Download Media Kit - Perosphere

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.