A Phase IIb trial of CSL Behring’s post-heart attack protection candidate met its co-primary safety endpoints. The result, when paired to data supporting the mechanism of action, prompted CSL to start looking toward a Phase III trial, despite the drug failing to best placebo in a secondary efficacy endpoint.
CSL enrolled 1,258 patients in the clinical trial and randomized them to receive one of two doses of its intravenous formulation of plasma-derived apolipoprotein A-I (apoA-I) or a placebo. The participants had all had heart attacks in the week preceding enrollment in the study. More than 90% of the subjects received all four planned infusions of CSL112 or the placebo.
The main goal was to assess changes in drug-induced liver injury and renal status in the 29 days after the first infusion. On these measures, which were the co-primary endpoints of the study, incidence rates for both cohorts of CSL112 patients were comparable to the placebo arm. That resulted in the trial meeting its primary endpoint.
CSL112’s performance against a secondary efficacy endpoint was less conclusive. CSL tracked the time-to-first occurrence of a major adverse cardiovascular event, such as a heart attack or stroke. The endpoint could have suggested CSL112 protects patients in the dangerous 30-day period following a heart attack, but CSL found “the risk ... among the groups was similar.”
CSL is now hoping an adequately-powered Phase III trial will show CSL112 cuts the risk of major cardiovascular adverse events. The company’s belief in CSL112 is underpinned by understanding of its mechanism of action.
ApoA-I, a key component in high-density-lipoprotein, clears cholesterol from arterial plaque. As such, apoA-I-based CSL112 could stabilize plaque lesions by removing cholesterol, cutting the risk the build up will trigger another cardiovascular event. Cholesterol efflux capacity measures how effectively apoA-I removes cholesterol.
In the Phase IIb trial, participants in the CSL112 cohorts experienced “increases in apoA-I and ex vivo cholesterol efflux similar to that achieved in patients with stable coronary artery disease.” The data suggest to CSL that the formulation can improve outcomes by increasing cholesterol efflux capacity.
Multiple other drugmakers have tried assorted approaches to prevent cardiac events and tissue damage in the period following a heart attack, but the field has racked up more failures than successes. GlaxoSmithKline set out to run a 25,000-patient Phase III trial of its p38 inhibitor, only to scrap that plan after an interim analysis of 3,503 failed to show the drug cut incidence of cardiovascular events. NeuroVive Pharmaceutical and Zealand Pharma have also tried and failed to help heart attack patients.