Rome, 15th December 2015 Valeria Maida Medical Affairs Understanding SURVET Rome, 15th December 2015 Valeria Maida Medical Affairs

2005 2006 2007 2008

Patient demographics Russia Poland Czech Republic Slovakia Italy 205 (33%) Poland 166 (27%) Czech Republic 81 (13%) Slovakia 43 (7%) Italy 67 (11%) Romania 53 (9%) Andreozzi Circulation 2015

Primary efficacy endpoint Primary safety endpoint The population included adult patients with first-ever unprovoked VTE who had completed 3–12 months of VKA therapy SURVET was a multicentre, randomised, double-blind, parallel-group, placebo-controlled trial in adult patients with first-ever unprovoked VTE Sulodexide 500 LSU orally twice daily + compression therapy Primary efficacy endpoint Confirmed recurrence of VTE* Primary safety endpoint Major or clinically relevant non-major bleeding† Patients aged ≥18 years with first-ever unprovoked VTE who had completed oral anticoagulation therapy RANDOMISATION n=308 Placebo twice daily + compression therapy n=309 3–12 months 1–12 weeks 2 years DVT = Deep Vein Thrombosis LSU = Lipasemic Units PE = Pulmonary Embolism VTE = Venous Thromboembolism * The primary efficacy outcome was symptomatic, objectively confirmed recurrence of VTE, defined as the composite of deep vein thrombosis (DVT) objectively confirmed by compression ultrasonography, or non-fatal or fatal pulmonary embolism (PE) objectively confirmed by computed tomography or lung scanning.1 † The principal safety outcome was major or clinically relevant non-major bleeding.1 An overt bleeding event was defined as major if fatal, or occurred in a critical location, or required a transfusion of ≥2 units of whole blood or red cells.1 Clinically relevant non-major bleeding was defined as overt bleeding that did not meet the criteria for major bleeding but was associated with the need for medical intervention, contact with a physician, or interruption of the study drug or with discomfort or impairment of activities of daily life.1 Andreozzi Circulation 2015

VTE: a definition www.DVTanswers.com

VTE: a definition

Nothing can be said about efficacy in PE Treatment groups were well balanced with respect to baseline characteristics Baseline characteristics Characteristic Sulodexide (n=307) Placebo (n=308) Age, years±SD 55.7±14.1 55.9±14.4 Male, n (%) 175 (57) 155 (50) Index event DVT, n (%) 284 (92) PE, n (%) 23 (8) 24 (8) Sample was calculated to detect differences in VTE Nothing can be said about efficacy in PE Andreozzi Circulation 2015

Primary efficacy endpoint Primary safety endpoint The population included adult patients with first-ever unprovoked VTE who had completed 3–12 months of VKA therapy SURVET was a multicentre, randomised, double-blind, parallel-group, placebo-controlled trial in adult patients with first-ever unprovoked VTE Sulodexide 500 LSU orally twice daily + compression therapy Primary efficacy endpoint Confirmed recurrence of VTE* Primary safety endpoint Major or clinically relevant non-major bleeding† Patients aged ≥18 years with first-ever unprovoked VTE who had completed oral anticoagulation therapy RANDOMISATION n=308 Placebo twice daily + compression therapy n=309 3–12 months 1–12 weeks 2 years DVT = Deep Vein Thrombosis LSU = Lipasemic Units PE = Pulmonary Embolism VTE = Venous Thromboembolism * The primary efficacy outcome was symptomatic, objectively confirmed recurrence of VTE, defined as the composite of deep vein thrombosis (DVT) objectively confirmed by compression ultrasonography, or non-fatal or fatal pulmonary embolism (PE) objectively confirmed by computed tomography or lung scanning.1 † The principal safety outcome was major or clinically relevant non-major bleeding.1 An overt bleeding event was defined as major if fatal, or occurred in a critical location, or required a transfusion of ≥2 units of whole blood or red cells.1 Clinically relevant non-major bleeding was defined as overt bleeding that did not meet the criteria for major bleeding but was associated with the need for medical intervention, contact with a physician, or interruption of the study drug or with discomfort or impairment of activities of daily life.1 Andreozzi Circulation 2015

