MC-1 shows promise in reducing MI post-CABG, lowering BP
Shelley Wood
December 8, 2005 Winnipeg, MA - MC-1, a metabolite of vitamin B6, may reduce the risk of MI following CABG surgery, early results from the MC-1 to Eliminate Necrosis and Damage in CABG (MEND-CABG) study suggest. The 30-day primary-end-point results were released this week during a conference call hosted by the drug developer, Medicure Inc (Winnipeg, MA).
Full results of the 90-day study, including safety information, will not be made public until early next year, although company representatives said yesterday that unblinded review of the results by the data safety and monitoring committee halfway through the trial showed "no signals of concern."
MC-1 is also being tested in combination with lisinopril (dubbed MC-4232) in the phase 2 MC-1 and ACE Therapeutic Combination for Hypertensive Diabetics (MATCHED) study, the results of which were also recently released by the company. MC-1 plus lisinopril reduced systolic and diastolic blood pressure in these patients to a greater degree than lisinopril alone and positively affected glucose control.
To renalwire, MEND-CABG lead investigator Dr Jean Tardiff (Montreal Heart Institute, QC) explained that MC-1 is a naturally occurring small molecule believed to protect cardiomyocytes from ischemic reperfusion injury by inhibiting ATP-induced calcium influx. The agent has also been studied in the phase 2 MEND-1 study of patients undergoing PCI.
Mending the heart MEND-CABG was a 901-patient study designed to demonstrate the clinical efficacy of MC-1 during and after CABG, as well as identify the appropriate dose. As such, patients at 42 centers were randomized to a 250-mg dose, a 750-mg dose, or placebo before undergoing CABG, then maintained on this dose or placebo for 30 days postsurgery. The primary end point of the study is a combination of death, MI, and stroke at 30 days, while the secondary end point?for which results have not yet been released?is reduction in death, MI, and stroke at day 90, difference in CK-MB area under the curve between 0 and 24 hours, and neurological protection.
As Medicure spokespeople revealed during a webcast presentation, the 250-mg dose emerged as the more effective dose of MC-1. This dosage reduced the composite primary end point of death, nonfatal MI (defined as peak CK-MB >50 ng/mL), and nonfatal stroke by 14%, compared with placebo, although this result was not statistically significant. When MI was redefined by a CK-MB >100 ng/mL, however?a definition in keeping with major recent trials, such as PRIMO-CABG?the reduction in death, MI, and stroke was a statistically significant 37.2%.
Medicure president and CEO Dr Albert D Friesen explained that the >50-ng/mL definition was chosen for the phase 2 study as the most conservative estimate of MI but ultimately yielded too much "noise" to distinguish a difference in true MI between the two groups.
Assessed in isolation, nonfatal MI as defined by peak CK-MB >100 ng/mL was reduced by 46.9% compared with placebo (p=0.008).
Tardiff, speaking during the webcast, acknowledged that the >100-ng/mL definition might be "a more reasonable cut-off value" than the >50-ng/mL definition. Elaborating in an interview with renalwire, Tardiff pointed out that in the recent GUARDIAN study, six-month mortality for patients following CABG was 8% for patients with a CK-MB between 50 and 100 ng/mL, whereas it was 20% for patients with a CK-MB greater than 100 ng/mL, suggesting that the >100-ng/mL definition might be more clinically meaningful.
"I would anticipate the company would pursue a phase 3 study using the >100-ng/mL definition of MI," Tardiff commented.
Moreover, as Tardiff highlighted in the press conference, the higher cut point also mirrored clinically reported MI: the 250-mg dose of MC-1 was associated with a 78.7% reduction in physician-diagnosed myocardial infarctions vs placebo (p=0.0065).
MC-1/ACE-inhibitor combo also promising In the MATCHED study, 120 patients with coexisting type 2 diabetes and hypertension were randomized in a crossover, double-blind fashion to a 100-, 300-, or 1000-mg dose of MC-1 alone and in combination with 20 mg of lisinopril, or placebo, for eight weeks before being switched to a different treatment arm for an additional eight weeks. At follow-up, the 300-mg MC-1 dose combined with 20-mg lisinopril produced greater reductions in diastolic and systolic blood pressure than lisinopril alone. Patients taking the combination agent also experienced improvements in primary and secondary metabolic end points, including glycemic control, as measured by fasting serum glucose and glycated hemoglobin, as well as lipid control, after 16 weeks of treatment. Notably, the 300-mg MC-1/20-mg lisinopril and 1000-mg MC-1/20-mg lisinopril doses of MC-4232 demonstrated comparable clinical efficacy for both the hypertensive and metabolic end points, without raising any red flags for safety or drug intolerance. Principal investigator for the MATCHED trial was Dr Yves Lacourciere (Universit¿ Laval Saint-Foy, Quebec, QC).
The company is moving ahead with plans for a phase 3 study of this combination agent.
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