Phillip Gutis didn't expect biotech companies Biogen (BIIB) and Eisai to cure his Alzheimer's disease. But the former New York Times reporter did see his participation in a clinical study of the experimental drug, aducanumab, as a step toward finding an Alzheimer's treatment.
XThat is, until researchers terminated the study, saying the drug would fail. It was one of many failures that have stacked up in Alzheimer's research over the last several years, and no clear path to an effective treatment seems to be in sight.
The debilitating neurodegenerative disease has frustrated not only the estimated 6 million Americans suffering from it. It's also stymied some of the biggest powerhouses in medical research, including Roche (RHHBY), Merck (MRK), Johnson & Johnson (JNJ), AstraZeneca (AZN) and Eli Lilly (LLY), all of them seeking a cure.
Still, they persist in their efforts to crack the code and obliterate Alzheimer's disease — or, at least arrest its swift progress. The Alzheimer's treatment market could be a boon for the biopharma company that gets there first. Without intervention, the number of patients will more than double to 14 million by 2050, according to the Alzheimer's Association.
The industry's persistence translates into a glimmer of hope for Gutis.
"Not that I thought they were going to come up with a solution in time to save me, but I felt like participating in the trial made me part of the solution," Gutis said in an interview. "This is terrible, but I'm not going to disappear into that deep hole."
Why Is Alzheimer's Treatment Such A Challenge?
Two biotech companies went public this year on the hopes of finding an Alzheimer's treatment. Other biotech companies are on the periphery with early- and mid-stage efforts. Giants Biogen and Roche also are still working on other potential methods of wrangling the disease.
"We need to find the right drug at the right time for the right target," said Irfan Qureshi, executive director of neurology for Biohaven Pharmaceutical (BHVN). "We haven't quite cracked that yet."
Gutis acknowledges he isn't the typical face of Alzheimer's disease. He was diagnosed with early-onset Alzheimer's disease three years ago at age 54 after screening for a Biogen and Eisai study. On a test of cognitive impairment, Gutis needed a score of 85 or lower to proceed with further screening.
He scored a 71.
"I knew something was wrong," he said. "I wasn't surprised, but I was kind of shocked. Knowing something is wrong and getting a diagnosis are very different things."
So, Gutis enrolled in one of the biotech companies' studies of aducanumab, involving 3,200 patients. The experimental Alzheimer's treatment belongs to a class of drugs that aim to remove an abnormal protein in the brain known as beta amyloid. Beta amyloid is a hallmark of Alzheimer's disease.
Expensive Failure For Biogen
But on March 21 Biogen scrapped two studies of aducanumab, citing the likelihood of failure. The company lost more than $18 billion off its market cap that day. Shares still haven't recovered.
Here's the trick with finding an Alzheimer's treatment: Scientists still don't agree on what causes the disease. Billions of dollars have been poured into the theory that removing or preventing beta amyloid plaques in the brain would reverse the neurological damage.
Technically speaking, drugs like aducanumab have succeeded. The treatments removed beta amyloid plaque in the brain, says Dr. Christian Camargo, an instructor and clinician for the University of Miami's Miller School of Medicine.
"At the same time, the patients didn't improve cognitively," he said in an interview. "Even though you removed the thing that defined the disease (beta amyloid), that doesn't mean you repaired the damage."
Where Is The Field Today On Beta Amyloid?
Biotech companies Biogen and Eisai are actively testing other beta amyloid approaches to solving the Alzheimer's treatment puzzle. The duo are testing two drugs — elenbecestat and BAN2401. Both rely on the amyloid theory of Alzheimer's disease.
Biopharma player Roche is testing another beta amyloid-targeting drug known as gantenerumab. The company says gantenerumab differs in mechanism from another drug called crenezumab. In January, Roche said crenezumab would probably fail, and it terminated two studies of the AC Immune (ACIU)-partnered drug.
Researchers are split on whether targeting beta amyloid has a place in Alzheimer's treatment.
Rebecca Edelmayer, director of scientific engagement for the Alzheimer's Association, says a "robust discussion" is underway in treatment circles when it comes to the beta amyloid theory. Some say the community has spent enough time and money on the approach, she said in an interview.
"I think to lump every amyloid therapy into the same bucket would be very incorrect," she said.
Different Approaches To Problem
These experimental Alzheimer's treatments have taken different approaches to targeting beta amyloid plaque in the brain, she says. Further, each of the clinical studies has differed in design as well as patient populations.
"I wouldn't necessarily say any of the drugs tested have been redundant in terms of their method of action," she said.
Others are harder on beta amyloid. Arnon Rosenthal, chief executive of biotech company Alector (ALEC), likens the theory to a gunshot wound. He acknowledges beta amyloid is an indicator of Alzheimer's disease but says once beta amyloid is apparent, it's too late to stop the damage.
"Stopping beta amyloid is not going to help," he said in an interview. "Once you shoot the bullet and you cause the damage, taking the gun away is not going to help. You have to deal with the consequences of the bullet."
Do Genetics Have A Role To Play?
Alector is among a handful of biotech companies to go public this year. It began trading in February.
The biotech company believes genetic mutations or the aging process weaken the immune system in the brain. This allows debris to accumulate, causing damage. Rosenthal says Alector's goal is to "make the immune cells stronger and younger."