Hypercoagulable State Trauma Surgery of lower extremities Thrombophilia….. VTE: Virchow’s Triad Hypercoagulable State Circulatory Stasis Vascular Wall Injury Trauma or sugery Atherosclerosis Venepuncture….. Immobility or paralysis Venous insufficiency Obesity or pregnancy

Cumulative r-VTE incidence r-DVT Epidemiology After 6 months 3.7% After 1 year with transitory risk factors 7.8% 6.7% Cumulative r-VTE incidence in patients without transitory risk factors After 2 years 17.5-18.1% After 5 years 24.6% After 8 years 30.3% Agnelli J Thromb Thrombolys 2008; van Gogh’ Investigators NEJM 2007

r-VTE: EPIDEMIOLOGY Patients who present with thrombotic episodes of unknown origin have a more than two-fold higher risk of recurrences than that observed in patients with temporary risk factors The risk of recurrence increased with age both in the entire cohort and in the subgroup of patients with unprovoked VTE Prandoni Haematologica 2007

Provoked and unprovoked VTE: stratification Distribution of VTE patients All VTE patients All VTE patients Provoked Unprovoked Extended Anticoagulation Recent surgery Pregnancy Immobilization Trauma Idiopathic More VTE episodes Serious thrombophilia APS PE Pulmonary hypertension 25% 50% 25% low risk (surgery) medium risk (non surgery) high risk very high risk

Primary efficacy endpoint Primary safety endpoint The population included adult patients with first-ever unprovoked VTE who had completed 3–12 months of VKA therapy SURVET was a multicentre, randomised, double-blind, parallel-group, placebo-controlled trial in adult patients with first-ever unprovoked VTE Sulodexide 500 LSU orally twice daily + compression therapy Primary efficacy endpoint Confirmed recurrence of VTE* Primary safety endpoint Major or clinically relevant non-major bleeding† Patients aged ≥18 years with first-ever unprovoked VTE who had completed oral anticoagulation therapy RANDOMISATION n=308 Placebo twice daily + compression therapy n=309 3–12 months 1–12 weeks 2 years DVT = Deep Vein Thrombosis LSU = Lipasemic Units PE = Pulmonary Embolism VTE = Venous Thromboembolism * The primary efficacy outcome was symptomatic, objectively confirmed recurrence of VTE, defined as the composite of deep vein thrombosis (DVT) objectively confirmed by compression ultrasonography, or non-fatal or fatal pulmonary embolism (PE) objectively confirmed by computed tomography or lung scanning.1 † The principal safety outcome was major or clinically relevant non-major bleeding.1 An overt bleeding event was defined as major if fatal, or occurred in a critical location, or required a transfusion of ≥2 units of whole blood or red cells.1 Clinically relevant non-major bleeding was defined as overt bleeding that did not meet the criteria for major bleeding but was associated with the need for medical intervention, contact with a physician, or interruption of the study drug or with discomfort or impairment of activities of daily life.1 Andreozzi Circulation 2015

VTE: Treatment a long time ago… present time ACUTE TREATMENT fondaparinux LMWH up to 7 days up to 3 months LMWH VKA VKA NOAC

First approval r-DVT approval October 2010 April 2014 August 2011 July 2011 February 2012 September 2008 January 2013 December 2012 August 2014 May 2011 June 2014 Boehringer Ingelheim Janssen (US), Bayer Pfizer (US), BMS January 2015 July 2015 July 2015 DaichiiSankyo

r-DVT: stopping anticoagulation 3 months of anticoagulant treatment resulted in a similar risk of recurrence after treatment was stopped to a longer duration of treatment and that shortening treatment to 1.0 or 1.5 months doubled recurrence rates. The risk of recurrence after stopping treatment is about double when venous thromboembolism is unprovoked compared with if it is provoked by a temporary risk factor Boutitie BMJ 2011

from 3 months to indefinite VTE: Treatment a long time ago… present time ACUTE TREATMENT fondaparinux LMWH fondaparinux LMWH up to 7 days up to 3 months LMWH VKA VKA VKA NOAC EXTENDED TREATMENT from 3 months to indefinite VKA VKA NOAC NOAC aspirin aspirin aspirin

