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1 Media Kit 2 Kenosia Avenue Danbury, CT

2 1 To Industry Media: Perosphere is pleased to present this packet of background information for your use in covering the new, developing pharmaceutical area of anticoagulant reversal agents. Should you wish to have additional scientific or medical information please contact the following: For Scientific Inquiries James C. Costin, M.D. Vice President, Clinical & Medical Affairs and Chief Medical Officer Phone: For Business Inquiries Erik Steiner Vice President, Chief Operating Officer Phone: Perosphere appreciates your interest in this rapidly developing field. 2 Kenosia Avenue, Danbury, CT 681 (23)

3 Table of Contents Cover Letter and Contact Information About Perosphere Scientific Background Anticoagulation Reversal PER977 Bibliography and Publications Glossary

4 2 About Perosphere Inc. Perosphere Inc. is a private specialty pharmaceutical company established in 211 and located in Danbury, Connecticut, USA. Perosphere develops rescue drugs for use in emergency settings. Perosphere's lead drug product candidate, PER977, is an intravenously administered synthetic, small molecule invented by Perosphere for use as a reversal agent for anticoagulants including low molecular weight heparin, unfractionated heparin and the new oral anticoagulants (NOACs). The NOACs include Daiichi Sankyo Co., Ltd.'s Savaysa TM /Lixiana (edoxaban), Boehringer Ingelheim GmbH's Pradaxa (dabigatran), Johnson & Johnson's and Bayer HealthCare AG's Xarelto (rivaroxaban), and Bristol-Myers Squibb Company's and Pfizer Inc.'s Eliquis (apixaban). There is currently no approved reversal agent for these NOACs. PER977 is currently undergoing Phase 2 clinical trials in the United States. A New Drug Application (NDA) submission to the United States Food and Drug Administration (FDA) is anticipated in 215, followed by submissions to the European Medicines Agency (EMA) and Japan s Pharmaceuticals and Medical Devices Agency (PMDA). Perosphere employs rational drug design to invent proprietary new small molecules for targeted therapeutic indications. Perosphere selectively identifies and develops new chemical entities and other therapeutics that can be used as rescue drugs. Perosphere identifies market opportunities where application of drug delivery technology to an already marketed drug can create a new patent-protected medical use or enhance safety, efficacy or ease of use. Perosphere's proprietary drug delivery technology is protected by more than 3 issued and 1 pending patents. For more information, please visit

5 3 Scientific Background Anticoagulation Reversal Introduction Annually, millions of patients in the United States require anticoagulation. The new oral anticoagulant (NOAC) a factor Xa or IIa inhibitors have numerous advantages: rapid therapeutic effectiveness, ease of dosing, and lack of monitoring requirements. However, increased risk of major bleeding in cases of overdose, trauma, or emergency surgery remain a significant issue as does the need for temporary discontinuation in the event of an elective invasive procedure. 1-4 Currently there is no approved reversal agent for the NOACs or for low molecular weight heparin (LMWH). An anticoagulant reversal agent would allow for rapid emergency response to overdose or trauma, minimize the time patients are off their anticoagulant prior to elective procedures, and provide a level of confidence regarding restarting anticoagulant therapy. PER977 An Anticoagulant Reversal Agent PER977 is an intravenously administered synthetic molecule designed by Perosphere as a reversal agent for anticoagulants. Early clinical trial data has shown that PER977 reverses anticoagulation associated with edoxaban and with the LMWH enoxaparin. In addition, preliminary clinical data suggest PER977 is effective in reversing unfractionated heparin (UFH). Phase 2 clinical trials of PER977 are currently ongoing in the United States. NDA submission is foreseen in 215, followed by filings in Europe and Asia. The PER977 Pre-clinical Program PER977 is a product of rational design efforts in which a small (512 Da), peptide-like molecule was specifically created to bind to the charged sites on UFH. Pre-clinical testing demonstrated PER977 binding to the NOACs (dabigatran, edoxaban, apixaban, rivaroxaban), as well as to LMWH and fondaparinux. This direct binding prevented the anticoagulant from interacting with the blood coagulation cascade and, thus, reversed its anticoagulant effects. In rat tail transection and internal bleeding models, PER977 reversed anticoagulation and significantly decreased blood loss. These studies suggested PER977 reversed anticoagulation biomarkers and also stopped bleeding induced by various anticoagulants. PER977 does not bind to warfarin nor does it have any anticoagulation reversal effects on warfarin or related vitamin K antagonists. The PER977 Clinical Program In its first in human clinical trial, PER977 demonstrated safety and tolerability in intravenous bolus doses ranging from 5 to 3 mg. Rapid (i.e., within 2-5 minutes), complete and sustained reversal of anticoagulation following edoxaban 6 mg was demonstrated as determined by whole blood clotting time with no rebound. PER977 infusion was not a Daiichi Sankyo Co., Ltd. Savaysa TM /Lixiana (edoxaban), Boehringer Ingelheim GmbH Pradaxa (dabigatran), Johnson & Johnson and Bayer HealthCare AG Xarelto (rivaroxaban), and Bristol-Myers Squibb Company and Pfizer Inc. Eliquis (apixaban)

