Alzheimer’s: Learning From a Legacy of Bitter Setbacks
by SHEHLA SHAKOOR, JOHN CARROLL, ARSALAN ARIF, and the ENDPOINTS NEWS TEAM
In biopharma R&D, the biggest and best drug targets always involve unmet medical need—and Alzheimer’s fits that definition better than any other major disease.
There’s good reason for that, and it’s inside our heads. The circuitry of the human brain is incredibly complex, with some 100 trillion synapses ferrying electrical messages between neurons in a constant frenzy. In the brains of Alzheimer’s patients, those biologic processes break down. Messages go awry, often to catastrophic results.Investigators have been focusing on toxic concentrations of amyloid beta that clog up those synapses and on a substance called tau that’s found inside neurons. While some big players like GlaxoSmithKline and AstraZeneca have stepped back in recent years, preferring to focus their resources in diseases where they’re likely to make a bigger impact, and more quickly, a group of big and small drug developers remain stubbornly committed to the field.
To understand why they’ve doubled down, you need to understand the numbers. And they all point to a crushing cost from a deadly serious aging disease.
Of the 5.5 million Americans with Alzheimer’s, 4% are under 65, according to a new report from the Alzheimer’s Association. That number swells to 16% among seniors between 65 and 74, then 44% for the next decade and 38% in the 85-and-older group. That’s a lot of people, and in an aging population, the numbers are about to grow.
It’s not just patients, either. There are close to three unpaid caregivers for each of the Americans with Alzheimer’s, and they’re devoting increasing amounts of time to their afflicted family members.
The cost of Alzheimer’s care will hit $259 billion this year. And that pales in comparison to what’s coming.
By 2050, the cost of care is expected to quadruple, to more than a trillion dollars. Medicare can’t handle that kind of math. Nor can the healthcare systems in other countries that will have to adjust to even bigger patient pools as population demographics go increasingly gray.
Numbers like that are scary for society, but they spell a big opportunity for drugmakers. If anyone creates a treatment that modifies the progression of the disease—or even delivers gains on the symptomatic side—that’s a golden ticket. The potential payoff could drive billions in annual profit.
As a result, companies like Eli Lilly, Roche and Merck & Co. have been pumping billions of dollars into late-stage research projects. The payoff over the past 14 years: $0.
As a result, companies like Eli Lilly, Roche and Merck & Co. have been pumping billions of dollars into late-stage research projects.
The payoff over the past 14 years: $0
Pharma companies have announced one failed study after another. The growing litany includes every single Phase III readout. Alzheimer’s R&D hasn’t even produced new additions to the short list of modestly effective symptom-focused drugs on the market.
That’s the bad news. The good news is that each failure has offered at least marginal insight into what went wrong before. Deepening experience and improvements in technology illuminate which paths researchers should continue to follow, and where new paths should be blazed.
Large concentrations of non-Alzheimer’s patients were accidentally scooped up into earlier studies; now, diagnosis is more precise and patient recruitment more discriminating. Trials are better run, thanks to the emergence of a global network of sites. They’re sharpening standards as investigators track the cognitive and functional abilities of trial participants.
Meanwhile, researchers’ thinking has evolved, pushing steadily upstream to earlier and earlier stages of the disease.
Old conflicts between disease triggers have begun to resolve into a better appreciation of the kind of drug cocktails necessary to change the current Alzheimer’s prognosis—dementia and death—to a manageable, chronic disease that no longer wipes out memories and personalities.
Still, experts in the field agree that something concrete needs to happen in drug development. Something that will actually benefit patients. And the sooner the better.
The state of the art

Paul Solomon has been a principal investigator in 140 clinical trials involving Alzheimer’s.
“There are not many Alzheimer’s drugs we didn’t work on,” says Solomon, the clinical director of the Boston Center for Memory. And since 2003, a remarkable 14-year stretch, none of them has significantly benefited patients.
