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1. 1CONFIDENTIAL
Eribis Pharmaceuticals AB
Novel Treatment of
Acute Myocardial Infarction (AMI)

2. 2CONFIDENTIAL
Todays agenda
 The Company
 The indication – background & market
 EP94
 Pre-clinical Development
 General Properties
 Clinical Development
 Intellectual Property
 Funding need

3. 3CONFIDENTIAL
The Company

4. 4CONFIDENTIAL
The Company
Eribis Pharmaceuticals AB is an Uppsala-based
biotech company founded in 2006, with the aim to
develop new therapies for cardiovascular disease.

5. 5CONFIDENTIAL
 Gerhard Wikström, MD, Ph.D., Ass Prof Cardiology, Uppsala
University Hospital
 Lars Grip, MD, Ph.D., Professor in Cardiology, Sahlgrenska
University Hospital
 John Pernow, MD, Ph.D., Prof in Cardiology, Karolinska
University Hospital
 Garrett Gross, Ph.D.,Professor of Pharmacology, Medical
College of Wisconsin
 Dan Atar, MD, Ph.D., Professor in Cardiology, Division of
Cardiology, Oslo University Hospital Aker
Scientific Advisors

6. 6CONFIDENTIAL
Acute Myocardial Infarction (AMI)
background and market

7. 7CONFIDENTIAL
Cardiovascular disease (CVD)
the major health problem
 CVD include;
 acute coronary syndromes (ACS)
 stroke
 periphereal arterial disease (PAD)
 Burden of CVD is increasing in parallel with increase in life
expectancy
 Acute Myocardial Infarction (AMI) is the number one cause
of death in the Western world
 mortality rates near 10%
 first cause of chronic heart failure

8. 8CONFIDENTIAL
Acute coronary syndrome (ACS) is comprised of three diseases
involving the coronary arteries: ST elevation myocardial infarction
(STEMI), non ST elevation myocardial infarction (non-STEMI) and
unstable angina.
While ACS mortality declined in the last four decades in the USA as life
expectancy increased, the decline largely represents the postponement
of ACS deaths until older age.
Thus, the burden of ACS is increasing in parallel with the increase in life
expectancy.
Acute coronary syndrome (ACS)

9. 9CONFIDENTIAL
Coronary Artery By-pass
Graft (CABG)
Percutaneous Coronary
Intervention (PCI)
Reperfusion therapy
Primary Treatment Options for AMI
 Across the seven major markets in 2006 the number of
cardiovascular procedures, including CABG and PCI were
estimated at 7.0m
 Incidence rates for PCI amounts to 3.7m (nonSTEMI + STEMI)

10. 10CONFIDENTIAL
The American Heart Association (AHA) estimates that
there were 1.2 million cases of ACS in 2007 in the US.
This number includes both patients experiencing their first
event as well as patients with relapses.
Patients’ experiencing their first event is around 700,000;
STEMI and NSTEMI accounting for 85% of these events.
This incidence is similar to that in the five major markets in
Europe.
The total number of ACS cases in the US and the five
major EU markets is therefore estimated at around
2.5 – 3.0 million annually.
Large unmet need
Acute Coronary Syndrome – the major markets

11. 11CONFIDENTIAL
Metabolic and biochemical changes
caused by reperfusion
Reperfusion injury (RI) limits the beneficial effects of
revascularisation
Studies in different species suggest that 20-70% of myocardial damage may come from RI
(Gomes L 2007, Penna C 2008, Zhao ZQ, 2006)
RI leads to functional and structural myocardial damage
– generation of ROS
– a fast restoration of pH
– intracellular calcium overload
– mitochondrial dysfunction
– Apoptosis
(Yellon DM, 2007)
Cardioprotective strategies to minimize RI represents an
large unmet medical need

12. 12CONFIDENTIAL
Principles of ischemic pre- and
postconditioning
Brief episodes of coronary artery occlusion are applied either before (preconditioning) or
immediately after (postconditioning) the prolonged ischemic insult
Ref; Zhao ZQ et al., Am J Physiol Heart Circ Physiol, 2003;285:579-88

13. 13CONFIDENTIAL
EP94
Cardioprotection in acute
myocardial infarction (AMI)

14. 14CONFIDENTIAL
EP94 – First in class drug
 Novel pharmacological cardioprotective intervention
 Tetrapeptide (stabilized)
 Injectable, small volume
 Microgram dosage
 Cardioprotective effects in rodent and non-rodent animal
models
 Low COGS (solid phase peptide synthesis)
 Backup compounds available
 Patent protected

15. 15CONFIDENTIAL
Tentative molecular signaling pathways
involved in cardioprotection

16. 16CONFIDENTIAL
Mode of Action
 Acute Myocardial Infarction induces an
ischemia/reperfusion-induced tissue damage
 It is anticipated that EP94’s mode of action reduces the
ischemia/reperfusion damage through
 opoid receptors
 KATP channels
 iNOS

17. 17CONFIDENTIAL
Preclinical results

18. 18CONFIDENTIAL
• Rodent dose finding study
• Pig study, closed chest, iv.
• Pig study, open chest, infusion
• Pig study, closed chest, dose finding, iv.
• Pig study, closed chest, high-dose range finding, iv.
• Rodent study, dose finding, m.o.a. study
Key studies presented

19. 19CONFIDENTIAL
EFFICACY
• EP94 is effective in two different pig ischemia/reperfusion
models (open vs closed chest)
• EP94 produces a significant reduction of infarct size in pigs
already at 1 µg/kg
• The cardioprotective effect of EP94 is dose-dependent in pigs
• EP94 reduces the infarct size dose-dependently during both
pre- and post-conditioning in rats
Conclusions

