An international clinical trial evaluating whether two investigational drugs can slow memory loss and cognitive decline in people in the early stages of a rare, inherited form of Alzheimer's disease has yielded disappointing results, an initial analysis of the data has shown. However, the researchers continue to explore data from the trial's cognitive and clinical outcomes, and await analyses of biomarkers and other information so they can further understand the study's results.
The study (ClinicalTrials.gov Identifier: NCT01760005) is a phase 2/3 trial led by Washington University School of Medicine in St. Louis through its Dominantly Inherited Alzheimer Network-Trials Unit (DIAN-TU). The trial separately evaluated the effects of two drugs - solanezumab, made by Eli Lilly and Co., and gantenerumab, made by Roche and its U.S. affiliate, Genentech - in people with a rare, inherited, early-onset form of Alzheimer's called dominantly inherited Alzheimer's disease or autosomal dominant Alzheimer's disease. Such people experience declines in memory and thinking skills starting in their 50s, 40s or even 30s.
The initial analysis indicated that neither drug met the primary outcome of the study, which was a slowing of cognitive decline as measured by multiple tests of thinking and memory.
"Although the drugs we evaluated were not successful, the trial will move us forward in understanding Alzheimer's," said principal investigator Randall J. Bateman, MD, director of DIAN-TU and the Charles F. and Joanne Knight Distinguished Professor of Neurology at Washington University. "The trial's innovative design - developed in collaboration with a consortium of pharmaceutical companies, the National Institutes of Health (NIH), regulatory agencies and academic leaders - will make advances for future Alzheimer's trials. Ongoing and continued research and trials will bring us closer to our goal to stop Alzheimer's. We will continue until we are successful."
Despite the trial's results, the study yielded new insight into the development and progression of Alzheimer's, which can inform future research into the disease, including the more common form that typically strikes after age 65, Bateman said. The brain changes that occur as Alzheimer's progresses are much the same in people with the inherited, early-onset and the late-onset forms of the disease.
"Roche and Genentech are proud to work in partnership with Washington University and Lilly on this important study in a rare, inherited form of Alzheimer's disease," said Rachelle Doody, MD, PhD, global head of neurodegeneration at Roche and Genentech. "Along with the broader Alzheimer's community, we are disappointed that this study did not meet its primary objective yet remain confident that these results will help inform the direction of future research. We are grateful to be part of this close collaboration between industry, academia and patients as we continue to tackle the complex challenge of Alzheimer's disease."
Both the early-onset and late-onset forms of Alzheimer's have "silent" phases that begin up to two decades before symptoms arise. The process starts with the accumulation of plaques of the protein amyloid beta in the brain. Eventually, as the disease progresses and the damage to the brain becomes more extensive, people's memory, thinking and behavior start to deteriorate.
Both investigational drugs are designed to target and neutralize amyloid beta in the brain through different mechanisms and are being evaluated in other, more common forms of Alzheimer's.
"We are grateful to the courageous participants, their families, and clinical investigators for their dedication and commitment to the study," said Daniel Skovronsky, MD, PhD, Lilly's chief scientific officer and president of Lilly Research Labs. "These results reflect the difficult nature of treating Alzheimer's disease and the great need for continued research. If we have learned one thing after more than 30 years of Alzheimer's research, it is that even negative results propel the science forward."
The study followed 194 participants for up to seven years; the average was about five years. All participants come from families that carry a genetic mutation that causes early-onset Alzheimer's dementia. People who inherit the mutation are all but guaranteed to develop symptoms at about the same age their parents did. While devastating for families, such mutations allow researchers to identify people in the early stages of the disease before their behavior and memory begin to change.
Participants were randomly assigned to receive solanezumab, gantenerumab or a placebo. Family members who did not have the Alzheimer's mutations also were included as a comparison. As part of the innovative trial, doses of the investigational drugs were increased during the study to try to enhance potential beneficial effects.
The researchers recruited people who were expected to develop symptoms within 15 years of enrolling in the study or who already had very mild symptoms of memory loss and cognitive decline at the trial's outset. In most cases, their brains already showed early signs of disease. The goal of the study was to determine whether either investigational drug could slow, stop or prevent memory loss and cognitive decline related to Alzheimer's.
"We extend our heartfelt gratitude to the men and women who have been participating in the DIAN-TU prevention trial, as they are personally helping to advance our knowledge of the complexity of Alzheimer's disease and related dementias," said Richard J. Hodes, MD, director of the NIH's National Institute on Aging, which is providing funding support for the trial. "We look forward to learning more through the published, peer-reviewed data, which will provide a broad range of scientists with crucial information and guidance for further research."
While the trial primarily was geared toward evaluating whether drugs could slow or delay memory loss and cognitive decline, researchers also obtained brain scans and samples of blood and cerebrospinal fluid - the liquid that surrounds the brain and spinal cord - from participants so they could monitor biological signs of disease. The researchers now are analyzing the samples to better understand how Alzheimer's develops and how it can be stopped. The results will inform future clinical trials.
A more detailed analysis of the trial's data will be presented for the first time April 2 at the Advances in Alzheimer's and Parkinson's Therapies annual meeting in Vienna, followed by presentations at the Alzheimer's Association International Conference in Amsterdam in July.
"While the top-line data fell short, the Alzheimer's Association looks forward to a more complete report at upcoming scientific conferences," said Maria C. Carrillo, PhD, Alzheimer's Association chief science officer. "We learn from every clinical trial. In these findings there will be valuable lessons on how to best conduct clinical trials in people with and at risk for Alzheimer's, and where to focus our energies moving forward. The Alzheimer's Association will continue to partner in innovative studies like DIAN-TU.
"We thank the DIAN-TU participants and their families, and praise the researchers for the thoughtful and flexible design of the study, and their dogged pursuit of answers about treating and preventing Alzheimer's," Carrillo added.
In addition to the Alzheimer's Association, private funders, including FBRI and GHR Foundation, have provided substantial financial support to the trial.
Despite the study's disappointing results, DIAN-TU represents a successful, groundbreaking collaboration among academic institutions, pharmaceutical companies, patient-advocacy groups, the NIH and private supporters. The trial was conducted at 24 sites in Australia, Canada, France, Spain, the United Kingdom and the United States. The public-private partnership and researcher network created to conduct the trial can be leveraged for future studies of investigational Alzheimer's drugs.
"Our first attempt to slow Alzheimer's before symptoms manifest is the result of the heroic commitment of patients and families at risk for dominantly inherited Alzheimer's, leading global academic researchers, the NIH, the Alzheimer's Association, philanthropic supporters, the DIAN-TU Pharma Consortium, government and regulatory colleagues, and pharmaceutical companies whose drugs are being tested," Bateman said. "It wouldn't have been possible without all stakeholders coming together for the cause to stop Alzheimer's disease."
The trial is supported by Eli Lilly and Co., Roche, the Alzheimer's Association, NIH (NIH U01AG042791, PI RJ Bateman; NIH R01AG046179, PI RJ Bateman), GHR Foundation and FBRI. More information about the trial can be found on clinicaltrials.gov (ClinicalTrials.gov Identifier: NCT01760005) and on Washington University's Dominantly Inherited Alzheimer Network website.