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 gamma secretase functions—but not to shut the enzyme down all together. “It affects amyloid processing but leaves Notch processing alone,” Been says.
The Phase 1 trial will test multiple doses of EVP-0962 in healthy volunteers to determine its safety profile. EnVivo expects to finish the trial by the end of the year and hopes to start Phase 2 trials to determine the drug’s effectiveness in 2012.
EnVivo will probably need to find a Big Pharma partner to take the drug all the way through the clinical-trial process, Been says. “We’ll have to dose patients for a long time to test for disease modification. That’s the only way to separate the natural decline in Alzheimer’s from the effect of the treatment,” Been says. “But that’s a long and expensive affair.”
For now, EnVivo has the benefit of patient investors, Been says. In 2008, Fidelity Biosciences poured $65 million into the company in a Series D, buying out all of the previous investors, which included BCM Technologies, Cogene Ventures, and NeuroVentures Capital. EnVivo and Fidelity BioSciences are now developing a funding plan to get the startup through the next few years, Been says.
In addition to moving EVP-0962 through the clinic, EnVivo is continuing to explore a class of drugs known as alpha-7 agonists. The company’s lead compound, EVP-6124 seems to improve cognitive functioning in both Alzheimer’s and schizophrenia. It works by enhancing the transmission between synapses in the brain. EnVivo recently announced positive Phase 2 results from a trial in schizophrenia, and it expects to release Phase 2 results in Alzheimer’s next year.
EnVivo also has a number of novel molecules in its early-stage pipeline, including two that Been hopes will make it into clinical testing by the end of the year or early next year. “Our strategy is to build a broad pipeline,” he says. When it comes to diseases of the nervous system, he adds “We’re not believers in only one mechanism.”
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