6 associated with signs of a pro-coagulant effect. A single bolus injection of PER977 maintained anticoagulant reversal for up to 24 hours. Potentially related adverse events were transient mild perioral and facial flushing and dysgeusia as well as one report of moderate headache. One patient had a moderate muscle cramp and elevation in creatinine phosphokinase not considered to be related to PER977. In a separate trial, reversal of anticoagulation following the LMWH enoxaparin was observed at the same doses as with edoxaban. Additionally, a UFH reversal trial is ongoing. Single doses of PER977 of up to 5 mg have been administered with the same safety profile as observed with edoxaban and LMWH. The study is continuing with additional cohorts to establish the dose of PER977 to fully reverse UFH. References Please refer to the PER977 Bibliography for a complete listing of publications 1. Casciano JP, et al. Am J Cardiovasc Drugs.212;12(5): McConeghy K, et al. J Am Coll Cardiol. 213;61 (1-S).Abstract E Radecki RP. Ann Intern Med. 212; 157(1): Beyer-Westendorf J.Blood. 214;124(6): Perosphere Scientific Background Anticoagulation Reversal

7 4 PER977 Primary Publications, Abstracts, and Presentations Primary Publications Current as of November 12, 214 Ansell J, Bakhru SH, Laulicht BE, et al. Use of PER977 to Reverse the Anticoagulant Effect of Edoxaban. New Eng J Med Epub. November 5. DOI:1.156/NEJMc14118 Abstracts, Posters and Oral Presentations Included Laulicht B, Bakhru S, Lee C, et al. Small Molecule Antidote for Anticoagulants. Circulation. 212;126 (21 Meeting Abstracts):Abstract Oral Presentation at the 212 Annual Meeting of the American Heart Association, November 5, 212, Los Angeles, CA USA. Bakhru S, Laulicht B, Jiang X, et al. A synthetic small molecule antidote for anticoagulants. Eur Heart J. 213;34 (Abstract Supplement): Abstract 178. Oral presentation at the 213 European Society of Cardiology Congress, August 31 September 4, 213, Amsterdam The Netherlands Bakhru S, Laulicht B, Noveck R, et al. PER977 (aripazine) Preliminary First in Human Results. Circulation. 213; 128 (22 Meeting Abstracts): Abstract Oral Presentation at the 213 Scientific Sessions of the American Heart Association November 16-2, 213, Dallas, TX, USA Ansell JE, Laulicht B, Bakhru S, Steiner S, Noveck R, Brown K, Grosso M, Morishima Y, Dishy V, Mercuri M, Costin J. Aripazine reverses unfractionated and low molecular weight heparins, fondaparinux and new Xa and IIa oral anticoagulants: report of Phase I/II clinical trial with edoxaban. Eur Heart J.214; 35 (Abstract Suppl): Abstract Oral Presentation at the European Society of Cardiology Congress August 3 September 3, 214, Barcelona Spain Laulicht B, Bakhru S, Steiner S, et al. Aripazine (PER977) reverses unfractionated and low molecular weight heparins, fondaparinux and new oral anticoagulants: report of a clinical trial with edoxaban and anticoagulant reversal biomarker identification. Pharmacotherapy.214;34(1):e183. Abstract 18. Poster presented at the 214 American College of Clinical Pharmacy Annual Meeting, October 12 15, 214, Austin TX

