SCYNEXIS Proprietary and Confidential Information SCYX-6759, an Orally Bioavailable Oxaborole...
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Transcript of SCYNEXIS Proprietary and Confidential Information SCYX-6759, an Orally Bioavailable Oxaborole...
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.
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
SCYNEXIS Proprietary and Confidential Information
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
SCYNEXIS Proprietary and Confidential Information
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
SCYNEXIS Proprietary and Confidential Information
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
SCYNEXIS Proprietary and Confidential Information
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
SCYNEXIS Proprietary and Confidential Information
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
SCYNEXIS Proprietary and Confidential Information
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)
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 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.
SCYNEXIS Proprietary and Confidential Information
Acknowledgments
●Multi-center collaboration:♦ DNDi♦ Scynexis Inc.♦ Anacor Pharmaceuticals Inc.♦ Pace University - Haskins lab.♦ Swiss Tropical Institute
■ Dr Reto Brun
●For funding and leadership