August 31st, 2014
Preliminary Outcomes Results For PCSK9 Inhibitor
Amid a slew of new data demonstrating yet again that PCSK9 inhibitors lower LDL cholesterol—drastically and in a wide variety of different patient populations—data from one trial offers the first suggestion that the drugs may in fact improve cardiovascular outcomes. But the analysis, the authors cautioned, is a post-hoc analysis of a trial neither designed nor powered to study outcomes, so should be considered preliminary and speculative at best.
Four phase 3 trials with the Sanofi and Regeneron PCSK9 inhibitor alirocumab (pronounced “allee rock you mab” by Chris Cannon at a news conference) were presented today at the European Society of Cardiology meeting in Barcelona. The outcomes data was derived from the ongoing Odyssey Long Term trial, which is evaluating the long-term safety and efficacy of alirocumab in 2,341 high risk patients already taking statins and other lipid-lowering therapies. The results of Odyssey Long Term were presented by Jennifer Robinson.
In the post-hoc safety analysis, after a mean followup of 65 weeks the rate of cardiac death, MI, stroke, and unstable angina requiring hospitalization was 1.4% in the alirocumab group compared to 3% in the placebo group. This is the same composite endpoint that is being used in the ongoing 18,000 patient ODYSSEY Outcomes trial. In total there were 46 endpoint events. In the panel discussion following the trial’s presentation, Robert Califf urged caution when interpreting data like this with less than 100 events. Until the completion of the large outcomes trial, Califf said, it will be “a tough question” for regulators to decide how to handle this information.
Alirocumab was generally well tolerated. The company had previously disclosed that the FDA had asked about the potentially serious issue of neurocognitive disorders associated with alirocumab. The rate of events in Odyssey Long Term of neurocognitive disorders was 1.2% in the alirocumab group versus 0.5% in the placebo group. A Regeneron spokesperson said that the company has not released the overall pooled analysis across 10 phase 3 trials, but that “it was balanced between groups.”
As expected, alirocumab was highly effective at lowering LDL cholesterol. At 24 and 52 weeks, LDL was reduced by 61% and 57%, respectively, in the alirocumab group compared with a 1% increase and a 4% increase in the placebo arms. These differences were of course highly significant.
Three additional trials helped confirm the cholesterol-lowering effectiveness of alirocumab. In the ￼ODYSSEY COMBO II trial, 720 patients at high risk despite maximally-tolerated statin therapy received either alirocumab or ezetimibe. At 24 weeks, Chris Cannon reported, LDL was reduced by 51% in the alirocumab group versus 21% in the ezetimibe group.
In the ODYSSEY FH I and FH II trials, alirocumab was tested in 738 patients with heterozygous familial hypercholesterolemia. At 24 weeks, according to Michel Farnier, LDL cholesterol was reduced by 49% in each of the the alirocumab groups, compared to a 9% increase and a 3% increase in the placebo groups.
In his remarks, Califf likened the Odyssey trials to the World Cup. Odyssey Combo is equivalent to a successful qualifying match, the Odyssey FH trials are like quarterfinal matches, and Odyssey Long Term is like a semifinal match. But only the final match—the Odyssey Outcome trial—will be able to produce a true winner, said Califf.
A spokesperson said Amgen and Regeneron planned to file for approval in the US and elsewhere in the fourth quarter of 2014.
To view all of our coverage from the ESC meeting, go to our ESC.14 Headquarters page.