DURATION OF ANTICOAGULATION CRITERIA FOR SHORT AC AFTER 1ST VTE post major surgery (< 3 mo.) post bed resting post major trauma (< 3 mo.) post plasters or immobilization (< 3 mo.) High bleeding risk CRITERIA FOR EXTENDED AC more documented VTE episodes Active cancer Serious thrombophilia Antiphospholipid syndrome PE Pulmonary Hypertension Other indications for AC NYHA 3 or 4

Provoked and unprovoked VTE: stratification Distribution of VTE patients All VTE patients Provoked Recent surgery Pregnancy Immobilization Trauma 25% Extended Anticoagulation More VTE episodes Serious thrombophilia APS PE Pulmonary hypertension low risk (surgery) medium risk (non surgery) very high risk All VTE patients Provoked Recent surgery Pregnancy Immobilization Trauma 25% Unprovoked Idiopathic 50% Extended Anticoagulation More VTE episodes Serious thrombophilia APS PE (with shock or life-threatening) Pulmonary hypertension low risk (surgery) medium risk (non surgery) high risk very high risk

ACCP Guidelines do not specify the duration of extended anticoagulant therapy in patients with first-ever unprovoked VTE1 Recommended therapy:1 Parenteral anticoagulation with LMWH or fondaparinux for ≥5 days and until INR ≥2.0 for ≥24 hours VKA therapy started on same day Recommended duration of therapy:1 3 months of anticoagulant therapy in patients with high bleeding risk Extended anticoagulant therapy (for >3 months) in patients with low or moderate bleeding risk After 3 months of treatment, patients with unprovoked VTE should be evaluated for the risk-benefit ratio of extended therapy1 2012 ACCP = American College of Chest Physicians INR = International Normalised Ratio LMWH = Low Molecular Weight Heparin VKA = Vitamin K Antagonist VTE = Venous Thromboembolism 1. Kearon C, et al. Chest. 2012;141(Suppl. 2):e419S-94S.

r-VTE: WHO IS AT RISK? Fahrni VascHealthRiskManag 2015

D-Dimer D-dimer is a fibrin degradation product (or FDP), a small protein fragment present in the blood after a blood clot is degraded by fibrinolysis. It is so named because it contains two crosslinked D fragments of the fibrin protein. D-dimers are not normally present in human blood plasma, except when the coagulation system has been activated An abnormal D-Dimer at one month following discontinuation of anticoagulation after DVT treatment is an independent risk factor for recurrent DVT.

D-DIMER AND r-VTE Cumulative probability of recurrence according to normal (≤500 ng/ml) or abnormal D-dimer results obtained 3 months after anti-coagulation was stopped   HR=2.45 Palareti T&H 2002

Dulcis results in young and elderly patients who did not resume AC D-DIMER AND r-VTE Dulcis results in young and elderly patients who did not resume AC <= 70 y > 70 y p Negative DD recurrences 2.1% 8.9% 0.0008 Positive DD 14.3% 12.5% ns Palareti Blood 2014

D-Dimer: SANVAL REGISTRY RESULTS % of subjects with increased D-dimer p<0.05 Available pts 199 control 198 sdx 182 control 178 control 189 sdx Errichi Angiol 2004

r-VTE AND RISK OF BLEEDING In patients who receive extended anticoagulant therapy, the continuing use of treatment should be reassessed at periodic intervals (eg, annually), patient preference considered, and the choice of anticoagulant regimen reevaluated Fahrni VascHealthRiskManag 2015

1%–4% per year r-VTE and BLEEDING Incidence of major bleeding while on anticoagulation Case fatality rate for bleeding can be higher than case fatality rate for re-thrombosis Fahrni VascHealthRiskManag 2015

