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Media Kit 20 Kenosia Avenue Danbury, CT 06810 www.perosphere.com 203-885-1111 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 Bryan E. Laulicht, PhD Senior Executive Vice President, Research +1-203-885-1154 [email protected] Sasha H. Bakhru, PhD Chief Scientific Officer +1-203-885-1152 [email protected] For Clinical Inquiries For Business Inquiries James C. Costin, MD Chief Medical Officer +1-203-885-1369 [email protected] Erik Steiner Chief Operating Officer +1-203-885-1118 [email protected] Perosphere appreciates your interest in this rapidly developing field. 20 Kenosia Avenue, Danbury, CT 06810 | (203) 885 1111 www.perosphere.com Table of Contents Cover Letter and Contact Information About Perosphere Scientific Background – Anticoagulation Reversal PER977 Bibliography and Publications Glossary 2 About Perosphere Inc. Perosphere Inc. is a private specialty pharmaceutical company established in 2011 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 SavaysaTM/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 2015, 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 30 issued and 10 pending patents. For more information, please visit www.perosphere.com. 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 2015, 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 300 mg. Rapid (i.e., within 2-5 minutes), complete and sustained reversal of anticoagulation following edoxaban 60 mg was demonstrated as determined by whole blood clotting time with no rebound. PER977 infusion was not a Daiichi Sankyo Co., Ltd. SavaysaTM/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) 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 500 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.2012;12(5):313-323. 2. McConeghy K, et al. J Am Coll Cardiol. 2013;61 (10-S).Abstract E319. 3. Radecki RP. Ann Intern Med. 2012; 157(1):66-68. 4. Beyer-Westendorf J.Blood. 2014;124(6):955-962. Perosphere Scientific Background Anticoagulation Reversal 4 PER977 Primary Publications, Abstracts, and Presentations Current as of November 12, 2014 Primary Publications Ansell J, Bakhru SH, Laulicht BE, et al. Use of PER977 to Reverse the Anticoagulant Effect of Edoxaban. New Eng J Med. 2014. Epub. November 5. DOI:10.1056/NEJMc1411800 Abstracts, Posters and Oral Presentations Included Laulicht B, Bakhru S, Lee C, et al. Small Molecule Antidote for Anticoagulants. Circulation. 2012;126 (21 Meeting Abstracts):Abstract 11395. Oral Presentation at the 2012 Annual Meeting of the American Heart Association, November 5, 2012, Los Angeles, CA USA. Bakhru S, Laulicht B, Jiang X, et al. A synthetic small molecule antidote for anticoagulants. Eur Heart J. 2013;34 (Abstract Supplement):188-189. Abstract 1078. Oral presentation at the 2013 European Society of Cardiology Congress, August 31 – September 4, 2013, Amsterdam – The Netherlands Bakhru S, Laulicht B, Noveck R, et al. PER977 (aripazine) Preliminary First in Human Results. Circulation. 2013; 128 (22 Meeting Abstracts): Abstract 18809. Oral Presentation at the 2013 Scientific Sessions of the American Heart Association – November 16 - 20, 2013, 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.2014; 35 (Abstract Suppl): 854-855. Abstract 4766. Oral Presentation at the European Society of Cardiology Congress – August 30 – September 3, 2014, 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.2014;34(10):e183. Abstract 18. Poster presented at the 2014 American College of Clinical Pharmacy Annual Meeting, October 12 – 15, 2014, Austin TX 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 2012 – May 4, 2012, 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, 2013, 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, 2013. 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 2014 Scientific Sessions of the American Heart Association, November 15 – 19, 2014, Chicago, IL 2 PER977 Primary Publications, Abstracts, and Presentations Current as of November 12, 2014 The n e w e ng l a n d j o u r na l of m e dic i n e c or r e sp ondence 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 60-mg dose of the factor Xa inhibitor edoxaban.3,4 Pharmacokinetic and pharmacodynamic effects of escalating, single intravenous doses of PER977 (5 to 300 mg) administered alone and after a 60-mg oral dose of edoxaban were studied in a double-blind, placebo-controlled trial involving 80 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, 3.0%) 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 (100 to 300 mg) 3 hours after the administration of edoxaban, the whole-blood clotting time decreased to within 10% above the baseline value in 10 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 10% 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 250 nm to approximately 125 nm, P<0.001). The mean fibrin-fiber diameter was restored to normal 30 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 