8 Additional Publications Available Upon Request Bakhru S, Laulicht B, Lee C, et al. Small Molecule Antidote for Anticoagulants. Presented at the Thrombosis and Hemostasis Summit of North American 212 May 4, 212, Chicago, IL, USA Laulicht B, Bakhru S, Jiang X, et al. Antidote for New Oral Anticoagulants Mechanism of Action and Binding Specificity of PER977. Presented at the International Society on Thrombosis and Haemostasis July 4, 213, Amsterdam, The Netherlands. Bakhru S, Costin J, Laulicht B, Steiner S. PER977 (aripazine) Reversal Drug for NOACs, UFH, LMWH, and Fondaparinux. Oral Presentation at the Cardiovascular Clinical Trialists Forum -Thrombosis Trialists Workshop: Competing New Therapies in Atrial Fibrillation and Heart Failure. December 6, 213. Paris, France. Bakhru S, Laulicht B, Jiang X, et al. Reversal of Anticoagulant-induced Bleeding in External and Internal Bleeding Models by PER977, a Small Molecule Anticoagulant Antidote. Abstract and Poster presented at the 214 Scientific Sessions of the American Heart Association, November 15 19, 214, Chicago, IL 2 PER977 Primary Publications, Abstracts, and Presentations Current as of November 12, 214

9 The new england journal of medicine correspondence Use of PER977 to Reverse the Anticoagulant Effect of Edoxaban To the Editor: New target-specific oral anticoagulants are limited by the lack of a proven reversal agent. PER977 (Perosphere) is a small, synthetic, water-soluble, cationic molecule that is designed to bind specifically to unfractionated heparin and low-molecular-weight heparin through noncovalent hydrogen bonding and charge charge interactions (Fig. S1 in the Supplementary Appendix, available with the full text of this letter at NEJM.org). 1,2 PER977 binds in a similar way to the new oral factor Xa inhibitors, edoxaban, rivaroxaban and apixaban, and to the oral thrombin inhibitor, dabigatran. In thromboelastographic studies and rat-tail transection bleeding assays, PER977 has been shown to reverse anticoagulation with each of the new oral agents. 1,2 In nonclinical studies, PER977 did not bind to plasma proteins, including albumin, and showed no binding when tested against several common cardiovascular, antiepileptic, and anesthetic drugs. In this study, we assessed the safety, sideeffect profile, and effect on anticoagulation reversal of PER977 when administered alone and after a 6-mg dose of the factor Xa inhibitor edoxaban. 3,4 Pharmacokinetic and pharmacodynamic effects of escalating, single intravenous doses of PER977 (5 to 3 mg) administered alone and after a 6-mg oral dose of edoxaban were studied in a double-blind, placebo-controlled trial involving 8 healthy persons (Fig. S2 in the Supplementary Appendix). The study protocol is available at NEJM.org. Whole-blood clotting time was used to measure the anticoagulant effect of edoxaban and its reversal by PER977. In clinical trials of PER977, whole-blood clotting time showed low variability (interobserver variation, 3.%) and high reproducibility (intersubject variation, 3.6%), and correlated well with edoxaban plasma concentrations (Fig. S3 in the Supplementary Appendix). After the administration of edoxaban, the mean whole-blood clotting time increased by 37% over the baseline value (Fig. 1). In patients receiving a single intravenous dose of PER977 (1 to 3 mg) 3 hours after the administration of edoxaban, the whole-blood clotting time decreased to within 1% above the baseline value in 1 minutes or less, whereas in patients receiving placebo, the time to reach that level was much longer (approximately 12 to 15 hours). The whole-blood clotting time remained within 1% of the baseline value for 24 hours after the administration of a single dose of PER977. Scanning electron micrographs of clots obtained during measurement of the whole-blood clotting time were analyzed with a computer algorithm to determine the mean fibrin-fiber diameter. Edoxaban anticoagulation significantly reduced the mean fibrin-fiber diameter relative to baseline (from approximately 25 nm to approximately 125 nm, P<.1). The mean fibrin-fiber diameter was restored to normal 3 minutes after administration of PER977 at the same doses that showed reversal by whole-blood clotting time (Fig. S4 in the Supplementary Appendix). There was no evidence of procoagulant activity after administration of PER977, as assessed by measurement of levels of d-dimer, prothrombin fragment 1.2, and tissue factor pathway inhibitor and by whole-blood clotting time. Potentially related adverse events were transient mild perioral and facial flushing and dysgeusia; one person reported a moderate headache. In addition, one person had a moderate muscle cramp and elevation in creatinine phosphokinase levels, events that were not considered to be related to PER977. n engl j med nejm.org 1

