DIAN-TU Phase 2/3 Trial in Alzheimer’s Fails Primary Endpoint; Solanezumab and Gantenerumab Show No Cognitive Benefit in Dominantly Inherited AD

News Event

Today, scientists at Washington University in St. Louis (WashU) announced the top-line data from the DIAN-TU Phase II/III clinical trial for Alzheimer’s disease. The trial enrolled 490 patients with dominantly inherited Alzheimer’s disease (ADAD), who were treated with Eli Lilly’s amyloid-beta antibody solanezumab, Roche’s amyloid-beta antibody gantenerumab, or a placebo. The data released today are based on observations of 194 patients, with an average follow-up period of five years and a maximum of seven years. The results showed that neither drug improved cognitive function, failing to meet the primary endpoint of the trial. In response to this news, Eli Lilly’s stock initially dropped by 5%, but later rebounded to close with only a slight decline. Biogen, which has already submitted a marketing application for its similar drug aducanumab, was unaffected and closed with a modest gain.

Drug Source Analysis

Alzheimer’s disease (AD) is currently one of the most serious threats to human health, and amyloid-beta has emerged as the most promising therapeutic target. Amyloid-beta is not only the most iconic pathological feature of AD but also has support from human genetics linking it to the pathogenesis of the disease. However, to date, four amyloid-beta antibodies have failed across a total of nine Phase III clinical trials, while four BACE (beta-secretase) inhibitors and three gamma-secretase inhibitors have shown evidence of worsening the disease. Two of these antibodies had previously failed in several larger Phase III trials; the failure of solanezumab three years ago on Thanksgiving significantly impacted Eli Lilly. Nevertheless, due to factors such as insufficiently homogeneous study populations, potential missing of the optimal intervention window, non-maximized dosing, and relatively short follow-up periods, the current long-term follow-up trial in autosomal dominant Alzheimer’s disease (ADAD) has been initiated.

Autosomal dominant Alzheimer’s disease (ADAD) accounts for only 1% of all Alzheimer’s disease (AD) cases, but its pathogenesis is relatively well understood, as it is caused by mutations in one of three genes associated with amyloid protein and AD: APP, PSEN1, or PSEN2. These patients are almost certain to develop AD, with onset possible as early as their thirties. Initially, AD was defined as a condition characterized by cognitive impairment occurring before the age of 40; later, the definition was expanded to encompass all cognitive disorders associated with amyloid protein abnormalities. The observation period in this trial was considerably longer than that of previous Phase III clinical trials, averaging five years. Although not all patients received the highest dose from the outset, a substantial proportion eventually received doses of the two antibody drugs that were four to five times the initial dose. Patients in this trial were intervened at an earlier stage, with some being entirely asymptomatic. The failure to demonstrate sufficient efficacy despite early intervention, use of the highest doses, a relatively homogeneous patient population, and prolonged observation has further undermined the amyloid hypothesis.

The only success in this field to date has been the results from the high-dose arm (10 mg) of Biogen and its partner Eisai’s aducanumab in the Phase 3 Emerge trial last year. However, even that trial missed two secondary endpoints, and the low-dose arm failed to meet any of the trial endpoints. In another identical Phase 3 trial, named Engage, both the high- and low-dose arms missed all trial endpoints. Although these antibodies all target amyloid-beta protein, their binding sites differ; therefore, each drug may theoretically exhibit different efficacy. Nevertheless, the binding sites of aducanumab and gantenerumab are very similar, and both bind to amyloid-beta oligomers and plaques. Thus, today’s trial results somewhat evoke the idiom “a fire at the city gate brings disaster to the fish in the moat,” implying collateral damage. Of course, this trial had a small sample size and may have been significantly affected by noise, but we cannot rule out the possibility that the Emerge trial was a false positive. Even a stopped clock is right twice a day.

Powdered protein bears certain similarities to remdesivir in the treatment of COVID-19, as both represent the most promising therapeutic options for urgently needed disease interventions. Regrettably, diseases do not surrender simply because we have deployed our best available drugs. Powdered protein has been targeted by multiple agents in several large-scale Phase III clinical trials; however, current evidence suggests that even the optimally optimized aducanumab demonstrates only marginal efficacy, potentially amounting to mere statistical noise. While we certainly hope for better outcomes with remdesivir in treating COVID-19, it is crucial to recognize that successful drugs are exceedingly rare. Compounds exhibiting some activity in cellular assays and acceptable tolerability in humans remain far from becoming safe and effective medications.