20. 20CONFIDENTIAL
Post-
surgery
stabilization
phase
Vehicle
EP94 (0.01 µg/kg x 1)
25 min occlusion
2 hrs reperfusion
EP94 (0.1 µg/kg x 1)
EP94 (1 µg/kg x 1)
25
EP94 (5 µg/kg x 1)
0
= Vehicle administration
= EP94 administration-5
EP94 shows a dose dependent reduction of
myocardial infarction size in rats
EP94 (10 µg/kg x 1)
0
10
20
30
40
50
60
Vehicle
EP94 (0.01 ug/kg)
EP94 (0.1 ug/kg)
EP94 (1 ug/kg)
EP94 (5 ug/kg)
EP94 (10 ug/kg)
IS/AAR(%)
N=12 N=6 N=12 N=12 N=12 N=9
*
*
* *
Study number 64-06
Pre-conditioning

21. 21CONFIDENTIAL
EP94 i.v. administered early or late during ischaemia in
a closed chest MI pig model reduces myocardial
infarction size significantly
Post-
surgery
stabilization
phase
Vehicle
EP94 (1 µg/kg x 4) – Early intervention
40 min occlusion
4 hrs reperfusion
60 min
EP94 (1 µg/kg x 3) – Late intervention
EP94 (0.2 µg/kg x 3) – Late intervention
5 12 19 26 33 40
0
10
20
30
40
50
60
70
80
Vehicle
EP94 (1 ug/kg x 4)
EP94 (1 ug/kg x 3)
EP94 (0.2 ug/kg x 3)
IS/AAR(%)
N =7 N =4 N =6 N =6
Early Late Late
Mean ± SEM
*
**
Study Report 09-01, Karlsson et al., Eur J Pharmacol 2011:651 pp146-151
= Vehicle administration
= EP94 administration
Closed chest pig MI/reperfusion model

22. 22CONFIDENTIAL
Intracoronary infusion of EP94 in pigs reduces
myocardial infarction size significantly
Post-surgery
stabilization
phase
Vehicle
EP94 (0.2 µg/kg, 15 min)
40 min occlusion
4 hrs reperfusion
30’ 5’
0
10
20
30
40
50
60
70
80
90
100
Vehicle EP94
%ofareaatrisk
Mean ± SEM
**
N = 5 N = 5
Study Report 08-02, Karlsson et al., Eur J Pharmacol 2011:651 pp146-151
60 min
Open chest pig MI/reperfusion model
Infusion

23. 23CONFIDENTIAL
EP94 appears to reduce myocardial
infarction size dose-dependently
Post-
surgery
stabilization
phase
Vehicle
EP94 (1 µg/kg x 3)
40 min occlusion
4 hrs reperfusion
60 min
EP94 (5 µg/kg x 3)
EP94 (25 µg/kg x 3)
26 33 40
0
10
20
30
40
50
60
70
Vehicle 1 ug/kg 5 ug/kg 25 ug/kg
IS/AAR(%)
N=6 N=6 N=6 N=6
*
= Vehicle administration
= EP94 administration
Study Report 11-02
Mean ± SEM
Linear regression analysis,
* P < 0.05
Closed chest pig MI/reperfusion model

24. 24CONFIDENTIAL
Rat acute myocardial infarction model – a
combined dose response and mode of action
study
Post-
surgery
stabilization
phase
Vehicle
EP94 (0.1 µg/kg x 2)
25 min occlusion
2 hrs reperfusionEP94 (1.0 µg/kg x 2)
EP94 (2.5 µg/kg x 2)
105
EP94 (5.0 µg/kg x 2)
EP94 (10 µg/kg x 2)
-10 0
1) Opioid antagonists i.v.
a) Naltrindole (delta) – 5 mg/kg
b) Nor-BNI (kappa) – 0.3 mg/kg
c) CTOP (mu) – 0.1 mg/kg
d) Naltrindole + EP94
e) Nor-BNI + EP94
f) CTOP + EP94
2) KATP channel antagonists i.v.
a) HMR1098 (sarc KATP blocker) – 6 mg/kg
b) 5-HD (mito KATP blocker) – 10 mg/kg
d) HMR1098 + EP94
e) 5-HD + EP94
3) iNOS inhibitor i.v.
a) 1400W
b) 1400W + EP94
= Vehicle administration
= EP94 administration
Study protocol 2010-01
EP94 (0.5 µg/kg x 2)

25. 25CONFIDENTIAL
Rat acute myocardial infarction model – a combined dose
response and mode of action study - cont´d
0
10
20
30
40
50
60
70
Vehicle 0.1 0.5 1.0 2.5 5.0 10.0
EP94 (ug/kg, i.v.)
IS/AAR(%)
N = 9 N = 8 N = 10 N = 10 N = 8 N = 9 N = 8
*** ***
**
Mean ± SEM
*** p < 0.001 vs vehicle
** p < 0.01 vs vehicle
Bell-shaped dose-response relationship in rat confirms
previous results in rats

26. 26CONFIDENTIAL
Blocking of mu-opioid receptors abolish the cardioprotective
effects of EP94
Mean ± SEM
*** p < 0.001 vs vehicle
** p < 0.01 vs vehicle
CTOP = selective mu-antagonist
NT = naltrindole = selective delta-antagonist
Nor-BNI = selective kappa-antagonist
Rat acute myocardial infarction model – a combined dose
response and mode of action study - cont´d
0
10
20
30
40
50
60
70
Vehicle
EP94
(1
ug/kg)
CTO
P
(0.1
m
g/kg)
CTO
P+EP94
NT
(5
m
g/kg)
NT+EP94
Nor-BNI (0.3
m
g/kg)
nor-BNI+EP94
IS/AAR(%)
N = 9 N = 10 N = 9 N = 9 N = 9 N = 9 N = 9 N = 9
***
** **
mu-receptor delta-receptor kappa-receptor

27. 27CONFIDENTIAL
The non-selective opioid receptor antagonist naloxone completely inhibits the
cardioprotective effects of EP94 – pharmacological evidence of the
involvement of mu-receptors in the central nervous system
Mean ± SEM
*** p < 0.001 vs vehicle
Rat acute myocardial infarction model – a combined dos
response and mode of action study - cont´d
0
10
20
30
40
50
60
70
Vehicle
EP94 (1 ug/kg)
Naloxon (3 mg/kg)
Naloxon+EP94
Naloxon methiodide (10 mg/kg)
Naloxon methiodide+EP94
IS/AAR(%)
N = 9 N = 11 N = 9 N = 9 N = 9 N = 9
*** ***
Block of peripheral and CNS
opioid receptors
Block of peripheral
opioid receptors
Naloxone = non-selective opioid antagonist
Naloxone methiodide = quaternary-derivative of naloxone,
does not penetrate blood-brain barrier

