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1 subject withdrawn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