Regado-RADAR-summary-v6292011

Taking Science to Heart
REG1: A ground breaking
anticoagulant system
Opportunity summary including top line results
from the phase 2b RADAR trial
June 2011

REG1 overview
‣ An acute care specialty IV product designed to
complement a portfolio with a chronic oral therapy
‣ The only anticoagulant system that is truly reversible in
real time with its specific control agent
‣ Straightforward, cost-efficient path to clinical success and
regulatory approval
‣ Blockbuster commercial potential backed by robust
independent market research
‣ Positive data from RADAR (phase 2b) trial provide a sound
prediction of phase 3 success
2

REG1 is the optimal anticoagulant
‣ Novel FIXa inhibiting anticoagulant aptamer system
providing real time active control
‣ Unique and advantageous target upstream in the clotting
cascade (Factor IXa – proximal driver of propagation)
‣ Only product shown to reduce ischemia and bleeding in
ACS patients undergoing cardiac catheterization
‣ Strong IP position providing protection through 2025 and
beyond
‣ Unencumbered worldwide rights
3

RADAR (phase 2b) produces
unprecedented results
‣ First clinical study to demonstrate benefits in both bleeding and
ischemia in ACS
‣ FIXa inhibition validated as an advantageous target for
anticoagulation
‣ Phase 3 to be a classic, cost-minimized mortality/morbidity
study powered for superiority with traditional ischemic (efficacy)
and bleeding (safety) endpoints
‣ RADAR portends a high probability of success
‣ REG1 will provide major medical and pharmacoeconomic
benefits in ACS-PCI
4

REG1 is unique in offering
benefits in bleeding & ischemia
High risk of
ischemic events
“Sweet spot”
High risk of
bleeding events
REG1
Ischemia
Bleeding
Anticoagulation
Adapted from: Ferreiro & Angiolillo. Thromb Haemost 2010 (in press)
5

REG1 is a two component actively
controllable aptamer anticoagulant system
‣ Synthetic, single-strand oligonucleotides with low cost of goods (COGs)
‣ Convenient administration (IV bolus) with no dose adjustment in the
renally or hepatically impaired
‣ Metabolized by blood nucleases with no active metabolites, protein binding
or tissue accumulation
pegnivacogin
Anticoagulant aptamer
‣ Specific affinity
for Factor IXa
‣ 31 nucleotides
+ 40 kDa PEG
‣ t 1/2 > 24hr
‣ t max < 5 min
+
anivamersen
Active control agent
‣ Specific affinity
for pegnivacogin with
no other activity
‣ 15 nucleotides
‣ t 1/2 < 5 min
‣ t max ~ immediate
6

REG1 has a simple and well
characterized mechanism of action
Activated Inactivated Re-activated
pegnivacogin
anivamersen
Factor IX
Coagulating
Coagulation proceeds
unimpeded and
clots form
Anticoagulated
Pegnivacogin selectively
inhibits Factor IXa and
clotting cannot proceed
Coagulating
Anivamersen binds to
pegnivacogin; the
resulting complex is inert
and the clotting cascade
resumes
7

Factor IXa is an advantageous
target uniquely suited to REG1
Clotting Cascade
Tissue Factor
Factor VIIa
Factor VIIIa
Factor IXa
fondaparinux
apixaban
rivaroxaban
lepirudin
desirudin
dabigatran
bivalirudin
Factor Va
Factor Xa Thrombin Fibrin
pegnivacogin
unfractionated heparin
low molecular weight heparin
‣ Total anticoagulation - Complete Factor IXa inhibition results
in Factor X and thrombin “knock-out”
‣ More sensitive target - Factor IXa is 7x and 60x more
thrombogenic than Factor X and thrombin, respectively
‣ Reduced drug exposure - Lower intrinsic FIXa concentrations
allow high inhibition with less drug
‣ Congruous inhibition - Aptamers perfectly suited to blocking
the protein-protein interaction of the Factor VIIIa – Factor
IXa enzyme complex with Factor X
8

