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Once considered failures, some Alzheimer's drugs get 2nd chance in new trials

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This is the first story in an S&P Global Market Intelligence series focusing on Alzheimer's disease. The Healthcare News Team will examine promising therapies, and the failures that have riddled the drug pipeline along the way.

A promising type of Alzheimer's disease therapy that tackles a buildup of proteins called beta-amyloid in the brain has failed over and over in the clinic, but researchers are nevertheless continuing to tinker with these drug candidates to see if they can provide any pharmaceutical benefit whatsoever — perhaps at earlier stages of the disease.

Alzheimer's disease causes abnormal clumps of proteins called tau tangles and beta-amyloid plaques to form in the brain. Researchers have long thought that if they could just eliminate these clumps — specifically the beta-amyloid plaques — the disease could be reversed or at least slowed down.

Two drugs targeting beta-amyloid, Roche Holding AG's gantenerumab and Eli Lilly and Co.'s solanezumab have failed in the pharma giants' clinical trials, which included patients with early-stage mild Alzheimer's. Roche is still evaluating gantenerumab after taking over its development from partner MorphoSys AG.

Most recently, Biogen Inc. and Eisai Co. Ltd. halted their trials testing anti-amyloid antibody aducanumab.

In all these late-stage clinical trials, the companies did not see a benefit with treatment.

Other amyloid-related treatments include BACE, or beta-amyloid cleaving enzyme, inhibitors which have mostly been abandoned due to side effects and actual cognitive decline detected following treatment.

While pharmaceutical industry analysts have largely moved on from the possibility of an amyloid drug making it through the clinic without a backward glance, researchers are still covering all the bases before definitively declaring the amyloid theory moot.

Before Alzheimer's

One of the last possibilities for amyloid's success may be treating the presymptomatic population. Scientists from the Washington University in St. Louis are evaluating this population as part of their Dominantly Inherited Alzheimer's Network, or DIAN, project.

DIAN gathered a network of people with a certain gene mutation that guarantees they will develop Alzheimer's in their 30s to 50s. The program includes an observational study to observe patients and better understand progression of the disease, a trials unit testing prevention and treatment options such as amyloid targets, and an expanded registry. DIAN allows researchers to better understand the onset and progression of Alzheimer's disease because they already know the participants will develop the condition, Washington University professor and DIAN program investigator Eric McDade said.

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The first stage of the DIAN trials unit, now in phase 2/3 clinical trials, is using Roche's gantenerumab and Lilly's solanezumab, which target different components of the amyloid protein to decrease plaques in the brain, in presymptomatic patients.

These patients had already begun to develop amyloid build ups in the brain — even though many were not expected to show Alzheimer's symptoms for another 15 years when they began the trial, according to McDade. The DIAN trial intends to show whether decreasing amyloid in a presymptomatic population has effect on cognition.

The DIAN clinical trial has been running for four years, although some participants have been receiving treatment for up to six years. The trial will conclude at the end of 2019 and results are expected in early 2020, McDade said.

More challenges ahead for amyloid

But the DIAN trial suffers from the same problem that other Alzheimer's researchers struggle with: a mixed participant population. This can cause uncertainty around the results, according to McDade.

About 30% to 40% of participants in the DIAN trial were already symptomatic at the start. Plus, the trial only has 190 participants, a relatively small sample compared to other trials.

"We may see an effect, but it could be too small," McDade acknowledged. "There's less room to detect a smaller modest effect."

Regardless of the results, Washington University is planning another trial to test an even earlier population, which will begin enrollment in 2020. The trial will evaluate the presymptomatic mutation carriers before they have developed amyloid build ups in the brain. Researchers have not yet decided which anti-amyloid drug candidate to deploy in the study, dubbed the Primary Prevention Trial.

McDade said a failure of the ongoing trial would still raise the question of whether the therapy was, again, simply administered too late.

"We've already taken steps to go back and run what we feel is going to be the definitive trial to test the amyloid hypothesis," McDade said.

The DIAN project researchers are not the only ones still investigating amyloid: Eisai is forging ahead with a phase 3 trial testing another anti-amyloid antibody, and the Alzheimer's Prevention Initiative out of the Banner Alzheimer's Institute is using Roche's amyloid antibody crenezumab, also in currently healthy individuals with dominantly inherited Alzheimer's. The A4 study, coordinated by the University of Southern California, is conducting trials with anti-amyloid treatment in at-risk patients who have not yet shown symptoms.

Beta-amyloid's not dead

The possibility of combination therapies that include amyloid drugs has also revived some hope for the mechanism's viability.

Mizuho analysts Difei Yang and Salim Syed wrote April 22: "The beta-amyloid hypothesis is not dead, and … the next step is really to target multiple pathologies at the same time." Yang and Syed, continuing, said the "implication is a potential revival of beta-amyloid drugs like [Biogen's and Eisai's] aducanumab."

McDade said that if the current DIAN trial shows the amyloid drugs have positive effect but the individuals continue to progress towards Alzheimer's disease, the next step would be exploring combination therapies.

"So combining amyloid and tau, or amyloid and other innovative therapies, to start to target things like the inflammatory pathway … we have a strong interest in that," McDade said.

Anti-tau therapies will likely be the earliest non-amyloid Alzheimer's drug candidates, if successful, according to McDade. Genetically specific therapies, for example targeting APOE, a well-known gene that lends itself to a predisposition for Alzheimer's, may also be up next.

"One of the unique aspects of this disease, the autosomal dominant disease too, is that it potentially opens itself up to unique genetic targeting and precision therapies," McDade said. "Although we're not there quite yet, we have a strong interest in partnering with others who are developing therapies that could go in and actually correct the underlying problem."