At the Alzheimer Association International Conference in Copenhagen, Denmark, on July 15, researchers from the Banner Alzheimer's Institute in Phoenix introduced Novartis Pharmaceuticals Corporation as their partner in the upcoming Alzheimer's Prevention Initiative ApoE4 trial. Banner will work with the Swiss pharmaceutical company to test experimental therapies in people who carry two copies of the ApoE4 allele, the major genetic risk factor for late-onset Alzheimer's disease. The study complements the API ADAD trial, which will test the anti-Aβ antibody crenezumab in otherwise healthy people who carry an autosomal-dominant AD mutation and typically begin to show signs of the disease by age 50 (see May 2012 conference news). "We are excited about the chance to evaluate promising preclinical AD treatments in those at risk for developing AD at older ages," said Eric Reiman, who leads API together with Pierre Tariot and Jessica Langbaum at Banner. "We previously argued that now is the time to launch a new era in Alzheimer’s prevention research—one in which we could efficiently test the range of preclinical AD treatments and find those that work,” he said. Reiman told Alzforum that he believes that new era has arrived.
Since the API APOE4 trial was announced, researchers in the field have wondered who the industry partner would be and what intervention would be tested (see Sep 2013 community news). The choice of Novartis came after a long vetting process. It provides the opportunity to test two anti-amyloid treatments, rather than the one originally envisaged, in a study that is about twice as large as originally planned. Cognitively normal volunteers aged 60 to 75 will be randomized to placebo, an Aβ vaccine, or a β-secretase inhibitor. Full details are yet to emerge. CAD106, Novartis' active Aβ immunotherapy, has completed Phase 2 testing. The company's vice president, Michael Ryan, told Alzforum that Novartis has a BACE inhibitor poised to enter Phase 1 testing.
API APOE4 plans to recruit more than 1,300 volunteers in North America and Europe. Only 2 percent of the world's population carries two copies of the ApoE4 allele. The trial will recruit partly through API's Prevention Registry, which has 39,000 members and plans to enroll up to 250,000. Banner estimates the active immunotherapy part of the trial will begin in late 2015 and the BACE intervention a year later. Each part of the trial will run for five years. Each of the two treatment arms are expected to enroll 390 volunteers and each placebo arm 260, but the exact number could change based on regulatory agency input.
Reiman and colleagues are considering change in cognition judged by the API composite cognitive score as the primary outcome measure, although time to clinical onset is a possibility as well. The trial will analyze a suite of biomarkers, including brain Aβ and tau, through imaging and cerebrospinal fluid analysis, glucose metabolism via FDG PET, and structural imaging via MRI. There will be interim testing at two years as well as at the beginning and end of the study. Evaluating how biomarkers change in relation to clinical benefit (theragnostics) will be an important part of the trial, said Reiman, since that information will be crucial to validating biomarkers as endpoints in future prevention trials.
Cognition is likely to be tested more frequently. Reiman and Tariot stressed that full protocol is still under discussion and has yet to be submitted for regulatory approval. API APOE4 will also assess the short- and long-term impact of disclosing ApoE4 status. Potential volunteers must consent to genotyping and can avail themselves of genetic counseling provided by the trial. The infrastructure established as part of this trial will also serve as a platform for future API trials in persons at risk for late-onset AD, said Reiman.
The API ADAD trial was estimated to cost more than $100 million. The price tag for the much larger API APOE4 trial was not disclosed, but $33.2 million comes from the National Institutes of Health, $15 million from the Banner Alzheimer's Foundation, and additional funding will come from Novartis. Other private foundations and the Accelerating Medicines Partnership, which supports research into biomarkers and therapies for AD, will make up the balance (see Feb 2014 community news).
In keeping with the API philosophy of openness, Novartis has agreed that all data and samples will be shared with the research community once the trial finishes.—Tom Fagan
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