Updated 21 May 2012
On May 21, the New York Times editorial page commented on this upcoming trial.
This is Part 1 of a two-part series. See also Part 2.
16 May 2012. On 15 May at the Alzheimer’s Disease Research Summit 2012, a conference hosted by the National Institute on Aging, Francis Collins announced that $16 million of federal funds would go toward the first-ever therapeutic prevention trial in cognitively healthy people. The decision is part of the National Plan to Address Alzheimer’s Disease, said Collins, who directs the National Institutes of Health in Bethesda, Maryland. The unprecedented trial will be run by an international collaboration of researchers in academia and industry. The news came as Kathleen Sebelius, Secretary of the Department of Health and Human Services, formally introduced the long-awaited plan (see ARF related news story). Funding from a public-private partnership gives the green light to what is widely considered the cutting edge in the field of AD clinical research today, that is, the drive to evaluate mechanism-based experimental treatments in people who are on the path to Alzheimer’s but have not developed the disease’s neurodegeneration or symptoms yet.
The Alzheimer's Prevention Initiative is led by Eric Reiman, Pierre Tariot, and Jessica Langbaum at the Banner Alzheimer’s Institute in Phoenix, Arizona, and Francisco Lopera and his colleagues at the University of Antioquia in Colombia. Over the past two years, these scientists and other colleagues have enrolled members of the world’s largest kindred afflicted with a deterministic presenilin 1 mutation into a broad-based observational biomarker and cognition study while simultaneously laying the groundwork for secondary prevention trials. They consulted leading academic, biotech, and pharma researchers, regulators, and funders on the best approach. They navigated the legal and ethical challenges inherent in giving unapproved drugs to outwardly healthy people. The researchers got to know, and wrestled with finding, the most respectful ways of working with a vulnerable population living primarily outside of the U.S. (For background on API, see ARF related news story; ARF news story.)
Last fall, the scientists submitted to the National Institute on Aging a grant proposal for a first presymptomatic treatment trial in this population, as well as in people with autosomal-dominant AD mutations living in the U.S. The grant is being funded through $50 million from the 2012 NIH budget. In February, Sebelius had pledged that this money would be directed to select research projects this year (see ARF related news story). Slicing money out of the current fiscal year budget “is rarely done but was merited, given the urgency of this disease,” Collins said.
Scientists following the API’s progress have been curious about which investigational treatment the API scientists would choose as the most promising one to start with. Likewise, they wondered which pharma company would commit to making their leading experimental medicine available for a five-year trial in a genetically defined population while developing the drug for the much larger market of late-onset AD. The match eventually came to pass with Genentech of South San Francisco, a member of the Roche group.
A press release issued jointly by the Banner Alzheimer’s Institute and Genentech quotes its executive VP for Research, Richard Scheller, as saying: “Genentech is very excited to be a part of this landmark effort. If the study demonstrates that we can prevent the disease in this special group of patients, it may pave the way to preventing Alzheimer’s in the general population.”
Genentech licensed crenezumab from the Swiss biotech company AC Immune SA. Similar to bapineuzumab, solanezumab, and gantenerumab, three AD immunotherapies currently in Phase 3 and 2 trials, respectively, crenezumab is a humanized monoclonal antibody that binds the Aβ peptide. It differs in its technical details, such as which species of Aβ it binds and how strongly it activates microglial cells (see Alzforum Q&A with Ryan Watts). Watts is the lead scientist at Genentech on this project.
“The dominant mutations are definitely a model worth pursuing, as you can identify patients early,” said Rusty Katz, who directs the Food and Drug Administration’s Division of Neurology Products. Katz has advised the general process preparing for API trials over the years. Regulatory approval of this particular trial by the FDA and the Colombian drug regulatory agency Invima will take some months, putting the estimated start date for the trial into the first half of 2013, said Reiman.
Besides the NIH bolus, the $100 million trial gets $15 million of philanthropic funding coming through the Banner Alzheimer’s Institute, and Genentech will put up the rest. The company will also provide clinical and operational expertise to finalize design and conduct the study. Already, API scientists Langbaum, Yui Ayutyanont, and Suzanne Hendrix are collaborating with Carole Ho and others at Genentech to define a composite cognitive outcome measure and run power calculations.