"The notion was that Alzheimer's is a form of autoimmunity or inflammation and that you needed to quash the immune system," he said. "But research now suggests it's the opposite. It clearly indicated insufficient immune activity is causing the disease."
Alector is targeting two genes in the brain believed to have ties to Alzheimer's disease. The two genes are involved in how immune cells, known as microglia, function in the brain. But microglia can be a bit unwieldy. The biotech company is hoping to control how the immune cells flock to damage in the brain.
Rosenthal likens the experimental Alzheimer's treatments to immuno-oncology for the brain.
"You recruit the immune system to do the work for you," he said.
Inflammation Could Be The Culprit
Scientists agree certain genetics increase the risk of developing Alzheimer's disease. Researchers are now exploring the role of inflammation in the brain.
In 2015, Pfizer (PFE) reportedly found signs its blockbuster arthritis drug — an anti-inflammatory medicine — could potentially reduce the risk of developing Alzheimer's disease, according to The Washington Post. But the Dow Jones component opted against a clinical study, saying the effort would likely fail.
Another biotech company, Cortexyme (CRTX), is making a case for the inflammation theory. CEO Casey Lynch says an inflammatory bacteria could be the culprit behind Alzheimer's disease. Cortexyme went public this year, trading for the first time in May.
Cortexyme believes an inflammatory bacteria called porphyromonas gingivalis, or P. gingivalis, gets into the brain through the mouth. The bacteria is at the center of periodontal disease. Lynch says it can travel to the brain through the olfactory nerves, circulatory or immune systems.
In studies of 59 patients with Alzheimer's disease, all have tested positive for the bacteria in their cerebral spinal fluid, Lynch told IBD. Cortexyme is testing an experimental drug for Alzheimer's disease that would render the bacteria benign, and then starve it.
Roughly 80% of elderly people have P. gingivalis in their mouths, she said. But that's no guarantee they will develop Alzheimer's disease, Lynch says.
"You might have very good blood-brain barrier protection, you might have a great immune system that keeps the bacteria in your mouth and not moving to other parts of the body very easily," she said. "We know the risk factors for Alzheimer's include genetic risk factors."
A New Take On An Old Alzheimer's Treatment
If beta amyloid is the granddaddy of Alzheimer's disease theories, genetics and inflammation are the infants. Researchers are also studying how the food we eat could impact the neurodegenerative disease, says Camargo, of the University of Miami.
Further, biotech companies AC Immune, Denali Therapeutics (DNLI), Voyager Therapeutics (VYGR) and Biogen are targeting another plaque in the brain called tau. AC Immune is partnered with Roche. Denali has partnerships with Sanofi (SNY) and Takeda Pharmaceutical (TAK). Voyager is partnered with AbbVie (ABBV).
But where Camargo sees the most promise is in glutamate moderation. Glutamate is a neurotransmitter in the brain. It's responsible for sending signals between the nerve cells. Normal brain function requires glutamate. But too much can be toxic, he says.
Allergan (AGN) sells a drug called Namenda, which controls glutamate by targeting the NMDA receptor. Namenda works by blocking a specific channel of glutamate. But it's hard to know how much of the neurotransmitter is being inhibited, Camargo says. That can also be a problem.
Biotech company Biohaven, instead, is targeting a transporter of glutamate. The goal is to cut the levels of glutamate in the brain's synapses to slow the progression of Alzheimer's disease, Biohaven's Qureshi said.
Namenda's approval in 2003 "validated the mechanism in treating Alzheimer's disease," he said. "However, the way we target it, by targeting that transporter, is different from the other approach. It's more robust and effective in treating the symptoms and preventing progression."
Glimmers Of Hope In Alzheimer's Treatment
The Alzheimer's Association has invested $165 million through grants in 450 projects across 25 countries around the world, Edelmayer says. So, even in the wake of the Biogen and Eisai studies, there's still plenty of hope researchers will find an Alzheimer's treatment.
On that note, Biogen and Eisai are expected to release more detailed information from their tests of aducanumab. Edelmayer and Camargo both say it's irresponsible to toss out the beta amyloid theory without taking a deeper look into that data.
"There could have been specific populations where the drug was producing a benefit," Edelmayer said.
Meanwhile, academics and biotech companies are just beginning new Alzheimer's treatment tests, she says. The beta amyloid story took 15-20 years to reap data from clinical studies. The next new drug in Alzheimer's treatment could only now be starting its clinical journey.
Alzheimer's Disease Is A Thief
Meanwhile, Alzheimer's patient Gutis hopes he can enroll in one of those studies. He says trying to find himself in the wake of his diagnosis has been "a big hill."
Not only was Gutis a reporter, he also worked as a spokesperson for the American Civil Liberties Union and the National Resources Defense Council. So he is a communicator.
Alzheimer's disease is a thief, he says. Before stealing your memories, it steals your identity. So, in his time left, Gutis plans to use what he was given — for as long as he can.
"I can't imagine any other way for me to move forward, but to be an advocate and to use the tools and talents I still have before they're gone," he said. "And they will go. I know this. There are mornings I wake up and talking like this would be next to impossible. I will lose the ability to write; I know it's coming. So I want to use the time I have left to continue to make a difference."
Follow Allison Gatlin on Twitter at @IBD_AGatlin.
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