Two investigational treatments, solanezumab and gantenerumab, failed to prevent memory loss or cognitive decline in patients with a rare, inherited form of early-onset Alzheimer’s disease, who were enrolled in a Phase 2/3 clinical trial (NCT01760005).
Despite these results, the data collected will prove useful for identifying biomarkers and improving understanding of early-onset Alzheimer’s and the more common form of the disease that develops after the age of 65 (late-onset), researchers said.
“Although the drugs we evaluated were not successful, the trial will move us forward in understanding Alzheimer’s,” Randall J. Bateman, MD, the study’s principal investigator and a neurology professor, said in a news story.
Early-onset Alzheimer’s, also known as dominantly inherited Alzheimer’s disease, is an inherited form of the disease caused by a mutation in any one of three genes: PSEN1, PSEN2, or APP. Although it is a rare form of the disease, early-onset Alzheimer’s is similar in some ways to the late-onset form.
Both versions of the disease have a “silent” phase, where changes begin to occur in the brain, which can start up to 20 years before the typical Alzheimer’s symptoms are noticeable. One characteristic is that levels of amyloid-beta, the protein responsible for plaque formation in the brain, start to increase.
Solanezumab (being developed by Eli Lilly) and gantenerumab (being developed by Roche and U.S. affiliate Genentech) are two investigational antibody therapies that aim to target and reduce the build-up of amyloid-beta in the brain. These two therapies were used in the trial to understand if it was possible to slow, stop, or prevent memory loss and cognitive decline in Alzheimer’s patients.
The study was led by researchers at Washington University School of Medicine, in St. Louis, through its Dominantly Inherited Alzheimer Network-Trials Unit (DIAN-TU).
It enrolled 194 participants and took place at 24 sites in Australia, Canada, France, Spain, the United Kingdom, and the United States. All participants had a genetic mutation for early-onset Alzheimer’s and had a mild form of the disease or were expected to develop Alzheimer’s within 15 years of enrolling in the study.
The participants received either solanezumab (given via intravenous infusion, or through the vein), gantenerumab (given subcutaneously, or under the skin) or a placebo (delivered either subcutaneously or intravenously) every four weeks at escalating doses to improve the chances of any beneficial effect.
Results were compared to family members who did not have the Alzheimer’s mutation, and patients were followed up to seven years, with the average being roughly five years.
Memory tests and cognitive assessments were carried out, and brain scans, blood samples, and cerebrospinal fluid samples (the liquid that surrounds the brain and spinal cord) were collected.
Initial analysis of the study data showed that its main objectives — to slow cognitive decline and prevent memory problems — were not achieved with solanezumab or gantenerumab.
“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,” added Daniel Skovronsky, MD, PhD, Lilly’s chief scientific officer and president of Lilly Research Labs.
The research team is now analyzing the brain scans and patient samples in more detail to get a better understanding of how Alzheimer’s develops and how it can be stopped. This will be useful for the design of future studies.
“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 National Institute of Health’s National Institute on Aging.
The full results of the trial will be presented in April at the Advances in Alzheimer’s and Parkinson’s Therapies annual meeting in Vienna, and in July at the Alzheimer’s Association International Conference in Amsterdam.
Despite the initial disappointing results, this study represents a successful collaboration between many different partners.
“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 [National Institutes of Health], the Alzheimer’s Association, philanthropic supporters, the DIAN-TU Pharma Consortium, government and regulatory colleagues, and pharmaceutical companies whose drugs are being tested,” said Bateman, who’s also the director of DIAN-TU.
Solanezumab and gantenerumab are still being investigated in other forms of the disease, and several ongoing clinical trials (NCT02008357 for solanezumab, and NCT03443973 and NCT03444870 for gantenerumab).
“Ongoing and continued research and trials will bring us closer to our goal to stop Alzheimer’s,” Bateman said. “We will continue until we are successful.”
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