When Eli Lilly stopped developing an Alzheimer’s compound a year ago due to side effects and lack of effectiveness, some experts expressed doubt about a similar drug being developed by Watertown, MA-based EnVivo Pharmaceuticals. Those doubts may have intensified last week, when pharmaceutical giant Lilly released more data on the drug, called semagacestat, which is in a drug class known as gamma secretase inhibitors. During the Alzheimer’s Association International Conference in Paris, a senior medical director for Lilly said patients taking semagacestat experienced worse cognitive functioning than did patients taking the placebo—even seven months after they stopped taking the drug.
But EnVivo CEO Kees Been, who spoke to Xconomy just before the conference, is undeterred. EnVivo moved its own gamma secretase-targeting drug, EVP-0962, into Phase 1 testing on June 27. In animal trials, the company says, the drug reduced brain inflammation caused by Alzheimer’s, reversed behavioral defects, and appeared to have a better safety profile than gamma secretase inhibitors.
Gamma secretase is an enzyme that contributes to the buildup of amyloid plaques in the brain—a major feature of Alzheimer’s. Problem is, says Been, “gamma secretase is a very pluripotent enzyme,” meaning it serves many functions in the body. “If you inhibit it, you can create all kinds of side effects.”
For example, gamma secretase is critical for the processing of a protein called Notch, which controls cell differentiation and communication. By inadvertently inhibiting Notch, semagacestat may have touched off the severe gastrointestinal side effects seen in some Lilly patients, Been says. Participants in Lilly’s trial also faced a higher risk of developing skin cancer.
The difference between Lilly’s and EnVivo’s compounds is that EVP-0962 is a gamma secretase modulator, not an inhibitor. That means it was designed to target certain