REG1 phase 1 demonstrated
well tolerated active control
3 studies, 174 patients, placebo controlled, randomized, double-blinded
RB006=pegnivacogin
RB007=anivamersen
ULN = Upper Limit of Normal
LLN = Lower Limit of Normal
Inject
RB006
Chan MY, et al. J Thromb Haemost 2008; 6:789–96
9

Activated Clotting Time (seconds)
Elective PCI was safely and effectively
performed with REG1 in phase 2a
Safe immediate sheath removal post-reversal was demonstrated
350
300
Arm 1
50% then
100% reversal
N=10
250
200
ACT=200: (Average
value above which most
catheter labs will
initiate PCI in
heparinized patients)
ACT=170: (Average
value below which
most catheter labs will
pull the arterial sheath
in heparinized
patients)
Arm 2
100% reversal
N=10
150
Control
heparin
N=4
Cohen et al., Eur Heart J 2009;30:101 (Abstract Supplement)
Baseline
5 min Post
Study Drug
15 min Post
Study Drug
End of PCI
15 min Post
1 st anivamersen
Dose
15 min post
2 nd anivamersen
Dose
10

RADAR (phase 2b) protocol
summary
‣ Adaptive design dose
ranging study for anivamersen
‣ Heparin or low molecular
weight heparin comparator
‣ ACUITY bleeding and
standard ischemic composite
endpoints
‣ Pharmacoeconomic
indicator endpoints included
‣ ACS patient population
‣ ACS - NSTEMI/UA patients
intended for cardiac
catheterization within 24 hours
‣ Multinational Study
‣ 69 enrolling sites in USA,
Canada, Poland, France,
Germany, Netherlands
11

RADAR patient flow and
final enrollment
25% reversal
n = 41
Eliminated by
DSMB as part of
adaptive design
NSTEMI-ACS
n = 640
Planned
catheterization

RADAR used traditional and prospective
endpoints predictive of phase 3 success
‣ Composite of major and minor (non-CABG) ACUITY
bleeding through day 30
[anivamersen dose selection]
‣ Proportion of subjects with a composite of death,
nonfatal MI, recurring ischemia or urgent target vessel
revascularization (TVR) through day 30
[estimate of anticoagulant efficacy]
‣ Incidence of major and minor (non-CABG) ACUITY
bleeding and ischemic events through hospital discharge
[phase 3 endpoint]
13

RADAR objectives
‣ Verify 1 mg/kg dose of pegnivacogin yields
rapid, precise, reproducible and complete
Factor IX inhibition
‣ Determine the dose range of anivamersen
that allows safe immediate sheath removal
‣ Assess the efficacy of REG1 in comparison
to heparin based on ischemic event rates
14

RADAR enrolled a typical ACS
(phase 3 target) population
Median age, yrs
Age ≥ 70
REG1
n = 479
63.5
34.0
Heparin
n = 161
62.2
27.3
Male, % 67.6 70.8
BMI, mean 28.6 28.5
Diabetes Mellitus, % 32.3 26.1
Tobacco use, % 56.8 59.6
Prior MI, % 48.4 46.6
Prior PCI, % 43.1 42.9
Prior CABG, % 14.2 14.3
Enrollment Criteria
Elevated biomarkers, % 52.6 54.7
ST changes, % 24.6 28.6
History of CAD, % 50.9 48.4
15

RADAR subject treatment comprised current
standard of background medications and care
REG1
n = 473
Heparin
n = 161
Study Drug, % 98.3 95.0
Anivamersen (of patients treated w/REG1, %) 99.4 -
Aspirin, % 99.6 95.7
Thienopyridine, % 79.9 82.6
Glycoprotein 2b/3a Inhibitor, % 9.7 16.6
Vascular Closure Device, % 12.9 16.8
Median Time to Sheath Removal (min) 24 180
Management Strategy
Catheterization, % 99.4 99.4
Medical Therapy, % 30.9 25.5
PCI, % 58.4 68.9
CABG, % 9.1 6.2
16

1 mg/kg of pegnivacogin completely
inhibits Factor IXa accurately and precisely
RADAR PK/PD Sub-study
‣ PK/PD in ACS
patients is
consistent
with that in
stable CAD
patients and
healthy
volunteers
RB006=pegnivacogin
Povsic et al., abstract presented at AHA, 2010
17

