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.

Conflict of Interest   Clinical Advisory Board, Ischemix

Incidence & Implications of Peri-Procedural MI: A Controversy of Definitions & Pathophysiology  Resolute All Comers  2,121 patients Incidence: % 3 yr mortality: 2-8%

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  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)

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)

The SUPPORT 1 Study Safety and Efficacy of CMX-2043 in Subjects Undergoing PCI and Peri- Operative Reperfusion Treatment

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

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

SUPPORT-1 Sites and Investigators

SUPPORT I: Patient Accrual/Randomization

SUPPORT-1 Baseline Characteristics

SUPPORT I: Arteries Stented Per Rx Group

Primary Endpoint: 24 Hr CK-MB Change from Baseline

Hr CK-MB Change From Baseline (ng/mL) CMX-2043 treatment p=0.05 vs. Placebo p = 0.05

Hr Troponin T Change from Baseline CMX-2043 treatment

Hr Peri-Procedural MI by CK-MB >X3 ULN CMX-2043 treatment p=0.024 vs. Placebo

Hr Peri-Procedural MI by Troponin T >X3 ULN CMX-2043 treatment p=0.050 vs. Placebo

SUPPORT-1 Adverse Events Summary Category 0.8 mg/kg (N = 36) 1.6 mg/kg (N = 35) 2.4 mg/kg (N = 36) Placebo (N = 34) Any AEs7 ( 19.44%)14 ( 40.00%)11 ( 30.56%)10 ( 29.41%) Drug Related AEs0 ( 0.00%)3 ( 8.57%)1 ( 2.78%)2 ( 5.88%) Serious AEs1 ( 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%) Deaths0 ( 0.00%)

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

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