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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.
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20090417
Conflict of Interest Clinical Advisory Board, Ischemix
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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%
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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)
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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)
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20090417
The SUPPORT 1 Study
Safety and Efficacy of CMX-2043 in Subjects Undergoing PCI and Peri-Operative Reperfusion Treatment
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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
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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
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20090417
SUPPORT-1 Sites and Investigators
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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
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20090417
SUPPORT-1 Baseline Characteristics
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SUPPORT I: Arteries Stented Per Rx Group
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Primary Endpoint:24 Hr CK-MB Change from Baseline
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20090417
24 Hr CK-MB Change From Baseline (ng/mL)
CMX-2043 treatment
p=0.05vs. Placebo
p = 0.05
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20090417
24 Hr Troponin T Change from Baseline
CMX-2043 treatment
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20090417
24 Hr Peri-Procedural MI by CK-MB >X3 ULN
CMX-2043 treatment
p=0.024vs. Placebo
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20090417
24 Hr Peri-Procedural MI by Troponin T >X3 ULN
CMX-2043 treatment
p=0.050vs. Placebo
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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%)
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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
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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