It may seem that the COVID-19 vaccines appeared almost suddenly, like rabbits pulled from a magician’s hat, but the invention of mRNA-based vaccines that protect against COVID-19 was the endpoint of a long journey. In a stirring New York Times article, authors Gina Kolata and Benjamin Mueller wrote:
“…the breakthroughs behind the vaccines unfolded over decades, little by little, as scientists across the world pursued research in disparate areas, never imagining their work would one day come together to tame the pandemic of the century.”
Scientific discovery doesn’t happen in an instant. It almost always results from bringing together knowledge accumulated over time. Coronavirus vaccines were actually the result of some two decades of research, 20 years of blood, sweat, tears and disappointment. That process, with its frustrations and eventual triumphs, is seen in the development of therapeutics for countless other diseases, Alzheimer’s among them.
We Stand to Lose Public Health Impact
Despite the nature of the drug development process, we’re now seeing naysayers gloat over deceleration of Biogen’s Alzheimer’s therapy, Aduhelm. There’s no lack of trade media obituaries and Monday-morning quarterbacks casting blame generously. It’s hard to understand their glee, since all of us — scientists, regulators, patients, caregivers, physicians, media and yes, even private and public payers who foot the health bills of people with dementia — stand to lose dearly if we don’t fully explore the drug’s potential impacts.
Adulhelm isn’t an isolated example. Remember Merck’s Mevacor? The first cholesterol-reducing statin to reach the market and precursor of more effective blockbusters, Mevacor finally passed regulatory muster after much FDA Advisory Committee hand wringing. The drug was marginally effective compared to later statin entries. Today, science has generated data from more than 20 statin trials with some 135,000 patients showing how statins compare to placebo or no medication. The results show an impressive 23 percent reduction in heart attacks — a truly meaningful result. Mevacor, substandard to follow-on statins, was the door-opener that saves millions of lives globally. Then the health system embraced its possibility.
Amyloid Plaque the Holy Grail for Alzheimer’s Drug Targets
Is there be a similar path forward for Alzheimer’s? The FDA concluded there could be, when in April 2021, they approved Adulhelm, the first drug cleared for Alzheimer’s use since 2003. But regulatory approval of the medicine meant more than hope for patients and their caregivers, and more than market success. Adulhelm offers the potential to finally, definitively identify the clinical catalyst for Alzheimer’s, and the opportunity to data from real-world use that could pave the way for other therapies.
We can’t afford not to solve the Alzheimer’s puzzle and to study this medication in a real-world setting. We are facing a veritable tsunami onslaught of Alzheimer’s cases as the vast generation of baby boomers ages, and this epidemic of dementia could bankrupt us. In the absence of effective medicines, the estimated cost of Alzheimer disease management in 2020 alone was $305 billion, expected to increase to more than $1 trillion in the next generation. That astronomical figure accounts for skilled nursing care, home healthcare and hospice care, among other expenses.
For close to 25 years, the theory that amyloid plaque is the primary cause of Alzheimer’s disease has dominated clinical research and drug development. For that quarter-century, scientists have neither been able to confirm or disprove that theory. We are at an inflection point where we must either confirm amyloid plaque as the cause of Alzheimer’s, or move on.
Approval of Aduhelm set the stage to do that, at last. When FDA decided to accelerate approval for Aduhelm, the first drug to reduce amyloid plaque, perhaps they did so in large part to stimulate the generation of sufficient data to inform our path forward on addressing dementia-related illnesses. In this way, Aduhelm may be more important to the future of Alzheimer’s drug development and public health than its very vocal critics realize.
Despite the critical role Aduhelm is poised to play in the future of Alzheimer’s research, the media has gleefully focused on making it a “poster drug.” When the Centers for Medicare and Medicaid Services (CMS) issued draft National Coverage Determination (NCD) for Aduhelm use and reimbursement for patients in randomized controlled trials it opened the door for the cascade of players around the table to think differently. While the CMS pathway for use creates a significant stumbling block to access for the Medicare patient population, it is also a call to organize around making clinical research economically possible. Balance for patient access must be struck.
Neurology’s Who Moved My Cheese Moment
There should be no celebration that CMS has narrowly defined how Alzheimer’s patients can gain access to Aduhelm. We should be disappointed. And yet, CMS’s action could actually be a catalyst for decision-makers in drug development companies, government agencies, academia, medicine and payers to work together. It is a collective opportunity to unite in a massive public health research project to determine if amyloid plaque is or is not a worthwhile surrogate target. This may be a “Who Moved My Cheese” moment.
In fighting COVID-19, a combination of competitive spirit and collaborative mindset made breakthrough treatments possible. The world community — fractured on many other things –recognized a common threat and mobilized. Here, the Federal government rallied to support drug developers through public funds, flexible regulatory decisions to speed access to experimental treatments and fostering collaboration to accelerate therapies for the virus. Just as we are succeeding in protecting lives from the virus, we can collaborate to overcome Alzheimer’s.
Have We Chased a Surrogate Target Clue for Naught?
For decades, we have studied Alzheimer’s disease and chased our tails. We have spent billions on research, yet our progress in this category is still defined by what doesn’t work. We mustn’t let this opportunity pass us by; too much is at stake. If Aduhelm is struggling to gain traction with private and public payers, we must work together to find a path to getting it to the patients who need it for their benefit and for the generation that follows. This could become a massive public health real-world evidence effort and in doing so provide answers to questions we have pondered for decades. We must harness data, talent and resources, working across political and geographic boundaries to better serve the people we seek to help.
Appearances can deceive. Just as the COVID-19 mRNA discoveries are not the result of the past two years but are the outcome of two decades of arduous trial and error in research, Alzheimer’s research is on a long path, that will also have setbacks and successes. The proven collaborative approach to addressing COVID-19 provides a lesson we must now apply to Alzheimer’s if we’re to meet the coming wave of cases that, if unchecked, will undoubtedly cripple us.
[My thanks to colleague John Bianchi for his review of this article.]