All VTE patients RISK OF BLEEDING High History of major bleeding events Known inherited bleeding disorder Platelet count <50.000 mmc Need for double antiplatelet therapy Portal hypertension (bleeding esophageal varices) Known cerebral alterations in the elderly (amyloidosis, micro-bleeds) Moderate History of clinically relevant non-major bleeding Treatment with an antiplatelet drug Platelet count <100.000 mmc Low Negative history for bleeding No bleeding during previous AC treatment No associated pro-hemorrhagic drugs There are few data assessing outcomes in patients with different risks of bleeding, and there is a lack of well-validated tools for stratifying risk of bleeding in patients with VTE Kearon Chest 2012

Primary efficacy endpoint Primary safety endpoint The population included adult patients with first-ever unprovoked VTE who had completed 3–12 months of VKA therapy SURVET was a multicentre, randomised, double-blind, parallel-group, placebo-controlled trial in adult patients with first-ever unprovoked VTE1 Sulodexide 500 LSU orally twice daily + compression therapy Primary efficacy endpoint Confirmed recurrence of VTE* Primary safety endpoint Major or clinically relevant non-major bleeding† Patients aged ≥18 years with first-ever unprovoked VTE who had completed oral anticoagulation therapy RANDOMISATION n=308 Placebo twice daily + compression therapy n=309 3–12 months 1–12 weeks 2 years Adapted from Andreozzi et al. 2015.1 DVT = Deep Vein Thrombosis LSU = Lipasemic Units PE = Pulmonary Embolism VTE = Venous Thromboembolism * The primary efficacy outcome was symptomatic, objectively confirmed recurrence of VTE, defined as the composite of deep vein thrombosis (DVT) objectively confirmed by compression ultrasonography, or non-fatal or fatal pulmonary embolism (PE) objectively confirmed by computed tomography or lung scanning.1 † The principal safety outcome was major or clinically relevant non-major bleeding.1 An overt bleeding event was defined as major if fatal, or occurred in a critical location, or required a transfusion of ≥2 units of whole blood or red cells.1 Clinically relevant non-major bleeding was defined as overt bleeding that did not meet the criteria for major bleeding but was associated with the need for medical intervention, contact with a physician, or interruption of the study drug or with discomfort or impairment of activities of daily life.1 Andreozzi Circulation 2015

Sulodexide 500 LSU orally twice daily demonstrated half the risk of recurrent VTE vs placebo1 Statistically significant reduction in risk of recurrent VTE vs placebo1 Recurrent VTE occurred in 15 (4.9%) patients treated with sulodexide compared with 30 (9.7%) patients treated with placebo (HR: 0.49; 95% CI: 0.27– 0.92; p=0.02)1*† Cumulative risk of recurrent VTE in patients assigned to sulodexide (n=307) or placebo (n=308)1* Sulodexide Placebo CI = Confidence Interval; DVT = Deep Vein Thrombosis; HR = Hazard Ratio; LSU = Lipasemic Units; PE = Pulmonary Embolism; VKA = Vitamin K Antagonist; VTE = Venous Thromboembolism * The analysis adjusted for age, sex, index event, country, duration of exposure to VKA, and delay from end of VKA treatment and randomisation, confirmed that sulodexide treatment reduced the risk of recurrence (adjusted HR: 0.45; 95% CI: 0.24–0.84; p=0.01).1 No association was found between recurrent VTE and length of exposure to VKA (HR: 0.79; 95% CI: 0.41–1.53; p=0.48).1 † Of the 15 episodes of recurrent VTE with sulodexide, 12 (75%) were DVT and 3 (25%) were PE.1 Of the 30 episodes in the placebo group, 24 (80%) were DVT and 6 (20%) were PE.1 Andreozzi Circulation 2015

Cumulative r-VTE incidence r-DVT Epidemiology After 6 months 3.7% After 1 year with transitory risk factors 7.8% 6.7% After 2 years 17.5-18.1% After 5 years 24.6% After 8 years 30.3% Cumulative r-VTE incidence in patients without transitory risk factors After 6 months 3.7% After 1 year with transitory risk factors 7.8% 6.7% After 5 years 24.6% After 8 years 30.3% Agnelli J Thromb Thrombolys 2008; van Gogh’ Investigators NEJM 2007