Solomon has also been treating patients for decades, with an armamentarium of four therapies that are still in use. Three cholinesterase inhibitors—donepezil (or Aricept), galantine (Razadyne) and rivastigmine (Exelon, oral as well as through a patch)—are all designed to boost levels of a chemical messenger in the brain called acetylcholine, which declines as the disease advances. And then there’s memantine, or Namenda, the most recently approved therapy. It targets glutamate and can be used in later stages of the ailment.
All of these are symptom-relieving drugs that do nothing to slow disease progression. Few people are positioned as well as Solomon to understand the changes in the clinic over the last few years, as well as the frustrations with the slow pace of progress.
That frustration amped up considerably over the past year with a series of landmark setbacks. At the top of everyone’s list: The Expedition 3 trial failure. It marked solanezumab’s third straight stumble in the clinic, raising fresh questions about the amyloid beta hypothesis on which solanezumab is based.
Lundbeck, partnered with Otsuka, had to write off its 5HT6 drug for symptomatic relief, after an earlier flop on the same target from Pfizer.
These failures followed bitter upsets for late-stage studies on Pfizer and Johnson& Johnson’s bapineuzumab, and Roche’s gantenerumab. Finally, just weeks ago, a Phase III for verubecestat, Merck’s leading BACE drug—which moves up the amyloid chain of supply to choke off production of the substance—joined the scrap heap.
Merck is still sorting through the data, but some clear lessons still shine through.
“I think we have an informative study,” says Merck’s David Michelson, vice president of neuroscience. “We’ll look at subgroups, but for the overall population we have a pretty clear result. This is not a failed study, it is interpretable.” And for these patients, “the drug didn’t work.”
“The fact is that we had a pretty flat study at the end of the day,” adds Michelson, “with no trend toward an effect.”
That’s a major conclusion. Merck was testing the drug—which inhibits beta-secretase, thus interrupting a cascade of changes to prevent amyloid beta production—in mild to moderate Alzheimer’s patients, where investigators have repeatedly found themselves staring down the barrel of insignificant clinical results.
Now, the company has an ongoing Phase III for prodromal patients, to see whether verubecestat works earlier in the development of the disease. And the pharma giant isn’t exhibiting any signs of regret that it’s still maneuvering through the pipeline with new Alzheimer’s drugs.
Neither is Roche, which has spent the past two years quietly figuring out how to regroup on gantenerumab.
“The first generation of trials has taught us a lot,” says Paulo Fontoura, the global head of neuroscience development at Roche.

That last failed gantenerumab study used a dose 4-to-5 times lower than what was necessary to have an effect, says Fontoura. What Roche’s team has been doing since the end of the study, he says, is exploring those higher doses to see whether they could be used without triggering ARIA-E, Alzheimer’s Related Imaging Abnormality-Edema, or brain swelling.
“It does seem to be so,” says Fontoura, “which is why we went public now” with a new late-stage study that will test a much higher dose.
Investigators have also been learning a lot about managing a side effect like ARIA-E, he adds. They’re coming to understand how doses might be titrated for each patient, by starting and stopping doses as side effects appear. Understanding how to safely manage those outcomes is having a major effect on studies as well.
Almost simultaneous to its decision to move forward on gantenerumab, Roche’s Genentech team pushed ahead with its second Phase III study on crenezumab, partnered with AC Immune in Switzerland, which would be needed for an approval.
Crenezumab’s advantage lies in a solid safety profile that hasn’t required a lot of hands-on management, says Fontoura.
“When you’ve seen one monoclonal,” he says, “you’ve seen one monoclonal. Each is different, with a different mechanism.” And crenezumab helps illustrate why.
Where solanezumab only goes after amyloid beta monomers, crenezumab also targets the more toxic soluble A-beta oligomers. Crenezumab is also under testing in a population of patients with an even milder form of the disease, with baseline Mini-Mental State Examination scores of 22-plus and Global Clinical Dementia ratings of 0.5 or 1.0. Researchers believe that crenezumab’s IgG4 backbone will tamp down inflammatory responses, helping investigators increase dosage for greater effects.