Importantly, the trial is intended not as an exploratory study, but as a registration trial, meaning a positive outcome might form the basis for a new drug application, said Reiman. Toward this end, primary outcome measures will be a composite cognitive battery and other cognitive tools. Various brain imaging tests, including amyloid PET and fluid biomarkers, will be secondary outcomes.
Three hundred people in Colombia will participate in the trial. One hundred mutation carriers will receive monthly injections of crenezumab, 100 will get placebo, plus 100 non-carriers will receive placebo to ensure that study participants will not know whether they carry the pathogenic mutation or not. All participants will be asymptomatic, said Reiman.
In addition, some 24 people living in the U.S. will join the trial at five U.S. sites, said Reiman. The Banner Alzheimer’s Institute will be one; the others will be determined with the help of the Dominantly Inherited Alzheimer Network (DIAN), which collaborates with API. Genentech is a member of DIAN’s Pharma Consortium (see ARF related news story). Trial participants will be 30 years of age and older.
Conducting trials internationally can be a sensitive business, particularly in vulnerable genetic cohorts living in countries less affluent than the U.S. For his part, Lopera has been seeking a biopharma partner willing to recognize that. “We consider this a unique opportunity. These patients are a sacred group of people for Alzheimer’s research, and everything will be done with the utmost respect,” said Watts. “Genentech intends to provide study participants support for their time and efforts. We are currently working with Dr. Lopera and Banner on the details of this plan,” Ho wrote to Alzforum in an e-mail. API researchers themselves have set up a small nonprofit initiative to support the families' ongoing needs.
Should this trial work and the antibody eventually be approved, how will these families be able to afford a U.S.-made biologic therapy? “Genentech is committed to patients having access to our therapies. We have a number of patient access programs for our other therapies and will likewise ensure that the appropriate access to crenezumab is obtained after completion of the trial. We have discussed this with both Dr. Lopera and Banner,” Ho wrote to Alzforum.
Once the trial is complete, information will be made available to researchers worldwide. “We want to help develop faster ways for everybody to evaluate potential prevention drugs. It’s not just about testing this drug. It’s more broadly about helping the field link biomarker changes to clinical outcomes, and stimulating more prevention studies,” Reiman said. Ho confirmed that clinical data as well as placebo samples will be made available in an ADNI-like format after the trial is completed.
“In addition, Genentech and Banner intend to provide access to biomarker samples from treatment patients within 18 months of the completion of the five-year treatment period,” Ho wrote. This pledge is a highly unusual step. Companies generally refuse to share patient samples that contain their proprietary investigational drug. At this point, the prospect remains some seven years off into the future.
While this trial is gearing up, the API scientists are planning for the next one, which aims to test investigational drugs in ApoE carriers at elevated risk of developing Alzheimer’s. They also hope that this initial trial will stimulate more presymptomatic treatment trials throughout the field. They have developed an online registry as a tool to enable people to express their interest to join such trials in the future, and to help sponsors enroll the needed participants for such trials. Alzforum provides a quarterly newsletter in partnership with this registry.
The crenezumab trial was one of two announced as part of the National Plan to Address Alzheimer’s Disease. The other one is a five-year, $7.5 million trial headed by Suzanne Craft at the University of Washington, Seattle, to test whether an intranasal insulin spray improves cognition in 240 people diagnosed with mild cognitive impairment.
Secretary Sebelius came to present the historic plan on her birthday; she began her remarks after being serenaded by an auditorium full of conference attendees. Congressman Ed Markey (D) of Massachusetts was there as well. Markey cared for his mother when she had Alzheimer’s. He co-sponsored the National Alzheimer’s Project Act (NAPA), which mandates the implementation of a national plan. The plan is available for download.
However, aside from the trial news, the long-awaited unveiling of the plan felt a tad anticlimactic to scientists at the summit because it came without additional funds beyond those announced earlier this year. The scientific community is hoping for $1 billion to $2 billion to implement the plan’s stated goal of stopping Alzheimer’s by the year 2025. For now, speakers are limited to professing their resolve to making the plan more than a document. Ron Petersen, Mayo Clinic, Rochester, Minnesota, who chaired the NAPA advisory council, spoke about ways of monitoring progress and ensuring accountability. “Today marks a momentous occasion, but the work has just begun,” Petersen said. For her part, Sebelius concluded, “We look forward to the day when Alzheimer’s becomes another disease that hard work and partnership have beaten.”—Gabrielle Strobel.
This is Part 1 of a two-part series. See also Part 2.