10 correspondence 5 PER977 administered 6 mg edoxaban Pooled placebo Percent Change from Baseline in Whole-Blood Clotting Time * * *** * * * * * * 25 mg PER977 1 mg PER977 3 mg PER977 *P<.5 vs. placebo Hours after Edoxaban Administration Figure 1. Effect of PER977 on Whole-Blood Clotting Time. Shown are the mean whole-blood clotting times after administration of a single oral 6-mg dose of edoxaban, followed 3 hours later by a single intravenous dose of 25 mg, 1 mg, or 3 mg of PER977 or placebo. In this study, baseline hemostasis was restored from the anticoagulated state within 1 to 3 minutes after administration of 1 to 3 mg of PER977 and was sustained for 24 hours. Additional phase 2 clinical studies are ongoing. Jack E. Ansell, M.D. Hofstra North Shore LIJ School of Medicine Hempstead, NY Sasha H. Bakhru, Ph.D. Bryan E. Laulicht, Ph.D. Solomon S. Steiner, Ph.D. Perosphere Danbury, CT Michael Grosso, M.D. Karen Brown, Ph.D. Victor Dishy, M.D. Daiichi Sankyo Pharma Development Edison, NJ Robert J. Noveck, M.D. Duke University Medical Center Durham, NC James C. Costin, M.D. Perosphere Danbury, CT Funded by Perosphere, Danbury, CT; Clinicaltrials.gov number, NCT Disclosure forms provided by the authors are available with the full text of this letter at NEJM.org. This letter was published on November 5, 214, at NEJM.org. 1. Laulicht B, Bakhru S, Jiang X, et al. Antidote for new oral anticoagulants: mechanism of action and binding specificity of PER977. Presented at the 24th Congress of the International Society on Thrombosis and Haematosis, Amsterdam, June 29 July 4, 213. abstract (http://www.eventure-online.com/eventure/ publicabstractview.do?id=226718&congressid=6839). 2. Laulicht B, Bakhru S, Lee C, et al. Small molecule antidote for anticoagulants. Circulation 212;126:A abstract. 3. Giugliano RP, Ruff CT, Braunwald E, et al. Edoxaban versus warfarin in patients with atrial fibrillation. N Engl J Med 214; 369: The Hokusai-VTE Investigators. Edoxaban versus warfarin for the treatment of symptomatic venous thromboembolism. N Engl J Med 213;369: [Erratum, N Engl J Med 214;37:39.] DOI: 1.156/NEJMc14118 Correspondence Copyright 214 Massachusetts Medical Society. 2 n engl j med nejm.org

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12 Circulation (21): Abstract Oral Presentation at the American Heart Association 212 Scientific Sessions. November 3 7, 212. Los Angeles, CA

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14 Eur Heart J. 213;34 (Abstract Supplement): Abstract 178 Oral Presentation at the 213 European Society of Cardiology Congress, August 31 September 4, 213, Amsterdam Netherlands Abstract: 178 A synthetic small molecule antidote for anticoagulants Authors: S. Bakhru 1, B. Laulicht 1, X. Jiang 1, L. Chen 1, M. Grosso 2, Y. Morishima 3, K. Brown 2, H. Masumoto 2, J. Costin 1, S. Steiner 1, 1 Perosphere Inc. - Bedford, NY - United States of America, 2 Daiichi Sankyo, Inc. - Edison, NJ - United States of America, 3 Daiichi Sankyo Co., Ltd. - Tokyo - Japan, Topic(s): Drug therapy Citation: European Heart Journal ( 213 ) 34 ( Abstract Supplement ), The new oral anticoagulants (NOACs) offer significant advantages over the heparins and warfarin therapies with regards to route of administration, drug interactions and predictability of bioactivity. However, the NOACs currently lack a specific reversal agent. As such concern over serious bleeding, emergency procedures and potential overdosage is heightened. We set out to rationally design, synthesize, and characterize a synthetic small molecule anticoagulant antidote (PER977). Blood was drawn from healthy human volunteers. Plasma was immediately collected and spiked with rivaroxaban or apixaban at 1x and 2x the therapeutic Cmax. Factor Xa activity was measured before and after PER977 addition using a chromogenic anti-xa kit (Hyphen-BioMed, France). PER977 completely reversed the anti- Xa activity of rivaroxaban and apixaban in a dose-dependent fashion ex vivo in human plasma, and no pro-coagulant effects were observed. Additionally, in a rat tail transection bleeding assay, weightmatched rats were overdosed with edoxaban (see figure), rivaroxaban, apixaban, or dabigatran as confirmed by large increases in blood loss volume. PER977 or sham was administered and after thirty minutes, blood loss volume was quantified. PER977 significantly decreased bleeding in vivo in rats treated with NOACs, reducing it to within the normal range for naïve rats and no pro-coagulant effects were observed. In vivo and in vitro toxicology and safety studies have been completed and a first-in-human clinical trial to demonstrate safety and efficacy in healthy human volunteers with PER977 and edoxaban will follow. In conclusion, PER977 is a synthetic small molecule new chemical entity under development that reverses NOACs ex vivo in human blood and decreases bleeding in vivo in a rat tail transection bleeding model.

