 mg/kg

SCYX-6759 Rat PO 12 mg/kg

SCYX-6759 Cyno PO 12 mg/kg

In vitro MIC

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Efficacy: Murine Stage 2 HAT Model

●SCYX-6759 Achieves 100% Cure following 14 days of oral 50 mg/kg bid (Q12hr) dosing.

0 20 40 60 80 100 120 140 160 1800

20

40

60

80

100

Berenil D4Berenil D21AN3520-25mg (14d)AN3520-50mg (7d)AN3520-50mg (14d)SCYX-6759-50mg (14d)

Days Post-infection

% A

nim

al P

aras

ite

Fre

e

0 20 40 60 80 100 120 140 160 1800

20

40

60

80

100

Berenil D21SCYX-6759-50mg (10d)

Days Post-infection

% A

nim

al P

aras

ite

Fre

e

T.b. brucei: TREU-667 T.b. brucei: GVR-35

T.b. brucei: GVR-35 data were kindly provided by Dr Reto Brun, STI.

SCYNEXIS Proprietary and Confidential Information

0.01

0.1

1

10

100

0 4 8 12Time post dose (hr)

Co

nc

en

tra

tio

n (

µg

/ml)

PO - 6 mg/kg - PL PO - 6 mg/kg - BR

PO - 12.5 mg/kg - PL PO - 12.5 mg/kg - BR

PO - 25 mg/kg - PL PO - 25 mg/kg - BR

PO - 50mg/kg - PL PO - 50mg/kg - BR

Understanding the PK-PD Relationship for SCYX-6759 in HAT

● After 7 days of Q12hr oral treatment 50mg/kg maintains exposure above MIC in brain.

● 50mg/kg b.i.d is the likely CNS efficacious dose.

In vitro MIC

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Impact of Concentration on In Vitro Time Kill

● >MIC exposure is required to kill within 24hr

● Maximum effect observed at 3 fold MIC.

● 50mg/kg oral b.i.d. in mice may not deliver maximal effect.

0 5 10 15 20 250

20

40

60

80

100

120

0.039ug/ml0.078ug/ml0.156ug/ml0.312ug/ml0.625ug/ml1.25ug/ml2.5ug/ml

5ug/ml10ug/ml20ug/ml

SCYX6759

Time (Hrs)

Via

bili

ty (

% C

on

tro

l)

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Dose Response in Murine Model of CNS HAT ( Day 147 Update)

0 20 40 60 80 100 120 1400

20

40

60

80

100

Berenil D4

Berenil D216759-6mg/kg

6759-12.5 mg/kg6759-25 mg/kg6759-50 mg/kg

Days Post-infection

% A

nim

als

Par

asit

e F

ree

OB

ON

OCF3

F

SCYX-6759

b.i.d. (Q12hr) PO

SCYNEXIS Proprietary and Confidential Information

Dose Response in Murine Model of CNS HAT ( Day 147 Update)

0 20 40 60 80 100 120 1400

20

40

60

80

100

Berenil D4

Berenil D217158-6mg/kg

7158-12.5 mg/kg

7158-25 mg/kg7158-50 mg/kg

Days Post-infection

% A

nim

als

Par

asit

e F

ree

0 20 40 60 80 100 120 1400

20

40

60

80

100

Berenil D4

Berenil D216759-6mg/kg

6759-12.5 mg/kg6759-25 mg/kg6759-50 mg/kg

Days Post-infection

% A

nim

als

Par

asit

e F

ree

0 10 20 30 40 50

0

20

40

60

80

100

SCYX-6759

SCYX-7158

Oral Dose (mg/kg)

% A

nim

als

Par

asit

e F

ree

at D

ay 1

33 P

ost

-tre

atm

ent

OB

ON

OCF3

F

OB

ON

OCF3

F

SCYX-7158 SCYX-6759

b.i.d. (Q12hr) POq.d. PO

Poster #829: Jacobs, B. et alSession C, Exhibit Hall A, Noon- 1.30pm

SCYNEXIS Proprietary and Confidential Information

Conclusions

●SCYX-6759:♦ Discovered by a collaboration of DNDi, Anacor, PACE

University and Scynexis.♦ A new class of anti-trypanosomal drug.♦ Achieved 100% efficacy in a murine stage 2 HAT model.♦ Readily crosses the blood-brain and blood-testicular

barriers.♦ Efficacy can be predicted from brain exposure.♦ Led to SCYX-7158 - a pre-clinical candidate for HAT.

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Acknowledgments

●Multi-center collaboration:♦ DNDi♦ Scynexis Inc.♦ Anacor Pharmaceuticals Inc.♦ Pace University - Haskins lab.♦ Swiss Tropical Institute

■ Dr Reto Brun

●For funding and leadership