Additional analysis of secondary endpoints and biomarkers are expected to be presented at the Advances in Alzheimer’s and Parkinson’s Therapies (AAT-AD/PD) Focus Meeting in April 2020.
Levi Garroway, MD, PhD
Results from the Dominantly Inherited Alzheimer Network Trials Unit (DIAN-TU) platform trial of solanezumab (Eli Lilly) and gantenerumab (Genentech/Roche) showed that both drugs failed to reach the primary end point in patients with early-onset, inherited form of Alzheimer disease (AD).1,2
The phase 2/3 double-blind, placebo-controlled, randomized study began as a 2-year biomarker target engagement study and evolved into a registration study that measured cognitive outcomes over a maximum 7-year follow-up period across 2 separate treatment arms. The trial used the unique DIAN Multivariate Cognitive Endpoint to measure cognitive performance in patients with autosomal-dominant AD.
The solanezumab arm of the trial included 50 patients who were administered 400 mg of intravenous solanezumab every 4 weeks, while 40 participants received placebo.1 At the end of the minimum 4-year treatment period, 36 patients who received solanezumab and 32 who received placebo completed the trial. Investigators enacted an amendment late during the study that allowed an increase of dosing, resulting in approximately 25% of total doses at the 1600-mg level. Analysis showed that treatment with the drug did not significantly slow cognitive decline.
As a result, Eli Lilly does not plan to pursue a submission of solanezumab for patients with autosomal dominant AD,1 although the drug continues to be evaluated in the large-scale A4 study, a phase 3 trial including patients with amyloid plaque who are at risk for AD but are asymptomatic.
"Lilly is committed to finding treatments for patients and remains excited about the potential of our medicines under development in the area of Alzheimer's," Daniel Skovronsky, MD, PhD, chief scientific officer and president of Lilly Research Labs, said in a statement.1
The trial also evaluated Roche/Genentech’s gantenerumab. That treatment arm included 52 participants who were randomly assigned to receive gantenerumab for up to 7 years.2 Participants enrolled in the study came from families that carry a genetic mutation that causes inherited AD, as well as a small subset study that included participants who were presymptomatic.
Treatment with gantenerumab, too, did not show any significant slowing of cognitive decline in people with autosomal-dominant AD. The failed results do not have an impact on Roche’s 2 ongoing investigational studies of gantenerumab in people with early AD not directly caused by gene mutations.
Those trials, GRADUATE 1 and 2 (NCT03444870, NCT03443973), are phase 3 trials in which patients will be exposed to the maximum target dose of gantenerumab over a 104-week treatment period. The GRADUATE program is currently enrolling more than 2000 patients spanning 350 study centers.
“Although DIAN-TU didn’t reach its primary endpoint, the trial represents the first of its kind and a bold undertaking by all partners involved. Given its experimental nature, we are unable to draw firm conclusions about the impact of gantenerumab in autosomal-dominant Alzheimer's disease. This outcome does not reduce our confidence in the ongoing Phase III GRADUATE clinical program,” Levi Garroway, MD, PhD, Roche’s chief medical officer and head of Global Product Development, said in a statement.2
Additional data from the DIAN-TU study will be presented at the Advances in Alzheimer's and Parkinson's Therapies (AAT-AD/PD) Focus Meeting in April 2020.
“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 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,” Maria Carrillo, PhD, chief science officer, Alzheimer’s Association, said in a statement.3 “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.”
1. Lilly announces topline results for solanezumab from the dominantly inherited Alzheimer Network Trials Unit (DIAN-TU) study [news release]. Indianapolis, ID. Eli Lilly. February 10, 2020. prnewswire.com/news-releases/lilly-announces-topline-results-for-solanezumab-from-the-dominantly-inherited-alzheimer-network-trials-unit-dian-tu-study-301001653.html. Accessed February 10, 2020.
2. Roche provides topline results from investigator-led phase 2/3 trial with ganterenumab in rare inherited form of Alzheimer disease [news release]. Roche. Basel, Switzerland. February 10, 2020. roche.com/media/releases/med-cor-2020-02-10.htm. Accessed February 10, 2020.
3. DIAN-TU Phase 3 Clinical Trials, Topline Results [news release]. Chicago, Ill: Alzheimer’s Association. February 10, 2020. alz.org/news/2020/dian-tu-phase-3-clinical-trials-topline-results. Accessed February 10, 2020.