15 Eur Heart J. 213;34 (Abstract Supplement): Abstract 178 Oral Presentation at the 213 European Society of Cardiology Congress, August 31 September 4, 213, Amsterdam Netherlands

16 Circulation. 213;128(22 Meeting Abstracts): Abstract 1889 Oral presentation at the 213 Scientific Sessions American Heart Association. November 16 2, 213 Dallas, TX

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18 European Heart Journal. 215; 35 (Abstract Suppl): Abstract 4766 Presented as a Rapid Fire Oral Presentation at the 214 European Society of Cardiology Congress Barcelona Spain, September 2, 214. Abstract: 4766 Aripazine reverses unfractionated and low molecular weight heparins, fondaparinux and new Xa and IIa oral anticoagulants: report of Phase I/II clinical trial with edoxaban Authors: J.E. Ansell 1, B. Laulicht 2, S. Bakhru 2, S. Steiner 2, R. Noveck 3, K. Brown 4, M. Grosso 4, Y. Morishima 4, V. Dishy 4, M. Mercuri 4, 1 New York University School of Medicine - New York - United States of America, 2 Perosphere Inc. - Danbury, CT - United States of America, 3 Duke University Medical Center - Durham - United States of America, 4 Daiichi Sankyo - Edison, NJ - United States of America, Topic(s): Thrombosis and coagulation Citation: European Heart Journal ( 214 ) 35 ( Abstract Supplement ), Purpose: Aripazine (PER977) is a small molecule designed to bind unfractionated and low molecular weight heparins (UFH, LMWH), fondaparinux, and the new oral anticoagulants (NOACs). Its non-covalent binding to anticoagulants prevents them from binding to their endogenous targets, reversing their anticoagulation. Aripazine is ready for intravenous injection; has no significant toxicity effects in animals at clinical doses; no affects on CYP metabolism; and no drug-drug binding. In animals anti-coagulated with NOACs (both Xa & IIa) or UFH or LMWH, aripazine restores normal hemostasis in rat tail transection and liver laceration bleeding models. Moreover, aripazine reduced bleeding when given immediately after an induced injury in NOAC anticoagulated rats. Methods: A first in human, 7 cohort, 2 period, ascending dose (5 3 mg) trial with aripazine alone and after 6 mg edoxaban was completed in volunteers. Results: Aripazine alone showed no serious adverse events and no pro-coagulation signal (D-dimer, F1.2, TFPI). At 5-3 mg doses, aripazine reversed the anticoagulation of 6 mg edoxaban with no evidence of rebound over 24 hrs (Fig. 1). Aripazine also restored normal clot formation and fibrin integrity within the clot, which had been altered with edoxaban therapy, as shown by scanning electron micrographs. Conclusions: Aripazine is safe and well tolerated at doses that reverse the anticoagulation of therapeutic edoxaban. In preclinical studies, aripazine also reverses the anticoagulant effect of other NOACs as well as UFH, LMWH and fondaparinux suggesting it should have similar effects in humans. Its advantages include small size, unlikely immunogenicity; single bolus injection; quick onset (1 minutes); prolonged effects; quick metabolism and renal clearance.

