1. …driving discovery
An improved potent direct thrombin inhibitor shows efficacy with low bleeding risk
Anirban Datta et al.

2. Reversible covalent inhibition of thrombin
Unique mechanism of action
Verseon compounds are composed of a “carrier” and a “warhead”
Only the parent compound is active, carrier or warhead alone are inactive
Warhead is transferred to the enzyme and carrier leaves active site
Carrier becomes the primary metabolite
Nucleophilic attack of water molecule regenerates active enzyme
Cleared for disclosure – Verseon 2017

3. Potency and selectivity
(µM)
Argatroban
Dabigatran
VE-2851
Thrombin
0.2
0.03
0.003
Factor VIIa
> 50
40.7
> 100
Factor IXa 50
Factor Xa
5.8
7.26
Factor XIa
4.7
3.89
Factor XIIa
aPC
41.3
100
Plasmin
>100
8.4
1.41
Chymotrypsin
2.06
β-Tryptase
5.3
Trypsin
1.23
VE-2851 is a low nanomolar inhibitor of thrombin
Shows high selectivity against other related serine proteases
A potent and selective thrombin inhibitor
Cleared for disclosure – Verseon 2017

4. Preclinical efficacy: Arteriovenous shunt model
Tissue-factor-induced arteriovenous shunt (AVS) model* in rats
Tissue-factor-soaked silk thread provides a realistic representation of the physiological injury mechanism
VE-2851 reduces thrombus size with efficacy comparable
to dabigatran and apixaban
Shows dose-dependent reduction of thrombus weight
VE-2851: Tissue-factor AVS
Vehicle
Vehicle
Dabigatran, 0.1 mg/kg
0.1 mg/ kg
Apixaban, 3mg/kg
1 mg/ kg
VE-2851,1mg/kg
10 mg/ kg
Thrombus weight (mg )
2 0 0
50 100
150
200
Thrombus weight (mg)
* e.g. JM Altenburger et al. Bioorganic & Medicinal Chemistry ;12:1713–1730
Comparable efficacy to NOACs in AVS model
Cleared for disclosure – Verseon 2017

5. Endogenous substrates for thrombin
Activity (µM)
Argatroban
Dabigatran
VE-2851
Thrombin (IC50)
0.2
0.03
0.003
Factor Xa (IC50)
>50
5.8
7.3
TGA (EC50)
0.4
0.7
Fibrinogen cleavage
0.1
Protein C activation
0.01
0.004
TAFI activation
0.02
Platelet activation in mouse plasma
0.005
0.8
Platelet activation in human plasma
0.007
0.3
VE-2851 shows potency comparable to the NOACs against fibrinogen cleavage, protein C, and TAFI
As expected, argatroban and dabigatran are potent inhibitors of platelet activation
VE-2851 shows about 30–40x less inhibition of platelet activation in human plasma
Weak inhibition of thrombin-mediated platelet activation in vitro
Cleared for disclosure – Verseon 2017

6. Platelet activation in vivo
Arteriovenous shunt thrombosis model in rats
Platelet activation monitored by flow cytometry
Whole blood obtained from shunt at various timepoints over 15min
Platelet activation remains low (<10%) for dabigatran and apixaban for duration
Maximum platelet activation for VE-2851 comparable to saline
>5x higher platelet activation observed for VE compared to apixaban
Maximum platelet activation AV shunt
Saline
Dabigatran,0.1mg /k g
Apixaban, 3mg/kg
V E- 2851,1mg/kg
Activated platelets (%)
4 0
Significantly reduced impact on platelet function
Cleared for disclosure – Verseon 2017

7. Preclinical efficacy: Venous stasis thrombosis model
Venous stasis thrombosis model in rats
Surrogate for deep vein thrombosis and venous embolism pathophysiology
Vehicle-treated samples show large thrombus size
VE-2851 effectively reduces thrombus weight, similar to the NOACs
Dose-dependent reduction of thrombus weight observed
VE-2851: Venous stasis thrombosis
Vehicle
Vehicle
Dabigatran,0.1mg /kg
0.1mg/kg
Apixaban, 3mg/kg
1 mg/kg
10 mg/kg
V E- 2851,1mg/kg 5
Thrombus weight (mg)
2 0
2 5
4 0
Thrombus weight (mg)
Excellent efficacy in venous stasis thrombosis model
Cleared for disclosure – Verseon 2017

8. Preclinical safety: Bleeding
Tail bleeding time test in mice
Observed blood cell loss measured over 25 min
Significantly increased total blood cell loss for dabigatran and apixaban (10–50x)
Blood cell loss for VE x higher than vehicle, but >15x lower relative to apixaban
Untreated
Dabigatran,0.1mg /kg
Apixaban, 3mg/kg
V E- 2851,10mg/kg
Total blood cell count (millions)
VE-2851 demonstrates significantly lower bleeding
Cleared for disclosure – Verseon 2017

9. Preclinical safety: Bleeding
Saphenous vein bleeding model
Time for blood clots to form during puncture of saphenous vein
About 2-fold increase in clotting rate for apixaban and dabigatran
Clotting rate almost unaffected by VE-2851
Dabigatran,0.1mg /kg
Apixaban, 3mg/kg
V E- 2851,10mg/kg
2 .5
Bleeding Time (fold change over vehicle)
Confirmation of lower bleeding risk
Cleared for disclosure – Verseon 2017

10. Stability and pharmacokinetics
Tested in multiple species
Good plasma stability (>100 min) and liver microsome stability (>460 min) in rat, dog, and human
Good pharmacokinetics in rats and dogs
Acceptable oral bioavailability in rats (30%) and dogs (41%)
Plasma concentration
Plasma concentration
VE-2851: PK in rats
VE-2851: PK in dogs
IV , 1 m g / k g
(ng/mL)
IV , 0 .5 m g / k g
(ng/mL)
P O , 5 m g / k g
P O , 3 m g / k g
1 0 0
1 0 0
1 0
1 0 1
IV AUC: 4200 h*ng/mL PO AUC: h*ng/mL
4 8 1
IV AUC: 2542 h*ng/mL
PO AUC: h*ng/mL
0 .1
0 .1
1 2
Time (h )
1 6
2 0
2 4 2 4
Time (h ) 6 8
PK profile suitable for oral dosing
Cleared for disclosure – Verseon 2017

11. Tolerability 14-day dose-range finding studies in dogs
VE-2851 was well-tolerated at all dose-levels
No deaths nor abnormal clinical observations at any dose
No significant changes in body or organ weight
No signs of internal bleeding and hematology appears normal
Histopathology results do not show any test-article related findings
Serum blood chemistry and hematology were normal, except for a mild extension of aPTT
Additionally, in vitro toxicology is clean
Very well-tolerated compound
Cleared for disclosure – Verseon 2017

12. VE-2851: Summary Efficacy and safety ADMET
VE-2851 shows strong efficacy in in vivo preclinical models of thrombosis
Inhibits fibrinogen cleavage and regulates thrombin generation without disruption of platelet activation Substantially lower bleeding compared to NOACs observed in preclinical studies
ADMET
Shows good PK exposure and oral bioavailability in rat and dog
Well tolerated in 14-day dose-range-finding study in dog
Phase I studies expected in 2018
Cleared for disclosure – Verseon 2017