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© 2012 PEROSPHERE INC. 1 © 11/11
CONFIDENTIAL
1 © 11/11
CONFIDENTIAL
Small Molecule Antidote for Anticoagulants
Bryan Laulicht, Sasha Bakhru, Connie Lee,
Christopher Baker, Xuan Jiang, Edith Mathiowitz, James Costin and
Solomon Steiner
AHA, Los Angeles, CA Nov 5, 2012
© 2012 PEROSPHERE INC. 2
Disclosures • Bryan Laulicht, Sasha Bakhru, Connie Lee, Christopher
Baker, Xuan Jiang, James Costin and Solomon Steiner are employees of Perosphere Inc.
• Edith Mathiowitz is a consultant of Perosphere Inc.
• All of the Authors own shares and/or options in Perosphere Inc.
© 2012 PEROSPHERE INC. 3
Introduction § PER977 is a synthetic small molecule § As demonstrated by dynamic light scattering (DLS), PER977
directly binds all approved new oral anticoagulants (NOACs): § Dabigatran, rivaroxaban, apixaban and edoxaban
§ Completed 14 day repeat dose PER977 i.v. two species (dog and rat) toxicology study shows no significant adverse events
§ Completed safety study with PER977 + rivaroxaban and PER977 + dabigatran showing no significant adverse events in beagle dogs
§ Completed metabolite identification § No CYP inhibition or metabolism in vitro § Expected to be in clinical trials in Q1 2013
© 2012 PEROSPHERE INC. 4
PER977-apixaban dynamic light scattering (DLS) binding
• PER977 binds apixaban at a mass ratio of 1:1 :: PER977:apixaban
0 10 20 30 40
0.1 1 10 100 1000
Volu
me
(%)
Diameter (nm) PER977 Apixaban 1:1 :: PER977:Apixaban 10:1 :: PER977:Apixaban
© 2012 PEROSPHERE INC. 5
Factor Xa or IIa
PER977 competitively binds new oral anticoagulants (NOACs) restoring blocked coagulation factor activity
PER977
Reversal: Factor Xa or IIa activity restored when PER977 binds NOAC
NOAC Xarelto®
Anticoagulation: Factor Xa or IIa activity inhibited by NOAC
NOAC
Factor Xa or IIa
© 2012 PEROSPHERE INC. 6
Overview PER977: § Reduces blood loss and bleeding time, reversing the
anticoagulant activity of dabigatran, rivaroxaban, apixaban and edoxaban in rat tail transection and incision assays
§ Reversal confirmed by aPTT and Xa assays in human blood ex vivo
§ PER977 alone has no dose-dependent effect on coagulation (by platelet aggregation or TEG) ex vivo
§ Presence of rivaroxaban or dabigatran delays PER977 metabolism and increases the MTD of PER977 in blood serum (rats)
© 2012 PEROSPHERE INC. 7
12.5mg PER977 reduces blood loss in dabigatran (15mg p.o.) treated rats to normal levels
§ Full reversal at a dose mass ra.o of 0.83:1, N=3 **p<0.01 ***p<0.001
0
100
200
300
400
500
0 5 12.5 Sham
5 mg PER977 NO PER977 12.5 mg PER977
Blo
od lo
ss [m
g]
PER977 [mg]
***
*** **
No anticoagulant control
© 2012 PEROSPHERE INC. 8
12.5mg PER977 reduces blood loss in rivaroxaban (2mg p.o.) treated rats to normal levels
0
100
200
300
400
500
0 2.5 12.5 Sham
Blo
od lo
ss [m
g]
PER977 [mg]
*
§ Full reversal at a dose mass ra.o of 6.25:1, N=3 *p<0.05
2.5 mg PER977 NO PER977 12.5 mg PER977
No anticoagulant control
© 2012 PEROSPHERE INC. 9
5mg PER977 reduces blood loss in apixaban (1.25mg p.o.) treated rats to normal levels
§ Full reversal at a dose mass ra.o of 4:1, N=3 ***p<0.001
Blo
od lo
ss [m
g]
PER977 [mg]
***
0
200
400
600
800
0 5 12.5 Sham
5 mg PER977 NO PER977 12.5 mg PER977
No anticoagulant control
© 2012 PEROSPHERE INC. 10
PER977 (12.5 mg) reduces blood loss in edoxaban (5 mg p.o.) treated rats to normal levels
NO PER977 12.5mg PER977
§ Full reversal at a dose mass ra.o of 2.5:1, N=5 **p<0.01, ***p<0.001
0
100
200
300
400
500
0 31.25 sham
Blo
od lo
ss [m
g]
PER977 [mg]
*** **
12.5 No anticoagulant control
© 2012 PEROSPHERE INC. 11
50
150
250
350
15 25 35 45 55
Ble
edin
g tim
e (s
)
Minutes post PER977 dose