REG1 is measurable using standard
tests but measurement is not required
Procedure initiates sooner using REG1 due to faster
onset of action
‣ Standard and readily available ACT and aPTT tests can be
employed to determine REG1 anticoagulation
5.6
‣ Level of anticoagulation (pegnivacogin effect) and level of
reversal (anivamersen effect) can be easily determined
‣ Reliability of REG1 effects (as evidenced by minimal
pegnivacogin redosing in RADAR and reproducibility across
all clinical 3.2 studies) precludes the requirement for
measurement
‣ More subjects reached ACT >200 faster with pegnivacogin than
with heparin in RADAR
18

REG1 control is
predictable and reproducible
Target Reversal Dose
Target reversal accurately achieved across entire study
population over 69 sites in 6 countries
100%
92.6
75%
75.6
50%
52.5
25%
20.0
8 (20.0)
0
66.1
20.0
40.0
60.0 80.0 100.0
Mean Actual Percentage Reversal Achieved
19

Bleeding (%)
REG1 reversal doses ≥ 50% achieve
hemostasis with immediate sheath removal
REG1 demonstrates a dose response in major bleeding with
a 30% reduction at highest reversal dose
70.0
60.0
50.0
40.0
30.0
20.0
10.0
0
N
Events
65.0
20.0
REG1-25%
reversal
40
26 / 8
REG1-25% v. REG1-100%
Total bleeding
OR 0.2 (0.1 – 0.5); p < 0.0001
Through day 30
32.7 34.5
REG1-50%
reversal
10.3 8.4 7.1
113
38 / 12
REG1-75%
reversal
119
41 / 10
REG-100% v. heparin
Total bleeding
OR 0.9 (0.6 – 1.5)
Major bleeding
OR 0.7 (0.3 – 1.5)
29.8 31.1
REG1-100%
reversal
194
59 / 14
Total Bleeding
Major Bleeding
9.9
Heparin
160
50 / 16
25% reversal dose eliminated by DSMB early in the study as anticipated in the adaptive design 20

Bleeding (%)
REG1 exhibits a dose response and a
reduction in total and major bleeding
Based on FDA interaction, this is the likely
phase 3 safety endpoint
70.0
60.0
62.5
Through discharge
Total Bleeding
Major Bleeding
50.0
40.0
30.0
20.0
10.0
0
20.0
REG1-25%
reversal
32.8
REG1-50%
reversal
29.7
10.3 8.5
REG1-75%
reversal
2
23.4
1
OR=0.4 (0.1-1.0); p=0.045
2
OR=0.6 (0.4-1.0); p=0.07
1
5.1
REG1-100%
reversal
2
30.6
1
10.0
Heparin
N
Events
40
25 / 8
116
38 / 12
118
35 / 10
197
46 / 10
160
49 / 16
25% reversal dose eliminated by DSMB early in the study as anticipated in the adaptive design 21

REG1 reduces ischemia
(through day 30)
Death, MI, Recurrent Ischemia,
Urgent TVR (%)
50% fewer ischemic events with REG1
6.0
5.7
OR=0.5 (0.2-1.38)
5.6
4.0
3.0
2.0
3.0
0
REG1
Heparin
22

REG1 reduces periprocedural
myocardial infarctions
Urgent TVR rates show no evidence of stent thrombosis at high reversal doses
5.7
REG1
25%
reversal
n = 40
REG1
50%
reversal
n = 116
REG1
75%
reversal
n = 119
REG1
100%
reversal
n = 198
REG1
Overall
n = 473
Heparin
n = 161
n (%) n (%) n (%) n (%) n (%) n (%)
Composite* 3 (7.5) 1 (0.9) 5 (4.2) 5 (2.6) 14 (3.0) 9 (5.7)
3.0
Death 0 - 0 - 1 (0.8) 0 - 1 (0.2) 1 (0.6)
*No
recurrent
ischemia was
observed in
any REG1
reversal
group
MI 3 (7.5) 1 (0.9) 4 (3.4) 4 (2.1) 12 (2.6) 7 (4.3)
Urg TVR 1 (2.5) 0 - 1 (0.8) 1 (0.5) 3 (0.6) 1 (0.6)
23