19 European Heart Journal. 215; 35 (Abstract Suppl): Abstract 4766 Presented as a Rapid Fire Oral Presentation at the 214 European Society of Cardiology Congress Barcelona Spain, September 2, 214. Figure 1

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21 PER977 Reverses Unfractionated and Low Molecular Weight Heparins, Fondaparinux and New Oral Anticoagulants: Report of a Clinical Trial with Edoxaban and Anticoagulant Reversal Biomarker Identification ACCP 214 Annual Meeting, Austin TX October 12 15, 214 Presentation Session II Poster # 18 Dr. Bryan Laulicht, PhD1, Dr. Sasha Bakhru, PhD2, Dr. Solomon Steiner, PhD1, Dr. Jack Ansell, MD1, Dr. Karen Brown, PhD3, Dr. Hiroshi Masumoto, PhD4, Dr. Yoshiyuki Morishima, PhD5, Dr. Michael Grosso, MD 6, Dr. Michele Mercuri, MD, PhD 7, Dr. Robert Noveck, MD, PhD 8 and Dr. James Costin, MD1 1Perosphere Inc, Danbury, CT; 2Perosophere Inc, Danbury, CT; 3Clinical Pharmacology, Daiichi-Sankyo, Edison, NJ; 4Global Project Management, Daiichi-Sankyo, Edison, NJ; 5Research and Development Division, Daiichi-Sankyo, Tokyo, Japan; 6Cardiovascular Clinical Research, Daiichi-Dankyo, Edison, NJ; 7Clinical Development, Daiichi-Sankyo, Edison, NJ; 8Clinical Research Unit, Duke University School of Medicine, Durham, NC Results (continued) * p <.5 vs placebo mg Edoxaban p.o., mg PER977 i.v. *** 2% Cohort 1 EDX+5 mg PER977 Cohort 3 EDX+25 mg PER977 Cohort 4 5 mg PER977 Cohort 4 EDX+5 mg PER977 Cohort 5 1 mg PER977 Cohort 5 EDX+1 mg PER977 Cohort 6 2 mg PER977 Cohort 6 EDX+2 mg PER977 Cohort 7 EDX+3 mg PER977 First in human study includes: Safety and tolerability of PER977 (7 escalating doses) alone and with edoxaban PK for PER977, edoxaban and their primary metabolites PD measures (Whole Blood Clotting Time, Electron Microscopy of Clots, TEG, PT) Clinical safety measures (F1.2, D-Dimer, TFPI) Complete data will be published in a peer reviewed journal 6 mg Edoxaban p.o, 1 mg PER977 i.v. 6 mg Edoxaban p.o., 3 mg PER977 i.v. ** * 25 * 1% % * *** * * * * * 3 * * BASELINE (Pre-edoxaban) ANTICOAGULATED (Pre-reversal) Scale Bar: 1 inch Baseline (pre-edoxaban) ANTICOAGULATED (Pre-PER977, 2 hrs 45 min post 6 mg edoxaban p.o.) REVERSED (1 hr post 1 mg i.v. bolus PER977) 1 1 hour post PER977 (1 mg i.v.) 24 PER977 Shows No Effect on F1.2 (Pro-coagulant Biomarker) in Clinical Trial 6mg PO edoxaban + IV 6mg PO edoxaban + 25mg saline placebo IV PER977 6mg PO edoxaban + 1mg IV PER977 6mg PO edoxaban + 3mg IV PER977 2 Native * p<.5, ** p<.1, *** p<.1 PER977 Period 1 PK 1, 8, 5mg PER977 15mg PER977 25mg PER977 5mg PER977 1mg PER977 2mg PER977 3mg PER Saline 5mg PER977 15mg PER977 25mg PER977 5mg PER977 1mg PER977 2mg PER977 3mg PER , 12 Hours post PER977 administration 