“I think we believe in the strength of the science of both of these projects,” he adds.
One of the reasons why Roche jumped back into the clinic with gantenerumab can be found at Biogen, which sparked some real enthusiasm with early-stage data that demonstrated a dose-dependent response among patients, after its drug pulled down levels of amyloid beta.
Late last year, after looking over early-stage data on patients taking Biogen’s aducanumab, investigators reported that they had tracked significant decreases in amyloid plaque in the brains of patients taking a titrated 10 mg dose of the drug compared with placebo. The decreases occurred during 12 months of treatment in patients who tested positive for ApoE4, a gene linked to Alzheimer’s risk, and who had prodromal or mild AD.
The researchers tied the decrease in plaque burden to a clear and significant slowing of the disease. And titrating the drug appeared to help rein in ARIA-E compared to fixed dosing.
“We are one of three sites in Boston doing the Biogen study, and we’re excited by this monoclonal antibody,” says Solomon.
It’s still early days, though, with a considerable amount of work to come before the researchers prove whether it’s relatively safe and effective. “It’s a small study and we have to be careful, but we have reason to believe something is going on there,” he says.
Meanwhile, Lilly is still digging into the data on Expedition 3, which will be published later, says Eric Siemers, a distinguished medical fellow at Lilly who led the effort. And despite three straight clinical failures, the company isn’t done with this drug.
“It is important to note that solanezumab continues to be in development for preclinical Alzheimer’s disease,” Siemers says.
And then there’s everything else still in the clinic, including the work Lilly is doing with the National Institutes of Health on A4, a study testing solanezumab in at-risk patients, and on the Dominantly Inherited Alzheimer’s network (DIAN), an effort to identify predictive biomarkers.
In A4, investigators are still focused on amyloid beta, looking at people over the age of 65 who are cognitively normal but plaque determined by a PET scan. DIAN explores the genetic triggers of risk, aiming to identify patients who will certainly develop the disease, or those who have a 50% chance, despite lacking any symptoms.
More data brings more insights. And eventually all programs face a do-or-die moment.
“I think it’s safe to say there will be no Expedition 4 study. We’re not going to do that,” says Siemers.
The symptomatics: Shooting for incremental gains
The past year has been as tough on the symptomatic drug class in Alzheimer’s as it has on the disease-modifying crowd. Not only did Lundbeck’s drug idalopirdine—an add-on to donepezil—flop in three late-stage clinical trials, prompting the company to drop the effort, but a lower-profile drug at a Boulder, CO-based biotech called Accera also recently failed in a Phase III study.
Dubbed AC-1204, the Accera drug is aimed at amping up neuronal health by boosting ketones among mild-to-moderate patients without the ApoE4 gene abnormality. Accera blamed a formulation change-up between Phase II and Phase III for the failure.

Whatever the cause, the setbacks peeled back the late-stage symptomatic drug pipeline largely to a candidate from Axovant. The Bermuda-based biotech is taking a discard from GlaxoSmithKline back into the clinic, following mid-stage data indicating that the right dose in the right group of patients might work.
“Perhaps we haven’t see the best allocation of our focus and resources over the past 5-to-10 years,” says Ilise Lombardo, the senior vice president of research at Axovant. “There are many targets, molecules and symptoms that we could focus on. What we see now are failed programs weighted to amyloid.”
Axovant says its lead program for intepirdine (RVT-101) is one of the few that doesn’t take a leap of faith in an area of biology that’s not well understood. By blocking 5HT6 scientists know that they can increase levels of acetylcholine, with an expectation that adding it to donepezil should further delay the downward slide that Alzheimer’s patients experience.
GlaxoSmithKline gave up this drug for a cash payment of only $5 million, which might blunt enthusiasm for the approach. But Axovant CEO Vivek Ramaswamy managed to train a bright spotlight on the field, in a very dramatic way. He used this drug to mount a record-setting biotech IPO.