28. 28CONFIDENTIAL
Mean ± SEM
*** p < 0.001 vs vehicle
Effects of selective KATP ion channel antagonists
HMR 1098 = sarcolemmal KATP channel antagonist
5-HD = mitochondrial KATP channel antagonist
0
10
20
30
40
50
60
70
Vehicle
EP94
(1
ug/kg)
HM
R
1098
(6
m
g/kg)
HM
R
1098
+
EP94
5-HD
(10
m
g/kg)
5-HD
+
EP94
IS/AAR(%)
N = 9 N = 9N = 9N = 10 N = 9 N = 9
***
Rat acute myocardial infarction model – a combined
dose response and mode of action study - cont´d
Block of sarcolemmal KATP
channels
Block of mitochondrial KATP
channels

29. 29CONFIDENTIAL
Mean ± SEM
n = 9/group
*** p < 0.001 vs vehicle
Effects of inducible NOS (iNOS) inhibition on EP94-induced cardioprotection
1400W = selective iNOS inhibitor
0
10
20
30
40
50
60
70
Vehicle
EP94 (1 ug/kg ipx2) - 24-h
1400W (0.1 mg/kg iv) - acute
1400W (acute) + EP94 (acute)
EP94 (24-h) + 1400W (24-h)
IS/AAR(%)
*** ***
Rat acute myocardial infarction model – a combined
dose response and mode of action study - cont´d

30. 31CONFIDENTIAL
A follow up study evaluating a higher dose
range of EP94 resulted in an absence of
cardioprotection at all dose levels
Post-
surgery
stabilization
phase
Vehicle
EP94 (1 µg/kg x 3)
40 min occlusion
4 hrs reperfusion
60 min
EP94 (25 µg/kg x 3)
EP94 (125 µg/kg x 3)
40
OPTIONAL: EP94 (625 µg/kg x 3)
0 3326
= Vehicle administration
= EP94 administration
Study protocol 2011-01
N = 12/group

31. 32CONFIDENTIAL
A follow up study evaluating a higher dose
range of EP94 resulted in an absence of
cardioprotection at all dose levels – cont´d
0
10
20
30
40
50
60
70
IS/AAR(%)
IS/AAR (%) 59,37 61,79 57,31 57,10
Placebo 1 ug/kg 25 ug/kg 125 ug/kg
n = 10 n = 10 n = 11 n = 8
Closed chest pig MI/reperfusion model

32. 33CONFIDENTIAL
Why was the EP94 dose range finding study in
closed chest AMI pigs completely absent of
cardioprotective effects?
• Previously five (5) AMI EP94 protection studies in pigs have
been conducted with significant and promising results.
• In the present study the pigs were not healthy due to scabies.
The veterinarian decided for this reason to treat all pigs with
Doramectin. (A drug approved by FDA for the treatment of
parasites in animals, such as roundworms, lungworms,
eyeworms, grubs, sucking lice and mange mites in cattle).
• This is the only study where EP94 have been used in
combination with Doramectin

33. 34CONFIDENTIAL
Why was the EP94 dose range finding study
in closed chest AMI pigs completely absent
of cardioprotective effects? - Cont´d
Cardioprotective dose-response effects from 2 studies conducted in an AMI pig model
BUT without pretreatment with Doramectin
0
10
20
30
40
50
60
70
Vehicle 1 ug/kg 5 ug/kg 25 ug/kg
IS/AAR(%)
N = 6 N = 6 N = 6 N = 6
0
10
20
30
40
50
60
70
125 ug/kg
N=5
Pilot studyStudy Report 11-02

34. 35CONFIDENTIAL
Doramectin – Mode of action
• ActivationActivation of GABAergic receptors causes an influx of chloride ions,of GABAergic receptors causes an influx of chloride ions,
hyperpolarization, paralysis of the nervous system andhyperpolarization, paralysis of the nervous system and death of thedeath of the
parasiteparasite..
• High dosesHigh doses causescauses neurotoxicologicalneurotoxicological effects in mammalseffects in mammals
• Large difference in sensitivity among different mammal seciesLarge difference in sensitivity among different mammal secies
Why was the EP94 dose range finding study in closed
chest AMI pigs completely absent of cardioprotective
effects? - Cont´d

35. 36CONFIDENTIAL
Mu-opioid receptors are linked to GABAergic systems
• GABAergic neurons co-express mu-opioid receptorsGABAergic neurons co-express mu-opioid receptors in the CNS of rats (Kalyuzhny et al, Neuroreportin the CNS of rats (Kalyuzhny et al, Neuroreport
1997, 8:3367-72; Kalyuzhny et al J Comp Neurol 1998, 392:528-47).1997, 8:3367-72; Kalyuzhny et al J Comp Neurol 1998, 392:528-47).
• GABAergic and opioidergic systems are closely linkedGABAergic and opioidergic systems are closely linked. Mu-opioid receptor KO mice down-regulates. Mu-opioid receptor KO mice down-regulates
GABA-gated chloride channel binding sites (Tien et al., Neurochem Res. 2007, 32:1891-1897).GABA-gated chloride channel binding sites (Tien et al., Neurochem Res. 2007, 32:1891-1897).
Possible interactions points between Doramectin and EP94
Why was the EP94 dose range finding study in
closed chest AMI pigs completely absent of
cardioprotective effects? - Cont´d
Nitrix Oxide (NO) and iNOS
• Avermectin (analogue to doramectin) has been reported toAvermectin (analogue to doramectin) has been reported to block LPS-induced secretion of NOblock LPS-induced secretion of NO
(Viktorov et al, Bull Exp Biol Med. 2003, 136:569-71; Zhang et al, Int Immunopharmacol. 2009, 9:(Viktorov et al, Bull Exp Biol Med. 2003, 136:569-71; Zhang et al, Int Immunopharmacol. 2009, 9:
354-359).354-359).
• Ivermectin (analogue of doramectin)Ivermectin (analogue of doramectin) inhibits mRNA and protein expression of iNOSinhibits mRNA and protein expression of iNOS and COX-2and COX-2
enzymes (Zhang et al, Int Immunopharmacol. 2009, 9: 354-359).enzymes (Zhang et al, Int Immunopharmacol. 2009, 9: 354-359).
• Ivermectin at therapeutic dosesIvermectin at therapeutic doses increases the plasma NO levels in rabbitsincreases the plasma NO levels in rabbits (Atakisi et al, Eur Rev(Atakisi et al, Eur Rev
Med Pharmacol Sci. 2009, 13:425-429).Med Pharmacol Sci. 2009, 13:425-429).

