There was one event of possible concern that has been reported to the Food and Drug Administration. An alirocumab-treated patient was diagnosed with Miller Fisher syndrome, a rare variant of Guillain-Barre syndrome, at week 27 after a prodromal severe gastroenteritis. At week 24, just 3 weeks earlier, the patient had an LDL of 1.5 mg/dL. The double vision and other symptoms of Miller Fisher syndrome resolved completely after treatment discontinuation.
During a panel discussion of the ODYSSEY clinical trial series, which includes 14 phase III studies, Dr. Henry N. Ginsburg predicted that further experience will eventually show that the dramatic LDL-lowering achieved with alirocumab not only doesn’t promote neurocognitive dysfunction, but actually protects against it.
“I think an important point to make is that, despite our neurology colleagues having tried for about a decade to completely separate the clinical phenotype of Alzheimer’s disease from vascular dementia, we all know that if you have both you’ll do much worse. So if we reduce cerebrovascular atherosclerosis and you have any predisposition to Alzheimer’s disease, you’ll do better. I think there will be studies to show that,” said Dr. Ginsburg, professor of medicine and director of the Irving Institute for Clinical and Translational Research at Columbia University in New York, who earlier in the session presented the findings from the phase III ODYSSEY High FH trial.
Another potential safety concern emerged during Dr. Dean J. Kereiakes’ presentation of the results of the phase III ODYSSEY Combo I study. Thirteen of 199 alirocumab-treated patients (6.6%) developed treatment-emergent, low-titer antialirocumab antibodies. The median time to their detection was 12 weeks. Four of the 13 patients had neutralizing antibodies, and all 4 became antibody negative by 24 weeks.
The presence of these antidrug antibodies had no discernible effect on treatment safety or efficacy. However, Combo I was a 52-week study. Whether the prevalence of these antibodies will increase over time and interfere with what is expected to be lifelong treatment is an unanswered question, noted Dr. Kereiakes, medical director for the Christ Hospital Heart and Vascular Center, Cincinnati.
Discussant Dr. Joshua W. Knowles, medical director of the FH Foundation, commented that “it’s really incredible to see the reductions in LDL that we’re getting with PCSK9 inhibitors in FH patients, the vast majority of whom require more than two standard medications to get to optimal LDL cholesterol levels.”
“The PCSK9 inhibitors are really the poster child for drug discovery in the modern genetic era. It has been a beautiful 10-year journey for them,” declared Dr. Knowles, a cardiologist at Stanford (Calif.) University.
In light of the powerful LDL-lowering effect of these agents, it’s not too soon to start thinking about how to carry out studies of atherosclerotic plaque stabilization and/or regression in treated patients, he added.
Other PCSK9 inhibitors in phase III clinical trials, besides alirocumab, are Amgen’s evolocumab and Pfizer/Renat’s bococizumab. In addition, Eli Lilly’s LY3015014 is in phase II studies, as is Roche/Genentech’s RG7652.
The ODYSSEY studies are funded by Sanofi and Regeneron Pharmaceuticals. Dr. Robinson, Dr. Ginsburg, and Dr. Kereiakes reported serving as consultants to those and other pharmaceutical companies.