And now, Lombardo is happy to explain why the company is winding through a study that will read out this fall.
“What I think we should be doing is, build on the knowledge we have to make incremental improvement, think in the ways in which we can tackle the disease, and build step by step on the knowledge we have,” says Lombardo.
The best path for anyone going into Phase III is to avoid making changes from Phase II, she says. Often, investigators get a positive read-out in Phase II, and then they’ll make changes to dosing or patient population. “We should be treating this like Phase III, not making substantial changes from the positive data we’ve seen in the past.”
“We had positive data in Phase II in cognition and function at the 35 mg dose,” she says. “We have very thoughtfully looked to replicate that in the next study, with the same patient population, the same dose and dosing regimen, the same endpoints that were shown to be positive.”
That kind of continuity was lacking in the two big 5HT6 failures at Lundbeck and Pfizer, she points out.
“I think that our program is importantly differentiated from those two programs,” she says. “We do know that Pfizer had a very unusual program.”
Patients enrolled in the PF-05212377 trial had psychiatric symptoms. They had difficulty enrolling patients. And it wasn’t tested for very long, she said.
“Lundbeck was very interesting,” Lombardo adds. “They had a lovely Phase IIb very similar to ours. And it looked like they had a nice drug candidate in hand to move into Phase III. They did have issues with the liver, perhaps increased effects on the liver, with increased dropout in Phase II. You can connect the dots in the Phase III design.”
Axovant isn’t out to stop the disease, just hit the brakes to buy more time for patients.
“When we think of our drugs on top of donepezil,” says Lombardo, “we do think about time and altering the course of the symptoms, and what we’ve seen in the Phase IIb study is what looks like six to nine months in terms of what you get back.”
“We will have an impact on people’s lives,” says the researcher. “That’s the focus of what we should be thinking about. It’s certainly an incremental benefit, but I don’t want it to sound small. It’s no smaller than some of the antibody studies we’re expecting to see.”
“I think that it’s certainly important to cast a wide net and look around, with continued approaches at cognition and function,” she goes on. “I have to say that there are other symptoms that patients with Alzheimer’s disease suffer from as well; agitation, sleep disturbance, psychosis and other aspects of dementia are just as important.”
The big players on the disease modifying side don’t pooh-pooh drugs that go after symptoms rather than the underlying disease, either.
“We’re not opposed to symptomatic treatment, there’s nothing wrong with that,” says Lilly’s Siemers. “They can be used in combination with any disease modifier. These combinations will be important.”
And at least one scientist says that improving cholinergic neurotransmission as the 5TH6 approach attempts to do could be seen, in a different light, as a disease modifier.
“Treating cholinergic deficit might have a disease-modifying effect,” says Howard Fillit, the chief science officer at the Alzheimer’s Drug Discovery Foundation. And that’s something that deserves careful exploration.
In the meantime, other players are coming up with new drugs looking at making a mark on disease symptoms.
Allergan paid $125 million to buy out Chase Pharma last fall, picking up a Phase III-ready cholinergic blocker called solifenacin, which is combined with donepezil into a drug dubbed CPC-201. And they’re pursuing higher doses to amp up the cognitive and functional effect of the therapy.
Solomon, though, believes that the big drugs in the Alzheimer’s future clearly will be disease modifiers.
“There’s an enormous interest in having new treatments,” Solomon says, “but in the absence of a noticeable effect, sales will be questionable.” The big blockbusters to come, he says, will be able to slow disease progression, particularly in cognitive decline.
The trial masters: Getting better at going deeper on cognition
One reason why Solomon and others in the field are still hopeful is that recruiting patients has improved dramatically. Go back over the patients enrolled in earlier studies, Solomon says—in a comment echoed over and over in other interviews—and you’ll find 20% to 30% of patients who were misdiagnosed, without any evidence of amyloid.
