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Prevention studies next big test for Alzheimer’s research

A study set to read out early next year could be the final curtain for an Alzheimer’s disease hypothesis that has prevailed for more than 20 years — or it could spur a re-evaluation of why past efforts failed.

Efforts to reverse the devastating neurodegenerative disorder in symptomatic patients by targeting amyloid beta lesions in the brain have come up empty time and time again. The DIAN-TU study and a number of parallel trials, however, are seeking to prevent Alzheimer’s from developing in the first place among patients genetically predisposed to the condition.

Many call these long-shot studies. But the rationale is that early intervention in patients with a high probability of developing amyloid-driven cognitive impairment will delay disease onset and help lessen symptoms, with possible lessons for physicians eager to prevent Alzheimer’s in the broader population.

“If this trial is successful, if it really shows that intervening in amyloid alone prior to symptom onset has a clear effect on slowing disease progression in this population, then I think most in this field would agree that it’s likely that this would translate to the larger population in a similar state of the disease,” said Eric McDade, the DIAN-TU trial’s associate director and an associate neurology professor at Washington University in St. Louis.

As a sign of how difficult it will be for DIAN-TU to tease out a positive benefit, three similar prevention trials have been terminated early in the past 15 months, albeit using experimental drugs with a different mechanism of action than those in DIAN-TU.

Aducanumab increases amyloid doubts

Much of the biopharma sector has already voted with its feet when it comes to the strategy of blocking amyloid to treat Alzheimer’s. Companies are now pursuing alternative hypotheses such as accumulation of another protein called tau, as Eli Lilly and Biogen are exploring, or a novel hypothesis that a bacterial infection is at the root of the disease.

This is the consequence of major setbacks in studies of symptomatic patients, most recently that of Biogen’s aducanumab. Widely viewed as the best amyloid-blocking antibody in the clinic, aducanumab’s pivotal ENGAGE and EMERGE trials were halted in March because data reviewers calculated the drug would not slow the disease’s progress in patients showing early symptoms. Failure at an interim analysis surprised much of the biopharma sector, which at least expected the trial to proceed to a final readout.

“There have been so many failures of amyloid it should be clear now to everyone it’s not going to succeed,” said Casey Lynch, CEO of Cortexyme, a company that is testing a competing hypothesis: that Alzheimer’s disease has its origins in infections by a bacteria called Porphyromonas gingivalis.

She points to data suggesting that beta amyloid is an immunological response. “It’s predictable that blocking it would be a bad idea” if the bacterial hypothesis is true, she said.

“There have been so many failures of amyloid, it should be clear now to everyone it’s not going to succeed.” (Casey Lynch CEO, Cortexyme)

McDade and the DIAN-TU researchers are following an approach which holds that by the time patients start exhibiting symptoms the amyloid beta deposits have already caused too much damage to reverse or slow Alzheimer’s. In the preventive setting, researchers have sought to enroll patients with several mutations known to be associated with frequent disease onset.

For example, DIAN-TU, which is being coordinated by Washington University in St. Louis, enrolled patients with uncommon mutations that are responsible for seven out of 10 cases of early onset disease, a design that may be more likely to detect a benefit than broad trials of patients with unknown causes of disease.

Prevention trials still underway
Trial Institution Drugs Population
A4 University of Southern California Solanezumab 1,150 patients with evidence of amyloid brain pathology
API-ADAD Banner Alzheimer’s Institute Crenezumab 252 patients with PSEN1 E280A mutation
DIAN-TU Washington University in St. Louis Solanezumab, gantenerumab 490 patients with PSEN1, PSEN2 or APP mutations


The first results from this trial are expected to emerge in early 2020, in patients treated with Eli Lilly’s solanezumab and Roche’s gantenerumab. These agents are antibodies that bind with forms of amyloid beta and prevent them from accumulating in the brain. The last doses are expected to be administered in November.

As treatments for patients with symptomatic disease, solanezumab and gantenerumab both have failed, with the former showing no benefit in three separate pivotal trials and the latter missing in the Phase 3 SCARLET ROAD trial. Roche has another Phase 3 trial underway in very early-stage patients.

Three failures

DIAN-TU differs from the preventive trials that have failed in the past 15 months. All three of those studies tested another type of amyloid-targeting drug, called BACE inhibitors, and in different populations.

EARLY, which studied Johnson & Johnson’s atabecestat, was terminated early because of liver enzyme elevations that were described as “serious in nature.” It enrolled high-risk patients, defined by family history of dementia, signs of amyloid accumulation, or having an APOE4 mutation, which increases the risk of Alzheimer’s by twice as much or more.

Terminated prevention trials
Trial Sponsor Drug Population Reason for termination
Early Johnson & Johnson atabecestat 90 patients with evidence of amyloid pathology (100 planned) Liver toxicity
Generation S1 Banner Alzheimer’s Institute umibecestat, CAD106 481 patients homozygous for APOE4 (1,340 planned) Worsening cognitive function
Generation S2 Banner Alzheimer’s Institute umibecestat 1,140 patients with APOE4 mutations, with heterozygotes needing to show signs of elevated brain amyloid (2,000 planned) Worsening cognitive function


About 25% of people have one copy of APOE4, which doubles risk, and 2% have two copies, which raises the risk by three to five times.

The GENERATION trials run by the Banner Alzheimer’s Institute in Phoenix were the latest to fall short, failing at an interim review because of “worsening in some measures of cognitive function” in patients taking umibecestat, an experimental Amgen and Novartis drug. This trial also enrolled patients with one or two copies of APOE4, requiring evidence of amyloid accumulation in patients with one copy.