RESULTS: PRIMARY END POINT Risk of recurrent VTE vs placebo Adverse event Treatment Treatment duration (months) Risk of recurrent VTE vs comparator (HR [95% CI]) SURVET1 Sulodexide 24 0.49 [0.27–0.92] p=0.02 ASPIRE+WARFASA2 Aspirin 24 (48) 0.68 [0.51–0.90] p=0.008 RE-SONATE3 Dabigatran 6 0.08 [0.02–0.25] P<0.001 EINSTEIN-EXT4 Rivaroxaban 12 0.18 [0.09–0.39] p<0.001 AMPLIFY-EXT 25 Apixaban (2.5 mg) 0.19 [0.11–0.33] - Apixaban (5 mg) 0.20 [0.11–0.34] CI = Confidence Interval HR = Hazard Ratio LSU = Lipasemic Units VTE = Venous Thromboembolism 1. Andreozzi GM, et al. Circulation. 2015;132:1891-7. 2. Simes J, et al. Circulation. 2014;130:1060-71. 3. Schulman S, et al. N Engl J Med. 2013;368(8):709-18. 4. The EINSTEIN Investigators. N Engl J Med. 2010:363:2499-510. 5. Agnelli G, et al. N Engl J Med. 2013;368(8):699-708.

RESULTS: SECONDARY END POINT No episodes of major bleeding occurred in either treatment group Clinically relevant non- major bleeding occurred in 2 patients in each treatment group (HR: 0.97; 95% CI: 0.14–6.88; p=0.98) Andreozzi Circulation 2015

RESULTS: SECONDARY END POINT Risk of clinically relevant bleeding vs placebo Adverse event Treatment Treatment duration (months) Major bleeding events Risk of clinically relevant bleeding vs comparator (HR [95% CI]) SURVET1 Sulodexide 24 0.97 [0.14–6.88] p=0.98 ASPIRE+WARFASA2 Aspirin 24 (48) 8 1.50 [0.72–3.14] p=0.28 RE-SONATE3 Dabigatran 6 2 2.92 [1.52–5.60] p=0.001 EINSTEIN-EXT4 Rivaroxaban 12 4 5.19 [2.13–11.7] p<0.001 AMPLIFY-EXT 25 Apixaban (2.5 mg) 1.20 [0.69–2.10] - Apixaban (5 mg) 1 1.62 [0.96–2.73] CI = Confidence Interval HR = Hazard Ratio LSU = Lipasemic Units 1. Andreozzi GM, et al. Circulation. 2015;132:1891-7. 2. Simes J, et al. Circulation. 2014;130:1060-71. 3. Schulman S, et al. N Engl J Med. 2013;368(8):709-18. 4. The EINSTEIN Investigators. N Engl J Med. 2010:363:2499-510. 5. Agnelli G, et al. N Engl J Med. 2013;368(8):699-708.

Sulodexide 500 LSU orally twice daily was well tolerated Adverse events were similar for patients taking sulodexide or placebo Overall adverse events1 Adverse event Sulodexide (n=307) Placebo (n=308) Treatment-emergent AEs reported, n 368 397 Patients with ≥1 AE, n (%)* 150 (48.7) 162 (52.4) ≥1 serious AE, n (%)* 25 (8.1) 34 (11.0) AE resulting in discontinuation, n (%)* 28 (9.1) 42 (13.6) AE resulting in death, n (%)* 1 (0.3) 4 (1.3) AE = Adverse Event LSU = Lipasemic Units * No statistically significant differences for sulodexide vs placebo.1 Andreozzi Circulation 2015

Sulodexide 500 LSU orally twice daily was well tolerated Most frequent adverse events (>5%) Adverse event Sulodexide (n=307) Placebo (n=308) Pain in extremity, n (%) 15 (4.9) 16 (5.2) Deep vein thrombosis, n (%) 12 (3.9) 24 (7.8) Arthralgia, n (%) 13 (4.2) 8 (2.6) Hypertension, n (%) 10 (3.2) Oedema peripheral, n (%) 6 (1.9) Nasopharyngitis, n (%) 11 (3.6) Respiratory tract infection, viral, n (%) 9 (2.9) 7 (2.3) LSU = Lipasemic Units Andreozzi Circulation 2015

POST-THROMBOTIC SYNDROME

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