Seminal, Highly Anticipated Alzheimer’s Trial Falters
Top-line results from the seminal phase 2/3 Dominantly Inherited Alzheimer’s Network-Trials Unit (DIAN-TU) trial show that the novel drugs gantenerumab (Roche) and solanezumab (Lilly) did not meet the primary endpoint in patients with early stage dominantly-inherited Alzheimer’s disease (AD), investigators have announced.
In the international trial, which included almost 200 participants, the two experimental agents were evaluated separately. However, initial analyses showed that neither significantly slowed cognitive decline, the primary outcome measure, or memory loss.
Still, the researchers note they will continue exploring data from DIAN-TU’s cognitive and clinical outcomes and are awaiting analyses of various biomarkers.
“Although the drugs we evaluated were not successful, the trial will move us forward in understanding Alzheimer’s,” principal investigator Randall J. Bateman, MD, Washington University School of Medicine, St Louis, Missouri, said in a news release.
Funders for the trial included the National Institute on Aging and the Alzheimer’s Association.
“While the top-line data fell short, the Alzheimer’s Association looks forward to a more complete report at upcoming scientific conferences. We learn from every trial,” Maria Carrillo, PhD, chief scientific officer at the Alzheimer’s Association, noted in the organization’s own release.
Rebecca M. Edelmayer, PhD, director of scientific engagement for the Alzheimer’s Association, agreed with Carrillo that although the results were disappointing, the data will be beneficial for the field.
“It’s always a difficult day when we get news like this,” Edelmayer told Medscape Medical News. However, “this research is going to absolutely provide valuable information once we can really pick through all of the data.”
Dominantly-inherited AD, also known as familial AD or autosomal dominant AD, is rare but can affect memory and cognitive skills in individuals as young as age 30. It is caused by mutations on chromosomes 21, 14, and/or 1 that play a part in the breakdown of amyloid proteins and formation of amyloid plaques.
Both gantenerumab and solanezumab were created to target and neutralize amyloid beta, albeit through different mechanisms. Both are also being assessed in other trials as treatment for more common forms of AD.
As reported by Medscape Medical News, results of the phase 3 EXPEDITION3 trial of solanezumab in patients with mild AD were negative, as were two other phase 3 trials. The drug is now being evaluated in the ongoing solanezumab Anti-Amyloid Treatment in Asymptomatic Alzheimer’s (A4) study.
Although the phase 3 SCARLET ROAD trial of gantenerumab for mild AD was stopped early for futility in 2014, it was continued as an open-label extension at the high dose for 2 years. During that period, follow-up analyses showed a dramatic decline in Aβ (amyloid beta) deposition in the participants — leading to the launch of the phase 3 GRADUATE 1 and GRADUATE 2 trials.
Starting in 2012, DIAN-TU was conducted at 24 sites in the United States, the United Kingdom, Canada, Europe, and Australia. It followed 194 adult patients for up to 7 years (average duration, 5 years.) Its original estimated completion date was December 2020, as stated on clinicaltrials.gov.
All participants had family members with a genetic mutation that causes early-onset Alzheimer’s dementia. They already had very mild symptoms of cognitive decline and memory loss at the start of the trial or were expected to develop symptoms within 15 years of enrollment.
“People who inherit the mutation are all but guaranteed to develop symptoms at about the same age their parents did,” the release noted.
“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,” it added.
The Alzheimer’s Association noted in its release that a child of a parent with the mutation has a 50/50 chance of inheriting the disease. “This form affects less than 1% of the individuals living with Alzheimer’s disease today,” Edelmayer noted.
Detailed Data Coming Soon
Trial participants were randomly assigned to receive either solanezumab, gantenerumab, or matching placebo. To act as a comparator group, family members without the AD mutation were also included.
The primary measure was change from baseline in the DIAN-TU cognitive composite score. Secondary measures included changes on the Mini-Mental Status Examination, the Functional Assessment Scale, the Neuropsychiatric Inventory Questionnaire, the 12-item International Shopping List Test, the Memory Complaint Questionnaire, and the Wechsler Memory Scale Logical Memory/Paragraph Memory test.
The researchers also conducted imaging scans and collected samples of blood and cerebrospinal fluid.
Along with announcing the negative top-line results for the trial, the investigators noted that “a more detailed analysis of the trial’s data” will be presented at the Advances in Alzheimer’s and Parkinson’s Therapies in Vienna on April 2 and at the Alzheimer’s Association International Conference in Amsterdam in July.
The researchers will continue to explore all data gathered — but already new insights have been discovered into the development and progression of AD, Bateman noted.
Included among these discoveries is that brain changes that occur as the disease progresses are similar among those with the inherited, early-onset form of AD and the late-onset form.
“The trial’s innovative design…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,” Bateman said. “We will continue until we are successful.”
“These results reflect the difficult nature of treating [AD] and the great need for continued research,” said Daniel Skovronsky, MD, PhD, chief scientific officer and president of Lilly Research Labs.
“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,” he added.
Lilly noted in a statement that the DIAN-TU top-line results will not affect its ongoing A4 study of solanezumab. Roche noted in its own statement that the findings also will not affect the company’s ongoing GRADUATE studies of gantenerumab.
“The Work Doesn’t Stop Here”
Richard J. Hodes, MD, director of the National Institute on Aging, said that DIAN-TU will advance the field’s knowledge about a complex disease.
“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 future research,” he said.
Howard Fillit, MD, founding executive director and chief science officer at the Alzheimer’s Drug Discovery Foundation (ADDF), agreed.
“While we are disappointed that patients in this study did not see a benefit, we need to keep in mind that Alzheimer’s is a complicated disease due to complex, multifactorial causes,” he said in a statement.
“ADDF has long supported a broader approach that moves past targeting beta-amyloid and advances a diverse pipeline of drugs addressing multiple targets” in AD, Fillit added. “We need multiple ‘shots on goals’ to discover effective drugs.”
Edelmayer said the results emphasize that “this story isn’t yet completely told” and that there is still a lot to learn from the data, especially regarding the biomarkers that were tested.
“With that information, we will gain valuable insight into the outcomes that have been released but will also probably better understand where we should be putting our energies and focus moving forward,” she said.
Going forward, “we will continue this fight until we have an effective treatment for all individuals living with Alzheimer’s, whether it’s dominantly-inherited [AD] or the more common version, which is the late-onset or sporadic form of the disease,” said Edelmayer.
“We have to stay optimistic. The work doesn’t stop here.”
The trial was funded by Eli Lilly and Co, Roche, the Alzheimer’s Association, the National Institute on Aging, the GHR Foundation, and FBRI.
Follow Deborah Brauser on Twitter: @MedscapeDeb