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Idrabiotaparinux - Licensing opportunity Unique once weekly anticoagulant with excellent compliance and tolerance Idrabiotaparinux key points: Free from drug interaction and side effect linked to oral formulation: no dietary restriction, no gastro intestinal tract interaction, 100% bioavailability, low PK variability. Once-a-week administration leading to better compliance and protection. Availability of a specific and immediately active reversal agent (avidin) which simplifies anticoagulation management (for instance in case of invasive procedure). Efficacy and safety supported by completed large clinical trials. Ready for registration within 20 months with limited investment Significant upside with appropriate life cycle management Patent protection up to 2026. 1 DRUG PROFILE Idrabiotaparinux is a synthetic and selective indirect inhibitor of coagulation factor Xa via antithrombin activation, administered once-weekly by subcutaneous injection. Its activity, established in-vivo using different models of thrombosis, can be reversed by avidin, an injectable protein that has been developed in parallel. Its very high affinity for biotin enables avidin to immediately trap idrabiotaparinux which is consequently rapidly cleared from the blood. Idrabiotaparinux has a patent protection until September 2021, with possibly up to 5-year extension depending on the countries. Patents have been filed for additional idrabiotaparinux related inventions. Pharmacokinetic data Idrabiotaparinux s.c. is rapidly absorbed (tmax : 4 hours) and is 100% bioavailable. Its pharmacokinetic profile is highly predictable and shows low inter-individual variability. Idrabiotaparinux presents a small apparent volume of distribution, and a low total plasma clearance allowing a once weekly administration. Idrabiotaparinux is completely devoid of drug –drug interaction risk: it is neither a substrate nor an inhibitor of CYP450 enzymes; and idrabiotaparinux is not an inducer of CYP1A, CYP2C9 and CYP3A gene expression and enzyme activity. In addition no interaction of idrabiotaparinux (as substrate and inhibitor) with P-gp transporters has been observed. Idrabiotaparinux Product Summary 1/4 SSR126517E – May 2011 Clinical data All together, idrabiotaparinux and avidin have been assessed in 14 pharmacology studies. The overall outcomes confirm the good safety of both compounds. The large set of clinical data accumulated with idrabiotaparinux (over 3500 patients exposed for more than 3 months) provides a robust body of evidence supporting its efficacy and safety. The net clinical benefit of idrabiotaparinux is supported by 3 completed clinical studies: EQUINOX versus idraparinux, for the treatment of thromboembolic events in patients with deep vein thrombosis (DVT). CASSIOPEA versus vitamin K antagonist (VKA), for the treatment of thromboembolic events in patients with pulmonary embolism (PE) with or without DVT. BOREALIS versus VKA, for the prevention of stroke or non CNS Systemic Events in patients with atrial fibrillation (AF)1. EQUINOX showed: Similar efficacy profile between idrabiotaparinux and idraparinux (non biotinylated pentasaccharide) in accordance with that observed in the van Gogh DVT study 2 conducted with idraparinux on DVT patients. Trend towards for less bleeding, especially major bleeding in the idrabiotaparinux arm. Effective and rapid neutralization of idrabiotaparinux activity following avidin administration leading to a low residual anti-Xa activity without rebound of activity. CASSIOPEA showed: A similar efficacy to VKA at 3 and 6 months (p<0.0001) with a trend toward superiority (ITT and per protocol analysis), A better bleeding profile at 3 months (p=0.0098 ITT but non significant according to the per protocol analysis) and similar 6 months with a trend of superiority (odd ratio 0.81). It has to be mentioned that analysis at 12 months showed superiority of efficacy of idrabiotaparinux versus VKA together with a lower bleeding risk. Efficacy results 10 Bleeding results 15 idrabiotaparinux Idrabiotaparinux