That’s just one example of the ways past studies have fallen short. Drugmakers were also strained by expanding from core Phase II research sites to the larger networks needed in Phase III, and diagnostic sophistication may have suffered along the way.
The mechanics of Alzheimer’s trials are tough, and they’re not getting easier, from choosing endpoints to properly diagnosing patients to recruiting participants to evaluating patients along the way.
But standards are improving. “We’ve learned how to do clinical trials,” says Fillit, who’s gained perspective after 35 years of experience. “We’ve been doing trials in Alzheimer’s disease for only 30 years, not 75 to 80 years. We’ve had to learn how to do better clinical trials, particularly with better biomarkers.”
Even just two or three years ago, he adds, scientists learned they were routinely enrolling patients without the classic biomarkers for the disease.
Real diagnostic advances have been made as well; for example, in using MRI measures of the hippocampus and looking at functional brain activity as markers of disease specificity.
And proper diagnosis is only one of the challenges to enrolling enough patients for an Alzheimer’s trial. “It is a lot of work to take a single person through a study,” Solomon points out. “It takes months to get people started. And there are more studies than patients to fill them.”
Patients are excluded based on the medications they’re taking and their health histories. Beyond that, to qualify, they need to be in good general health. And sometimes, researchers need to work with patients to overcome distrust about drug studies. “It’s challenging to enroll the trials,” Solomon says.
As the technology advances, there’s also a growing dialogue about the endpoints that are standard in Alzheimer’s, where the FDA looks for two studies to confirm an advantage in cognition and daily function. Fontoura, for example, is interested in exploring new ways of looking at a drug’s effects on Alzheimer’s progress.
“There’s a debate looking at the time it takes to move from prodromal to a more advanced state, see how long you can delay that,” he says as a for-instance. “This is something we have debated with the FDA as well.”
None of that makes these studies any easier. If anything, the challenges are growing as developers are determined to nail down the right data—wherever they might lead.

Getting to the point of making a clear judgment about what fails and what eventually might succeed requires a dedication to consistency. Everyone in a study who’s rating patients’ progress needs to know exactly what to record and how to gather the necessary information, says David Miller, clinical vice president at Bracket Global, which provides specialty services to study sponsors and CROs.
One of those services is training raters on what to do when evaluating patients in Alzheimer’s studies. Recently, Bracket has begun recording encounters between raters and patients, to make sure the study personnel—who are always double-blinded on who’s on drug or placebo—stick strictly to the manual in administering a test.
“It is done in a very smooth way,” says Miller. “The audio is unobtrusive.”
Can an Alzheimer’s patient in a study recognize objects—for instance, a harmonica? There’s a prescribed way to handle that. If the patient doesn’t recognize it on sight, the rater can provide a clue. It’s a musical instrument, say. What the rater can’t do is blow on it, because that would corrupt the results.
“You can only provide a memory clue,” Miller adds. “You can’t touch the object.”
But mistakes happen, and the audio is there to catch them. “Occasionally,” Miller says, “you’ll find a rater that will blow on a harmonica.”
An electronic platform Bracket uses has significantly reduced the number of errors that tend to crop up, to the tune of 66% to 75%.
Another of Bracket’s tasks reflects the global nature of many of the Alzheimer’s studies. Rating has to be done consistently regardless of the language and culture involved. “We make sure the scales are translated carefully,” Miller says.
Bracket’s ultimate goal is to ensure the trial sponsor has the highest-quality data available, even if that data doesn’t tell the story the company wants to hear. “We would like every study to succeed,” he says. But the unfortunate fact is, not every one of them will.
What’s ahead, or beyond amyloid beta
Denali’s brand spanking new facilities down at The Cove in South San Francisco scream state of the art. An open floor plan keeps execs in circulation, with any empty work station available for the taking.
On one side, there’s the outer wall of the vivarium, where the biotech company keeps its mouse models. Chemists and researchers sketch chemical structures onto white boards.