36. 37CONFIDENTIAL
ATP-gated ion channels and other ion channels
• ATP dependent P-glycoproteinATP dependent P-glycoprotein (mediates multidrug resistance) is inhibited by doramectin.(mediates multidrug resistance) is inhibited by doramectin.
• Binds and activatesBinds and activates ATP-gated purinergic P2X receptorsATP-gated purinergic P2X receptors (Priel at al., J Gen Physiol. 2004, 123:281-(Priel at al., J Gen Physiol. 2004, 123:281-
293; www.tocris.com)293; www.tocris.com)
• Binds and activatesBinds and activates αα7 nicotinic acetylcholine receptors7 nicotinic acetylcholine receptors ((www.tocris.comwww.tocris.com))
• Binds and modulatesBinds and modulates glutamate-activated chloride channels (glutamate-activated chloride channels (www.tocris.comwww.tocris.com))
• Binds and modulatesBinds and modulates GABA-activated chloride channelsGABA-activated chloride channels ((www.tocris.comwww.tocris.com))
• PotentiatesPotentiates glycine-gated currentsglycine-gated currents (www.tocris.com(www.tocris.com))
Possible interactions points between Doramectin and EP94
Why was the EP94 dose range finding study in
closed chest AMI pigs completely absent of
cardioprotective effects? - Cont´d

37. 38CONFIDENTIAL
SUMMARY
Doramectin may interact with the cardioprotective effects of EP94 through…..
• GABA receptors cross-communicating with mu-receptors in the CNS.
• NO and iNOS.
• Ion channels such as KATPchannels or unspecific mitochondrial permiability transition
pores.
Possible interactions points between Doramectin and EP94
Why was the EP94 dose range finding study in
closed chest AMI pigs completely absent of
cardioprotective effects? - Cont´d

38. 39CONFIDENTIAL
Doramectin – The next step
Outline of study addressing the possibility of an
interaction between EP94 and Doramectin
• Species – rat due to backlogs in the pig facility
• Animal model – traditional rat MI model
• Study groups - Vehicle
- Preconditioning (positive control)
- EP94 (1 ug/kg x 2 ; i.v.)
- EP94 (1 ug/kg x 2 ; i.v.) + Doramectin (intermediate, tbd)
- EP94 (1 ug/kg x 2 ; i.v.) + Doramectin (high, tbd)
• Study to be commenced: July 2011
• Study site: Sahlgrenska University Hospital, Gothenburg, Sweden

39. 40CONFIDENTIAL
EFFICACY
• EP94 is effective in two different pig ischemia/reperfusion
models (open vs closed chest)
• EP94 produces a significant reduction of infarct size in pigs
already at 1 µg/kg
• The cardioprotective effect of EP94 is dose-dependent in pigs
• EP94 reduces the infarct size dose-dependently during both
pre- and post-conditioning in rats
Conclusions

40. 42CONFIDENTIAL
General properties
Toxicology and Safety
Pharmacology

41. 43CONFIDENTIAL
EP 94 – General properties
 Tetrapeptide
 Manufactured by solid phase peptide synthesis
 Lyophilized powder
 Solubility: Good solubility in water
 Stability of drug substance:
 Stable at +4°C for more than 2 years
 Stability of drug product:
 Stable at -18°C, +4°C and 25°C for more than 6 months in saline

42. 44CONFIDENTIAL
Planned
-Toxicology & Safety
 Single dose tox. study in rats and pigs
 Repeat dose tox. study, 14 days, in rats and pigs
 Safety Pharmacology
 Genotoxicity
 Pharmacokinetics and ADME

43. 45CONFIDENTIAL
Clinical Development

44. 46CONFIDENTIAL
Key factors for success with EP94 in a
clinical development programme
 Selection of patient population
STEMI patients
An adequate risk stratification algoritm
 Selection of primary endpoint
Optimal method used to detect infarct size reduction

45. 47CONFIDENTIAL
Clinical development of EP 94
Phase I study
 Study Objective: Dose-escalation study to evaluated
the safety, and tolerability in healthy individuals
 Design: single-center, double-blind
 Estimated number of healthy volunteers: 40
 Primary outcome measures: tolerability, safety, PK
and hemodynamic parameters

46. 48CONFIDENTIAL
 Study Objective: Dose-escalation study to investigate the cardioprotective
effect of ERIBIS Peptide 94 given as an adjunct to percutaneous coronary
intervention (PCI) in subjects with an acute STEMI
 Design: randomized, placebo-controlled, double-blind and multicenter
 Estimated number of patients: 350-400
 Primary outcome measure:
 To demonstrate a dose-dependent positive trend for myocardial salvage
and myocardial salvage index using a modified single contrast enhanced
steady-state free precession (SSFP) cine cardiovascular magnetic
resonance (CMR) examination performed one week after the acute event
Clinical development of EP 94
Phase II, proof-of-concept study

47. 49CONFIDENTIAL
 Secondary outcome measure:
 ST-resolution on 12 lead ECG 90 minutes after PCI
 Troponin, CK-MB 3 to 6 hrs, 6 to 12 hrs, 18 to 24 hrs and 36 hrs after
randomization (Peak and AUC)
 To determine Left Ventricular Ejection Fraction (LVEF) and Wall Motion
Score Index (WMSI) 6 weeks and 6 months after PCI
 Myocardial salvage index 6 months after PCI
 Incidence of cardiac death and total mortality, stroke, new-onset heart
failure, and re-hospitalization for any congestive heart failure 6 month
follow-up visit
Clinical development of EP 94
Phase II, proof-of-concept study