warfarin Warfarin idrabiotaparinux Idrabiotaparinux warfarin Warfarin 9 8 End of treatment Cumulative incidence (%) Cumulative incidence (%) 7 6 End of treatment 5 4 10 5 3 2 1 Hazard ratio: 0.49 95% CI: 0.35 to 0.70 Hazard ratio: 0.79 95% CI: 0.62 to 1.00 0 0 0 30 60 90 120 1556 1565 1530 1535 1517 1518 1494 1478 Idrabio Warfarin 1599 1603 150 180 210 240 270 300 330 360 1124 1105 1107 1088 1023 982 975 936 933 895 Time since randomization (days) Number at Risk 1482 1466 1461 1450 1153 1139 0 30 60 90 120 1526 1505 1492 1470 1471 1452 1438 1418 Idrabio Warfarin 1599 1603 150 180 210 240 270 300 330 360 1066 1057 1048 1045 967 951 920 910 878 872 Time since randomization (days) Number at Risk 1415 1399 1395 1375 1100 1088 Idrabiotaparinux has a better and significant net clinical benefit at 3 and 6 months with a protective effect up to 12 months without increase risk of bleeding. 1 BOREALIS-AF was discontinued in December 2009 (3774 patients enrolled) for strategic reason. Non-inferiority study comparing idraparinux to LMWH followed by VKA Idrabiotaparinux product summary 2/4 2 SSR126517E – May 2011 Detailed results will be presented at the ISTH congress (Kyoto, July 2011). Cassiopea together with Equinox brings strong evidence that idrabiotaparinux is an efficient and safe treatment in secondary prevention of VTE indication and a good alternative to current treatment. 2 DOMAIN OF APPLICATION Thrombosis is a major cause of morbidity and mortality. According to epidemiological data, VTE events rate is 0.18% of total population. Diagnosed & alive DVT/PE patients in France, Germany, Italy, Spain, UK+US will be about 1.16 M in 2020. Recommended duration of treatment is 3 to 6 months depending on risk. Most patients (90%) are treated for 6 months because of permanent risk factors, but also because of hospital practice irrespective of their VTE risk factor. The poor compliance of the patients to VKA is mainly explained by drug and food interactions, responsible for increased adverse effects and leading to dietary restrictions. There is a clear need for a drug with less frequent dosing, devoid of any drug-drug interactions and dietary restrictions, able to improve patient compliance, quality of life and health quality care. In addition to the above mentioned targeted indication, there are several additional indications that could be considered for idrabiotaparinux: Primary prevention of VTE: in medical patients and/or in cancer patients. Cardiac surgery with extra corporeal circulation. With current data available, idrabiotaparinux could be registered for treatment and secondary prevention of thromboembolic events in patients with PE and/orDVT. 3 REFERENCES “Idraparinux versus standard therapy for venous thromboembolic disease”. The van Gogh Investigators, NEJM 2007, 357:1094-104. “Convenience of the new long acting anticoagulant idraparinux versus vitamin K antagonist in patients with DVT” M. Prins, abstract ISTH 2007. “In-vitro and ex-vivo properties of long acting reversible oligosaccharide” J.P. Herault, abstract ISTH 2007. “Reversible biotinylated oligosaccharide: a new approach for a better management of anticoagulant therapy” P. Savi et all, JTH 2008 6:1697-1706. “The efficacy and safety of re-administering avidin to reverse the anticoagulant activity of biotinylated idraparinux in healthy subjects” M. Trellu, abstract ESC 2008. “Reversibility of the anti-FXa activity of idrabiotaparinux (biotinylated idraparinux) by intravenous avidin infusion “Paty et all, JTH 2010, 722-729. “Efficacy and safety of once weekly subcutaneous idrabiotaparinux in the treatment of patients with symptomatic deep venous thrombosis” The EQUINOX investigators, JTH 2010, 9:92-99. Idrabiotaparinux product summary 3/4 SSR126517E – May 2011 4 CONTACTS Guy Claude Anne Marie SIGOT Vice President Out-Licensing &Special Projects Senior Manager Out-licensing and Special Projects Strategy & Business Development Strategy & Business Development Corporate Licenses Corporate Licenses [email protected] [email protected] Idrabiotaparinux product summary 4/4 SSR126517E – May 2011