4, Hours post PER977 administration Ŧ One outlier (F1.2~1,8ng/mL) excluded 2 PER977 (3 mg, i.v. Bolus) Alone Has No Effect on WBCT in Healthy Volunteers BAP Period 1 PK 1,2 8 25mg PER977 5mg PER977 1mg PER977 2mg PER977 Conclusions 3mg PER PER977 Has No Effect on Human Tissue Factor Pathway Inhibitor ("TFPI") in Healthy Volunteers 2, 1, Edoxaban Anticoagulated (6 mg p.o.) 12 Hours post PER977 administration 12, BASELINE (Pre-edoxaban) 15 SALINE (1 hr post Saline) Hours post edoxaban administration Cohort 2 EDX+15 mg PER977 Cohort 3 25 mg PER977 6 mg Edoxaban p.o., 25 mg PER977 i.v. Saline 5mg PER977 15mg PER977 25mg PER977 5mg PER977 1mg PER977 2mg PER977 3mg PER977 1 F1.2 fraction of pre-dose Cohort 1 5 mg PER977 6 mg Edoxaban p.o., mg PER977 i.v. 3 ng PER977/mL serum Period 2 PER977 or Placebo Cohort 7 3 mg PER977 3% PER977 Shows No Effect on D-dimer (Pro-coagulant Biomarker) in Clinical Trial 1.5 PER977 Restores Clot Integrity Period 1 PER977 or Placebo Cohort 2 15 mg PER977 4% -1% Results 6 mg edoxaban Placebo reversal 25 mg PER977 aripazine reversal 1 mg PER977 aripazine reversal PER977 reversal 3 mg aripazine PER977 Administered ng BAP/mL serum A Phase I-II, 7 cohort, 2 period, ascending dose (5 3 mg) trial with PER977 alone and following 6 mg edoxaban evaluated PER977 and edoxaban PK and PD as well as biomarker suitability for anticoagulation reversal. 5% Results (continued) PER977 Restores CFI in a Dose-dependent Fashion in Edoxaban Anticoagulated Humans Fibrin diameter [nm] Methods PER977 Clinically Reverses Edoxaban Measured by WBCT Change from baseline whole blood clotting time (WBCT) This study was done to evaluate the safety and tolerability of PER977 and to establish its anticoagulant reversal effects in a first in human study. PER977, a small molecule designed to bind to UFH, LMWH, fondaparinux, and NOACs (edoxaban, apixaban, rivaroxaban, dabigatran), prevents anticoagulant binding to their endogenous targets, thereby reversing anticoagulation. PER977 restores normal hemostasis in external (rat tail transection) and internal (liver laceration) bleeding models and corrects abnormal coagulation assays. Results (continued) D-dimer fraction of pre-dose Purpose Hours post PER977 administration PER977 is safe and well tolerated at doses that reverse edoxaban anticoagulation. In preclinical in vivo studies, PER977 reverses the anticoagulant effect of other NOACs as well as UFH, LMWH and fondaparinux suggesting a similar effect in humans. Its advantages include small size, unlikely immunogenic reactions; single bolus injection; quick onset (<1 minutes); and prolonged effects. WBCT correlates well with edoxaban PK levels and is a suitable biomarker for clinical trials.