48. 50CONFIDENTIAL
Intellectual Property

49. 51CONFIDENTIAL
The IPR comprises patent protection for:
 Chemical structure of peptides and peptide-based compounds
 Clinical Utility
 Pharmaceutical Composition
 PCT application was filed in August 2007
 Regional and National patent applications submitted early
2009 in EU, USA, Canada, Australia, India, China and Japan.
 EU patent grant subject for approval, EPO decision to grant
obtained Feb 2011
Intellectual Property

50. 52CONFIDENTIAL
Significant cardioprotective effect
Pre-clinical Proof of Principle achieved
Clear unmet medical need & large market size
First in class
First in man within 18 months
Summary

51. 53CONFIDENTIAL
Project Plan
Step 1 (3 MSEK end: Q4/2011)
Confirm Doramectin interaction in rats and pigs
If confirmed - Dose finding study in relevant model
(most likely in pigs)
Mode of action – cont’d studied to elucidate MoA
Step 2 (12 MSEK; end: Q3/2012)
Start regulatory studies for a CTA/IND
CTA/IND submission Q3/2012
Step 3 (7 MSEK; end: Q2/2013)
Phase I study
Step 4 (45 MSEK; start 2013)
Phase II study

52. 54CONFIDENTIAL
Project Plan
ID Aktivitet
1 CMC
2 Manufacture, Polypeptides
8 DP development
9 DS, GMP
14 DP, GMP
17 Pharmacology
18 Efficacy
19 Efficacy studies in rats (1) and pigs (3)
20 Dose response studyin rats (Gross)
21 Dose response studyin pigs (Grip)
22 Doramectin study, rats
23 Doramectin study, pigs
24 New dose response study in pigs
25 Interaction studies
26 Mode of action studies
27 Penetration of BBB
28 Guinea-pig ileum bio-assay
29 Mouse vas deferens bio assay
30 Receptor screen
31 Dosing intervals, number of administrations
32 Effect at end of occlusion/end of reperfusion
33 MILESTONE1, EFFICACY
34 Bioanalysis
39 Pharmakokinetics and ADME
42 Scientific advice MPA
45 MILESTONE2, GMP BATCH #2 and MPA
46 Safety pharmacology and toxicology
66 MILESTONE3, TOX & SAFETY
67 Regulatory Affairs
71 MILESTONE4, CTA
72 Phase I
2011-06-06
2011-10-31
2012-07-09
2012-10-01
Kv4 Kv1 Kv2 Kv3 Kv4 Kv1 Kv2 Kv3 Kv4 Kv1 Kv2 Kv3 Kv4 Kv1 Kv2 Kv3 Kv4 Kv1 Kv2 Kv3 Kv4 Kv1 Kv2 Kv3 Kv4 Kv1 Kv2 Kv3 Kv4 Kv1 Kv2 Kv3 Kv4 Kv1 Kv2 Kv3 Kv4 Kv1 Kv2 Kv3 Kv4 Kv1 Kv2
2005 2006 2007 2008 2009 2010 2011 2012 2013 2014 2015 2016
Project Plan

53. 55CONFIDENTIAL
Investment Plan up to end of
Phase I
Step 1
3 MSEK - Date: August 2011
Step 2
12 MSEK - Date: December 2011
Step 3
7 MSEK - Date: August 2012
TOTAL
22 MSEK

54. 56CONFIDENTIAL
Thank you for listening!
Contact;
Erik Bissessar
erik.bissessar@eribispharma.se

55. 57CONFIDENTIAL
Question & Answers

56. 58CONFIDENTIAL
1. Does the peptide pass the blood brain barrier?
2. Does the NO-group give rise to worries in relation to
toxicology?
3. Does the NO-group give rise to worries in relation to
Carcinogenicity?
4. Are other receptors hit by this peptide?

57. 59CONFIDENTIAL
NO-study
EP94 has been evaluated with and without NO and acylation in response to
the EU patent office’s questions regarding Eribis application. To show
that the specific groups at position 2, acylation, and pos 4, NO-group,
are both necessary to have the cardioprotective effect shown with EP94.
5 different peptides were compared with EP94 in this pre-conditioning study.
•without NO-group of the 4th amino acid
•without acylation of 2nd amino acid
•without both acylation and NO-group
•with Asp instead of acylation on 2nd amino acid
•with Arg-Asp instead of acylation on 2nd amino acid
EP94 does not exert a significant level of cardioprotective activity without
these specific groups in the second and fourth position on EP94.

58. 60CONFIDENTIAL
Do you have rodent data?
How does EP94 and morphine perform
together in the models?
Any efficacy measures/differentiation from
morphine/other opioids.
Eribis has performed a series of studies on
rodents that answer these questions.
This data will be available when Zealand
performs a DD. There is too much data to
discuss during this initial meeting.