Death, MI, Recurrent
Ischemia, Urgent TVR,%
REG1 reduces ischemic events
by 66% (through discharge)
Based on FDA interaction, this is the likely
phase 3 efficacy endpoint
6.0
OR=0.34 (0.21-1.13)
5.7
7.9
4.0
1.9
2.0
1.9
4.2
0
REG1
REG1
Heparin
Heparin
24

RADAR Serious Adverse Events
were similar to heparin
Most events were endpoint related with more events in the REG1
25% group
Adverse
Event
REG1
100%
REG1
75%
REG1
50%
REG1
25%
REG1
total
All AEs 57% 62% 58% 82% 61% 56%
All SAES 14% 21% 12% 23% 16% 11%
SAEs by organ system
Cardiac 5% 7% 3% 3% 5% 4%
Vascular/
bleeding
4% 5% 7% 15% 6% 2%
Respiratory 0 3% 1% 3% 1% 2%
Heparin
Immune
system
Noncardiac
chest pain

RADAR Adverse Events
were similar to heparin
Most events were endpoint related with more events in the REG1
25% group
Adverse
Event
REG1
100%
REG1
75%
REG1
50%
REG1
25%
REG1
total
All AEs 57% 62% 58% 82% 61% 56%
All SAES 14% 21% 12% 23% 16% 11%
AEs by organ system
Cardiac 12% 15% 17% 21% 15% 15%
Vascular/
bleeding
39% 41% 38% 74% 42% 33%
Respiratory 7% 5% 8% 5% 6% 5%
Heparin
Immune
system
2% 3% 0 0 1% 1%
GI 8% 6% 2% 15% 6% 7%
Skin 4% 3% 0 0 2% 4%
Neurologic 9% 5% 4% 15% 7% 6%
26

The REG1 safety database
supports a well tolerated drug profile
No safety signals in preclinical or phase 1/2a studies
‣ Preclinical safety package deemed acceptable and complete by
FDA at end-of-phase 2a meeting
5.6
‣ RADAR AEs and SAEs other than bleeding and ischemic events
were rare and evenly distributed among arms
‣ 3 female patients had allergic-like SAEs shortly after receiving
pegnivacogin clustered near the end of the RADAR trial and in
Europe3.2
‣ No other signals for allergic-like reactions seen in overall
RADAR AEs
‣ Reactions are linked to a pre-existing patient condition which
is not REG1 specific and is expected to be rare
27

REG1 earlier sheath removal
contributes to increased hospital efficiency
REG1 enables safe sheath removal 4-6 times sooner than heparin
Time from Catheterization
to Sheath Removal (median)
Time from End of Procedure
to Sheath Removal (median)
100% Group
1.0
100% Group
0.4
75% Group
1.0
75% Group
0.4
50% Group
1.0
50% Group
0.4
25% Group
1.1
25% Group
0.6
REG1 Combined
1.0
REG1 Combined
0.5
Heparin
3.8
Heparin
3.0
2.2
0
2
4
0
2
4
Hours
Hours 28

RADAR successfully
achieved all objectives
Confirmed 1 mg/kg dose of pegnivacogin
resulted in complete factor IX inhibition
Determined that ≥ 50% reversal doses of
anivamersen allowed immediate safe
sheath removal post procedure
Demonstrated that REG1 reduces ischemic
event rates (vs. heparin) in the ACS
population
29

RADAR confirms the
ground breaking profile of REG1
‣ REG1 is the first and only anticoagulant to reduce
bleeding and ischemia simultaneously in ACS patients
undergoing cardiac catheterization
‣ Factor IXa inhibition is validated as an advantageous
anticoagulation target
‣ REG1 pharmacologic and pharmacodynamic behavior is
predictable, reproducible and controllable in real time in
the relevant patient populations
‣ REG1 delivers pharmacoeconomic benefits such as
improved administration convenience, faster onset of
action, virtually instantaneous reversal, immediate
sheath pull and better outcomes
30

