Illustration courtesy of CatPiper
Failing toward success
In today’s issue of The New England Journal of Medicine (NEJM), a team of scientists, including Paul Aisen, MD, professor of neuroscience and director of the Alzheimer’s Disease Cooperative Study, issued a sort of post-mortem on semagacestat, a small-molecule gamma-secretase inhibitor that drug developer Eli Lilly hoped would prove to be an effective treatment for Alzheimer’s disease (AD).
Existing drugs used to treat AD (and most of those in development) attempt only to slow progression of the neurodegenerative disease, and often with barely perceptible benefit. Actually curing or preventing AD, which afflicts roughly one in eight Americans over the age of 65, remains but a distant hope.
Semagacestat was never deemed a cure, but it had promise, based upon animal models that suggested the drug might effectively block the proteolysis or breakdown of amyloid precursor protein, a necessary ingredient of the neuron-killing plaques that characterize AD.
But the drug proved problematic in clinical test and, in the NEJM paper, Aisen and colleagues describe in great detail why semagacestat’s phase 3 clinical trial (typically the final stage before market approval) was halted in 2010.
Rather than improve the condition of Alzheimer’s patients, semagacestat seemed to make things worse. In comparisons of cognitive status, patients taking semagacestat fared no better than those taking a placebo. Patients who took higher doses of semagacestat experienced significant worsening of their functional abilities. They also lost more weight and had higher rates of skin cancer and infection.
For Alzheimer’s patients and their caregivers, the demise of semagacestat was a blow, further evidence of the frustrating complexities and difficulties of AD. It has been more than a decade since memantine, the last AD drug to be successfully tested and approved.
But hope endures, and a battle lost can still help win the war.
Aisen said efforts to develop semagacestat helped further collaboration between industry and academia, a partnership that will be vital to any eventual success. More to the point, lessons were learned.
“Additional papers on the semagacestat study will follow,” Aisen said, “advancing our understanding of biomarkers and their relationship to drug mechanisms.”
Elsewhere, prospects look brighter.
“We are now launching a new paradigm of AD drug development: testing anti-amyloid therapies at the asymptomatic stage of AD,” Aisen said. “The first such trial, the ADCS A4 study (Anti-Amyloid treatment in Asymptomatic Alzheimer’s) will begin by the end of this year. This new approach, enthusiastically endorsed by the FDA, is a big step toward achieving effective therapy.”