correspondence Percent Change from Baseline in Whole-Blood Clotting Time 50 PER977 administered 60 mg edoxaban Pooled placebo 25 mg PER977 40 100 mg PER977 300 mg PER977 30 *P<0.05 vs. placebo 20 * * *** * * * * * 10 * * 0 −10 0 3 6 9 12 15 18 21 24 27 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 60-mg dose of edoxaban, followed 3 hours later by a single intravenous dose of 25 mg, 100 mg, or 300 mg of PER977 or placebo. In this study, baseline hemostasis was re- James C. Costin, M.D. stored from the anticoagulated state within 10 to Perosphere 30 minutes after administration of 100 to 300 mg Danbury, CT [email protected] of PER977 and was sustained for 24 hours. AdFunded by Perosphere, Danbury, CT; Clinicaltrials.gov numditional phase 2 clinical studies are ongoing. ber, NCT01826266. Disclosure forms provided by the authors are available with Jack E. Ansell, M.D. the full text of this letter at NEJM.org. Hofstra North Shore–LIJ School of Medicine Hempstead, NY This letter was published on November 5, 2014, at NEJM.org. [email protected] 1. Laulicht B, Bakhru S, Jiang X, et al. Antidote for new oral Sasha H. Bakhru, Ph.D. Bryan E. Laulicht, Ph.D. Solomon S. Steiner, Ph.D. 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, 2013. 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 2012;126:A11395. abstract. 3. Giugliano RP, Ruff CT, Braunwald E, et al. Edoxaban versus warfarin in patients with atrial fibrillation. N Engl J Med 2014; 369:2093-104. 4. The Hokusai-VTE Investigators. Edoxaban versus warfarin for the treatment of symptomatic venous thromboembolism. N Engl J Med 2013;369:1406-15. [Erratum, N Engl J Med 2014;370:390.] 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 2 DOI: 10.1056/NEJMc1411800 Correspondence Copyright © 2014 Massachusetts Medical Society. n engl j med nejm.org Circulation. 2012.126(21): Abstract 11395 Oral Presentation at the American Heart Association 2012 Scientific Sessions. November 3 – 7, 2012. Los Angeles, CA Eur Heart J. 2013;34 (Abstract Supplement):188-189. Abstract 1078 Oral Presentation at the 2013 European Society of Cardiology Congress, August 31 – September 4, 2013, Amsterdam –Netherlands Abstract: 1078 A synthetic small molecule antidote for anticoagulants Authors: S. Bakhru1, B. Laulicht1, X. Jiang1, L. Chen1, M. Grosso2, Y. Morishima3, K. Brown2, H. Masumoto2, J. Costin1, S. Steiner1, 1Perosphere Inc. - Bedford, NY - United States of America, 2Daiichi Sankyo, Inc. Edison, NJ - United States of America, 3Daiichi Sankyo Co., Ltd. - Tokyo - Japan, Topic(s): Drug therapy Citation: European Heart Journal ( 2013 ) 34 ( Abstract Supplement ), 188-189 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 antiXa 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. Eur Heart J. 2013;34 (Abstract Supplement):188-189. Abstract 1078 Oral Presentation at the 2013 European Society of Cardiology Congress, August 31 – September 4, 2013, Amsterdam –Netherlands Circulation. 2013;128(22 Meeting Abstracts): Abstract 18809 Oral presentation at the 2013 Scientific Sessions American Heart Association. November 16‐20, 2013 Dallas, TX European Heart Journal. 2015; 35 (Abstract Suppl):854-855. Abstract 4766 Presented as a Rapid Fire Oral Presentation at the 2014 European Society of Cardiology Congress – Barcelona Spain, September 2, 2014. 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. Ansell1, B. Laulicht2, S. Bakhru2, S. Steiner2, R. Noveck3, K. Brown4, M. Grosso4, Y. Morishima4, V. Dishy4, M. Mercuri4, 1New York University School of Medicine - New York - United States of America, 2 Perosphere Inc. - Danbury, CT - United States of America, 3Duke University Medical Center - Durham United States of America, 4Daiichi Sankyo - Edison, NJ - United States of America, Topic(s): Thrombosis and coagulation Citation: European Heart Journal ( 2014 ) 35 ( Abstract Supplement ), 854-855 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 (5–300 mg) trial with aripazine alone and after 60 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 50-300 mg doses, aripazine reversed the anticoagulation of 60 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 (10 minutes); prolonged effects; quick metabolism and renal clearance. European Heart Journal. 