Will Alzheimer’s disease researchers miss seeing the forest from the trees?

By | October 14, 2019

The National Institute of Aging (NIA) just announced $ 73 million over five years to fund two new research centers. “The Alzheimer Centers for the Discovery of New Medicines are designed to diversify and reinvigorate the Alzheimer’s disease drug development pipeline,” says the NIA online. The AlzForum.org has more details, quoting researchers saying they will change the direction away from amyloid-beta and tau (the presumed main culprits, but failures as targets so far).

From a money perspective, Bill Gates already pledged at least $ 80 million last year for Alzheimer’s Disease (AD); $ 30 million was for early diagnosis and $ 50 million to a UK-based consortium. This new NIA expenditure of $ 73 million is about 3 percent of the $ 2 billion funding that Alzheimer’s and related dementia (ADRD) achieved with Congressional budget approval last year. By ironic coincidence, the boxer Canelo Alvarez has a five-year contract that has a value of $ 73 million, but it’s for each year, so his total is actually $ 365 million. He is in a risky profession.

But what is the research perspective? “Translational medicine” is usually characterized by the concept of facilitating ideas from the “bench to the bedside.” That phrase refers to ideas in basic science, done at a research bench, and developing the findings into something useful for sick human beings. (I was a wannabe, running SDS-PAGE on a bench long ago, and administered Phase I-II agents to sick children.) So the idea isn’t new.

But these two newly funded centers evidently won’t be translational in that way at all. One group will develop “new therapeutic hypotheses” and build “tools” based on the hundreds of potential targets already identified by the $ 185 million Accelerated Medicines Partnership-AD (AMP-AD) that started five years ago. These are targets that are thought to have something to do with clinical dementia. The science involved has been impressive and sophisticated: in one study, published in Nature this year, single-cell RNA transcripts from over 80,000 cells were examined and compared, derived from 48 heterogeneous brains, but only 24 were heavy with AD pathology.

The other group, it seems, will also focus on optimizing animal models to test ideas for those same AMP-AD potential targets (some don’t think existing animal models are predictive). Of course, genetically modified rodent models already exist, and some have even used the flatworm C. elegans. I won’t dwell on canine cognitive disorder here.

Each center has expertise in “data science, computational biology, disease biology, structural biology, assay development, medicinal chemistry, pharmacology, and clinical science.” Dredging data seems like panning for gold, trying to find that rare nugget that no one could find without a Cray or Watson supercomputer. Reminds me of a William Gibson cyberpunk novel.

Folks have already been at this for awhile, for example linking certain herpes viruses with dementia, maybe finding some markers of inflammation, doing “in silico” (meaning computer-based) investigations and simulations. But it’s still far from the bedside.

One can see the rationale for these new centers’ missions. It implies that this was work that the AMP-AD couldn’t do, and seems to be yet another step in the process. After these new centers do their work, what’s the next step after that?

Work done in clinical trials has not been encouraging. There have been a number of failures published this year, but at least that shows how hard people were trying. The newly submitted NIH ADRD budget for 2021 still has “Translational and Clinical Interventions” at only 32 percent of the pie graph. Remember, the National Alzheimer’s Project Act date for the goal of having a working therapy is 2025.

Cummings, Ritter, and Zhong wrote a detailed and thoughtful review last year of the complexity of doing clinical trials in dementia. Cummings had written about potential repurposing targets before and this year wrote about doing combination trials, but I like to remind folks that the first combination trials in childhood leukemia were done over 60 years ago, by J. Burchenal and others. It was a simpler time to do trials, of course, but progress was made.

The NIA Alzheimer Clinical Trial Consortium (ACTC), announced 20 months ago, initially hoped to have $ 70 million over five years to support clinical trials at 35 institutional sites. Already existing was the NIA AD Research Centers (ADRC) and the AD Cooperative Study group (ADCS).

It’s a bit unclear to me if there’s an overall coordination or overlap in this alphabet soup, as listed on the NIA website. Even in this era of open access to data, news outlets have reported a lawsuit over data sharing. In contrast, as I’ve written before, cancer has about 2000 sites, run by the National Clinical Trials Network with a budget of $ 150 million, supporting 17,000 patients on trials.

All this begs the question: even if one of the new drug discovery centers identifies a strong target tomorrow, how soon can an agent be developed, and by whom, and who would run a trial to test it in humans, and when could it ever get to a person who might need it?

This may all be predicated on the assumption that the pathological process in dementia is based on a single target. This whole construct might fail if the problem is a multi-hit, multi-cellular incremental process. Even with the elegant precision of CAR-T therapy for multiply relapsed childhood ALL now available, the primary initial goal for most of these children is to avoid relapse and achieve cure with standard combination chemotherapy. Because CAR-T therapy may not be durable, using myeloablative transplant is still a consideration. The approach is not precise, it has toxicity, but it works.

The deadline for AD and related dementias is six years away; as rational and precise as targeting might be, will researchers miss seeing the forest from the trees? We hope not; we sincerely hope the process is productive. Readers of this blog know what I think is missing: an overall comprehensive research strategy, outspoken clinical research leadership, a willingness to do empiric, repurposing, combination trials, and, most of all, a sense of urgency.

Ron Louie is a pediatric oncologist.

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