Despite solanezumab (Eli Lilly) and gantenerumab (Roche and Genentech) failing to meet the DIAN-TU trial primary end point in inherited Alzheimer disease, the international undertaking provided some positive takeaways for the clinical community.
Howard Fillit, MD
Earlier this year, researchers from Washington University School of Medicine in St. Louis announced negative topline results for the phase 3 Dominantly Inherited Alzheimer Network-Trials Unit (DIAN-TU) clinical trial of solanezumab (Eli Lilly) and gantenerumab (Roche and Genentech) in the treatment of inherited Alzheimer disease.1,2
Last week, the trial (NCT01760005) results were presented in a virtual session of the Advances in Alzheimer’s and Parkinson’s Therapies annual meeting, and additional presentations are planned for the Alzheimer’s Association International Conference (AAIC) later this year, in Amsterdam. The data ultimately showed that neither drug met the primary end point of the study: a slowing of cognitive decline as measured by multiple tests of thinking and memory.
“The bright side is that we can do rigorous trials with biomarkers and that we can show target engagement using these biomarkers, such as PET Amyvid scans, but also emerging other biomarkers like PET tau scans, many analytes in CSF and blood,” Howard Fillit, MD, founding executive director and chief science officer, Alzheimer’s Drug Discovery Foundation (ADDF), told NeurologyLive. “The data also help us to further consider that beta-amyloid mutations, or deposition in the brain, in both familial and sporadic Alzheimer’s, may not be enough to cause dementia. There must be other processes that need to be targeted therapeutically.”
Eli Lilly noted in a company statement that the negative outcome will not affect the ongoing solanezumab Anti-Amyloid Treatment in Asymptomatic Alzheimer's (A4) Study. It also stated that there are no plans to pursue a submission for solanezumab in those with dominantly inherited Alzheimer's disease (DIAD), based on the results.3 A representative from Genentech/Roche told NeurologyLive that gantenerumab led to sustained, ongoing reduction of beta-amyloid levels in the brain in both symptomatic and asymptomatic participants, as shown by amyloid PET imaging analysis, and the ongoing phase 3 studies in early-stage sporadic AD (GRADUATE 1 and 2) are unaffected. DIAN-TU, the companies noted, did not adequately test the hypothesis of whether the higher dose of gantenerumab could be clinically efficacious in people with autosomal dominant Alzheimer, and thus, the overall results were not conclusive for the cognitive outcome and are more informative for the biomarker outcomes.
“It is possible that gantenerumab might play a role in sporadic disease, although the studies to date do not indicate that,” Fillit explained. “Gantenerumab binds aggregated beta-amyloid, somewhat similar to aducanumab (Biogen). Solanezumab, though, binds ‘soluble’ beta-amyloid, so it is different and may not be the right therapeutic target.”
The phase 2/3 DIAN-TU included 194 participants who were followed for up to 7 years (mean, 5 years). Participants were randomly assigned to receive solanezumab, gantenerumab, or placebo, with family members without the Alzheimer mutations included as a comparison. The primary efficacy analysis including 50 patients on solanezumab and 40 placebo participants. The minimum 4-year treatment period was completed by 36 patients on solanezumab and 32 placebo participants. Initial study dose was 400 mg every 4 weeks, though a late change to the study increased the dose—as an attempt to enhance potential beneficial effects—thus approximately one-quarter of the total doses were administered at 1600 mg.
The researchers aimed to recruit those who were expected to develop symptoms within 15 years of enrolling in the study or who currently had mild symptoms of memory loss and cognitive decline. In the majority of instances, early signs of disease were already apparent.
Several experts from Lilly, Genentech, Roche, and the involved institutions1-3 have suggested that despite the negative result, some additional positives can be drawn from the trial’s design and undertaking. The trial, which originally began as a 2-year biomarker target engagement study before evolving into the current framework, was the first disease prevention trial to assess multiple investigational Alzheimer disease compounds with different mechanisms of action from more than 1 pharmaceutical company.
Even without revealing a successful therapy, the data yielded additional insight into the development and progression of Alzheimer disease that may inform future research into the disease—including the most common type of disease that strikes those over age 65 years.
Principal investigator Randall J. Bateman, MD, director of DIAN-TU, and Charles F. and Joanne Knight Distinguished Professor of Neurology, Washington University, noted in a statement that “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,” Bateman said.
1. Bhandari T. Investigational drugs didn’t slow memory loss, cognitive decline in rare, inherited Alzheimer’s, initial analysis indicates. Washington University in St. Louis website. Published February 10, 2020. Accessed April 3, 2020. medicine.wustl.edu/news/alzheimers-diantu-trial-initial-results.
2. Alzheimer’s Drug Discovery Foundation (ADDF) Statement on DIAN-TU Trial Results [press release]. New York, NY: ADDF; Published February 10, 2020. Accessed April 3, 2020. alzdiscovery.org/news-room/announcements/alzheimers-drug-discovery-foundation-addf-statement-on-dian-tu-trial-result.
3. Lilly Announces Topline Results for Solanezumab from the Dominantly Inherited Alzheimer Network Trials Unit (DIAN-TU) Study [press release]. Indianapolis, IN: Eli Lilly; Published February 10, 2020. Accessed April 3, 2020. investor.lilly.com/news-releases/news-release-details/lilly-announces-topline-results-solanezumab-dominantly-inherited.