Alzheimer funding reached $3.1 Billion in December, but otherwise, Good Riddance 2020! Can a research program, dubbed “DREAM,” help identify a drug anytime soon, for Alzheimer’s and Related Dementias (ADRD)??
Before people living with dementia start looking for therapy with the new funding, let’s look at the 52 drugs FDA did approve last year. NOT ONE was therapeutic for dementia. Aducanumab was not approved (maybe it didn’t deserve it?), but evidently there’s a lot of politics (see AlzForum link below); a “final” determination may be announced this year. Yes, a tau imaging agent was approved, and there were some neuro therapies for infant spinal muscular atrophy, MS, migraines and Parkinson symptoms. The list with annotation can be read in this link: Endpoints News.
Most were for cancer; they avoided touting themselves as “cures,” but could demonstrate prolonging survival, sometimes just for months, presumably with acceptable toxicity and quality of life. Prolonging survival for someone with very late stage dementia might be an ethical conundrum. ADRD trials are difficult; durable changes in cognition and abilities are harder to measure than counting survivors.
Most cancer therapies target unique structural or metabolic alterations of cancer cells. An esteemed oncology colleague asked why amyloid and tau were even targets in ADRD, since what seems effective in oncology is attacking the cells themselves or cancer metabolism, not the pathological proteins left behind as biomarkers.
Well, an intramural program at the National Institute of Aging (NIA) has been thinking about that concept, and developed “Drug Repurposing for Effective Alzheimer’s Medicines (DREAM).” Their concept paper was published last year. Drug repurposing is not new, of course; some 35,000 trials of all sorts with various diseases have been done according to one review. One striking example: Sildenafil (aka Viagra) for male sexual dysfunction is now also FDA approved for pulmonary arterial hypertension, a very serious condition.
The NIA DREAM team wants to avoid targeting just the “tombstones” [ADGadfly’s term] or biomarkers of dementia; they want to emphasize processes that precede clinical dementia. That’s a reiteration of the ADRD Holy Grail Quest of the last 100+ years, ever since the clinical syndrome and neuropathology were correlated, and reported separately by Oskar Fischer and Alois Alzheimer.
To oversimplify, the authors of this paper outline drug discovery by 1) “hypothesis generating,” looking at what is already known about dementia molecular biology (metabolomic, proteomic, and transcriptomic analyses); 2) identifying pathways that might be affected by FDA approved agents; 3) using observations in Medicare and UK electronic medical records to “refine” hypotheses for candidate agents (yes, Viagra might be one!), and then somehow doing in silico (i.e computer simulation) “validation.” Much of the paper explains potential biases and confounders. It’s the kind of virtual research that can be done in this COVID isolation era.
While one wishes the investigators well, with a concrete, actionable result, it’s a bit hard to conceive how a promising agent would leap off the screen into a human randomized pragmatic or explanatory clinical trial.
Doesn’t this process all sound familiar? Anyone remember the announcement in 2014 of $130M for the private-public Accelerated Medicines Partnership? It started with four centers, one about using “-omics” to find targets and doing preclinical validation. How about the further details in 2019, an NIA announcement of $73M to AMP-AD with two new centers? It’s unclear whether they might be for novel, proprietary single agents, but the process seems similar.
Much of the $3.1B that Congress approved for ADRD research is already allocated, but how much can be deployed that will result in therapy sooner than later? There exists an ADRD clinical trials network. But if agents are identified, what leadership will pivot to do the trials necessary for FDA scrutiny, to reassure patients of efficacy, and get that agent to the patient? Funding has improved, but there seems to be no sense of urgency, no “Operation Warp Speed” or “Moonshot” for ADRD.
From an Op-Ed in the Seattle Times, Dec 2015: “Appoint AD Czar, Treat It Like AIDS or Cancer,” five years ago from this writer:
“How could a therapy czar help the effort? He or she could create a strategy to quickly but definitively … create research templates, define outcome standards, further simplify consent issues, accelerate recruitment in nursing homes, prioritize and activate trials of existing drugs that seem promising but have no sponsors (“repurposing drugs”).
Brilliant minds in the Alzheimer’s dementia research community have been attacking the problem for years….Can we create a coordinated and comprehensive research structure to accelerate clinical improvements in treating Alzheimer’s dementia and be more aggressive, even radical in trials? It seems time to empower an Alzheimer’s dementia therapy czar.”
Like most years, 2020 did see a lot of advances in ADRD science. For a masterful 2020 review that was just published yesterday, Jan 4 online, Alzforum discusses the issues with aducanumab, and many other agents that were stalled, and some others in the pipeline.
The Asian Zodiac had last year as the Year of The Rat…is this now the Year to be Bullish, or will it all be just Bull?