Denali has a team of chemists working in China with Wuxi, but CEO Ryan Watts likes to have experts on hand, working directly in the company as its 100-plus staffers devote themselves to understanding the genetic drivers of Alzheimer’s, and how that knowledge can be used to break the disease down into groups that can be more directly targeted with a therapeutic.
“Don’t pay any attention to that,” says Watts with a smile as he guides Endpoints News past the white boards, indicating a rough drawing of a chemical structure of interest. Watts and his team are working on the rough draft of a new chapter in Alzheimer’s research.
They are happy to let the giants tackle amyloid beta.
Amyloid beta belongs to Big Pharma now, as Fillit says. Meanwhile, with the enthusiastic backing of Arch and some other forward-thinking venture capitalists, ambitious upstarts are carving a new path to the clinic. It’s early days, yet, but the treatments we’ll be seeing in the future will be coming from companies like Denali.
And even the most experienced players know that there’s plenty yet to be learned about Alzheimer’s—and, importantly, how it fits into the broader aging process.
“What we haven’t learned is gerontology. Alzheimer’s disease, cancer, lung and heart disease are all diseases of aging,” says Fillit. “The disease process is multifactorial. It affects all organs.”
Fillit ticks off a variety of Alzheimer’s features: neuronal mitochondreal failure, insulin resistance, vascular problems. Epigenetic machinery is damaged with age, he notes.
“It’s not going to be one silver bullet, but two, three, four drugs, like cancer, where you hit multiple pathways,” he predicts, and one area he remains fixed on is neuroprotection.
“Brain cells are laid down at 3,” says Fillit. “When you’re 80 and tying your shoes, you’re still using the same cells.”
“This is a uniquely human disease,” he adds, “with impairments in abstract reasoning and judgment. We’ve cured mice engineered with this disease over 500 times. The mouse models don’t translate into humans. We know for a fact that mice don’t write books.”
The next big thing in cocktail therapies

You have to start getting new drugs approved before you can start to plan on combinations. But there’s been plenty of thinking going into the cocktails of the future, and one side effect of that is an acknowledgement that the amyloid vs. tau debate is irrelevant.
The two-camp system is going away. Investigators now understand better than ever that they’re all in the same boat, pulling oars in the same direction.
“I’m getting of an age to talk about the last 10 years,” Lilly’s Siemers says. Investigators understand that plaque deposition comes first, “and then tau deposition happens after that. That really has just come together in the last 10 years.”
At Lilly, “[t]au is certainly on our list, something we’re looking at quite a bit,” Siemers says. Lilly has a monoclonal antibody for tau now in an early phase clinical trial, and it’s looking at some small molecule approaches to tau as well, he says.
Fontoura thinks tau “is the next big thing everyone will look at.” And further down the pipeline, he adds, the big question will be what’s needed to build the right combination of therapies that can help patients tame this disease.
”Combination therapy is being discussed more and more,” agrees Siemers. “That’s where we’ll get the best effect, with combination therapy.”
Should that include a BACE/tau monoclonal? An antibody that targets MP3G? Add aducanumab? Maybe a BACE plus a monoclonal directed at plaques?
“We were rooting for the Merck BACE to be successful after Expedition 3,” Siemers says. “We were not entirely surprised that the study wasn’t positive, but we were surprised by the futility analysis stage.”
Siemers was reluctant to comment on the study, as he wasn’t involved in running it. Eli Lilly has a BACE in Phase III and another in Phase II, “which is actually even more potent.”
The bottom line is that these Big Pharma stalwarts and ambitious start-ups are far from giving up on conquering Alzheimer’s disease—and that there’s likely to be plenty of room in the field for all of them.
“If I were talking to a young researcher in the field I would still say that this is an exciting time,” says Siemers. “We know so much more about the disease than we did 10 years ago. It’s not going to be one drug that is going to cure the disease, there needs to be a lot of drugs.”
And they are all waiting to be developed.
This Deep Dive is an editorial publication from Endpoints News, and made possible with the sponsorship of Bracket Global.