This is Part 1 of a two-part series. See also Part 2.
7 August 2012. At this year’s Alzheimer’s Association International Conference, 14-19 July 2012, in sunny Vancouver, Canada, some sessions unfolded, somewhat lonesomely, in large, sparsely populated lecture halls. This could not have been more different for a session titled "Collaboration for Alzheimer’s Prevention: Common Issues Across Presymptomatic Treatment Trials." People streamed into the room long after every seat was filled, and the crowd standing around them grew so large that fire safety rules forced closure of the room, resulting in dozens of conference attendees being turned away. For those who were shut out, here is a summary of what went on inside. First, a new group called CAP introduced itself, then three prevention initiatives gave a brief update and stood for extended discussion with the audience.
The ongoing prevention initiatives—A4, DIAN, and API—are separate, but interconnected, long-term projects. Their leaders have formed an umbrella group they call Collaboration for Alzheimer’s Prevention (CAP). "Why another acronym?" a consortia-weary reader might well ask. In short, CAP exists as a forum for A4, DIAN, and API to maintain a regular dialogue as they plan and implement their preclinical treatment trials. One goal is to avoid duplicating effort on their part and on the part of the many outside partners necessary to pull off public-private trials. Another is to ensure that the initiatives find regulatory solutions jointly and construct their trials in such a way that as many data as possible can be compared and shared with the field at large. While each initiative is unique (e.g., in which population it enrolls and in how it negotiates with pharmaceutical companies), all three have much in common, and CAP exists to exploit those synergies.
Who is in CAP? For the Anti-Amyloid Treatment in Asymptomatic AD (A4) Trial, members include Paul Aisen of the University of California, San Diego, and Reisa Sperling of Harvard Medical School; for the Dominantly Inherited Alzheimer Network (DIAN), John Morris, Randy Bateman, and Anna Santacruz of Washington University, St. Louis, Missouri; for the Alzheimer’s Prevention Initiative, Eric Reiman, Pierre Tariot, and Jessica Langbaum of the Banner Alzheimer’s Institute, Phoenix, Arizona. Working together is sometimes easier said than done; hence, facilitating the necessary conversations are Neil Buckholtz and Laurie Ryan of the National Institute on Aging; Maria Carrillo of the Alzheimer’s Association; Rusty Katz of the Food and Drug Administration; and Stacie Weninger of the Fidelity Biosciences Research Initiative.
CAP members meet several times a year to brief each other and work out points of collaboration. For example, they have been comparing notes while analyzing which psychometric tests might best measure drug effect in asymptomatic trial participants. API’s original work to look for composites in longitudinal cohorts has inspired A4 and now DIAN to do the same. In another example of collaboration under CAP, DIAN will assist in the selection and training of U.S. sites, most likely including some DIAN sites, for the first API trial of crenezumab in preclinical mutation carriers. This is done in order to distribute the burden, risk, and potential benefit of this trial between Colombia and the U.S. The Colombian regulatory authority INVIMA had indicated that it would prefer joint trial participation, and DIAN agreed to help out. Finally, to avoid measurement variability in fluid biomarkers, CSF samples from both DIAN and API will be performed in the laboratory of Anne Fagan at Washington University, St. Louis, Missouri.
The joint conversations have led to one success already. Regulators have indicated that preclinical treatment trials using a single cognitive composite and biomarkers may be able to be considered for review as registration studies in these presymptomatic populations. Typically, regulators require a co-primary, including a functional or clinical outcome.
Where does each initiative stand at this point? For A4, Aisen cited multiple longitudinal cohort studies that are showing decline among initially cognitively normal people with brain amyloid. Essentially, among healthy controls without a memory concern, the trajectories split apart when those with and without brain amyloid are analyzed separately. “This suggests that we can conduct a therapeutic trial in an asymptomatic population with amyloid, targeting changes in a primary cognitive composite that is sensitive at this period and in atrophy,” Aisen said. The A4 leaders have proposed such a trial in people 70 years of age and older with a biologically active anti-amyloid compound as part of a large application to the National Institute on Aging to renew the Alzheimer’s Disease Cooperative Study grant. They are hoping for a thumbs-up call this summer.
Aisen and Sperling propose to enroll 500 people per group. Besides its primary outcome, the trial would explore computerized tasks and patient-reported outcome measures as well as a range of biomarkers including functional connectivity—an imaging modality that requires no radioactive tracer and appears to show change early in the disease course. The trial includes two adaptive features. An early futility analysis will check whether the intervention is changing amyloid biomarkers, and a later interim analysis will confirm that the placebo group declines on the cognitive composite and re-estimate group sizes.
The choice of drug will happen in December, when ongoing Phase 3 immunotherapy trials have readout and more safety data on some Phase 2 drugs are available. “We are waiting for every last piece of information to make the best decision,” Aisen said.
Both DIAN and API have been covered in detail on Alzforum. In Vancouver, Randy Bateman reminded the audience that no group has yet offered a trial specifically for families with autosomal-dominant mutations, even though their participation in research enabled advances in AD research over the past three decades. DIAN started in 2008 as a network to support clinical trials, and has since then produced a trajectory model of presymptomatic biomarker change based to date on cross-sectional data (see ARF related news story; see also also upcoming companion AAIC story). DIAN has resubmitted a proposal to the NIA to partially fund a biomarker trial testing simultaneously three different drugs against a pooled placebo group for two years, enrolling 40 per group who are up to 15 years younger than their affected parents' age at onset. “We think there is excellent power to detect reported effect sizes on the individual biomarkers,” Bateman said.
This trial, too, has adaptive features. If one or more drug(s) work, DIAN plans to extend the study three more years to a cognitive endpoint trial using a composite. If not, then a new generation of drugs can be started on a biomarker trial. Both scenarios can happen simultaneously, provided DIAN’s expansion efforts enroll additional participants. Both DIAN and API have created registries in which prospective participants can express their interest to join a treatment study (see DIAN Expanded Registry; Alzheimer’s Prevention Registry). Bateman noted that, contrary to conventional wisdom, large numbers of autosomal-dominant AD populations are now being found, in part because DIAN is becoming widely known internationally.
For his part, Reiman noted that scientists involved in CAP use the term "prevention trial" loosely. The FDA has made clear it would not grant a claim of prevention without proof that the disease has been truly prevented for the rest of a person’s life. Therefore, the proper term is "preclinical AD treatment." API has received trial funding, made its drug choice (see ARF related news story), and is preparing to get the trial going in the first half of 2013 in people within 15 years of their affected parents' age of onset. This trial, too, foresees an interim analysis to decide whether biomarker outcomes warrant continuation of treatment. For a panel discussion with the audience, see Part 2 of this series.—Gabrielle Strobel.
This is Part 1 of a two-part series. See also Part 2.