59. 61CONFIDENTIAL
Do you have rodent data? – Cont´d
Partial list – not complete!
REPORT
NUMBER
TYPE PROJECT TITLE
PRINCIPAL
INVESTIGATOR(S)
COMMENTS Released
ESR07-001
Exploratory Study
Report (ESR)
EP94
A study of the analgesic effects of peptides no 91,
92, 93, 94, 95 in CD-1 mice
Kustanova GA,
Murashev AN
FINAL
ESR08-001
Exploratory Study
Report (ESR)
EP94
Pharmacokinetic study of peptides 91 and peptide
94 in CD rats Rzhevsky, D. I. FINAL
ESR08-002
Exploratory Study
Report (ESR)
EP94
Effect of naloxone on cardioprotective efficiency
of peptide 94 on CD rats with infarct myocardium
Kustanova GA,
Murashev AN FINAL
ESR08-003
Exploratory Study
Report (ESR)
EP94
Maximum tolerated dose finding test for peptide
91 in mice
Kustanova GA,
Murashev AN
FINAL
ESR08-004
Exploratory Study
Report (ESR)
EP94
Single intravenous cardiovascular study of peptide
91 in CD rats
Kustanova GA,
Murashev AN
FINAL
ESR08-005
Exploratory Study
Report (ESR)
EP94
Maximum tolerated dose finding test for peptide
94 in mice
Kustanova GA,
Murashev AN
FINAL
ESR08-006
Exploratory Study
Report (ESR)
EP94
Single intravenous cardiovascular study of peptide
94 in CD rats
Kustanova GA,
Murashev AN
FINAL
ESR08-007
Exploratory Study
Report (ESR)
EP94
A study of the protective effects of peptides No
91 and 94 on the modelof an infarct myocardium
in CD rats - Peptide preconditioning and fractional
administration of peptides during occlusion
Kustanova GA,
Murashev AN
FINAL
ESR08-008
Exploratory Study
Report (ESR)
EP94
Effect of morphine on cardioprotective efficiency
of peptide 94 on CD rats with acute infarct
myocardium
Kustanova GA,
Murashev AN FINAL
ESR08-009
Exploratory Study
Report (ESR)
EP94
Effect of naloxone on cardioprotective efficiency
of peptide 91 on CD rats with infarct myocardium
Kustanova GA,
Murashev AN FINAL
ESR09-001
Exploratory
Technical Report
(ESR)
EP94
Qualitative RP-HPLC analysis of peptides stability
in saline solution
Dorosh Yo. M, Burov
SV
FINAL
ESR09-002
Exploratory
Technical Report
(ESR)
EP94
Investigation of tested peptides stability in human
and rat blood plasma
Dorosh Yo. M, Burov
SV
FINAL
3 11-03 Study Report
Cardioprotective Effects of Eribis Peptide EP94
in a Rat Model of Ischemia/Reperfusion Injury
Garrett Gross Draft

60. 62CONFIDENTIAL
Morphine cont’
Morphine is regularly used as pre-medications in the pig studies. EP94
exerts its cardioprotective properties despite approx 13-333-fold higher
morphine doses in pigs. However, morphine has not regularly been
used as pre-medication in the explorative rat efficacy (cardioprotection)
studies conducted in Moscow.
MI patients are usually treated with morphine in the emergency room to
reduce pain and anxiety. Thus, one exploratory study in rats has been
conducted to address the possibility of an interaction between EP94
and morphine. This study did not reveal any synergistic, additive or
antagonistic effects of morphine on EP94-induced cardioprotection.
Consequently, EP94 has been used in combination with morphine in the
pig studies to mimic the clinical situation as closely as possible. The
pigs are routinely premedicated with 0.5 mg/kg/hr of morphine.

61. 63CONFIDENTIAL
How is the peptide cleared?
It is anticipated that EP94 is degraded by various endo-
and exo-peptidases in the blood stream. The
degradation products are believed to be excreted in the
urine or partly utilized by the body. This will be verified
by dedicated ADME studies in the near future.

62. 64CONFIDENTIAL
Have you tried the peptide, but without the NO-group, in
your models?
Data from Rodents (cardio protective effect with EP94
(with and without NO)
- Yes see study 257/10
How does nitroglycerin perform in your models?
- Not evaluated
How does nitroglycerin and morphine perform together in
the models? (against EP94)
- Not evaluated
Models where EP94 does not work (MOA)?
- EP94 has been shown to be cardioprotective in all models
tested so far, i.e. 2 different species and in total 5 different
models.

63. 65CONFIDENTIAL
Any cellular assays (all in vitro receptor data (cell lines
over-expression the receptors)) and work performed on
primary cells and specific cell lines that express the
receptors).
Receptor binding to the human opioid receptors (µ,
δ, κ) expressed on CHO and HEK-293 cells.
- Study available during the DD process (Study
Report 08-03).

64. 66CONFIDENTIAL
Speculations on down stream target?
To investigate a possible downstream pathway which
may be mediating the beneficial effect of EP94 we
administered either the sarcolemmal KATP channel
antagonist, HMR 1098, or the mitochondrial KATP
channel antagonist, 5-HD, to rats prior to EP94
administration.
Both antagonists completely abolished the
cardioprotective effect of EP94 which suggests an
important role for the KATP channel as a key mediator
in the pathway by which EP94 reduces infarct size
similar to that seen with a number of other
cardioprotective agents as well as ischemic
preconditioning and postconditioning.

65. 67CONFIDENTIAL
Are the coronary arteries also affected?
Potential effects on coronary arteries have not been
investigated.

66. 68CONFIDENTIAL
Speculations on general cardiovascular
safety of EP94.
• EP94 does not affect blood pressure or heart rate in
anaesthesized animals (rats and pigs) at doses levels
ranging from 20 – 75 µg/kg (cf. pharmacological efficacy
studies)
• EP94 does not have significant effects on blood pressure in
and only a minor and late effect on heart rate in consious
rats at doses of 5-10 mg/kg (ESR08-006).
• The very low doses needed for pharmacological efficacy and
the short t1/2 (approx 40 min) is anticipated to reduce
cardiovascular safety risks to a minimum.

67. 70CONFIDENTIAL
"In-vivo SAR" (opioid component vs. the nitric oxide
effects).
Unknown
Toxicology: Metabolism/metabolites and their
distribution.
No evaluation of metabolites has been performed. It is anticipated
that the bond between amino acid 2 and 3 is susceptible to
proteolytic cleavage and that the major metabolites will contain 2
amino acids each.
ADME will be performed in the near future.

