By Deborah Borfitz 

June 21, 2023 | The latest report on clinical trials in the Alzheimer’s drug development pipeline points to the growing potential of anti-amyloid monoclonal antibodies for treating the brain-robbing condition. Anti-inflammatory agents comprise the single largest therapeutic category with 25 drugs, but astoundingly no two are aimed at the same target, according to lead author Jeffrey Cummings, M.D., research professor in the school of integrated health sciences at the University of Nevada, Las Vegas, and director of its Chambers-Grundy Center for Transformative Neuroscience. 

By far the most prominent player on the biomarker front is amyloid positron emission tomography (PET), which was the basis for accelerated approval of Leqembi (lecanemab-irmb) by the U.S. Food and Drug Administration (FDA) earlier this year. In addition to its presumed ability to predict the clinical benefit of experimental treatments, the imaging test is typically needed to confirm the presence of the telltale amyloid plaques in the brain when enrolling participants into studies, says Cummings. 

The move was sparked by the discovery that “at least 20%” of previously diagnosed patients, before amyloid PET scanning became standard practice, turned out to be amyloid-free, he adds. That suggests a similar proportion of participants in earlier Alzheimer’s disease (AD) studies never had the disease, throwing trial results into question. 

Blood tests for screening patients are a real possibility by next year and that “might change the dynamic of the pipeline very strikingly,” says Cummings. Having a primary care gateway for identifying patients with AD could help address the recruitment bottleneck for the 187 treatment trials now underway that will collectively require more than 57,000 participants to fully populate. 

The pipeline report, published recently in Alzheimer’s & Dementia: Translational Research and Clinical Interventions (DOI: 10.1002/trc2.12385), is based on an analysis of all current phase 1, 2, and 3 clinical trials for AD on ClinicalTrials.gov and mild cognitive impairment attributed to AD. Cummings has been producing the report annually since 2016, for the last two years with funding from the National Institutes of Health (NIH) that awarded him a first-of-its-kind leadership award for the project. 

An initial survey published in 2014 (Alzheimer’s Research & Therapy, (DOI: 10.1186/alzrt269), where Cummings and his colleagues examined ongoing trials from 2002 to 2012, showed that the failure rate for AD drugs was 99.6%. The influential “99% paper” was downloaded 75,000 times and was the impetus for the more systematic investigation, he says. 

The pipeline reports are intended to improve clinical development by watching and learning from what is and isn’t working in terms of clinical trial design, clinical outcome measures, biomarker use in trials, and the drug mechanisms of action and biological targets being pursued. The 2023 edition is based on the most AD trials ever on record, assessing 141 drugs. 

Key Drivers 

Out of the 187 current AD trials, 58 are new drugs that have entered the pipeline in the past year. The agents are predominantly (79%) disease-modifying therapies. 

Recruitment challenges continue to plague phase 2 and 3 trials with the average recruitment time stretching more than 100 weeks and, in some cases, twice that long. The situation may worsen once Medicare starts funding approved AD treatments, when interest in trial participation might logically wane.  

The high volume of trials is related in part to increasing recognition that AD is a major public health issue, says Cummings, which the Alzheimer’s Association says affects 6.7 million Americans but could double over the next 30 years. The NIH is also funding more research on AD pathways and treatments. 

Success is also a major driver of research activity, he points out. The FDA granted accelerated approval for Aduhelm (aducanumab), the first anti-amyloid monoclonal antibody, in 2021, a short five years after the first trial began. 

It is no coincidence that so many biologics are making their way into the pipeline—among phase 1 trials, it is the only well-populated drug category in the latest report. The number of participants needed for AD trials could become less daunting with the advent of decentralized clinical trials and blood biomarkers in the future, says Cummings. 

Among the diversity of targets for anti-inflammatory agents are microglial cells, as well as cytokines and the chemokines they secrete, Cummings reports. “Maybe a couple of them will be directionally positive and we can combine them.” 

Although 65% of AD patients carry the E4 version of the apolipoprotein E (APOE) gene, only one trial in the pipeline has that as a target, he continues, owing to the difficulty in altering a person’s genetic makeup. “Gene therapy in general is fairly new, and we haven’t seen a small molecule pathway that looks like it would meaningfully interfere with the E4 influence.” 

Nearly 30% of the pipeline is comprised of candidate therapies repurposed from other diseases that share the same pathway, says Cummings. The advantage of drug repurposing is the ability to skip phase 1 trials because the agent already has a well‐established safety and toxicity profile. Studies can start at phase 2 or occasionally phase 3 to “drastically shorten the development process.” 

Despite the lack of success in this area, drug repurposing trials are “highly informative” because they can point to a pathway, biomarker, or cognitive test worth pursuing, he adds, in addition to training the next generation of trialists. Work in this area is conducted in academia and supported largely by NIH funding, since repurposed drugs have poor intellectual property that companies can’t protect. 

Industry otherwise dominates AD clinical research, accounting for sponsorship of 58% of trials in the latest pipeline report. The trend with NIH grants is an investment in phase 2 studies where proof of concept occurs, shaping the targets the pipeline will chase, says Cummings. Companies might jump in to acquire promising agents that need to progress into global phase 3 trials.   

Lessons Learned 

It is noteworthy that the evidence supporting market approval of Leqembi involved an exceptionally large randomized, double-blind phase 2 clinical trial that utilized a Bayesian design with response-adaptive randomization to assess dosing, says Cummings. The trial started off testing five doses versus placebo and, based on interim reanalysis of outcomes, determined that only the high doses were working. 

Only one dose was advanced to phase 3, he continues. A panel of expert advisors recently recommended that the FDA convert Lequmbi from accelerated to regular approval, which is expected to happen on July 6. 

Biomarkers, including liquid biopsies as well as amyloid PET, have been particularly impactful in moving AD trials forward, says Cummings. Their benefit extends broadly to other neurodegenerative diseases, as evidenced by the FDA’s recent approval of Qalsody (tofersen) to treat patients with amyotrophic lateral sclerosis based on clinically predictive information from a blood test.     

To date, a small molecule has yet to be found that changes the biology of AD as dramatically as anti-amyloid monoclonal antibodies, Cummings says. “We have had two classes of drugs that decrease the production of amyloid and they’ve been very effective, but they don’t make patients better—in fact, they make patients slightly worse.” 

The lesson here is that efforts may need to shift from stopping the production of amyloid, which has been the focus of unfruitful research for years, to working on removing it, which is what the monoclonal antibodies do with demonstrated clinical benefit, says Cummings.   

Two additional monoclonal antibodies are likely to be approved this year, Cummings adds, including donanemab as well as BIIB080, the first antisense oligonucleotide targeting tau expression to enter clinical trials. Healthcare systems should start preparing now to treat AD patients with biologics, including the management of potential side effects and associated imaging tests, he says. Unlike small molecule drugs, monoclonal antibodies are generally administered intravenously or (in the case of BIIB080) via spinal tap and initially require regular MRI scans. 

In the future, combination therapies—perhaps an anti-inflammatory drug coupled with an anti-amyloid or anti-tau biologic—may well be used to treat patients. “Science is providing hope... and I am very enthusiastic about where we are as a field right now,” says Cummings.