Alzheimer’s Drugs Worth Repurposing?

Nearly every Alzheimer’s clinical trial has been deemed a failure, yet some participants have positively responded to experimental treatment. Now, scientists are developing predictive biomarkers to match patients with well-suited drugs, regardless of past trial results.

Alzheimer’s disease (AD) clinical trials carry a dismal failure rate of 99 percent, even with an ever-growing pipeline of drug candidates. But despite a grim track record, scientists are examining these failures with an optimistic line of questioning: Could this graveyard of failed Alzheimer’s clinical trials hold decades of compelling results relevant to different niches of the Alzheimer’s patient population?

Nearly half of the drugs currently being tested for Alzheimer’s have already been approved by the FDA for non-dementia-related applications such as asthma, arthritis and cancer. Drug repurposing significantly reduces cost and time to approval, and is therefore a leading priority for the National Institute on Aging. Certain previously-approved medications have appeared particularly promising due to their well-documented neuroprotective qualities, including non-steroidal anti-inflammatory drugs (NSAIDs) such as ibuprofen and high-dose aspirin, as well as anti-diabetic drugs such as rosiglitazone — but perplexingly, these too have failed in Alzheimer’s clinical trials. 

While these studies did not meet their predefined outcome measures, subsets of trial participants exhibited stable or improved cognition following treatment. Now, researchers and drugmakers are taking a closer look at the small numbers of people for whom these prospective Alzheimer’s treatments did appear to help. Within these data sets, they suspect, may be the key to unlocking just why effective treatments have been so hard to find.

Ongoing research continues to reveal the complexity and heterogeneity of Alzheimer’s disease as distinct molecular and pathological subtypes have recently been identified. In other words, researchers are beginning to suspect that there may be more than one “type” of Alzheimer’s. This growing concept has led many scientists to believe that Alzheimer’s clinical trials continue to fail due to the “one-size-fits-all” approach of most medications — these medications, and the studies that evaluate them, may not be taking into account the various subgroups of individuals that make up the diverse Alzheimer’s patient population. 

“The general hypothesis here is that although AD patients present with the same symptoms and often have a similar course, that AD is actually a spectrum of diseases,” Dr. Robert Rissman, associate professor of neurosciences at University of California San Diego, and founding director of the Biomarker Core for the Alzheimer’s Disease Cooperative Study (ADCS), told Being Patient. “These subtypes of AD have different etiology and are responsive to different interventions or doses of interventions.”

Therefore, Rissman and other like-minded scientists, argue that if a treatment is only effective in a single subgroup that makes up a small percentage of the Alzheimer’s population, a clinical trial testing said drug is doomed to fail if most of the selected participants aren’t appropriate candidates. However, if the relevant fraction of patients could be targeted based on their biological factors, it could allow for optimal treatment outcomes to be observed that likely would have been missed in a standard trial design and perceived as a failure. 

To tackle this emerging paradigm of Alzheimer’s disease, Rissman and his team applied a first-of-its-kind precision medicine approach to investigate the utility of NSAIDs, despite the fact that results of past clinical trials using these drugs to treat Alzheimer’s have failed to reach statistical significance. 

Rissman’s team accessed data and plasma samples from a previously published ADCS anti-inflammatory clinical trial that recruited participants with a diagnosis of probable Alzheimer’s between December of 1999 and November of 2000. Participants were randomized to receive rofecoxib, naproxen, or placebo for one year. Both NSAIDs were determined to have no overall benefit for Alzheimer’s progression. However, 41 percent of participants showed a stable or improved Mini-Mental State Examination (MMSE) score over the course of the trial. 

Rissman’s team analyzed the baseline-visit plasma samples from all participants and used assays to evaluate whether a companion diagnostic panel of inflammatory proteins (tumor necrosis factor alpha (TNFα), C-reactive protein (CRP), interleukin (IL)-6, and IL-10 detected in the plasma could be used to predict responsiveness to treatment. Researchers hypothesized that those with high levels of inflammation would respond positively to treatment while those with low levels of inflammation would experience an adverse response.

The team found that the naproxen- and rofecoxib-specific companion diagnostics were able to predict treatment response with 97 and 98 percent accuracy, respectively. Their results provide strong evidence that precision medicine can and should be applied to Alzheimer’s therapeutics, and that companion diagnostics can identify patients who are likely to experience cognitive benefit or decline from NSAID therapy. 

Rissman’s team recently applied the same research strategy to rosiglitazone, an insulin sensitizer, as there is considerable literature linking diabetes and Alzheimer’s disease. The researchers accessed plasma samples from multiple trials of rosiglitazone therapy in Alzheimer’s, which they tested for proinflammatory and metabolic biomarkers (CRP, IL-6, IL-10, TNFα, fatty acid binding protein [FABP]-3, and pancreatic polypeptide [PPY]). The companion diagnostic algorithm comprised of these six proteins exhibited 100 percent accuracy in classifying participants as responders or non-responders to treatment.

Rissman’s team has now demonstrated two subsets of patients that could be screened from the Alzheimer’s patient population and enrolled into clinical trials based on their likelihood to respond favorably to NSAID or rosiglitazone therapies. 

In addition to these anti-inflammatory and anti-diabetic medications, “we are moving slowly into other drug classes,” Rissman said, noting, “There has been a lot of resistance in the field to accept this type of perspective. It seems very obvious to me that we’re all different and with a disease as complex as AD we need to understand individual biology, but this does not seem as obvious to our most senior scientific leaders at the moment.”