22 Reversal of Anticoagulant-induced Bleeding in External and Internal Bleeding Models by PER977, a Small Molecule Anticoagulant Antidote Sasha Bakhru1, Bryan Laulicht1, Xuan Jiang1, Lirong Chen1, Michael Grosso2, Yoshiyuki Morishima3, Karen Brown2, Michele Mercuri3, Hiroshi Masumoto4, James Costin1 and Solomon Steiner1 1 Perosphere AHA Scientific Sessions 214, Chicago, IL November 15 19, 214 Presentation Number: South Hall A2 Inc, Danbury, CT; 2Clinical Pharmacology, Daiichi-Sankyo, Edison, NJ; 3Research and Development Division, Daiichi-Sankyo, Tokyo, Japan; 4Global Project Management, Daiichi-Sankyo, Edison, NJ Purpose Background Results (continued) Results (continued) The new oral anticoagulants (NOACs) offer significant advantages over heparins and warfarin therapies. However, concern over serious bleeding and potential over-dosage is heightened with the lack of a specific reversal agent. PER977 is a synthetic small molecule in clinical development as an anticoagulant reversal agent. In the current studies, PER977 reversal was evaluated in two preclinical bleeding models, recapitulating the clinical scenarios of reversal in actively bleeding cutaneous wounds and internal large organ lacerations. Additionally, whole blood clotting time (WBCT) was evaluated as a biomarker for assessing edoxaban-induced anticoagulation and reversal by PER977. PER977 PER977 Significantly Reduces Internal Bleeding Time in an Edoxaban-anticoagulated Rat Liver Laceration Model PER977 Reverses Edoxaban Anticoagulation as Measured by Clot Fibrin Diameter in Rats C H2 C NH 2 N N H CH H N N NH 2 H2 C CH C H C H2 C H N NH 2 2 NH O Composed of naturally occurring amino-acid derived substituents (piperazine and arginine) with short linking elements Mw=512Da, C22H48N12O2, acetate salt Freely water soluble Stable as a ready-to-use sterile i.v. solution for > 2 years External Bleeding Model Bleeding was evaluated in a rat liver laceration model of internal bleeding. Following calibrated cuts to the medial lobe of the exposed liver, bleeding time was determined to the nearest 15 seconds. This rat liver laceration internal bleeding model demonstrated that edoxaban can significantly increase the bleeding time after the rat liver is lacerated. Moreover, the i.v. administration of PER977 can fully reverse the anticoagulant effect of edoxaban on internal bleeding time 1 minutes after PER977 administration. Whole Blood Clotting Time Whole blood clotting time (WBCT) was assessed as a biomarker for assessing both edoxaban-induced anticoagulation and reversal of anticoagulation by PER977 in a rat model. In this study, WBCT was evaluated at baseline ( min), edoxaban was administered intravenously, and either PER977 or saline was administered fifteen minutes later (n=5 per group). Edoxaban administration lead to a significant increase in WBCT over baseline levels, and PER977 administration (2 mg/kg) reversed edoxaban anticoagulation within 3 minutes. Notably, reversal of WBCT was achieved at the same PER977 dose level at which reversal was achieved in the liver laceration bleeding model, demonstrating a correlation between WBCT and cessation of bleeding in an animal model of internal bleeding. Placebo (saline) 15% 1 mg/kg PER977 1% 5% 2 mg/kg PER977 % edoxban control 1 mg/kg PER977 2 mg/kg PER977 3 mg/kg PER977 * p<.5 PER977 Rapidly Returns Edoxabananticoagulated Bleeding to Baseline in an Active Bleeding Model 25 2 * ** PER977 Reverses Edoxaban Anticoagulation as Measured by Whole Blood Clotting Time in Rats Edoxaban control PER977 reversal ** ** 5 Blood loss during Interval 1 (-7.5 min) Placebo sham 15 1 Intravenous edoxaban significantly increased bleeding time Intravenous administration of PER977 at 2 mg/kg and 3 mg/kg following edoxaban fully reversed the anticoagulant effect of edoxaban within 1 minutes of PER977 administration. Blood loss during Interval 2 ( min) * p<.5, ** p<.1 Oral edoxaban increased blood loss to roughly 3x baseline (sham) values Intravenous administration of PER977 at 3 mg/kg after rat tail transection fully reversed the anticoagulant effect of oral edoxaban (1 mg/kg, p<.5) and reduced the blood loss to baseline level (sham, p>.5). Reversal was sustained for duration of the experiment mg/kg PER977 2 mg/kg PER977 * T = min T = 15 min T = 6 min Baseline Anticoagulated/ Pre-treatment PER977 or Placebo/ 45 min post-treatment Placebo Fibrin diameter (nm) Internal Bleeding Model * 2% Results Weight of blood pellet (mg) Reversal of anticoagulation-induced, active bleeding was demonstrated in a rat tail transection model. Rats were dosed with the direct factor Xa inhibitor, edoxaban, resulting in large increases in blood loss mass. Briefly, the rat was orally dosed with edoxaban. After 75 min, rat tails were fully transected 2 mm from the tip. Immediately after tail transection, PER977 solution or saline was administered through the jugular vein. Blood from the tail was collected for 7.5 minutes and then transferred into a second collection tube for an additional 7.5 minutes. PER977 significantly decreased bleeding in vivo in rats treated with edoxaban within the first 7.5 minutes after PER977 administration. 25% C Change from baseline bleeding time N H H 2N H2 C H2 C C Percent of Baseline WBCT Methods O NH 3 1mg/kg PER977 2mg/kg PER977 *** min min 6 min Time post edoxaban administration 15 (PER977 or placebo administered at 15min) 1 *** p<.1 PER977 returns clo1ng to normal in edoxaban- an:coagulated rats at the same 2 mg/kg dose in the liver lacera:on model, WBCT and clot fibrin diameter 95 9 min (baseline) 15 min (pretreatment) 6 min (posttreatment) * p<.5 Intravenous edoxaban significantly increased WBCT relative to baseline Intravenous administration of PER977 at 1 mg/kg and 2 mg/kg following edoxaban restored WBCT to baseline in a PER977 dose-dependent fashion. Conclusions PER977 is a synthetic small molecule new chemical entity under development that reverses NOAC anticoagulation in animal models of active and internal bleeding, and is currently in clinical development in phase 2 clinical studies with edoxaban, low molecular weight heparin and unfractionated heparin.

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