Eli Lilly and F. Hoffman-La Roche announced the failure of the clinical trial named DIAN-TU, which was testing two monoclonal antibody (mAb) drugs for Alzheimer’s disease (AD), Roche’s gantenerumab and Eli Lilly’s solanezumab, in patients who have a rare genetic mutation that causes early-onset AD.
DIAN-TU was a phase two / three, randomised, double-blind, placebo-controlled study to test solanezumab and gantenerumab in subjects with a rare inherited form of early-onset dementia called autosomal-dominant AD (ADAD). As these individuals show signs of degeneration at a predictable age, researchers hoped to be able to show clinical efficacy in a small study population.
The study was determined not to have achieved its primary endpoint, the DIAN Multivariate Cognitive Endpoint, which is designed to assess cognitive performance in ADAD patients. Eli Lilly stated that it would not pursue the submission of the drug for approval to treat people with dominantly inherited AD.
Data from DIAN-TU presented disappointing results in some earlier studies, but the doses in this study ranged up to four to five times higher and researchers had hoped that would prove more effective, as was seen with Biogen’s aducanumab. However, in the DIAN-TU study, the very small sample size and the late increase of doses affected the results of the trial. Some positive signals are likely to emerge in the full results, which will be presented in April at the Advances in Alzheimer’s and Parkinson’s Therapies (AAT-AD / PD) conference in Vienna.
Key opinion leaders (KOLs) interviewed by GlobalData explained that solanezumab remains under investigation in the Anti-Amyloid Treatment in Asymptomatic Alzheimer’s (A4) study, which is targeting preclinical participants, cognitively normal people with amyloid beta (Aβ) accumulation. This target may be particularly appropriate for treatment with solanezumab.
However, for gantenerumab, they believe that the drug has a lot of similarities with aducanumab. It was tested in two studies in people with early symptomatic AD where it did not seem to be effective for the total study group. However, in a subgroup of people that reached higher plasma concentrations, it seemed to show a clinical signal and also good target engagement. An increased dose of gantenerumab is currently being studied in two trials, GRADUATE 1 and 2, that target early symptomatic AD patients, so mild cognitive impairment and mild AD results are expected in 2022.
Several AD clinical trials have been discontinued due to failure to reverse or even slow the cognitive decline associated with the disease, leading some researchers to question whether they are pursuing the right target. The long list of phase three clinical trial failures has raised doubts about the approach and not all scientists are convinced that Aβ is the primary cause of AD, casting doubts about the potential of these drugs to be successful clinically and commercially.