Amgen and Novartis said today they will expand their two-year-old collaboration with the Banner Alzheimer’s Institute by launching a new Phase II/III trial designed to assess whether the oral beta-site APP-cleaving enzyme-1 (BACE1) inhibitor CNP520 codeveloped by the companies can prevent or delay symptoms in people at high risk for the memory-robbing ailment.

The value of the expanded collaboration was not disclosed.

The new trial—the Alzheimer's Prevention Initiative (API) Generation Study 2 (NCT03131453)—will be a five-year study set to recruit approximately 2000 cognitively healthy participants, ages 60 to 75, deemed to be at high risk of developing Alzheimer's due to their age and their carrying either two copies of the apolipoprotein E (APOE) 4 gene—a major genetic risk factor for late-onset Alzheimer's disease—or one copy of the gene with evidence of elevated brain amyloid.

Primary endpoints include diagnosis of mild cognitive impairment due to Alzheimer’s or dementia due to Alzheimer’s, whichever occurs first during the study, and change in the Alzheimer's Prevention Initiative Composite Cognitive (APCC) test score.

Generation Study 2 started enrolling U.S. patients in August and will eventually include more than 180 sites in more than 20 countries. Patients will be randomized to receive placebo or one of two doses of CNP520 (15 mg or 50 mg).  CNP520 is the lead compound of the Amgen–Novartis neuroscience collaboration launched in September 2015, and also of undisclosed value.

Testing will also determine the participant’s amyloid status, which will be disclosed by qualified medical personnel. Genetic counseling will be provided in person or by phone.

“Through the unique combination of genetic testing and counseling in cognitively healthy adults, the Generation Study 2 exhibits an innovative clinical approach that may offer insight toward Alzheimer's prevention for those at highest risk for developing the disease,” Sean E. Harper, M.D., EVP of R&D at Amgen, said in a statement.

Breakthrough Potential

BACE1 is an enzyme known to play a key role in the production of amyloid-beta, a protein that accumulates in the brains of people with Alzheimer’s years before the onset of clinical symptoms.

“If we determine that our BACE1 inhibitor can prevent or delay the onset of symptoms in healthy yet high-risk populations, this would represent a tremendous breakthrough for those that may face this debilitating disease,” added Vas Narasimhan, M.D., Novartis’ global head of drug development and CMO.

Patients for Generation Study 2 will be recruited via multiple venues—which in the U.S. will include the Alzheimer's Prevention Registry's GeneMatch registry, led by the Banner Alzheimer’s Institute. GeneMatch is a first-of-its-kind program designed to identify a large group of people interested in volunteering for Alzheimer's disease prevention research studies, based in part on their APOE genetic information.

“This approach continues to shift the Alzheimer's research paradigm from reversing disease damage to attacking its root cause before symptoms surface,” stated Pierre N. Tariot, M.D., co-director of the API and director of the Banner Alzheimer’s Institute. “It is our hope that by targeting people earlier, we will have a better chance of delaying or preventing the onset of the disease.”

The new trial differs from Generation Study 1 (NCT02565511), which launched last year and is funded by a $33.2 million NIH grant. The 1340-patient Generation Study 1 is designed to assess whether two investigational anti-amyloid compounds—CNP520 and the Novartis anti-amyloid active immunotherapy CAD106—can prevent or delay Alzheimer’s symptoms among higher-risk cognitively healthy older adults with two copies of the E4 type of the APOE gene, one from each parent.

Roughly one in four people carry a single copy of the APOE4 gene, but only about 2% of the world's population carry two copies.

Drug developers have long struggled to create successful new drugs for the disease. Only a handful of drug successes have ever won marketing approvals, and those treatments have only slowed progression of symptoms by 6–12 months. A 2014 Cleveland Clinic study found a 99.6% failure rate of clinical trials for Alzheimer's drug candidates between 2002 and 2012.

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