Semagacestat for Alzheimer’s Disease

Published - Written by Daniela Lamas

The 80-year-old woman started forgetting nearly a year ago. First, it was little things, car keys and phone numbers. Then she couldn’t remember to shut off the stove. Now, her daughter’s face holds only a glimmer of recognition.

Although the symptoms started just one year ago, the insidious destruction of Alzheimer’s disease must have begun decades before. Then, unbeknownst to our patient, proteins called amyloid-beta peptide plaques had started accumulating silently in her brain’s cortex and hippocampus – beginning the process that, now, renders her unable to recognize her own daughter.

This understanding of the pathogenesis of Alzheimer’s sparked researchers to question whether they could halt the progression of disease with a drug that interferes in production of the faulty protein. While early data were hopeful, results published in this week’s NEJM, “A Phase Three Trial of Semagacestat for Treatment of Alzheimer’s Disease,” show the recently developed drug to actually do more harm than good.

Why was this drug supposed to work?   Researchers believe that accumulated amyloid-beta peptide plaques are at least partially responsible for disease symptoms. These proteins are created from another precursor protein, through the activity of enzymes called beta and gamma secretases. It stands to reason, then, that if researchers could block the activity of one of these enzymes, perhaps they could disrupt the process that causes Alzheimer’s.

To that end, scientists tested an oral agent, called semegacestat, which was designed to inhibit the production of gamma secretase with the goal of reducing the production of beta amyloid. This wasn’t without risk. Gamma secretase isn’t specific to the production of beta amyloid, and might also play a role in other essential cellular processes. But there seemed to be a potential for real benefit.  In an initial phase 1 trial, blood levels of amyloid-beta peptide effectively decreased in healthy volunteers after 14 days of treatment with a low dose of the experimental drug. In studies with higher doses of the drug in patients with Alzheimer’s disease, the blood levels of the peptide decreased, but there was a trade-off. Those treated with the drug had complications with blood clotting and skin reactions. But, the question remained open whether patients with this decimating disease might see some useful clinical benefit. This led way to a phase 3, multinational study.

The study enrolled just over 1,500 patients, all with mild or moderate Alzheimer’s Disease. They were randomly assigned to receive a placebo or the study drug and were tested on their cognitive and functional deficits over 76 weeks. Ultimately, however, the study was stopped early when the reviewers found that the patients receiving the drug declined at a greater rate than those receiving placebo. In addition, those getting the study drug had higher rates of skin cancer and infections. These adverse events did not continue to accumulate after the study drug was stopped.

What can researchers learn from this promising treatment’s failure? In their discussion, Doody and colleagues note that the gamma secretase inhibitor might also interfere with other aspects of cell-to-cell signaling. This could account for some of the adverse effects, like skin cancer and gastrointestinal problems. But, the authors admit frankly that it is a lot  harder to account for the worsened cognitive and functional deficits. As they continue to better understand this unexpected finding, perhaps this drug’s disappointing failure will, somehow reveal new clues in the continuing mystery of Alzheimer’s Disease.