68. 71CONFIDENTIAL
A list of all published patent applications
and patents and their status.
PCT application PD53743CA00 - Novel Enkephalin
Analogues - Eribis Pharmaceuticals AB
EU pat appl. No 07 794 118.5
A “Decision to Grant” will be announced in Q2-2011
Eribis Pharmaceuticals AB owns the IP rights

69. 72CONFIDENTIAL
FTO analysis of key IP ?
FTO analysis has not been performed, however
patentability has been evaluated by third party
patent attorneys.
- statements are in the DD room

70. 73CONFIDENTIAL
Back-up bilder

71. 74CONFIDENTIAL
Chemistry Manufacturing
Control (CMC)

72. 75CONFIDENTIAL
EP 94 – General properties
 Tetrapeptide
 Manufactured by solid phase peptide synthesis
 Lyophilized powder
 Solubility: Good solubility in water
 Stability of drug substance:
 Stable at +4°C for more than 2 years
 Stability of drug product:
 Stable at -18°C, +4°C and 25°C for more than 6 months in saline

73. 76CONFIDENTIAL
Specification
Test Method Specifications
Appearance Visual observation Off-white to yellow powder
Mass spectral analysis EP 2.2.43; ESI M = 571.2 +/- 1.0
Amino acid analysis Pre-column derivatisation
with OPA/Fmoc-Cl
EPA 2.2.56
Gly:1; Tyr:1; Dab:1;
Phe (pNO2).1
RP-HPLC EP 2.2.29 Purity > 98.0% (area%)
Related Impurities by
RP-HPLC
EP 2.2.29 Sum impurities < 2%
Water content Karl Fischer, EP2.5.12 To be reported
Acetate HPLC with UV detection To be reported
Residual TFA HPLC with UV detection < 0.1% (tentative)

74. 77CONFIDENTIAL
Specification cont’d
Test Method Specifications
Residual organic
solvents
GC <USP 467> Individual according to ICH
Q3
Bioburden EP 2.6.12
<USP 61>
Aerobic bacteria < 10 CFU/0.1g
Anerobic bacteria < 10 CFU/0.1g
Yeasts and moulds < 10 CFU/0.1g
Bacterial endotoxins EP 2.6.14 <USP
85>
< 5 EU/mg (tentative)
Net peptide content
(NPC)
by AAA
Pre-column
derivatisation
with OPA/Fmoc-
Cl
EPA 2.2.56
To be reported
Mass balance Calculation
NPC+acetate+wa
ter
To be reported

75. 78CONFIDENTIAL
Lot no HPLC analysis Date
CF 07314 97.7% 26.3.2008
CF 07314 95,8% 11.2.2010
EP 94
 Manufactured by Polypeptide
 Part no: SP080384
 Storage temp: 4°C

76. 79CONFIDENTIAL
EP 94
Lot no HPLC analysis Date
MZ77114 98.9% 07.05.2009
 Manufactured by Polypeptide
 Part no: SP080384B
 Storage temp: 4°C

77. 80CONFIDENTIAL
Drug Product
Stability of EP 94 in Saline
Stability (non- ICH) of EP94, 0.1mg/mL in 9 mg/mL NaCl
(preserved with NaN3 1mg/mL)
Temp Time 0 14 days 2.5 mo 4.5 mo 6 mo
-18°C 96.5 96.5 96.6 96.5
4°C 96.5* 96.5 96.6 96.4 96.2
Ambient 96.6 96.6 96.0 95.5
* Area %

78. 81CONFIDENTIAL
CMC - To do list
 Drug Substance
 Analytical development
 Specification
 Stability ICH
 Manufacturing?
 Drug Product
 Analytical development
 Preformulation
 Interaction with packaging mtr
 Stability ICH
 Manufacturing for tox and clinical
 Regulatory
 IND/CTA chapter

79. 82CONFIDENTIAL
Refererences
1. Thom T, Haase N, et al. Writing Group Members. Heart
Disease and Stroke Statistics--2006 Update.
Circulation; A Report From the American Heart
Association Statistics Committee and Stroke Statistics
Subcommittee; January 11, 2006; 2006.
CIRCULATIONAHA.105.171600.
2. Bishop E. Heart disease may actually be rising;
researchers claim deaths are now being delayed to a
later age group. Wall Street Journal. 1996 November
13, 1996; pB3(W) pB6(E) col 1 (11 col in)
3. Gerber Y, Jacobsen SJ, Killian J, Weston S, Roger VL.
Impact of Participation Bias in a Population-Based
Study of Myocardial Infarction in Olmsted County,
Minnesota, 2002 to 2004. Circulation. 2006;13:e827.

80. 83CONFIDENTIAL
 Herman Krapf, Chied Executive Officer
 Erik Bissessar, Chief Business Officer and Medical Scientific
Liason
 Peter Båvenholm, MD, Ph.D., Ass. Prof. Internal Medicine,
Chief Medical Officer
 Fredrik Röök, Business Development
 Stefan Persson, Ph.D., Pharmacology and Toxicology
 Claes Lundberg, Ph.D., Project Management
Management

81. 84CONFIDENTIAL
BACK-UP SLIDES

82. 85CONFIDENTIAL
Doramectin – Mode of action
• Stimulates theStimulates the release of GABArelease of GABA..
• GABAergic receptors are found at the neuromuscular junction inGABAergic receptors are found at the neuromuscular junction in
nematodesnematodes
• GABAergic receptors are found primarily in the brain ofGABAergic receptors are found primarily in the brain of mammalsmammals..
• This class of compounds pass theThis class of compounds pass the BBB poorlyBBB poorly at therapeutic doses.at therapeutic doses.
• ActivationActivation of GABAergic receptors causes an influx of chloride ions,of GABAergic receptors causes an influx of chloride ions,
hyperpolarization, paralysis of the nervous system andhyperpolarization, paralysis of the nervous system and death of thedeath of the
parasiteparasite..
Why was the EP94 dose range finding study in closed
chest AMI pigs completely absent of cardioprotective
effects? - Cont´d

