Biotech Tracker News - Treatment Regimen for Pexelizumab Starting to Take Shape
November 19, 2002 Alexion (NASDAQ: ALXN) and Procter & Gamble’s (NYSE: PG) pexelizumab (5G1.1-SC) generated encouraging, preliminary phase II survival data in two ambitious investigations of its therapeutic profile for patients that have had myocardial infarctions (MI, heart attack). Although the data did not demonstrate that pexelizumab administration is associated with a comparative reduction in the size of the infarcted heart muscle, they do suggest that the construct provides a survival advantage to certain recipients.  Earlier phase IIb data had shown that pexelizumab could contribute to a reduced incidence of the accelerated cognitive dysfunction frequently observed following coronary artery bypass grafting (CABG). In the CABG setting, fewer pexelizumab recipients, compared to placebo recipients, lost visual and spatial recognition and integration skills. Trends toward global cognitive preservation existed over multiple parameters. Given these new survival data, our modeling estimates pexelizumab’s probability of FDA approval at 60-70%.  Duke Clinical Research Institute investigator, Dr. Christopher Granger presented the data from the COMMA and COMPLY trials at the American Heart Association scientific sessions in Chicago.  COMMA (Complement Inhibition in Myocardial Infarction Treated with PTCA) assessed pexelizumab for acute MI patients who underwent primary percutaneous transluminal coronary angioplasty (PTCA). Although pexelizumab did not achieve its primary endpoint of infarct size reduction at 72 hours, one of its dosing schedules was associated with a dose-dependent, statistically and clinically significant 70% reduction in 90-day mortality (1.8% versus 5.9%, p=.014). The investigation was conducted with the concomitant use of other appropriate coronary artery reperfusion and revascularization strategies such as aspirin, coronary stents, gpIIb/IIIa blockers, and beta-blockers.  COMMA is an 814 angioplasty patient, randomized, double-blind investigation in which study subjects receive either pexelizumab 2.0 mg/kg, bolus pexelizumab 2.0 mg/kg followed by a 20 hour infusion at 0.05 mg/kg/hr, or placebo. The mortality benefit with pexelizumab bolus/infusion observed at 90 days was maintained through 180 days, at which time it was associated with a 57% relative mortality reduction compared to placebo (3.2% versus 7.4%, p=0.035). The construct’s adverse effect profile was not only reassuring, but the incidence of cardiogenic shock was also significantly lower for pexelizumab bolus/infusion recipients (2.8% versus 5.2%, p=0.19) compared to placebo.  COMPLY (Complement Inhibition in Myocardial Infarction Treated with Thrombolytics) assessed pexelizumab for MI patients treated with thrombolytics. Again, pexelizumab did not achieve its primary endpoint of infarct size reduction at 72 hours. COMPLY is a 920-patient, randomized, double-blind investigation in which study participants were similarly grouped. 90-day mortality was not reduced in this trial. However, subset analyses suggested that North American pexelizumab recipients achieved a survival advantage. Again, it was the bolus/infusion strategy that was associated with survival benefit. Recipients of bolus/infusion experienced a 55% reduction in 90-day mortality (2.8% versus 6.3%, p=.019) compared with placebo recipients. In the entire cohort, not only was pexelizumab’s adverse effect profile reassuring, but it was also associated with a decreased risk of stroke (1.4% versus 2.6%) compared to placebo.  The aggregate results to date suggest that pexelizumab-associated mortality risk reduction is not associated with infarct size reduction. Ongoing studies will need to clarify this issue, but inhibition of complement-mediated inflammation is the most likely process at work. The precise mechanisms behind the disconnect between anti-inflammation and infarct size will also need to be worked out. Also, the risk reduction seen with co-administration of thrombolytics will have to be clarified with a larger sample size at least in the North American population. That population may have been more amenable to pexelizumab, or any other therapy, due to key differences in both the degree of cardiac pathology and the availability of revascularization options available for North American, Eastern European and South American populations.  Pexelizumab is an anti-C5 monoclonal antibody fragment. Alexion and Procter & Gamble have initiated a phase III pexelizumab investigation in cardiopulmonary patients, and are continuing to evaluate patients and data from these large phase II studies in acute myocardial infarction patients. In mid-February, Alexion initiated enrollment in a pivotal phase III clinical trial of pexelizumab in approximately 3,000 patients undergoing coronary artery bypass graft (CABG) surgery on cardiopulmonary bypass (CPB). The trial is called the Pexelizumab for Reduction in Infarction and Mortality in Coronary Artery Bypass Graft Surgery (“PRIMO-CABG”) trial. Alexion and Procter & Gamble have designed the trial to assess the safety and efficacy of pexelizumab in reducing the composite endpoint of the incidence of death and myocardial infarction patients undergoing CABG on CBP.
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