PER977 reversal
0.9% injection saline (sham)
Baseline
*** ♯♯
*** ♯♯
** ♯♯♯
PER977 dabigatran reversal is confirmed by a rat tail incision bleeding time model
** p<0.01, ***p<0.001 compared to PER977 group
♯♯ p<0.01, ♯♯♯ p<0.001 compared to baseline (pre-dose bleeding time)
"
50
150
250
350
15 25 35 45 55
Ble
edin
g tim
e (s
)
Minutes post PER977 dose
PER977 reversal
0.9% injection saline (sham)
Baseline
***"♯♯"
***"♯♯"
**"♯♯♯"
"
50
150
250
350
15 25 35 45 55
Ble
edin
g tim
e (s
)
Minutes post PER977 dose
PER977 reversal
0.9% injection saline (sham)
Baseline
***"♯♯"
***"♯♯"
**"♯♯♯"
© 2012 PEROSPHERE INC. 12
0
10
20
30
40
50
60
70
Saline sham 0.25μg/ml Xarelto®
0.25μg/ml Xarelto® + 50μg/ml PER977
50μg/ml PER977
aPTT [s]
APTT testing confirms PER977 reverses rivaroxaban in fresh human whole blood ex vivo
rivaroxaban rivaroxaban
© 2012 PEROSPHERE INC. 13
0
50
100
150
200
250
300
350
218μg/L Xarelto®
218μg/L Xarelto® + 1.25μg/L PER977
218μg/L Xarelto® + 12.5μg/L PER977
218μg/L Xarelto® + 125μg/L PER977
218μg/L Xarelto® + 1,250μg/L PER977
Effec.v
e riv
aroxab
an con
centra.o
n [μg/L]
PER977 restores Factor Xa activity in a dose-dependent fashion ex vivo in human plasma
MEC
PER977 restores Xa activity to an effective rivaroxaban concentration below MEC
rivaroxaban rivaroxaban rivaroxaban rivaroxaban rivaroxaban
© 2012 PEROSPHERE INC. 14
PER977 alone shows no dose-dependent effects on platelet aggregation in human blood ex vivo
Agg
rega
tion
ohm
s 10
µM A
DP
Agg
rega
tion
ohm
s 5µ
G/m
L C
olla
gen
50
40
30
20
10
0 0 0.5 5 50
µM PER977 0 0.5 5 50
µM PER977
80
60
40
20
© 2012 PEROSPHERE INC. 15
PER977 alone shows no dose-dependent effects on thromboelastography (TEG) ex vivo
0 0.5 5 50 µM PER977 0 0.5 5 50 µM PER977
0 0.5 5 50 µM PER977 0 0.5 5 50 µM PER977
TEG
R [m
in]
TEG
K [m
in]
TEG
ang
le [d
eg]
TEG
MA
[min
]
2
4
6
8
10
2
4
6
20
40
60
80
20
40
60
80
© 2012 PEROSPHERE INC. 16
PER977
Metabolizing Enzyme
PER977
NOAC
Metabolizing Enzyme
X
Metabolism of PER977 occurs in the blood
Metabolism of PER977 in the blood is slowed in the presence of new oral anticoagulants (NOACs)
PER977
NOAC
Metabolizing Enzyme
X
PER977
NOAC
Metabolizing Enzyme
X
© 2012 PEROSPHERE INC. 17
0.5
1
1.5
2
PER977 PER977 + rivaroxaban
PER977 + dabigatran
Rel
ativ
e se
rum
hal
f-life
NOAC increases the clearance half-life of PER977 in blood serum
§ PER977-NOAC complex is protected from enzymatic metabolism
© 2012 PEROSPHERE INC. 18
NOAC increases the maximally tolerated dose (MTD) of PER977 in rats
§ Toxicologic effects of high doses of PER977 are reduced in the presence of NOAC, further evidencing complex formation
0
0.5
1
1.5
2
PER977 PER977 + Rivaroxaban
PER977 + Apixaban
Rel
ativ
e M
TD
© 2012 PEROSPHERE INC. 19
Review PER977 is a synthetic small molecule that:
§ Reduces blood loss and bleeding time, reversing the anticoagulant activity of dabigatran, rivaroxaban, apixaban and edoxaban in rat tail transection and incision assays
§ Reversal confirmed by aPTT and Xa assays in human blood ex vivo § PER977 alone has no dose-dependent effect on coagulation § Presence of rivaroxaban or dabigatran delays PER977 metabolism in
blood serum and increases the MTD of PER977 (rats) § Completed 14 day repeat dose PER977 i.v. two species (dog and rat)
toxicology study shows no significant adverse events § Completed safety study with PER977 + rivaroxaban and PER977 +
dabigatran showing no significant adverse events in beagle dogs § No CYP inhibition or metabolism in vitro § Expected to be in clinical trials in Q1 2013
© 2012 PEROSPHERE INC. 20
Thank you!
For more information please contact: Dr. Solomon Steiner, CEO (914) 241-0191 [email protected]