83. 86CONFIDENTIAL
• DoramectinDoramectin has the pharmacological profile inhas the pharmacological profile in
rats of an anxiolytic/anticonvulsant drug withrats of an anxiolytic/anticonvulsant drug with
GABAergicGABAergic properties (de Souza Spinosa et al,properties (de Souza Spinosa et al,
Comp Biochem Physiol Toxicol Pharmacol. 2000,Comp Biochem Physiol Toxicol Pharmacol. 2000,
127:359-66).127:359-66).
• GABAergic neurons co-express mu-opioidGABAergic neurons co-express mu-opioid
receptorsreceptors in the CNS of rats (Kalyuzhny et al,in the CNS of rats (Kalyuzhny et al,
Neuroreport 1997, 8:3367-72; Kalyuzhny et al JNeuroreport 1997, 8:3367-72; Kalyuzhny et al J
Comp Neurol 1998, 392:528-47).Comp Neurol 1998, 392:528-47).
• GABAergic and opioidergic systems are closelyGABAergic and opioidergic systems are closely
linkedlinked. Mu-opioid receptor KO mice down-. Mu-opioid receptor KO mice down-
regulates GABA-gated chloride channel bindingregulates GABA-gated chloride channel binding
sites (Tien et al., Neurochem Res. 2007, 32:1891-sites (Tien et al., Neurochem Res. 2007, 32:1891-
1897).1897).
Possible interactions points between Doramectin and EP94
- GABA and mu-opioid receptors -
Doramectin may interact with the cardioprotective effect of EP94
through GABAergic neurons in the CNS expressing mu-receptors.
Why was the EP94 dose range finding study in
closed chest AMI pigs completely absent of
cardioprotective effects? - Cont´d
CTOP = selective mu-antagonist
0,00
10,00
20,00
30,00
40,00
50,00
60,00
70,00
Vehicle
EP94 (1 ug/kg)
CTOP (0.1 mg/kg)
CTOP+EP94
IS/AAR(%)
N = 9 N = 10 N = 9 N = 9
***

84. 87CONFIDENTIAL
• Avermectin (analogue to doramectin) hasAvermectin (analogue to doramectin) has
been reported tobeen reported to block LPS-inducedblock LPS-induced
secretion of NOsecretion of NO, prostaglandin E2, and to, prostaglandin E2, and to
increase the intracellular concentration ofincrease the intracellular concentration of
Ca (Viktorov et al, Bull Exp Biol Med. 2003,Ca (Viktorov et al, Bull Exp Biol Med. 2003,
136:569-71; Zhang et al, Int136:569-71; Zhang et al, Int
Immunopharmacol. 2009, 9: 354-359).Immunopharmacol. 2009, 9: 354-359).
• Ivermectin (analogue of doramectin)Ivermectin (analogue of doramectin)
inhibits mRNA and protein expression ofinhibits mRNA and protein expression of
iNOSiNOS and COX-2 enzymes (Zhang et al, Intand COX-2 enzymes (Zhang et al, Int
Immunopharmacol. 2009, 9: 354-359).Immunopharmacol. 2009, 9: 354-359).
• Ivermectin at therapeutic dosesIvermectin at therapeutic doses increasesincreases
the plasma NO levels in rabbitsthe plasma NO levels in rabbits (Atakisi et(Atakisi et
al, Eur Rev Med Pharmacol Sci. 2009,al, Eur Rev Med Pharmacol Sci. 2009,
13:425-429).13:425-429).
Doramectin may interact with the cardioprotective effect of EP94 through
NO/iNOS/eNOS pathways.
Why was the EP94 dose range finding study in
closed chest AMI pigs completely abscent of
cardioprotective effects? - Cont´d
0,00
10,00
20,00
30,00
40,00
50,00
60,00
70,00
Vehicle
EP94 (1 ug/kg ipx2) - 24-h
1400W (0.1 mg/kg iv) - Acute
1400W (acute) + EP94 (acute)
EP94 (24-h) + 1400W (24-h)
IS/AAR(%)
** **
Possible interactions points between Doramectin and EP94
- NO and NOS -

85. 88CONFIDENTIAL
• ATP dependent P-glycoproteinATP dependent P-glycoprotein (mediates(mediates
multidrug resistance) is inhibited bymultidrug resistance) is inhibited by
doramectin.doramectin.
• Binds and activatesBinds and activates ATP-gated purinergicATP-gated purinergic
P2X receptorsP2X receptors (Priel at al., J Gen Physiol.(Priel at al., J Gen Physiol.
2004, 123:281-293; www.tocris.com)2004, 123:281-293; www.tocris.com)
• Binds and activatesBinds and activates αα7 nicotinic7 nicotinic
acetylcholine receptorsacetylcholine receptors ((www.tocris.comwww.tocris.com))
• Binds and modulatesBinds and modulates glutamate-activatedglutamate-activated
chloride channels (chloride channels (www.tocris.comwww.tocris.com))
• Binds and modulatesBinds and modulates GABA-activatedGABA-activated
chloride channelschloride channels ((www.tocris.comwww.tocris.com))
• PotentiatesPotentiates glycine-gated currentsglycine-gated currents
(www.tocris.com(www.tocris.com))
Doramectin is a positive allosteric modulator (PAM, indirect activation of receptors).
An interaction with the cardioprotective effect of EP94 through ion channels such as KATP
channels or unspecific mitochondrial permiability transition pores can not be excluded.
Why was the EP94 dose range finding study
in closed chest AMI pigs completely abscent
of cardioprotective effects? - Cont´d
Possible interactions points between Doramectin and EP94
- ATP-gated ion channels and other ion channels-
0,00
10,00
20,00
30,00
40,00
50,00
60,00
70,00
Vehicle
EP94
(1
ug/kg)
HM
R
1098
(6
m
g/kg)
HM
R
1098
+
EP94
5-HD
(10
m
g/kg)
5-HD
+
EP94
IS/AAR(%)
N = 9 N = 9N = 9N = 10 N = 9 N = 9
***
HMR 1098 = sarcolemmal KATP channel antagonist
5-HD = mitochondrial KATP channel antagonist

86. 89CONFIDENTIAL
Doramectin – The next step
Outline of study addressing the possibility of an
interaction between EP94 and Doramectin
• Species – rat due to backlogs in the pig facility
• Animal model – traditional rat MI model
• Study groups - Vehicle
- EP94 (1 ug/kg; i.v.)
- EP94 (1 ug/kg; i.v.) + Doramectin (intermediate, tbd)
- EP94 (1 ug/kg; i.v.) + Doramectin (high, tbd)
• Study to be commenced: July 2011
• Study site: Sahlgrenska University Hospital, Gothenburg, Sweden