The prevailing theories behind the cause and potential treatment of Alzheimer's disease had already been on shaky ground when Genentech announced a key trial failure in June. In fact, controversy and doubt have surrounded beta amyloid and tau hypotheses for years. Now, trial outcomes like these are tearing the cracks wider open, some experts say.
Still, many companies developing Alzheimer's drugs have sunk millions into the theory that clearing amyloid plaques and tau tangles in the brain could lead to improvements for patients. And so far, the only drug being marketed to potentially slow the progression of Alzheimer’s — Biogen and Eisai’s Aduhelm — was approved by the FDA using this biomarker approach.
But in the case of Genentech, which is owned by Swiss drugmaker Roche, a focus on clearing beta amyloid plaques with the drug crenezumab did not slow or prevent cognitive decline in patients who were predisposed to early onset Alzheimer's disease. (The company will present further analysis of the data in August.)
Adding fuel to this fire, a recently published investigation by Science magazine revealed the 2006 study that pinpointed one of the amyloid biomarkers associated with memory loss may have been based on faulty or tampered data. If the allegations hold up, this discovery suggests that part of the basis for two decades of pharma research into amyloid plaques could have been misled.
So, now what? Although the industry’s pipeline for Alzheimer’s drugs is getting more diverse, many in the amyloid and tau game are in too deep to give up. And as some hang on to the belief that eventually, the amyloid approach will be shown conclusively to work, others are urging investors and scientists to move on.
"It really took this series of debacles for people to begin to say, you know, maybe we're looking at this a little bit wrong. But who wants to be the junior guy that goes to the CEO and says we just spent a billion dollars and it's been a total waste?"
Raymond J. Tesi
INmune CEO
Another shot on goal
Genentech has another round in the chamber with the drug gantenerumab — another antibody designed to clear amyloid plaques. The company is awaiting results from a phase 3 study called Graduate that focuses on early intervention of the disease — these should read out by the end of the year, says Genentech's vice president and chief medical partner, Gregory Rippon.
The results have been a long time coming, punctuated with the many failures from competitors and within Genentech itself. Can this time be different?
"It's truly been an exercise in persistence and perseverance," Rippon says. "This is a molecule that's been in development in preclinical and clinical [stages] for over 20 years at this point — so it's been quite a journey, but it's been a journey that really reflects what we believe to be what's needed in the field."
Rippon's position at Genentech is to ultimately bring the new therapy — if approved — to the clinical practice environment. He and the company believe in the amyloid theory to this day, albeit under certain conditions.
"You have to make sure that you're going into a clinical trial in the right population at the right time in their disease course where the evidence would suggest that intervening against a target like amyloid may translate to a clinical benefit," Rippon says. "There's been a growing body of evidence over a long time in the field that once the disease progresses to a certain point, it may shift from more of an amyloid-driven process to more of a tau-driven process, for example."
Examining these processes closely and methodically, researchers can learn more about the disease and what direction to go, Rippon says.
"Picking the appropriate time in the context of the disease course to then intervene with a target and anti-amyloid treatment is really important," he added. "But you have to have the clinical endpoints refined to be able to detect that treatment effect."
With endpoints based on cognitive decline and a cause-and-effect ambivalence between these targets and the disease, trials can become "noisy," making those outcome measures all the more important.
As with all medical research, humility in front of the science is crucial, Rippon says. The failures can be just as key to the development process as the wins.
"It's a matter of highlighting contributions to the field, from programs that haven't demonstrated efficacy, because that's where the current programs are all built upon the shoulders of those other prior programs," Rippon says. "Translating that to the work that's being done to advance these programs is also work that's being done to advance the overall field and the science of doing these studies — there is no way the current wave of potential treatments would be at the stage they were without those foundations of previous learning over the last decade plus."
Source: Alzheimer’s Association. All information current as of Jan. 25, 2022.
Nails in the coffin?
Not all Alzheimer's drug developers are holding out so much hope.
Raymond J. Tesi, the CEO of INmune Bio, believes these failures have shown that the focus on these targets in the industry has been a folly and that other methodologies have unjustifiably been pushed aside. INmune is developing a protein biologic called XPro1595 that targets neuroinflammation to slow progression of Alzheimer's disease. The treatment showed to reduce inflammation in a phase 1 trial, though a next-stage study was placed on hold due to manufacturing concerns.
Tesi says the amyloid-tau theory is an example of the industry circling around questionable science.
"I think the whole amyloid-tau story is a great example of 'group think' in medicine, and that happens all the time," Tesi says. "Everybody likes to think clinical scientific researchers and clinical researchers are so sophisticated, but they're actually quite boring — they get an idea and they stick with it, and it's quite dangerous."
The National Institutes of Health decided in the 1990s to issue research grants for studies in the amyloid-tau school of thought, Tesi says — and only that school of thought.
"So you had this perpetuation, and then as things began to fail, it was kind of like the emperor had no clothes and they kept making excuses," he says.
With more failures piling up, Tesi says he's begun to see a change in the way researchers are approaching the disease.
"It really took this series of debacles for people to begin to say, you know, maybe we're looking at this a little bit wrong," Tesi says. "But who wants to be the junior guy that goes to the CEO and says we just spent a billion dollars and it's been a total waste?"
A golden age
The technology to understand the brain, which has historically been a "black box," Tesi says, has allowed for improvements in finding brain structures and processes that could lead to breakthroughs in the field — if leaders can overcome these prevailing theories that have demonstrated repeated failures.
According to Genentech's Rippon, the amyloid theory can work in certain circumstances, but he agrees that it might not be a singular solution — combinations of approaches could be the answer.
"The more we've learned in the space around the relative biomarker signatures at various points in the disease process, the more we're led to the conclusion that at certain stages of the disease, it will likely require a multi-drug or multi-modality or multi-target approach to intervene effectively," Rippon says. "That's a potential path for the future treatment in the space — it makes sense based on what we understand around the pathophysiology of the disease."
Either way, researchers like Tesi believe there are great things to come for Alzheimer's and other brain conditions that have long eluded the medical community.
"The golden age of [central nervous system] drug development is upon us," Tesi says. "Just think of all the progress that was made in oncology in the last 20 years — that's what's going to happen in the next 20 years in CNS."
That future of drug development in Alzheimer's will depend on the embrace of new and effective treatments despite the history of ingrained systems, Tesi says.
"The next 10 years is going to be really exciting, and we just hope that the financial community and the FDA can keep up with us," he says.
