20090417

A Prospective Randomized Trial of CMX-2043, a Lipoic Acid-Based Cytoprotectant,

In Patients Undergoing Elective PCI: Primary Results of the SUPPORT-1 Trial

Mitchell W. Krucoff, C.K. Ponde, Jagdish Hiremath, Mullasari Ajit, Eddison Ramsaran, Manesh R. Patel, Alan S. Lader,

F. Howard Schneider, Reinier Beeuwkes, C. Michael Gibson, and James E. Tcheng.

20090417

Conflict of Interest Clinical Advisory Board, Ischemix

20090417

Incidence & Implications of Peri-Procedural MI:A Controversy of Definitions & Pathophysiology

Resolute All Comers 2,121 patients

Incidence: 3.6-17.8%

3 yr mortality: 2-8%

20090417

PCI: A Human Laboratory for Cytoprotection PCI produces enzymatic

events Selected protein elevations

(CPK-MB, Troponin) represent myocellular necrosis

PCI as a laboratory for RCT of cytoprotective strategies has FDA predicate (vitamin B6 metabolite pyridoxal-5’-phosphate monohydrate (MC-1) in the MC-1 to Eliminate Necrosis and Damage (MEND-1)

20090417

CMS-2043: A Novel Molecular Entity to Inhibit Ischemic Apoptosis

• Reactive oxygen species (ROS) anti-oxidant, AND

• Activates Akt (Ak mouse thymoma = Protein kinase B) via tyrosine kinase (TK)

20090417

The SUPPORT 1 Study

Safety and Efficacy of CMX-2043 in Subjects Undergoing PCI and Peri-Operative Reperfusion Treatment

20090417

SUPPORT-1: Study Design Phase IIa Safety & Efficacy: CMX-2043 Prospective, randomized 3:1

• 3 doses (0.8, 1.6 & 2.4 mg/kg) vs placebo Multi-center (N=6) Elective PCI Patients

• WNL biomarkers & Non-acute ECG• Receiving single stent of ≥ 18 mm or multiple stents

Primary Outcome Measures:• Incidence of CK-MB elevation <24 hours following

PCI• Change in cardiac biomarkers <24 hrs following PCI

CK-MB, Troponin T Secondary Outcome Measure: MI as >X3 peak CPK

20090417

SUPPORT-1 Exclusion Criteria Acute/unstable angina MI within 14 days Coagulopathy Clinical valvular disease Clinical peripheral vascular disease TIA, stroke or IC bleed within 90 days Creatinine level ≥ 1.5 times ULN

20090417

SUPPORT-1 Sites and Investigators

20090417

SUPPORT I: Patient Accrual/Randomization

Total patients enrolledN=142

0.8 mg/KgN= 36

1.6 mg/KgN= 35

PlaceboN= 35

2.4 mg/KgN= 36

0.8 mg/Kg(100%)

1.6 mg/Kg(97.1 %)

2.4 mg/Kg(100%)

Placebo(100%)

1 subject withdrawn

20090417

SUPPORT-1 Baseline Characteristics

20090417

SUPPORT I: Arteries Stented Per Rx Group

20090417

Primary Endpoint:24 Hr CK-MB Change from Baseline

20090417

24 Hr CK-MB Change From Baseline (ng/mL)

CMX-2043 treatment

p=0.05vs. Placebo

p = 0.05

20090417

24 Hr Troponin T Change from Baseline

CMX-2043 treatment

20090417

24 Hr Peri-Procedural MI by CK-MB >X3 ULN

CMX-2043 treatment

p=0.024vs. Placebo

20090417

24 Hr Peri-Procedural MI by Troponin T >X3 ULN

CMX-2043 treatment

p=0.050vs. Placebo

20090417

SUPPORT-1 Adverse Events Summary

Category0.8 mg/kg (N = 36)

1.6 mg/kg (N = 35)

2.4 mg/kg(N = 36)

Placebo(N = 34)

Any AEs 7 ( 19.44%) 14 ( 40.00%) 11 ( 30.56%) 10 ( 29.41%)

Drug Related AEs 0 ( 0.00%) 3 ( 8.57%) 1 ( 2.78%) 2 ( 5.88%)

Serious AEs 1 ( 2.78%) 2 ( 5.71%) 1 ( 2.78%) 0 ( 0.00%)

AEs leading to Study discontinuation

0 ( 0.00%) 1 ( 2.86%) 0 ( 0.00%) 0 ( 0.00%)

Deaths 0 ( 0.00%) 0 ( 0.00%) 0 ( 0.00%) 0 ( 0.00%)

20090417

SUPPORT I: Limitations

Serum marker elevations with elective PCI have biochemical relevance for NME testing vs. human apoptosis, however the clinical relevance of these findings is unproven

20090417

SUPPORT I Primary Results: Conclusions SUPPORT I was a prospective, randomized,

multicenter Phase IIa dosing study of protection from PCI-induced myonecrosis by CMX-2043 infusion

All doses of CMX-2043 studied (0.8, 1.6 and 2.4 mg/kg) appeared safe in this population

High dose (2.4 mg/kg) infusion of CMX-2043 was associated with statistically significant reduction of serum markers of myonecrosis and MI defined by >3X elevation above ULN

Results of SUPPORT I suggest the basis for further study and a Phase III study design