2015; 35 (Abstract Suppl):854-855. Abstract 4766 Presented as a Rapid Fire Oral Presentation at the 2014 European Society of Cardiology Congress – Barcelona Spain, September 2, 2014. Figure 1 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 2014 Annual Meeting, Austin TX October 12–15, 2014 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 < 0.05 vs placebo 0 mg Edoxaban p.o., 0 mg PER977 i.v. *** 20% Cohort 1 EDX+5 mg PER977 Cohort 3 EDX+25 mg PER977 Cohort 4 50 mg PER977 Cohort 4 EDX+50 mg PER977 Cohort 5 100 mg PER977 Cohort 5 EDX+100 mg PER977 Cohort 6 200 mg PER977 Cohort 6 EDX+200 mg PER977 Cohort 7 EDX+300 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 60 mg Edoxaban p.o, 100 mg PER977 i.v. 60 mg Edoxaban p.o., 300 mg PER977 i.v. ** * 250 * 10% 0% * *** * * * * * 0 3 * * 6 9 12 15 18 21 24 27 BASELINE (Pre-edoxaban) ANTICOAGULATED (Pre-reversal) 0 Scale Bar: 1 inch Baseline (pre-edoxaban) ANTICOAGULATED (Pre-PER977, 2 hrs 45 min post 60 mg edoxaban p.o.) REVERSED (1 hr post 100 mg i.v. bolus PER977) 100 1 hour post PER977 (100 mg i.v.) 24 PER977 Shows No Effect on F1.2 (Pro-coagulant Biomarker) in Clinical Trial 60mg PO edoxaban + IV 60mg PO edoxaban + 25mg saline placebo IV PER977 60mg PO edoxaban + 100mg IV PER977 60mg PO edoxaban + 300mg IV PER977 2 Native * p<0.05, ** p<0.01, *** p<0.001 PER977 Period 1 PK 10,000 8,000 5mg PER977 15mg PER977 25mg PER977 50mg PER977 100mg PER977 200mg PER977 300mg PER977 1.5 Saline 5mg PER977 15mg PER977 25mg PER977 50mg PER977 100mg PER977 200mg PER977 300mg PER977 1 0.5 0 6,000 0 12 Hours post PER977 administration 4,000 0 0 0.2 0.4 0.6 0.8 1 1.2 1.4 Hours post PER977 administration 1.6 1.8 Ŧ One outlier (F1.2~1,800ng/mL) excluded 2 PER977 (300 mg, i.v. Bolus) Alone Has No Effect on WBCT in Healthy Volunteers BAP Period 1 PK 1,200 800 25mg PER977 50mg PER977 100mg PER977 200mg PER977 Conclusions 300mg PER977 600 400 200 0 24 PER977 Has No Effect on Human Tissue Factor Pathway Inhibitor ("TFPI") in Healthy Volunteers 2,000 1,000 Edoxaban Anticoagulated (60 mg p.o.) 12 Hours post PER977 administration 12,000 BASELINE (Pre-edoxaban) 0 150 0 SALINE (1 hr post Saline) 0.5 200 50 Hours post edoxaban administration Cohort 2 EDX+15 mg PER977 Cohort 3 25 mg PER977 60 mg Edoxaban p.o., 25 mg PER977 i.v. Saline 5mg PER977 15mg PER977 25mg PER977 50mg PER977 100mg PER977 200mg PER977 300mg PER977 1 F1.2 fraction of pre-dose Cohort 1 5 mg PER977 60 mg Edoxaban p.o., 0 mg PER977 i.v. 300 ng PER977/mL serum Period 2 PER977 or Placebo Cohort 7 300 mg PER977 30% 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 40% -10% Results 60 mg edoxaban Placebo reversal 25 mg PER977 aripazine reversal 100 mg PER977 aripazine reversal PER977 reversal 300 mg aripazine PER977 Administered ng BAP/mL serum A Phase I-II, 7 cohort, 2 period, ascending dose (5 – 300 mg) trial with PER977 alone and following 60 mg edoxaban evaluated PER977 and edoxaban PK and PD as well as biomarker suitability for anticoagulation reversal. 50% 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 0 0.5 1 1.5 2 2.5 Hours post PER977 administration 3 3.5 4 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 (<10 minutes); and prolonged effects. WBCT correlates well with edoxaban PK levels and is a suitable biomarker for clinical trials. 5 GLOSSARY Activated partial thromboplastin time (APTT) An assessment of the efficacy of "intrinsic" and common coagulation pathways. Used clinically for assessment of anticoagulation associated with unfractionated heparin. Clotting Factors Xa and IIa Two factors necessary for blood to clot. The NOACs block these factors and thus prevent or slow blood from clotting, causing anticoagulation. D-dimer A pro-coagulation biomarker. When elevated, it suggest thrombosis or clotting is ongoing. Hemostasis A state or normal blood flow and clotting Low Molecular Weight Heparin (LMWH) Anticoagulants derived from unfractionated heparin (e.g., enoxaparin [Lovenox®] which have a small molecular weight and size. New Oral AntiCoagulants (NOAC)s Inhibitors of clotting factors Xa (rivaroxaban [Xarelto®], apixaban [Eliquis®], edoxaban [Savaysa™] and IIa (Dabigatran [Pradaxa®]) Pro-coagulant A precursor of blood factor(s) that promotes clotting Prothrombin time (PT) Measure of the extrinsic pathway of coagulation. Used in tests to determine the clotting tendency of blood, warfarin dosage, and liver damage. Prothrombin fragments 1 and 2 (F 1+2) Peptide fragments generated when clot activation is ongoing. Rational Design The strategy of creating new molecules with a specific functionality based on the ability to predict how the molecule’s structure will affect its behavior through physical design. Rebound Return of clotting-inhibition effect of an anticoagulant drug; essentially “re-anticoagulation.” Reversal Therapy Correction of anticoagulation levels in cases of excessive bleeding, to return hemostasis. Tissue Factor Pathway Inhibitor (TFPI) A single-chain polypeptide which can reversibly inhibit Factor Xa. Unfractionated Heparin (UFH) Commonly used injectable anticoagulant that inactivates thrombin and factor Xa through an antithrombin (AT)-dependent mechanism Whole Blood Clotting Time (WBCT) Method to determine the length of time required for a clot to form in a test tube of venous blood. The WBCT serves as a rough measure of all intrinsic clotting factors in the absence of tissue factors. It is not specific for any coagulation disorder but is often used to monitor coagulation during heparin therapy. The basis for this method is the standard Lee-White Clotting Time.