RADAR results support a standard
phase 3 study design and regulatory path
‣ Phase 3 to be a classic, cost-minimized
mortality/morbidity study powered for superiority with
traditional ischemic (efficacy) and bleeding (safety)
endpoints
‣ RADAR data portend a high probability of phase 3
success
‣ Phase 3 designed in close active collaboration with
leading international KOLs
‣ Phase 3 protocol provides multiple opportunities for
clinical success and commercially viable labelling
31

REG1 offers
many marketing advantages
Highly profitable commercial opportunity
‣ Cost-effective and uncomplicated commercialization due
to low COGs, small targeted (acute care) sales force
and a marketing budget focused on medical education
‣ Innovative, highly differentiated profile will drive early
acceptance and rapid adoption
‣ Complementary to an oral, chronic anticoagulant yet
can stand alone in an acute care specialty business
‣ Vast life cycle opportunity due to myriad additional
indications
32

Rigorous third party market research
confirms large REG1 commercial opportunity
Eight market studies with >400 physicians and key stakeholders
employed industry standard methodology
‣ Premium pricing is supported by a thorough pricing and
reimbursement analysis (private and government payers)
‣ Substantial cost savings to healthcare systems expected
based on favorable pharmacoeconomic profile
‣ Results from proposed phase 3 design will drive adoption
as confirmed by >130 interviewed interventional
cardiologists
‣ Considerable commercial upside emerged as REG1 profile
from RADAR is superior to profile tested in market
research
33

Market research confirms REG1 multibillion
dollar worldwide PCI opportunity
“All Comers” PCI
excluding STEMI
‣ Non-ST elevation acute
coronary syndrome undergoing
percutaneous coronary intervention
‣ Patients choosing elective PCI
for coronary artery disease
>
1.
5B $peak revenues:
(U.S., top five EU markets)
34

Regado patent estate provides
exclusivity for reversible aptamers
Composition of matter protection to 2025+
20
Issued or allowed
U.S. and foreign
patents
‣ Composition of matter for
pegnivacogin and anivamersen
‣ Anti-Factor IXa aptamers
‣ Oligonucleotide modulators of
aptamers
‣ REG1 and REG2 product claims
Other U.S. and foreign
applications pending:
‣ Methods of use for Anti-Factor IXa
aptamers and their modulators
‣ REG1 and REG2 product
administration
‣ Aptamers and modulators thereof for
antiplatelet targets (REG3)
‣ Additional molecular classes of
modulators
‣ Anti-FX/Xa, VII/VIIa, thrombin and
ANG2 aptamers and methods
35

REG1 is the optimal anticoagulant
‣ Novel FIXa inhibiting anticoagulant aptamer system
providing real time active control
‣ Unique and advantageous target upstream in the clotting
cascade (Factor IXa – proximal driver of propagation)
‣ Only product shown to reduce ischemia and bleeding in
ACS patients undergoing cardiac catheterization
‣ Strong IP position providing protection through 2025 and
beyond
‣ Unencumbered worldwide rights
36

Regado led by an experienced
management team
David J. Mazzo, Ph.D., President and Chief Executive Officer
(CEO of Aeterna Zentaris; CEO of Chugai Pharma USA; Sr. VP, Dev Ops, Schering-Plough)*
Chris Rusconi, Ph.D., Sr. VP and Chief Scientific Officer (Co-Founder)
(Director of Research, Combinatorial Therapeutics, Duke University)*
Steven Zelenkofske, D.O., F.A.C.C., Sr. VP and Chief Medical Officer
(VP Cardiovascular/Thrombosis Medical Unit-US, Sanofi-Aventis)*
Ellen McDonald, M.B.A., Sr. VP and Chief Business Officer
(Sr. VP Cardiovascular Marketing & Medical, Bristol-Myers Squibb; VP Oncology Franchise, J&J)*
Alexander R. Giaquinto, Ph.D., Sr. VP Reg. Affairs/Quality Assurance
(Sr. VP Worldwide Regulatory Affairs, Schering-Plough)* and Chief Compliance Officer
Chris Courts, C.P.A., M.B.A., VP Finance
(Director, Finance, ITC Deltacom)*
*Select Relevant Experience
37

Contact:
Ellen McDonald, Chief Business Officer
emcdonald@regadobio.com
908 580 2113