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

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

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

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 5 0 1 0 0 1 5 0 Thrombus weight (mg ) 2 0 0 50 100 150 200 Thrombus weight (mg) * e.g. JM Altenburger et al. Bioorganic & Medicinal Chemistry. 2004;12:1713–1730 Comparable efficacy to NOACs in AVS model Cleared for disclosure – Verseon 2017

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

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-2851 - compared to apixaban Maximum platelet activation AV shunt Saline Dabigatran,0.1mg /k g Apixaban, 3mg/kg V E- 2851,1mg/kg 10 20 3 0 Activated platelets (%) 4 0 Significantly reduced impact on platelet function Cleared for disclosure – Verseon 2017

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 1 0 1 5 Thrombus weight (mg) 2 0 2 5 1 0 2 0 3 0 4 0 Thrombus weight (mg) Excellent efficacy in venous stasis thrombosis model Cleared for disclosure – Verseon 2017

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-2851 2-4x higher than vehicle, but >15x lower relative to apixaban Untreated Dabigatran,0.1mg /kg Apixaban, 3mg/kg V E- 2851,10mg/kg 5 0 0 1 0 0 0 Total blood cell count (millions) 1 5 0 0 VE-2851 demonstrates significantly lower bleeding Cleared for disclosure – Verseon 2017

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 0 .0 0 .5 1 .0 1 .5 2 .0 2 .5 Bleeding Time (fold change over vehicle) Confirmation of lower bleeding risk Cleared for disclosure – Verseon 2017

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 1 0 0 0 0 1 0 0 0 0 IV , 1 m g / k g (ng/mL) IV , 0 .5 m g / k g (ng/mL) 1 0 0 0 P O , 5 m g / k g 1 0 0 0 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: 5400 h*ng/mL 4 8 1 IV AUC: 2542 h*ng/mL PO AUC: 5217 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

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

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